Swanson PA 2nd, Padilla M, Hoyland W, et al. AZD1222/ChAdOx1 nCoV-19 vaccination induces a polyfunctional spike protein-specific Th1 response with a diverse TCR repertoire. Sci Transl Med. 2021 Sep 30:eabj7211. PubMed: https://pubmed.gov/34591596. Full text: https://doi.org/10.1126/scitranslmed.abj7211
In AstraZeneca vaccine recipients aged 18 to 85 years who enrolled in a Phase II/III study (n = 296), vaccination “induced a polyfunctional Th1-dominated T cell response, with broad CD4+ and CD8+ T cell coverage across the SARS-CoV-2 spike protein.”
Anderson EM, Eiloa T, Goodwin E, et al. SARS-CoV-2 infections elicit higher levels of original antigenic sin antibodies compared to SARS-CoV-2 mRNA vaccinations. medRxiv 2021, posted 1 October. Full text: https://doi.org/10.1101/2021.09.30.21264363
In this small study (10 acutely infected health care workers and 23 individuals who received two doses of the BioNTech/Pfizer vaccine), “SARS-CoV-2 infections elicited a large proportion of original antigenic sin-like antibodies that bound efficiently to common seasonal human coronaviruses but poorly to SARS-CoV-2. In converse, vaccination only modestly boosted antibodies reactive to common seasonal human coronaviruses and these antibodies bound efficiently to SARS-CoV-2”. The authors conclude that SARS-CoV-2 mRNA vaccinations elicit fundamentally different antibody responses compared to SARS-CoV-2 infections.
McDonald JT, Enguita FJ, Taylor D, et al. Role of miR-2392 in Driving SARS-CoV-2 Infection. Cell Reports 2021, 29 September. Full text: https://www.cell.com/cell-reports/fulltext/S2211-1247(21)01303-6#%20
MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases. The authors show that miR-2392 is present in the blood and urine of patients positive for COVID-19 and discuss the potential for developing a minimally invasive COVID-19 detection method. They also designed an miRNA-based antiviral therapeutic that reduces SARS-CoV-2 viability in hamsters.
Townsend JP, Hassler HB, Wang Z, et al. The durability of immunity against reinfection by SARS-CoV-2: a comparative evolutionary study. Microbes 2021, published 1 October. Full text: https://doi.org/10.1016/S2666-5247(21)00219-6
How long will immunity against COVID-19 last? Here, the authors use data on the durability of immunity among close coronavirus relatives of SARS-CoV-2 (SARS-CoV-1, MERS-CoV, human coronavirus 229E, OC43, and NL63) to estimate times to reinfection. They conclude that “reinfection by SARS-CoV-2 under endemic conditions would likely occur between 3 months and 5.1 years after peak antibody response, with a median of 16 months.”
Feng S, Phillips DJ, White T, et al. Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection. Nat Med September 29, 2021. https://www.nature.com/articles/s41591-021-01540-1
Using data from 171 cases and 1404 controls, this study shows that higher anti-spike IgG, anti-RBD IgG, and neutralizing antibody titers were all associated with lower risk of symptomatic disease. The authors believe that their correlates of vaccine efficacy could be used to extrapolate efficacy to immunogenicity data for novel vaccines. However, data were based on cases of COVID-19 detected in a mainly white population in the UK, mostly due to Alpha variants.
Nakayama T, Lee IT, Jiang S, et al. Determinants of SARS-CoV-2 entry and replication in airway mucosal tissue and susceptibility in smokers. Cell Rep Med September 27, 2021. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00283-4
SARS-CoV-2 infection is present in all examined head & neck tissues, with a notable tropism for the nasal cavity and tracheal mucosa. This study also uncovered an association between smoking and higher SARS-CoV-2 viral infection in the human proximal airway, which may explain the increased susceptibility of smokers to developing severe COVID-19. This is at least partially explained by differences in IFN-β1 levels.
Luo L, Liang W, Pang J, et al. Dynamics of TCR repertoire and T cell function in COVID-19 convalescent individuals. Cell Discov September 28, 2021, 7, 89. https://www.nature.com/articles/s41421-021-00321-x
More on T cells. While the diversity of the TCR repertoire was increased in discharged patients, it returned to base level one 1 week after becoming virus free. The top expanded T cell clones (~ 10% of total T cells) display the key antiviral features in CD8+ T cells (explaining how a dramatically decreased level of CD8+ T cells can clear the virus in most SARS-CoV-2 infected individuals).
Wickenhagen A, Sugrue E, Lytras S, et al. A prenylated dsRNA sensor protects against severe COVID-19. Science September 28, 2021. https://www.science.org/doi/10.1126/science.abj3624
An all-in-one paper. OAS1 is an evolutionarily ancient interferon-stimulated gene that has maintained IFN responsivity for hundreds of millions of years. The authors not only found out that this gene potently inhibits SARS-CoV-2. They also describe how and how different gene variants are distributed in different populations and animals. Finally, it is shown that, among 499 hospitalized patients, expression of prenylated OAS1 is associated with protection from severe COVID-19 (34% vs 45%), suggesting this antiviral defense is a major component of a protective antiviral response.
Fröberg J, Gillard J, Philipsen R, et al. SARS-CoV-2 mucosal antibody development and persistence and their relation to viral load and COVID-19 symptoms. Nat Commun September 24, 2021, 12, 5621. https://www.nature.com/articles/s41467-021-25949-x
This study examined the development and persistence of nasal antibodies following infection with SARS-CoV-2 in a household contact study. Mucosal antibodies against S and RBD increased 7–9 days after symptom onset and remain elevated for at least 9 months. Mucosal antibodies may play a key role in limiting disease as they were found to be correlated with a lower viral load and were related to a faster decline in systemic symptoms.
Abishek C, Liu J, Yu J, et al. Prior infection with SARS-CoV-2 WA1/2020 partially protects rhesus macaques against re-infection with B.1.1.7 and B.1.351 variants. Science Translational Medicine September 21, 2021. https://www.science.org/doi/10.1126/scitranslmed.abj2641
This was a study on 27 brave Indian-origin adult rhesus macaques, demonstrating that natural immunity induced by the Wuhan strain provides robust short-term protection against re-challenge with the same SARS-CoV-2 strain but reduces protection against re-challenge with certain SARS-CoV-2 variants. A greater reduction of efficacy was observed against B.1.351 as compared with B.1.1.7.
Today we have an Immunology Special, mainly on T cells but also on new onset auto-antibodies that are observed in COVID-19, as well as on immune responses to vaccines in patients with complex co-morbidities.
Chang SE, Feng A, Meng W, et al. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nat Commun September 14, 2021, 12, 5417. https://www.nature.com/articles/s41467-021-25509-3
Approximately half of hospitalized COVID-19 patients develop serum autoantibodies against one or more antigens. Moreover, a surprisingly large number of anti-cytokine antibodies (ACA) were identified in this study (80%), far more than just the interferon autoantibodies described recently. Some autoantibodies are newly triggered by SARS-CoV-2 infection, suggesting that severe COVID-19 can break tolerance to self.
Mateus J, Dan JM, Zhang Z, et al. Low-dose mRNA-1273 COVID-19 vaccine generates durable memory enhanced by cross-reactive T cells. Science September 14, 2021. https://www.science.org/doi/10.1126/science.abj9853
Studying 35 vaccinated subjects out to 7 months, this research group from La Jolla, US found that a two dose 25 μg mRNA-1273 vaccination (Moderna) generated immune memory against spike comparable to that of SARS-CoV-2 infection for antibodies, CD4+ T cells, and CD8+ T cells. Furthermore, immune responses were significantly enhanced by the presence of pre-existing cross-reactive CD4+ T cell memory.
Niessl J, Sekine T, Lange J, et al. Identification of resident memory CD8+ T cells with functional specificity for SARS-CoV-2 in unexposed oropharyngeal lymphoid tissue. Science Immunology September 14, 2021. https://www.science.org/doi/10.1126/sciimmunol.abk0894
This study provides a comprehensive picture of pre-existing SARS-CoV-2-specific mCD4+ and mCD8+ T cell immunity (likely generated via previous encounters with common cold human coronaviruses) in the tonsils, representing key lymphoid organs in the upper respiratory tract and the intravascular circulation. SARS-CoV-2-specific mCD4+ T cells were distributed evenly between these compartments, whereas SARS-CoV-2-specific mCD8+ T cells were almost exclusively present in the tonsils. Earlier studies confined to analyses of peripheral blood samples have therefore likely underestimated the overall prevalence of heterologous mCD8+ T cell responses.
Lee S, Yu Y, Trimpert J, et al. Virus-induced senescence is driver and therapeutic target in COVID-19. Nature September 13, 2021. https://www.nature.com/articles/s41586-021-03995-1#author-information
Virus-induced senescence (VIS) is indistinguishable from other forms of cellular senescence and composed of pro-inflammatory cytokines, extracellular matrix-active factors and pro-coagulatory mediators. This study marks VIS as a pathogenic trigger of COVID-19-related cytokine escalation and organ damage, and suggests senolytic targeting of virus-infected cells as a novel treatment option.
Immune responses in co-morbidities
Le Bourgeois A, Coste-Burel M, Guillaume T, et al. Safety and Antibody Response After 1 and 2 Doses of BNT162b2 mRNA Vaccine in Recipients of Allogeneic Hematopoietic Stem Cell Transplant. JAMA Network September 14, 2021. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2784061?resultClick=1
A high response rate of 83% was found in this cohort of 117 allogeneic HSCT recipients after 2 doses of BNT162b2 vaccine.
Apostolidis SA, Kakara M, Painter MM, et al. Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy. Nat Med September 14, 2021. https://www.nature.com/articles/s41591-021-01507-2
Although most patients with MS treated with anti-CD20 therapy do not generate optimal antibody responses, T cell priming, especially of TH1 and CD8 T cells, is largely intact. However, treatment with anti-CD20 therapy as well as having B cell deficiency were associated with altered coordination of the immune response, and circulating TFH responses were compromised.
Kaplonek P, Wang C, Bartsch Y, et al. Early cross-coronavirus reactive signatures of humoral immunity against COVID-19. Science Immunology September 9, 2021. https://www.science.org/doi/10.1126/sciimmunol.abj2901
Convincing evidence on the importance of cross-coronavirus immunity as a correlate of protection against COVID-19. Individuals who survive COVID-19 may have an advantage as they may be able to rapidly redeploy S2-specific antibodies across coronaviruses in order to combat disease. Early development of SARS-CoV-2-specific immunity occurred in tandem with pre-existing common β-coronavirus OC43 humoral immunity in survivors, which was also selectively expanded in individuals that developed a paucisymptomatic infection.
Bertoletti A, Le Bert N, Qui M, et al. SARS-CoV-2-specific T cells in infection and vaccination. Cell Mol Immunol September 2, 2021. https://www.nature.com/articles/s41423-021-00743-3
Great review about the function of SARS-CoV-2-specific T cells in patients and in vaccinated individuals.
Smith N, Goncalves P, Charbit B. et al. Distinct systemic and mucosal immune responses during acute SARS-CoV-2 infection. Nat Immunol September 1, 2021. https://www.nature.com/articles/s41590-021-01028-7
This study compared systemic and local immune responses during active SARS-CoV-2 infection in a well-characterized COVID-19 cohort. Results demonstrate distinct tissue compartmentalization of SARS-CoV-2 immune responses and highlight a role for the nasopharyngeal microbiome in regulating local and systemic immunity that determines COVID-19 clinical outcomes.
Galván-Peña S, Leon J, Chowdhary K, et al. Profound Treg perturbations correlate with COVID-19 severity. PNAS September 14, 2021, https://www.pnas.org/content/118/37/e2111315118
Regulatory T cells (Tregs) are essential in maintaining immunologic homeostasis, self-tolerance, and to prevent runaway immune responses. This study found a unique and striking Treg deviation in COVID-19 patients, which results from the effects of several components of the pro-inflammatory storm.
Israelow B, Mao T, Klein J, et al. Adaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2. Science Immunology September 2021, https://www.science.org/doi/10.1126/sciimmunol.abl4509
More insights into both the immunologic determinants of viral clearance and protection. While T cells were important in the clearance of primary infection, they were not required for protection against reinfection or vaccine-mediated protection, likely due to sufficient antibody-mediated immunity.
Baggen J, Vanstreels E, Jansen S, et al. Cellular host factors for SARS-CoV-2 infection. Nat Microbiol September 1, 2021. https://www.nature.com/articles/s41564-021-00958-0
This review summarizes insights into the proviral host factors that are required for SARS-CoV-2 infection that were mainly obtained using functional genetic and interactome screens.
Loyal L, Braun J, Henze L, et al. Cross-reactive CD4+ T cells enhance SARS-CoV-2 immune responses upon infection and vaccination. Science August 31, https://www.science.org/doi/10.1126/science.abh1823
This study highlights the functional contribution of pre-existing spike-cross-reactive T cells in SARS-CoV-2 infection and vaccination. Cross-reactive immunity may account for the unexpectedly rapid induction of immunity following primary SARS-CoV-2 immunization and the high rate of asymptomatic/mild COVID-19 disease courses. The S816-830 peptide may serve as a conserved universal coronavirus target in the S2 portion of spike for both B cells and T cells.
Lempp FA, Soriaga L, Montiel-Ruiz M, et al. Lectins enhance SARS-CoV-2 infection and influence neutralizing antibodies. Nature August 31, 2021. https://www.nature.com/articles/s41586-021-03925-1
Transmembrane lectins act as attachment receptors, rather than entry receptors for SARS-CoV-2, thus facilitating infection via the canonical ACE2 pathway. This study shows that ranking of SARS-CoV-2 neutralizing antibodies is highly dependent on the level of ACE2 expression and on the presence of attachment receptors, and identifies a mechanism that possibly results in creation of multinucleate viral factories potentially enhanced by specific antibodies.
Sulaiman I, Chung M, Angel L, et al. Microbial signatures in the lower airways of mechanically ventilated COVID-19 patients associated with poor clinical outcome. Nat Microbiol August 31, 2021. https://www.nature.com/articles/s41564-021-00961-5
This study analyzed lower airway microbiome using a metagenomic and metatranscriptomic approach, along with host immune profiling, in critically ill patients with COVID-19. Data suggest that active lower airway SARS-CoV-2 replication and poor SARS-CoV-2-specific antibody responses (but not secondary respiratory infections) are the main drivers of increased mortality in COVID-19 patients requiring ventilation.
Zhang H, Deng S, Ren L, et al. Profiling CD8+ T Cell Epitopes of COVID-19 Convalescents Reveals Reduced Cellular Immune Responses to SARS-CoV-2 Variants. Cell Reports August 26, 2021. https://doi.org/10.1016/j.celrep.2021.109708
Variants are not only resistant to currently available neutralizing antibodies. According to this study, evading cellular immunity might also contribute to the increased transmissibility and disease severity associated with the new SARS-CoV-2 variants.
Sarma A, Christenson SA, Byrne A. et al. Tracheal aspirate RNA sequencing identifies distinct immunological features of COVID-19 ARDS. Nat Commun August 26, 2021. 12, 5152 (2021). https://doi.org/10.1038/s41467-021-25040-5
Assessing host gene expression in the lower airways, this study reveals distinct immunological features of COVID-19 ARDS. In contrast to a “cytokine storm,” the authors observed a reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes.
Giovannoni F, Li Z, Remes-Lenicov F, et al. AHR signaling is induced by infection with coronaviruses. Nat Commun August 26, 2021, 12, 5148. https://www.nature.com/articles/s41467-021-25412-x
The aryl hydrocarbon receptor (AHR) was recently identified as a host factor for Zika and dengue viruses. This study suggests that AHR activation is a common strategy used by coronaviruses to evade antiviral immunity and promote viral replication, which may also contribute to lung pathology.
Sposito B, Broggi A, Pandolfi L, et al. The interferon landscape along the respiratory tract impacts the severity of COVID-19. Cell August 18, 2021. DOI:https://doi.org/10.1016/j.cell.2021.08.016
“Landscape” is the new favorite word of immunologists (for about three years now). This “landscape” study shows that interferons have opposing roles along the respiratory tract, reconciling some of the seemingly contradictory findings on interferons in COVID-19 patients.
Loske J, Röhmel J, Lukassen S, et al. Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children. Nat Biotechnol (2021). https://doi.org/10.1038/s41587-021-01037-9
The authors provide evidence that the epithelial and immune cells of the upper airways (nose) of children are pre-activated and primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults.
Painter MM, Mathew D, Goel RR, et al. Rapid induction of antigen-specific CD4+ T cells is associated with coordinated humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination. Immunity 2021, published 12 August. Full text: https://doi.org/10.1016/j.immuni.2021.08.001
The authors compiled 26 measures of antigen-specific immunity across CD4 and CD8 T cells, antibodies, and memory B cells. After vaccination, the immune response was different for SARS-CoV-2 naive and recovered individuals. Naive people benefit from receiving both doses, while recovered people only need one. The universal CD4 response to the first dose (Th1 and Tfh) may be critical to overall immunity by amplifying responses to the second dose.
Vora SM, Lieberman J, Wu H. Inflammasome activation at the crux of severe COVID-19. Nat Rev Immunol (2021). Full text: https://doi.org/10.1038/s41577-021-00588-x
Obesity, diabetes, heart disease, hypertension and ageing, which may be etiologically linked through overactive inflammasome signaling, are prognostic of poor COVID-19 outcome. The authors discuss potential mechanisms of inflammasome activation and the implications for therapy.
Ortega N, Ribes M, Vidal M, et al. Seven-month kinetics of SARS-CoV-2 antibodies and role of pre-existing antibodies to human coronaviruses. Nat Commun 12, 4740 (2021). https://doi.org/10.1038/s41467-021-24979-9
Many studies have reported a lack of protection from infection with human coronaviruses causing common cold (HCoVs). The authors don’t agree. They analyzed data from a cohort of 578 health care workers followed up to 7 months and found that IgG and IgA to HCoV were significantly higher in asymptomatic than symptomatic SARS-CoV-2 seropositive individuals.
Hasenkrug KJ, Feldmann F, Myers L, et al. Recovery from Acute SARS-CoV-2 Infection and Development of Anamnestic Immune Responses in T Cell-Depleted Rhesus Macaques. mBio. 2021 Jul 27:e0150321. PubMed: https://pubmed.gov/34311582. Full text: https://doi.org/10.1128/mBio.01503-21
What is the role of T cells in protection against SARS-CoV-2 reinfection? The authors inoculated macaques and rechallenged them 6 weeks later. Their conclusion: T cells might not be critical for recovery from acute SARS-CoV-2 infections while B cell responses and antibodies could be the essential mediators of protection from re-exposure. The discussion about the importance of T cells continues.
Muecksch F, Weisblum Y, Barnes CO, et al. Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations. Immunity. 2021 Jul 29:S1074-7613(21)00294-6. PubMed: https://pubmed.gov/34331873. Full text: https://doi.org/10.1016/j.immuni.2021.07.008
The authors suggest that “increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.”
Fischer DS, Ansari M, Wagner KI, et al. Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through ‘reverse phenotyping’. Nat Commun 12, 4515 (2021). Full text: https://doi.org/10.1038/s41467-021-24730-4
The authors show barcoding through natural T cell receptor sequences can be used to identify SARS-CoV-2 antigen-reactive T cells after differential stimulation with and without antigen, followed by single-cell RNA sequencing.
Tortorici MA, Czudnochowski N, Starr TN, et al. Broad sarbecovirus neutralization by a human monoclonal antibody. Nature. 2021 Jul 19. PubMed: https://pubmed.gov/34280951. Full-text: https://doi.org/10.1038/s41586-021-03817-4
A new human monoclonal antibody, designated S2X259, recognized a highly conserved cryptic receptor-binding domain epitope, broadly neutralizing B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.427/B.1.429 and a wide spectrum of human and potentially zoonotic sarbecoviruses. Syrian hamsters were protected against challenge with the historical SARS-CoV-2 strain and the B.1.351 (Beta). The authors suggest that their antibody could be a promising candidate for the prevention and treatment of emergent variants and zoonotic infections.
Cohen KW, Linderman SL, Moodie Z, et al. Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells. Cell Rep Med July 14, 2021. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00203-2
Broad and effective immunity may persist long-term in recovered COVID-19 patients. In 254 COVID-19 patients who were followed longitudinally for up to 8 months, neutralizing antibodies showed a bi-phasic decay with half-lives > 200 days. Durable polyfunctional CD4 and CD8 T cells recognized distinct viral epitope regions.
Bui LT, Winters NI, Chung MIm et al. Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity. Nat Commun Jul 14, 2021, 12, 4314. https://www.nature.com/articles/s41467-021-24467-0
Chronic lung disease AT2 cells express higher levels of genes linked directly to the efficiency of viral replication and the innate immune response.
Janneh AH, Kassir MF, Dwyer CJ, et al. Alterations of lipid metabolism provide serologic biomarkers for the detection of asymptomatic versus symptomatic COVID-19 patients. Sci Rep July 7, 2021, 11, 14232. https://www.nature.com/articles/s41598-021-93857-7
While most asymptomatic donors had a slight increase in their serum sphingosine, symptomatic COVID-19 patients exhibited a robust decrease in their serum sphingosine levels, an almost 15-fold reduction, compared to asymptomatic donor levels.
Zhang Q, Ju B, Ge J, et al. Potent and protective IGHV3-53/3-66 public antibodies and their shared escape mutant on the spike of SARS-CoV-2. Nat Commun July 7, 2021, 12, 4210. https://www.nature.com/articles/s41467-021-24514-w
Analyzing a total of 165 antibodies from eight COVID-19 patients, the authors found that potent NAbs from different patients have disproportionately high representation of IGHV3-53/3-66 usage (termed as “public” antibodies). Crystal structural comparison of these antibodies reveals that they share a similar angle of approach to RBD, overlap in buried surface and binding residues on RBD, and have substantial spatial clash with receptor ACE2 with regards to binding to RBD.
Pan Y, Jiang X, Yang L, et al. SARS-CoV-2-specific immune response in COVID-19 convalescent individuals. Sig Transduct Target Ther July 7, 2021, 6, 256. https://www.nature.com/articles/s41392-021-00686-1
In a total of 212 samples from 171 COVID-19 convalescent individuals, NAbs were significantly correlated with the number of SARS-CoV-2-specific T and NK cells. This study indicates that B, T, and NK cells are involved in immune-mediated protection against viral infection.
Moriyama S, Adachi Y, Sato T, et al. Temporal Maturation of Neutralizing Antibodies in COVID-19 Convalescent Individuals Improves Potency and Breadth to Circulating SARS-CoV-2 Variants. Immunity July 02, 2021. https://www.cell.com/immunity/fulltext/S1074-7613(21)00259-4
Antibodies from late convalescents exhibited increased neutralization potency to variants of concern, suggesting persistence of cross-neutralizing antibodies in plasma. Maturation of the antibody response to SARS-CoV-2 potentiates cross-neutralizing ability to circulating variants, suggesting that declining antibody titers may not be indicative of declining protection.
Li C, Yu D, Wu X, et al. Twelve-month specific IgG response to SARS-CoV-2 receptor-binding domain among COVID-19 convalescent plasma donors in Wuhan. Nat Commun Jul 6, 2021, 12, 4144. https://www.nature.com/articles/s41467-021-24230-5
This 12-month longitudinal study using 1,782 plasma samples from 869 convalescent plasma donors shows that positive rate of IgG antibody against receptor-binding domain of spike protein (RBD-IgG) exceeded 70% for 12 months post diagnosis. The level of RBD-IgG decreased with time, with the titer stabilizing at 64.3% of the initial level by the 9th month.
Vanderbeke, L., Van Mol, P., Van Herck, Y. et al. Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity. Nat Commun Jul 5, 2021, 12, 4117. https://www.nature.com/articles/s41467-021-24360-w
In this prospective, case-control study of 61 patients with varying degrees of disease severity and 31 control patients, a quantitative and integrative qualitative immunophenotyping approach was used to characterize the cytokine responses. The authors identified a myeloid-driven atypical cytokine storm that is distinctly different from the so-called macrophage activation syndrome (MAS), with specific contributions of classical pro-inflammatory monocytes and neutrophils dominating COVID-19 immunopathology in the most critical cases.
Grandjean L, Saso A, Ortiz AT, et al. Long-Term Persistence of Spike Antibody and Predictive Modeling of Antibody Dynamics Following Infection with SARS-CoV-2. Clinical Infectious Diseases July 4, 2021. ciab607, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab607/6314536
A total of 1163 monthly samples were provided from 349 seropositive participants. S antibody was predicted to remain detectable in 95% of participants until 465 days. N antibodies decayed rapidly with a half-life of 60 days.
Liu W, Russell RM, Bibollet-Ruche F, Skelly AN, Sherrill-Mix S, Freeman DA, et al. Predictors of nonseroconversion after SARS-CoV-2 infection. Emerg Infect Dis June 30, 2021. https://wwwnc.cdc.gov/eid/article/27/9/21-1042_article
Non-seroconversion was associated with younger age and higher reverse transcription PCR cycle threshold values. Patients with low SARS-CoV-2 viral loads in their respiratory tract were less likely to mount a systemic antibody response.
Efrati S, Catalogna M, Abu Hamed R, et al. Early and long term antibody kinetics of asymptomatic and mild disease COVID-19 patients. Sci Rep July 2, 2021, 11, 13780. https://www.nature.com/articles/s41598-021-93175-y
Of 135 study participants, 97% were seropositive during the study. Two distinct clusters were identified that were significantly different in their inflammatory related symptoms. Systemic symptoms (i.e., fever, fatigue, pain, dry cough) were associated with higher antibody titers in mild symptomatic patients. Interestingly, the decay rate in antibody concentrations during the study period was similar in both clusters.
Neidleman J, Luo Y, George AF, et al. Distinctive features of SARS-CoV-2-specific T cells predict recovery from severe COVID-19. Cell Reports June 28, 2021. https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00827-5
This study indicates that lung-homing T cells activated through bystander effects contribute to immunopathology, while a robust, non-suppressive SARS-CoV-2-specific T cell response limits pathogenesis and promotes recovery from severe COVID-19.
Jung JH, Rha MS, Sa M, et al. SARS-CoV-2-specific T cell memory is sustained in COVID-19 convalescent patients for 10 months with successful development of stem cell-like memory T cells. Nat Commun June 30, 2021, 12, 4043. https://www.nature.com/articles/s41467-021-24377-1
In the present study, it is demonstrated that SARS-CoV-2-specific memory T cell responses were maintained in COVID-19 convalescent patients 10 months post-infection regardless of disease severity. Notably, SARS-CoV-2-specific stem cell-like memory T (TSCM) cells were successfully developed, indicating that T cell memory may be long-lasting in COVID-19 convalescent patients.
Choe PG, Kang CK, Kim KH, et al. Persistence of Neutralizing Antibody Response up to One Year after Asymptomatic or Symptomatic SARS-CoV-2 infection. The Journal of Infectious Diseases June 24, 2021, jiab339, https://doi.org/10.1093/infdis/jiab339
Of 16 patients (7 asymptomatic), all showed neutralizing antibody response up to 1 year after infection.
Li D, Edwards RJ, Manne K, et al. In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies. Cell June 18, 2021. https://doi.org/10.1016/j.cell.2021.06.021
A safety concern for the clinical use of antibodies (Abs) is antibody-dependent enhancement (ADE) of infection. This study identified potent in vitro infection-enhancing Abs from individuals infected with SARS-CoV or SARS-CoV-2, as well as the precise epitopes of infection-enhancing Abs. However, in vitro infection-enhancing Abs controlled virus in vivo and were rarely associated with enhanced lung pathology.
Aydillo T, Rombauts A, Stadlbauer D, et al. Immunological imprinting of the antibody response in COVID-19 patients. Nat Commun June 18, 2021, 12, 3781. https://www.nature.com/articles/s41467-021-23977-1
The induction of antibodies against conserved epitopes of seasonal coronaviruses may hinder the induction of specific antibodies toward divergent SARS-CoV-2 antigens. Immunity to other betacoronavirus spikes, like HKU1 and OC43, limited the induction of de novo responses to all SARS-CoV-2 antigens tested.
Iannetta M, Buccisano F, Fraboni D, et al. Baseline T-lymphocyte subset absolute counts can predict both outcome and severity in SARS-CoV-2 infected patients: a single center study. Sci Rep June 17, 2021, 11, 12762. https://www.nature.com/articles/s41598-021-90983-0
In this study on 160 patients, T lymphocyte subsets assessed at hospital admission were reduced in patients with increased risk of disease progression and unfavorable outcomes.
Wilk AJ, Lee MJ, Wei B, et al. Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19. J Exp Med June 15, 2021, 218 (8): e20210582. https://doi.org/10.1084/jem.20210582
These transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells.
Cheemarla NR, Watkins TA, Mihaylova VT, et al. Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics. J Exp Med June 15, 2021. https://rupress.org/jem/article/218/8/e20210583/212380/Dynamic-innate-immune-response-determines?searchresult=1
The role of host innate immune defenses in restricting early infection using transcriptomics and biomarker-based tracking in serial patient nasopharyngeal samples and experiments with airway epithelial organoids. SARS-CoV-2 initially replicated exponentially, with a doubling time of ∼6 h, and induced interferon-stimulated genes (ISGs) in the upper respiratory tract, which rose with viral replication and peaked just as viral load began to decline. Most interesting finding: rhinovirus infection before SARS-CoV-2 exposure accelerated ISG responses and prevented SARS-CoV-2 replication.
Lévy Y, Wiedemann A, Hejblum BP, et al. CD177, a specific marker of neutrophil activation, is associated with COVID-19 severity and death. iScience June 09, 2021. https://doi.org/10.1016/j.isci.2021.102711
This study highlights neutrophil activation as a hallmark of severe disease and CD177 assessment as a reliable prognostic marker for routine care.
Pušnik J, Richter E, Schulte B, et al. Memory B cells targeting SARS-CoV-2 spike protein and their dependence on CD4+ T cell help. Cell Rep June 11, 2021. https://doi.org/10.1016/j.celrep.2021.109320
This study identified CD4+ T cell subsets associated with the generation of B cell memory during SARS-CoV-2 infection. Compared to severely ill, individuals who recovered from mild COVID-19 develop fewer but functionally superior spike-specific memory B cells. Generation and affinity maturation of these cells is best associated with IL-21+CD4+ T cells in recovered individuals and CD40L+CD4+ T cells in severely ill individuals.
Wang Z, Muecksch F, Schaefer-Babajew D, et al. Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection. Nature June 14, 2021. https://doi.org/10.1038/s41586-021-03696-9
In this cohort of 63 COVID-19 convalescent individuals assessed at 1, 6 and 12 months after infection (41% also received mRNA vaccines), neutralizing activity and the number of RBD-specific memory B cells remain relatively stable for 6 to 12 months. Vaccination increases all components of the humoral response, and as expected, results in high serum neutralizing activities against variants of concern.
Goenka A, Halliday A, Gregorova M, et al. Young infants exhibit robust functional antibody responses and restrained IFN-γ production to SARS-CoV-2. Cell Rep Med June 09, 2021. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00170-1
This small study on four infants under 3 months old shows that immune responses in infants are distinct from those of their parents. Robust functional antibody responses alongside restrained IFN-γ production may help protect infants from severe COVID-19.
Camell CD, Yousefzadeh MJ, Zhu Y, et al. Senolytics reduce coronavirus-related mortality in old mice. Science Jun 8, 2021: eabe4832. https://science.sciencemag.org/content/early/2021/06/07/science.abe4832
Is this the explanation for the vulnerability of the elderly? Senescent cells (SnC) became hyper-inflammatory in response to SARS-CoV-2 S protein. Old mice acutely infected with a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation.
Nagler A, Kalaora S, Barbolin C, et al. Identification of presented SARS-CoV-2 HLA class I and HLA class II peptides using HLA-peptidomics. Cell Rep June 08, 2021. https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00681-1
The human leukocyte antigen (HLA)-bound viral antigens serve as an immunological signature that can be selectively recognized by T cells. This work identified 63 HLA-presented peptides derived from eight SARS-CoV-2 proteins. Shared SARS-CoV-2 peptides were identified in different cell types.
Amanat F, Thapa M, Lei T, et al. SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD and S2. Cell June 08, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00706-6
In this detailed profiling study of mRNA vaccine-induced polyclonal antibodies, polyclonal antibody responses in vaccinees were robust and comparable to or exceeded those seen after natural infection. However, the majority of vaccine-induced antibodies did not have neutralizing activity and were less heterogeneous. The vaccine induced cross-reactive antibodies to seasonal β-coronaviruses.
De Giorgi V, West KA, Henning AN, et al. Naturally acquired SARS-CoV-2 immunity persists for up to 11 months following infection. J Inf Dis, June 5, 2021, jiab295, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab295/6293992
Of the 116 donors presenting for repeat timepoints, 91.4% of donors had detectable IgG levels up to 11 months post-symptom recovery, while 63% had detectable neutralizing titers. Of note, 25% of donors had neutralizing levels that dropped to an undetectable titer over time.
Weingarten-Gabbay S, Klaeger S, Sarkizova S, et al. Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs. Cell June 1, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00701-7
An open reading frame (ORF) is the part of the reading frame that has the ability to be translated. This work uncovers previously uncharacterized SARS-CoV-2 HLA-I peptides from out-of-frame ORFs in the SARS-CoV-2 genome. About 25% of detected HLA-I peptides originated from such out-of-frame ORFs in S and N, and some elicited strong T cell responses, highlighting the contribution of these viral epitopes to the immune response in a mouse model and convalescent COVID-19 patients.
Yan L, Yang Y, Lu M, et al. Coupling of N7-methyltransferase and 3′-5′ exoribonuclease with SARS-CoV-2 polymerase reveals mechanisms for capping and proofreading. Cell May 24, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00663-2
Corona viruses have the largest RNA genomes amongst RNA viruses and employ a proofreading mechanism to ensure replication fidelity. This study provides a structural basis for understanding co-transcriptional modification of SARS-CoV-2 mRNA. Results also shed light on how replication fidelity in SARS-CoV-2 is maintained.
Liu Y, Soh WT, Kishikawa JI, et al. An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies. Cell May 24, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00662-0
Not only neutralizing antibodies but also enhancing antibodies are produced during SARS-CoV-2 infection. Screening a series of anti-spike monoclonal antibodies from COVID-19 patients, the authors found that some of antibodies against the N-terminal-domain (NTD) induce the open conformation of receptor binding domain (RBD) and thus enhance the binding capacity of the spike protein to ACE2 and infectivity of SARS-CoV-2. All the infectivity-enhancing antibodies bound to NTD in a similar manner and were detected at high levels in patients with severe COVID-19.
Virale J, Mumoli N, Clerici P, et al Assessment of SARS-CoV-2 Reinfection 1 Year After Primary Infection in a Population in Lombardy, Italy. JAMA Intern Med May 28, 2021. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2780557?resultClick=1
In this large observational study, incidence rate ratio (patients with/without prior infection) adjusted for age, sex, ethnicity, and the sanitarian area was 0.07 (95% CI, 0.06-0.08).
Leidi A, Koegler F, Dumont R, et al. Risk of reinfection after seroconversion to SARS-CoV-2: A population-based propensity-score matched cohort study. Clin Inf Dis 27 May 2021, ciab495, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab495/6287116
Among 8344 serosurvey participants from Geneva, Switzerland, 498 seropositive individuals were selected and matched with 996 seronegative controls. After a mean follow up of 35 weeks, there was a 94% (95% CI: 86% to 98%, P < 0.001) reduction in the hazard of having a positive SARS-CoV-2 test in seropositive people.
Dhindsa S, Zhang N, McPhail MJ, et al. Association of Circulating Sex Hormones With Inflammation and Disease Severity in Patients With COVID-19. JAMA Netw Open May 25, 2021;4(5):e2111398. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2780135?resultClick=24
Unlike the common presumption, testosterone may not be a propagator of COVID-19 severity. On the contrary, it may be protective in men: this single-center cohort study of 152 patients with COVID-19 found that men with severe COVID-19 had 65% to 85% lower testosterone concentrations compared with men with a milder disease course, and this difference was independent of other known risk factors associated with severity, such as age, BMI, co-morbidities, smoking, and race.
Kim MH, Salloum S, Wang JY, et al. Type I, II, and III interferon signatures correspond to COVID-19 disease severity. J Inf Dis May 24, 2021, jiab288, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab288/6283761
Patients with mild COVID-19 exhibited transient type I interferon responses, while ICU patients had prolonged type I interferon responses with hyper-inflammation mediated by interferon regulatory factor 1. Type II interferon responses were compromised in ICU patients. Type III interferon responses were induced in the early phase of SARS-CoV-2 infection, even in convalescent patients.
Grau-Expósito J, Sánchez-Gaona N, Massana N, et al. Peripheral and lung resident memory T cell responses against SARS-CoV-2. Nat Commun May 20, 2021, 12, 3010. https://doi.org/10.1038/s41467-021-23333-3
Some more insights on T cell response to SARS-CoV-2. The acute response of non-hospitalized patients is characterized by CD4+ and, to a lesser extent, CD8+ SARS-CoV-2-specific T cells secreting IL-10. In contrast, hospitalized patients show a bias towards an effector response characterized by IFNγ and IL-4 secretion as the main functions as severity increases. Secondly, depending on the SARS-CoV-2 viral protein targeted, different CD4+ and CD8+ T cell functional profiles are generated. Finally, and most importantly, SARS-CoV-2 resident memory T cells persist for 10 months after infection; nonetheless, the magnitude and profile of the lung SARS-CoV-2-specific T cells strongly differ from the response detected in blood.
Renner K, Schwittay T, Chaabane S, et al. Severe T cell hyporeactivity in ventilated COVID-19 patients correlates with prolonged virus persistence and poor outcomes. Nat Commun May 21, 2021, 12, 3006. https://www.nature.com/articles/s41467-021-23334-2
Low polyclonal T cell reactivity is a hallmark of COVID-19 patients and strongly correlated with disease severity. T cell reactivity was much lower in ventilated than in non-ventilated hospitalized patients, which was again somewhat lower than in healthy controls. Of note, T cell hyporeactivity was only detectable in assays with whole blood but not with purified PBMC and could be attributed to suppressive components present in the plasma of COVID-19 patients.
Wang EY, Mao T, Klein J, et al. Diverse Functional Autoantibodies in Patients with COVID-19. Nature May 19, 2021. https://www.nature.com/articles/s41586-021-03631-y
Is it all just dysregulated humoral immunity? This important paper reveals an expansive autoantibody landscape in COVID-19 and identified distinct autoantibodies that exerted striking immunological and clinical outcomes. COVID-19 patients exhibit dramatic increases in autoantibody reactivities compared to uninfected controls, with a high prevalence of autoantibodies against immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins. These autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signaling and by altering peripheral immune cell composition.
Low JS, Vaqueirinho D, Mele F, et al. Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2. Science 18 May 2021:eabg8985. https://science.sciencemag.org/content/early/2021/05/17/science.abg8985
COVID-19-recovered individuals display a robust CD4+ T cell response to naturally processed SARS-CoV-2 spike (S) and nucleoprotein (N), including effector, helper, and memory T cells. Using pre- and post-COVID-19 samples and S proteins from endemic coronaviruses, the authors also identified cross-reactive T cells targeting multiple S protein sites, also providing evidence for the recall of pre-existing cross-reactive memory T cells upon SARS-CoV-2 infection.
BergamaschiL, Mescia F, Turner L, et al. Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease. Immunity May 16, 2021. https://www.cell.com/immunity/fulltext/S1074-7613(21)00216-8
This analysis of serial samples from 207 SARS-CoV-2-infected individuals showed that an early robust bystander CD8+ T cell immune response, without systemic inflammation, characterizes asymptomatic or mild disease. Circulating plasmablasts and CD8+HLA‐DR+CD38+ activated T cells expanded earlier and in higher numbers than in more severe COVID‐19 groups, most notably in the first week after symptom onset.
Ma S, Zhang F, Zhou F, et al. Metagenomic analysis reveals oropharyngeal microbiota alterations in patients with COVID-19. Sig Transduct Target Ther May 13, 2021, 6, 191. https://doi.org/10.1038/s41392-021-00614-3
SARS-CoV-2 infection alters the composition of the oropharyngeal microbiota and causes dysbiosis of the local microbiome, which may induce translocation of oral pathogens into the lungs to cause pulmonary co-infections.
Yao L, Wang GL, Shen Y, et al. Persistence of Antibody and Cellular Immune Responses in COVID-19 patients over Nine Months after Infection. J Inf Dis May 12, 2021, jiab255, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab255/6274562
Of 59 COVID-19 patients, approximately 90% of patients had detectable IgG antibodies against spike and nucleocapsid proteins and neutralizing antibodies against pseudovirus, whereas ~ 60% of patients had detectable IgG antibodies against receptor binding domain and surrogate virus-neutralizing antibodies. Specific IgG + memory B cell and IFN-γ secreting T cell responses were detectable in over 70% of patients.
Dispinseri S, Secchi M, Pirillo MF, et al. Neutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival. Nat Commun 12, 2670 (2021). https://www.nature.com/articles/s41467-021-22958-8
In this study on 169 symptomatic COVID-19 patients, neutralizing antibody titers progressively dropped after 5–8 weeks but well still detectable up to 8 months in the majority of recovered patients regardless of age or co-morbidities, with IgG to spike antigens providing the best correlate of neutralization.
Panda AK, Pati A, Padhi S, et al. Granulin rs5848 (C>T) polymorphism is associated with SARS-CoV-2 infection and mortality. J Inf Dis 5 May 2021, jiab237, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab237/6265298
A common genetic polymorphism in the granulin gene (C>T, rs5848) has been reported to be associated with altered mRNA and protein levels. This preliminary data indicates that the C allele of the progranulin rs5848 polymorphism predisposes to SARS-CoV-2 infection susceptibility and mortality.
Roussel M, Ferrant J, Reizine F, et al. Comparative immune profiling of acute respiratory distress syndrome patients with or without SARS-CoV2 infection. Cell Rep Med May 06, 2021. https://doi.org/10.1016/j.xcrm.2021.100291
The immune landscape in COVID-19-associated ARDS compared to other causes of ARDS: an increase of CD169 positive monocytes, correlated with specific changes of T, plasma, and NK cell subsets, defined COVID-19-associated ARDS and was not found in bacteria-associated ARDS, suggesting a COVID-19-specific immune reprogramming.
Zheng M, Karki R, Williams EP, et al. TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines. Nature Immunology 07 May 2021. https://www.nature.com/articles/s41590-021-00937-x
TLR2 is a cell surface innate immune sensor with the ability to recognize diverse ligands from viruses, fungi, bacteria and parasites. This study provides the first genetic evidence that TLR2 can sense β-coronavirus infection via recognition of the E protein to induce release of inflammatory cytokines, including TNF-α and IFN-γ. The activation of TLR2 signaling in response to β-coronavirus infection was independent of viral entry and replication.
Dugan HL, Stamper CT, Li L, et al. Profiling B cell immunodominance after SARS-CoV-2 infection reveals antibody evolution to non-neutralizing viral targets. Immunity May 6, 2021. https://doi.org/10.1016/j.immuni.2021.05.001
This study characterized the SARS-CoV-2-specific B cell repertoire in 38 COVID-19 patients, both severe acute and convalescent, approximately 1.5–4.5 months post-symptom onset, using oligo-tagged antigen-bait sorting and single-cell RNA sequencing. Memory B cells ((MBC) displayed substantial reactivity toward NP and ORF8 and continued to expand and adapt to these targets over time, particularly in older patients. While SARS-CoV-2 RBD-specific monoclonal antibodies (mAbs) were potently neutralizing and protective, anti-NP and anti-ORF8 mAbs failed to neutralize and provide protection in vivo. Thus, preexisting MBC bias to non-neutralizing targets in SARS-CoV-2 could impact susceptibility to or severity of re-infection.
Hui X, Zhang L, Cao L, et al. SARS-CoV-2 promote autophagy to suppress type I interferon response. Sig Transduct Target Ther May 8, 2021. 6, 180. https://www.nature.com/articles/s41392-021-00574-8
Interesting novel finding: SARS-CoV-2 utilizes autophagy to escape host immune defense. SARS-CoV-2 M protein induced mitophagy to break the mitochondria networks to block the downstream innate immunity signaling that inhibits the type I IFN response.
Lucas C, Klein J, Sundaram ME, et al. Delayed production of neutralizing antibodies correlates with fatal COVID-19. Nat Med May 4, 2021. https://www.nature.com/articles/s41591-021-01355-0
Paper of the day. Although sera from 85% of patients displayed some neutralization capacity during their disease course, generation of neutralizing antibodies (NAb) before day 14 of disease onset emerged as a key factor for recovery. This analysis of 229 COVID-19 patients suggests that mortality does not correlate with the cross-sectional antiviral antibody levels per se but rather with the delayed kinetics of NAb production.
Anand SP, Prévost J, Nayrack M, et al. Longitudinal analysis of humoral immunity against SARS-CoV-2 Spike in convalescent individuals up to eight months post-symptom onset. Cell Rep Med May 4, 2021. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00118-X
Longitudinal assessment of humoral immune responses on 32 donors up to 8 months post-symptom onset indicate that anti-spike and anti-RBD IgM in plasma decay rapidly, whereas the reduction of IgG is less prominent.
Voss WN, Hou YJ, Johnson NV, et al. Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes. Science 04 May 2021: https://science.sciencemag.org/content/early/2021/05/03/science.abg5268
Important paper on the molecular composition and binding epitopes of the convalescent plasma IgG response to SARS-CoV-2. This response is oligoclonal and directed overwhelmingly toward non-receptor-binding domain (RBD) epitopes in the SARS-CoV-2 spike ectodomain, including public, near-germline, and potently neutralizing antibodies against the N-terminal domain (NTD). Genetic, structural, and functional characterization of a multi-donor class of “public” antibodies revealed an NTD epitope that is recurrently mutated among emerging SARS-CoV-2 variants of concern.
Garrett ME, Galloway J, Chu HY, et al. High resolution profiling of pathways of escape for SARS-CoV-2 spike-binding antibodies. Cell May 04, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00580-8
This brilliant study provides a granular view of potential antibody escape pathways: the authors tested all possible mutations on the S protein to provide a map of escape pathways within immunodominant linear epitopes targeted by the plasma of convalescent COVID-19 patients. The responses within an individual were consistent over time, but there were many unique pathways of escape that differed between individuals, even within the same epitope region. Findings suggest that the pattern of viral evolution within the growing pandemic is not likely to be driven by a single antibody escape mutation, which may explain the lack of emergence of circulating strains with mutations that disrupt antibody binding identified here.
Reynolds CJ, Pade C, Gibbons JM, et al. Prior SARS-CoV-2 infection rescues B and T cell responses to variants after first vaccine dose. Science 30 Apr 2021: eabh1282. https://science.sciencemag.org/content/early/2021/04/29/science.abh1282
T and B cell responses after first dose vaccination with the Pfizer/BioNTech vaccine were followed longitudinally in healthcare workers (HCW), with (n = 23) or without (n = 23) prior SARS-CoV-2 infection. After one dose, individuals with prior infection showed enhanced T cell immunity, antibody secreting memory B cell response to spike and neutralizing antibodies effective against B.1.1.7 and B.1.351.
Melms JC, Biermann J, Huang H, et al. A molecular single-cell lung atlas of lethal COVID-19. Nature April 29, 2021. https://doi.org/10.1038/s41586-021-03569-1
Single-nucleus RNA-sequencing of ~116,000 nuclei of lungs from 19 COVID-19 decedents and 7 control lungs, providing insights into the biology of lethal COVID-19: interplay among aberrantly activated monocytes/macrophages producing IL-1β, inflammation-induced impairment of alveolar epithelial regeneration, and expansion of pathological fibroblasts that promote fibrosis. Data also suggest that despite a potentially sufficient humoral immune response, T cell response was inadequate.
Delorey TM, Ziegler CG, Heimberg G, et al. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature April 29, 2021. https://doi.org/10.1038/s41586-021-03570-8
Complementing the above sister lung atlas above, these single-cell atlases of 23 lung, 16 kidney, 16 liver and 19 heart COVID-19 autopsy donor tissue samples, and spatial atlases of 14 lung donors elucidate the biological impact of severe SARS-CoV-2 infection across the body.
Zhou X, Ma F, Xie J, et al. Diverse immunoglobulin gene usage and convergent epitope targeting in neutralizing antibody responses to SARS-CoV-2. Cell Rep April 23, 2021. https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00443-5
Employing a high-throughput system combining isolation of receptor binding domain (RBD)-binding memory B cells, in vitro single cell culture, and functional screening, 54 potent neutralizing antibodies for SARS-CoV-2 were isolated. Fifty-two of them target the ACE2 binding surface on the RBD of SARS-CoV-2 spike protein, while the other two recognize epitopes that do not appear to overlap as extensively with the ACE2 binding site, among them 47D1 that binds a site on the backside of the receptor binding surface of the SARS-CoV-2 RBD (less susceptible to mutations?). 47D1 and was able to protect hamsters.
Wu Y, Ma L, Cai S, et al. RNA-induced liquid phase separation of SARS-CoV-2 nucleocapsid protein facilitates NF-κB hyper-activation and inflammation. Sig Transduct Target Ther 6, 167 (2021). https://www.nature.com/articles/s41392-021-00575-7
How does SARS-CoV-2 trigger dysfunctional inflammatory responses? Here, it is shown that the SARS-CoV-2 N protein promotes the activation of Nuclear Factor κB (NF-κB) signaling, which is one of the key transcription factors of IL-6 in both immune cells and non-immune cells.
Scheid JF, Barnes CO, Eraslan B, et al. B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV. Cell April 23, 2021. DOI:https://doi.org/10.1016/j.cell.2021.04.032
It is important to learn more about transcriptional pathways involved in the generation of efficient antiviral antibody (Ab) responses and the roles of different B cell sub-populations. This in-depth analysis of SARS-CoV-2 binding B cells from convalescent individuals show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations such as Ab secreting and activated B cells but also mature naïve B cells.
Asarnow D, Wang B, Lee WH, et al. Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia. Cell April 23, 2021. DOI: https://doi.org/10.1016/j.cell.2021.04.033
An important paper that shows bivalent binding and receptor blockade are not sole determinants of potent neutralization. In addition to blocking ACE2, antibodies either inhibit or enhance spike-mediated membrane fusion and formation of syncytia, associated with lung tissue damage. These findings suggest that potentiation of cell-cell fusion by antibodies may compromise the effectiveness of viral neutralization in the treatment of severe COVID-19.
Alshukairi AN, Zhao J, Al-Mozaini MA, Wang Y, Dada A, Baharoon SA, et al. Longevity of Middle East respiratory syndrome coronavirus antibody responses in humans, Saudi Arabia. Emerg Infect Dis April 14, 2021. https://wwwnc.cdc.gov/eid/article/27/5/20-4056_article
Learning from MERS? Antibody responses in 48 human MERS-CoV infection survivors who had variable disease severity in Saudi Arabia, MERS-CoV–specific neutralizing antibodies were detected for 6 years post-infection. Positive neutralizing antibodies were found in 21/31 survivors with mild disease, 12/12 moderate disease, and 5/6 survivors with severe disease.
Letizia AG, Ge Y, Vangeti S, et al. SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study. Lancet Resp Med April 15, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00158-2/fulltext
84% protection. In this large prospective cohort study of new US Marine recruits (18–20 years old, mostly male) without active infection, a lower proportion of participants who had baseline serum antibodies (n = 225) became infected during the 6-week study period than of those without detectable antibodies (n = 2851). After adjusting for the effects of race, age, and sex, the hazard ratio comparing seropositive participants and seronegative participants was 0.16 (95% CI: 0.10–0.25; p < 0·001). The risk of subsequent infection in seropositive individuals was associated with lower IgG antibody titers and absent or lower neutralizing antibody activity.
Alrubayyi A, Peppa D. Seeing SARS-CoV-2 variants through the eyes of T cells. Nat Rev Immunol April 14, 2021. https://www.nature.com/articles/s41577-021-00551-w
Best paper title of the day. It’s time to look at the T cells. They will do their job, irrespective as to what variant is present. The authors discuss a pre-print indicating a negligible impact of the SARS-CoV-2 variant mutations on global CD4+ and CD8+ T cell responses in COVID-19 convalescent donors and COVID-19 mRNA vaccine recipients. It’s not all about antibodies. Hopefully.
Suryamohan K, Diwanji D, Seshagiri S. Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2. Communications Biology 4 , 1–11, 12 April 2021. https://www.nature.com/articles/s42003-021-02030-3
ACE2 polymorphisms can alter host susceptibility to SARS-CoV-2 by affecting interaction. The authors analyzed over 290,000 samples from public genomic datasets and identified several ACE2 protein-altering variants. Some experiments indicate that ACE2 variants can modulate susceptibility to SARS-CoV-2.
Yang F, Nielsen SC, Hoh RA, et al. Shared B cell memory to coronaviruses and other pathogens varies in human age groups and tissues. Science 12 Apr 2021: eabf6648. https://science.sciencemag.org/content/early/2021/04/09/science.abf6648
Pre-pandemic children had class-switched convergent clones to SARS-CoV-2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. The authors hypothesize that previous HCoV exposures may stimulate cross-reactive memory, and that such clonal responses may have their highest frequencies in childhood.
Ferreira-Gomes M, Kruglov A, Durek P, et al. SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself. Nat Commun 12, 1961, March 30, 2021. https://www.nature.com/articles/s41467-021-22210-3
In 60 patients with severe COVID-19, the initial immune reaction (reflected by egress of antibody-secreting plasmablasts into the blood and antibody class switching to IgG1 and IgA1) was controlled by IFNs, IL-21, and TGF-β. At later time points (when IFN is no longer involved), the immune reactions are controlled by TGF-β (and IL-21), which drives cells to switch to the terminal antibody class IgA2. At these later time points, the immune reaction is no longer directed to SARS-CoV-2. Such cells do not relocate to the lung, are not specific for the spike protein and contribute little to humoral immunity to SARS-CoV-2.
Hall VJ; Foulkes S, Charlett A, et al. SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN). The Lancet April 09, 2021. DOI: https://doi.org/10.1016/S0140-6736(21)00675-9
In this large study on 25,661 HCW, previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection (93% lower risk of symptomatic infection), with median protective effect observed 7 months following primary infection. Of the 155 reinfections, 50% were symptomatic. This is good news because the levels of prevention of symptomatic infection seem to be similar to the new licensed vaccines and also work well against reinfection with the B.1.1.7 variant.
Pati A, Padhi S, Panda D, et al. A cluster of differentiation 14 (CD14) polymorphism (C-159T rs2569190) is associated with SARS-CoV-2 infection and mortality in the European population. J Inf Dis April 2, 2021. jiab180 https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab180/6209441?searchresult=1
Some early suggestions about a possible role of CD14 promoter variant with the predisposition and disease outcome of SARS-CoV-2 infections. Patients with this gene variant possibly produce elevated sCD14 and exacerbated inflammatory molecules.
Mazzitelli I, Bleichmar L, Ludueña MG, et al. IgG immune complexes may contribute to neutrophil activation in the course of severe COVID-19. J Inf Dis 02 April 2021, jiab174, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab174/6208275
Whole blood assays revealed that neutrophils from severe COVID-19 patients show a clear association with IgG immune complexes. Sera from severe patients contained high levels of immune complexes and activate neutrophils through a mechanism partially dependent on FcγRII (CD32). Results indicate that IgG immune complexes might promote the acquisition of an inflammatory signature by neutrophils to worsen the course of COVID-19.
Shuwa HA, Shaw TN, Knight SB, et al. Alterations in T and B cell function persist in convalescent COVID-19 patients. Med March 31, 2021. https://www.sciencedirect.com/science/article/pii/S266663402100115X
Alterations in B cell subsets observed in acute COVID-19 patients were largely recovered in convalescent patients. In contrast, T cells from convalescent patients displayed continued alterations with persistence of a cytotoxic program evident in CD8+ T cells as well as elevated production of type-1 cytokines and IL-17.
Lv J, Yu P, Wang Z, et al. ACE2 expression is regulated by AhR in SARS-CoV-2-infected macaques. Cell Mol Immunol, April 1, 2021. https://www.nature.com/articles/s41423-021-00672-1
The cytoplasmic transcription factor aryl hydrocarbon receptor AhR is able to bind the promoter of the ACE2 gene, thus promoting ACE2 expression and augmenting the subsequent pathology in SARS-CoV-2-infected lungs.
Sermet-Gaudelus I, Temmam S, Huon C, et al. Prior infection by seasonal coronaviruses, as assessed by serology, does not prevent SARS-CoV-2 infection and disease in children, France, April to June 2020. Euro Surveill. 2021;26(13):pii=2001782. https://doi.org/10.2807/1560-7917.ES.2021.26.13.2001782
See title. No evidence of cross-protective immunity linked to previous infection with seasonal HCoV. The seasonal HCoV prevalence in SARS-CoV-2-positive and -negative patients was similar. There was no significant correlation between SARS-CoV-2 and antibody levels of any HCoV, whatever the antigen considered (S or N), while SARS-CoV-2 antibodies to N and S correlated as expected.
Rendeiro AF, Ravichandran H, Bram Y, et al. The spatial landscape of lung pathology during COVID-19 progression. Nature March 29, 2021. https://www.nature.com/articles/s41586-021-03475-6
A comprehensive examination of the response of the human lung to infection from macroscopic to single-cell level.
Daamen AR, Bachali P, Owen KA, et al. Comprehensive transcriptomic analysis of COVID-19 blood, lung, and airway. Sci Rep March 29, 2021. 11, 7052 (2021). https://doi.org/10.1038/s41598-021-86002-x
More on the pathogenesis of COVID-19 driven by populations of myeloid-lineage cells with highly inflammatory but distinct transcriptional signatures in each compartment. The authors found a systemic, but compartmentalized immune/inflammatory response with specific signs of cellular activation in blood, lung and airways.
Thakkar A. Pradhan K, Jindal S, et al. Patterns of seroconversion for SARS-CoV-2 IgG in patients with malignant disease and association with anticancer therapy. Nat Cancer 2021, published 22 March. Full-text: https://doi.org/10.1038/s43018-021-00191-y
Two hundred and sixty-one patients with a cancer diagnosis underwent SARS-CoV-2 IgG testing and demonstrated a high rate of seroconversion (92%). Significantly lower seroconversion was seen in patients with hematological malignancies (82%), patients who received anti-CD-20 antibody therapy (59%) and stem cell transplant (60%). Notably, all 17 patients who received immunotherapy, including 16 that received anti-PD-1/PD-L1 monoclonal antibodies, developed SARS-CoV-2 IgG antibodies (100% seroconversion).
Stertz S, Hale BG. Interferon system deficiencies exacerbating severe pandemic virus infections. Trends Microbiol 2021, published 20 March. Full-text: https://doi.org/10.1016/j.tim.2021.03.001
An emerging concept is that genetic and non-genetic deficiencies in interferon system components lead to uncontrolled viral replication and severe illness in a subset of people. Intriguingly, new findings suggest that individuals with auto-antibodies neutralizing the antiviral function of interferon are at increased risk of severe COVID-19. The authors discuss key questions surrounding how such auto-antibodies develop and function, as well as the general implications of diagnosing interferon deficiencies for personalized therapies.
McCallum M, De Marco a, Lempp FA, et al. N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. Cell 2021, published 16 March. Full text: https://doi.org/10.1016/j.cell.2021.03.028
McCallum et al. describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultra-potently. The authors underline the importance of NTD-specific neutralizing mAbs for protective immunity and vaccine design.
Greaney AJ, Starr TN, Barnes CO, et al. Mutational escape from the polyclonal antibody response to SARS-CoV-2 infection is largely shaped by a single class of antibodies. bioRxiv 2021, posted 18 March. Full text: https://doi.org/10.1101/2021.03.17.435863
Although the human immune system can produce antibodies that target diverse RBD epitopes, in practice the polyclonal response to infection is dominated by a single class of antibodies targeting an epitope that is already undergoing rapid evolution. These “class 2” antibodies target the face of the receptor-binding ridge that is accessible in both “up” and “down” RBD conformations. A mutation (E484K) that escapes this antibody class is present in many emerging viral lineages, including B.1.351, P.1, P.2, and B.1.526.
Benedict C, Cedernaes J. Could a good night’s sleep improve COVID-19 vaccine efficacy? Lancet Respir Med. 2021 Mar 12:S2213-2600(21)00126-0. PubMed: https://pubmed.gov/33721558. Full text: https://doi.org/10.1016/S2213-2600(21)00126-0
Could the timing of vaccination affect the immune response to COVID-19 vaccines? Should we all take a nap after vaccination? It wouldn’t do any harm.
Clark SA, Clark LE, Pan J, et al. SARS-CoV-2 evolution in an immunocompromised host reveals shared neutralization escape mechanisms. Cell March 16, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00355-X
Viral evolution in a persistently infected immunocompromised individual: mutations found in late-stage evolved S variants confer resistance to a common class of SARS-CoV-2 neutralizing antibodies. Resistance extends to the polyclonal serum immunoglobulins healthy convalescent donors and to monoclonal antibodies in clinical use. This case shows how SARS-CoV-2 can evolve solutions to bind ACE2 while escaping neutralization by major classes of human neutralizing antibodies.
Wang Z, Yang X, Zhong J, et al. Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection. Nat Commun March 19, 2021, 12, 1724. https://www.nature.com/articles/s41467-021-22036-z
Close contacts who are SARS-CoV-2-exposed are often both PCR- and antibody-negative, indicating that SARS-CoV-2 failed to establish a successful infection in these individuals, presumably due to their exposure to limited numbers of viral particles or a short time of exposure. This interesting study has evaluated T cell responses in 90 recovered COVID-19 patients and 69 close contacts. 58% of close contacts had virus-specific memory CD4+ and 14% of close contacts had virus-specific memory CD8+ T cells. Pool sizes and quality of T memory cells from close contacts were around half of those from COVID-19 patients.
He Z, Ren L, Yang J, et al. Seroprevalence and humoral immune durability of anti-SARS-CoV-2 antibodies in Wuhan, China: a longitudinal, population-level, cross-sectional study. Lancet March 20, 2021 Volume 397, ISSUE 10279, P1075-1084, March 20, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00238-5/fulltext
This cross-sectional study from Wuhan suggests durable protection against SARS-CoV-2. Among 3599 randomly selected families with 9702 individuals, baseline adjusted seroprevalence was 6.9%. Although titers of IgG decreased over the 9-month study period, the proportion of individuals who had IgG antibodies did not decrease substantially. Neutralizing antibodies were found in 39·8% of the seropositive subgroup; encouragingly, this proportion was also sustained. Of note, more than 80% of those surveyed who were seropositive were asymptomatic.
Andolfo I, Russo R, Larorsa, et al. Common variants at 21q22.3 locus influence MX1 and TMPRSS2 gene expression and susceptibility to severe COVID-19. iScience March 17, 2021. https://www.cell.com/action/showPdf?pii=S2589-0042%2821%2900290-X
Analyzing the genome of 7970 individuals hospitalized for COVID-19, this Italian group found some host genetic factors to influence the course of COVID-19. Five SNPs within TMPRSS2/MX1 locus (chromosome 21) were associated with severe COVID-19. The minor alleles of these five SNPs correlated with a reduced risk of developing severe COVID-19 and a high level of MX1 expression in blood (note that the odds ratios were not that dramatic, ranging from 0.5 to 1.5).
Abayasingam A, Balachandran H, Agapiou D, et al. Long-term persistence of RBD-positive memory B cells encoding neutralising antibodies in SARS-CoV-2 infection. Cell Rep Med March 14, 2021. https://www.cell.com/action/showPdf?pii=S2666-3791%2821%2900044-6
Good news. The loss of neutralising antibodies (NAb) in plasma may be countered by the maintenance of neutralising capacity in the memory B cell repertoire. Despite the declining NAb titers, in the great majority of participants, memory B cells against RBD were maintained and even increased in numbers at four to six months following infection in 12/13 participants.
Szabo PA, Dogra P, Gray JI, et al. Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19. Immunity March 11, 2021. DOI: https://www.cell.com/action/showPdf?pii=S1074-7613%2821%2900117-5
More insights into the immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract. The authors have identified a key role for airway myeloid cells, primarily macrophages and monocytes, in driving and perpetuating immune cell recruitment and lung inflammation, consistent with their associations with older age and mortality.
Flynn RA, Belk JA, Qi Y, et al. Discovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions. Cell March 11, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00297-X
Using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), Ryan A. Flynn and colleagues identified 309 host proteins that bind the SARS-CoV-2 RNA during active infection. Their work provides a comprehensive catalog of functional SARS-CoV-2 RNA-host protein interactions, which can inform studies to understand the host-virus interface.
Paper of the Day
Amanat F, Thapa M, Lei T, et al. The plasmablast response to SARS-CoV-2 mRNA vaccination is dominated by non-neutralizing antibodies that target both the NTD and the RBD. medRxiv 2021, posted 9 March. Full-text: https://doi.org/10.1101/2021.03.07.21253098
Florian Krammer, Fatima Amanat and colleagues studied the plasmablast response to SARS-CoV-2 mRNA-based vaccination. The authors demonstrate that the antibody responses to SARS-CoV-2 mRNA vaccination comprise a large proportion of non-neutralizing antibodies and are co-dominated by NTD and RBD antibodies. The NTD portion of the spike represents, therefore, an important vaccine target. Since all viral variants of concern are heavily mutated in this region, these observations warrant further attention to optimize SARS-CoV-2 vaccines. Finally, broadly cross-reactive mAbs to β-coronavirus spike proteins are induced after vaccination and suggest a potential development path for a pan-β-coronavirus vaccine.
Ellebedy A, Turner J, O’halloran J, et al. SARS-CoV-2 mRNA vaccines induce a robust germinal centre reaction in humans. Research Square 2021, posted 9 March. Full-text: https://doi.org/10.21203/rs.3.rs-310773/v1
Did you feel that your arm is on “fire” after getting your SARS-CoV-2 mRNA vaccine? Did you get some fine needle aspirates of your draining axillary lymph nodes? You could have investigated the dynamics of antibody secreting plasmablasts (PBs) and germinal center (GC) B cells induced by these vaccines in SARS-CoV-2 naïve and antigen-experienced humans. Ellebedy et al did just that. They demonstrated that SARS-CoV-2 mRNA-based vaccination of humans induces a robust and persistent GC B cell response that engages pre-existing as well as new B cell clones. High-affinity, broad, and durable humoral immunity on the horizon?
Muecksch F, Weisblum Y, Barnes CO, et al. Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies. bioRxiv 2021, posted 8 March. Full-text: https://doi.org/10.1101/2021.03.07.434227
Might affinity maturation generate antibodies that are resilient to viral evolution? Paul Bieniasz, Frauke Muecksch and colleagues think so. After analyzing six independent antibody lineages, they found that for certain ones, maturation enabled neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. The authors conclude that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.
Grzelak L, Velay A, Madec Y, et al. Sex differences in the evolution of neutralizing antibodies to SARS-CoV-2. Journal of Infectious Diseases 07 March 2021, jiab127, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab127/6161322?searchresult=1
More robust humoral responses in women than in men? In 308 healthcare workers with mild disease, anti-S and anti-N antibodies were detected in 99% and 59% of individuals at 3-6 months, respectively. Anti-S antibodies and NAbs declined faster in males than in females, independently of age and BMI, suggesting an association of sex with evolution of the humoral response.
Paper of the Day
Huang L, Shi Y, Gong B, et al. Dynamic blood single-cell immune responses in patients with COVID-19. Sig Transduct Target Ther March 6, 2021, 6, 110. https://doi.org/10.1038/s41392-021-00526-2
More details on pathogenesis, mainly the host immune process, imbalances and pathways. In this incredible work, Lulin Huang and colleagues obtained single-cell mRNA sequencing data of 341,420 (!) peripheral blood mononuclear cells and 185,430 clonotypic T cells and 28,802 clonotypic B cells from 25 samples of 16 patients with COVID-19 for dynamic studies.
Gao L, Zhou J, Yang S, et al. The dichotomous and incomplete adaptive immunity in COVID-19 patients with different disease severity. Sig Transduct Target Ther 6, 113 (2021). https://doi.org/10.1038/s41392-021-00525-3
Specific B-cell and T-cell responses in 74 symptomatic patients with various disease severity: B cell responses were only transiently induced in early infection phase in asymptomatic or mild patients. In keeping with this, sustained GC responses that give rise to long-term memory B cells and IgG-secreting plasma cells were almost absent in these patients. This may explain that asymptomatic patients often fail to generate long-term SARS-CoV-2-specific IgG response. in contrast to humoral immunity, the virus-specific TH1 and CD8+ T cell immune responses were rapidly induced and sustained in asymptomatic or mild symptomatic patients as compared to patients with moderate or severe disease.
Casado JL, Häemmerle J, Vizcarra P, et al. SARS CoV-2 infections in health care workers with pre-existing T cell response: a prospective cohort study. March 02, 2021. https://doi.org/10.1016/j.cmi.2021.02.020
José L. Casado and colleagues from Madrid looked at pre-existing T-cell responses. Twenty of 38 HCWs included (53%) had a previous specific CD8+ T cell response that does not seems to reduce incident SARS-CoV-2 infections, but may contribute to asymptomatic or mild disease, rapid viral clearance and differences in seroconversion.
Tarke A, Sidney J, Methot N, et al. Negligible impact of SARS-CoV-2 variants on CD4+ and CD8+ T cell reactivity in COVID-19 exposed donors and vaccinees. bioRxiv 2021, posted 1 March. Full-text: https://doi.org/10.1101/2021.02.27.433180
Good news from the T cell front. Alessandro Sette, Alba Grifoni, Shane Crotty, Alison Tarke and colleagues did a comprehensive analysis of SARS-CoV-2-specific CD4+ and CD8+ T cell responses from COVID-19 convalescent subjects recognizing the ancestral strain, compared to variant lineages B.1.1.7, B.1.351, P.1, and CAL.20C as well as recipients of the Moderna (mRNA-1273) or the Pfizer/BioNTech (BNT162b2) COVID-19 vaccines. The comfortable result: CD4+ and CD8+ T cell responses in convalescent COVID-19 subjects or COVID-19 mRNA vaccinees are not substantially affected by mutations found in the SARS-CoV-2 variants.
Bost P, De Sanctis F, Canè S et al. Deciphering the state of immune silence in fatal COVID-19 patients. Nat Commun March 4, 2021 12, 1428. https://www.nature.com/articles/s41467-021-21702-6#citeas
This study shows innate and adaptive immune dysfunction, including loss of immune suppression by blood myeloid cells and the replacement of lung memory CD8+ T cells by naive T cells, suggesting a state of “immune silence” that correlates with a severe clinical manifestation and fatal outcome.
Le Bert N, Clapham HE, Tan AT. Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection. J Exp Med March 1, 2021. 218 (5): e20202617. https://doi.org/10.1084/jem.20202617
Nina Le Bert and colleagues from Singapore studies T cells longitudinally in a cohort of asymptomatic (n = 85) and symptomatic (n = 75) COVID-19 patients after seroconversion. Important findings: asymptomatic SARS-CoV-2-infected individuals are not characterized by weak antiviral immunity; on the contrary, they mount a highly functional virus-specific cellular immune response.
Paper of the Day
Shen B, Tasdogan A, Ubellacker JM, et al. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature, February 24, 2021. https://doi.org/10.1038/s41586-021-03298-5
Exercise will boost your immune system! What we all “knew” already, can now be explained. A specialized type of bone cell progenitor has been identified in the bone marrow and shown to support the generation of lymphocytes in response to movement. Bo Shen and colleagues have identified a role for movement in stimulating communication between one type of stromal cell and immune progenitors in mice, ultimately helping the animals to fight infection. The discovery that mechanosensitive osteogenic progenitors have a role in fighting infections is exciting.
Balz K, Kaushik A, Chen M, et al. Homologies between SARS-CoV-2 and allergen proteins may direct T cell-mediated heterologous immune responses. Sci Rep February 25, 2021, 11, 4792. https://doi.org/10.1038/s41598-021-84320-8
Different systematic bioinformatic approaches were used to identify potentially cross-reactive allergen- and SARS-CoV-2-T cell epitopes. Numerous candidate epitope pairs were identified, highlighting an important role of MHC class I inhalant allergens. According to Kathrin Balz and colleagues, findings generate further hypotheses in how the adaptive immune system responds differentially with respect to the atopy status of the host. Their study warrants an immediate investigation of these predicted T cell epitopes to link their possible role in driving the immune response against SARS-CoV-2 and eventually shape the COVID-19 outcome.
Pawlowski C, Puranik A, Bandi H. et al. Exploratory analysis of immunization records highlights decreased SARS-CoV-2 rates in individuals with recent non-COVID-19 vaccinations. Sci Rep 11, 4741 (2021). https://doi.org/10.1038/s41598-021-83641-y
Do existing vaccines afford protection against SARS-CoV-2 infection through trained immunity? By analyzing immunization records from 137,037 individuals, Colin Pawlowski and colleagues from Cambridge found that several vaccines such as polio, MMR, flu or hepatitis A/hepatitis B vaccines administered in the past 1-5 years were associated with decreased SARS-CoV-2 infection rates, even after adjusting for geographic SARS-CoV-2 incidence and testing rates, demographics, Comorbidities, and number of other vaccinations. But can we believe this? Can we control for the “healthy user effect” (that persons who have recently had other vaccines may engage in general health-seeking behaviors which decrease their risk of SARS-CoV-2 infection)? The authors say yes. In a “negative control” experiment on patients who have recently taken cancer screens (who may also have lower rates due to the “healthy user effect”), their propensity score matching method was able to correct for confounding.
Zhou S, Butler-Laporte G, Nakanishi T, et al. A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity. Nat Medicine February 25, 2021. https://www.nature.com/articles/s41591-021-01281-1
OAS proteins are part of the innate immune response against RNA viruses. They are induced by interferons and activate latent RNase L, resulting in direct viral and endogenous RNA destruction, as demonstrated in in vitro studies. In this large-scale study of 931 proteins assessed for COVID-19 outcomes in > 14,000 cases and 1.2 million controls of European ancestry, Sirui Zhou and colleagues from Montreal, Canada provide evidence that increased OAS1 levels in the non-infectious state are strongly associated with reduced risks (22-46%) of severe COVID-19, hospitalization and susceptibility. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection.
Paper of the Day
Tang J, Ravichandran S, Lee Y, et al. Antibody affinity maturation and plasma IgA associate with clinical outcome in hospitalized COVID-19 patients. Nat Commun 12, 1221 (February 22, 2021). Full-text: https://www.nature.com/articles/s41467-021-21463-2
A comprehensive longitudinal antibody analysis on 25 SARS-CoV-2 PCR-confirmed hospitalized COVID-19 patients. In more severe COVID-19 patients, even though they could generate high binding and neutralizing antibody titers, there was a block to antibody affinity maturation that may be linked to deficiency in CD4 cells, and especially T follicular helper cell subsets, which are required for entry into the germinal center. Sustained high levels of proinflammatory cytokines (IL-6 and IL-8), high serum IgA, and blunted affinity maturation against the pre-fusion spike protein were predictive of the worst outcome for hospitalized patients. An elevated inflammatory response may be augmented by low-affinity antibodies that are not efficient in controlling SARS-CoV-2 replication.
Neeland MR, Bannister S, Clifford V, et al. Innate cell profiles during the acute and convalescent phase of SARS-CoV-2 infection in children. Nat Commun 12, 1084 (2021). Full-text: https://www.nature.com/articles/s41467-021-21414-x
Melanie Neeland et al. provide a comprehensive characterization of innate cells responding during the acute and convalescent phase of mild pediatric COVID-19. The authors report acute and convalescent innate immune responses in 48 children and 70 adults infected with, or exposed to, SARS-CoV-2. The authors found that infection in children is characterized by increased activation of neutrophils and low circulating proportions of all monocyte subsets, dendritic cells and natural killer cells, in contrast to SARS-CoV-2-infected adults who showed reductions in the non-classical monocyte fraction only.
Paper of the Day
Schultze JL, Aschenbrenner AC. COVID-19 and the human innate immune system. Cell 2021, published 16 February. Full-text: https://www.cell.com/cell/fulltext/S0092-8674(21)00218-X
Variability in innate immune system components is probably a main contributor to the heterogeneous disease courses observed for COVID-19. Here, Joachim Schultze and Anna Aschenbrenner of the German Center for Neurodegenerative Diseases in Bonn, Germany, link the clinical observations with experimental findings that have been made during the first year of the pandemic. They provide a conceptual framework for the interaction of the human innate immune system with SARS-CoV-2.
Sherina N, Piralla A, Du L, et al. Persistence of SARS-CoV-2 specific B- and T-cell responses in convalescent COVID-19 patients 6-8 months after the infection. Med 2021, published 10 February. Full-text: https://www.cell.com/med/fulltext/S2666-6340(21)00038-6
Qiang Pan-Hammarström, Natalia Sherina and colleagues show that specific memory B and T cells develop in > 95% of COVID-19 patients and that memory B and T cell responses were maintained at least 6-8 months after infection. Levels of specific IgM/IgA antibodies declined after 1 month while levels of specific IgG antibodies and plasma neutralizing activities remained relatively stable up to 6 months after diagnosis. Anti-SARS-CoV-2 IgG antibodies were still present, though at a significantly lower level, in 80% of the samples collected at 6-8 months after symptom onset. The authors analyzed 119 samples from 88 convalescent donors who experienced mild to critical disease.
Gentili M, Hacohen N. Some antibodies can dampen antiviral defences in people with severe COVID. Nature 2021, published 16 February. Full-text: https://www.nature.com/articles/d41586-021-00352-0
Defects in the immune defenses induced by the protein interferon are associated with some severe cases of COVID-19. An analysis of patient blood samples sheds light on how antibodies might contribute to these defects. Nir Hacohen and Matteo Gentili comment on a study we presented on January 28: Combes AJ, Courau T, Kuhn NF, et al. Global absence and targeting of protective immune states in severe COVID-19. Nature 2021, published 25 January. Full-text: https://doi.org/10.1038/s41586-021-03234-7
CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to control of SARS-CoV-2 in both non-hospitalized and hospitalized cases of COVID-19. In this brilliant review of the adaptive immune response to SARS-CoV-2, Alessandro Sette and Shane Crotty discuss the specific functions and kinetics of these adaptive immune responses, as well as their interplay with innate immunity and implications for COVID-19 vaccines and immune memory against re-infection.
Lee HK, Knabl L, Pipperger L, et al. Immune transcriptomes of highly exposed SARS-CoV-2 asymptomatic seropositive versus seronegative individuals from the Ischgl community. Sci Rep 11, 4243 (2021). https://www.nature.com/articles/s41598-021-83110-6
The ski resort of Ischgl, Austria experienced a superspreading event in early March 2020. In April, a seroprevalence of approximately 42% was found in the Ischgl population (n = 1867), with approximately 17% of these being asymptomatic. This comparative investigation of immune cell transcriptomes from 43 asymptomatic seropositive and 52 highly exposed seronegative individuals 4 – 6 weeks following the superspreading event showed no statistically significant differences. These results demonstrate that development of an antibody response to COVID-19 following viral exposure and seroconversion in asymptomatic cases is not necessarily associated with sustained alterations in the immune system transcriptome.
Rha MS, Jeong HW, Ko JH, et al. PD-1-Expressing SARS-CoV-2-Specific CD8+ T Cells Are Not Exhausted, but Functional in Patients with COVID-19. Immunity. 2021 Jan 12;54(1):44-52.e3. PubMed: https://pubmed.gov/33338412. Full-text: https://doi.org/10.1016/j.immuni.2020.12.002
More about SARS-CoV-2-specific CD8+ T cells. The highlights: 1) SARS-CoV-2-specific CD8+ T cells are effector memory cells in convalescent individuals; 2) CCR7+CD45RA+ cells are increased among SARS-CoV-2-specific cells in the late phase; 3) SARS-CoV-2-specific CD8+ T cells have fewer IFN-γ+ cells than flu-specific cells; 4) PD-1-expressing SARS-CoV-2-specific CD8+ T cells are not exhausted but functional.
Wheatley AK, Juno JA, Wang JJ, et al. Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19. Nat Commun 12, 1162 (2021). https://www.nature.com/articles/s41467-021-21444-5
This longitudinal cohort of 64 participants who recovered from COVID-19 suggests that SARS-CoV-2 vaccines might require greater immunogenicity and durability than natural infection to drive long term protection. Both neutralizing and binding antibody responses decay after recovery from COVID-19, assessed by both polyclonal assays and at the level of single antibody clonotypes with a mass spectrometry-based assay.
Supasa P, Daming Z, Dejnirattisai W, et al. Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera. Cell 2021, published 18 February. Full-text: https://www.cell.com/cell/fulltext/S0092-8674(21)00222-1
Gavin Screaton, Piyada Supasa and colleagues mapped the impact of the N501Y mutation by structure/function analysis of a large panel of well-characterised monoclonal antibodies. B.1.1.7 was harder to neutralize but widespread escape from monoclonal antibodies or antibody responses generated by natural infection or vaccination was not observed (Supasa 2021).
Tarke A, Sidney J, Kidd CK, et al. Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases. Cell Rep Med. 2021 Jan 26:100204. PubMed: https://pubmed.gov/33521695. Full-text: https://doi.org/10.1016/j.xcrm.2021.100204
Alessandro Sette, Alison Tarke and colleagues show a broad T cell repertoire, suggesting that viral escape of T cell immunity is unlikely. CD4 immunodominant regions correlate with HLA binding and not with high common cold coronavirus homology. RBD is poorly recognized by CD4s. Epitope pools can be used to optimize detection of T cell responses.
Batra M, Tian R, Zhang C, et al. Role of IgG against N-protein of SARS-CoV2 in COVID19 clinical outcomes. Sci Rep 11, 3455 (2021). https://doi.org/10.1038/s41598-021-83108-0
Mehri Mirsaeidi, Mayank Batra and colleagues at the University of Miami studied 400 RT-PCR confirmed SARS-CoV-2 patients to determine independent factors associated with poor outcomes. Their findings suggest that titers of IgG targeting the N protein of SARS-CoV-2 at admission might be a prognostic factor for the clinical course of disease.
Wu KJ. The Body Is Far From Helpless Against Coronavirus Variants. The Atlantic 2021, published 12 February. Full-text: https://www.theatlantic.com/science/archive/2021/02/antibody-evolution/618004
The mission of the human immune system is threefold. 1. Memorize the features of dangerous microbes that breach the body’s barriers. 2. Launch an attack to bring them to heel. 3. Then squirrel away intel to quash future assaults.
Xavier Saelens and Bert Schepens comment on a paper we presented on 18 January. [Koenig PA, Das H, Liu H, et al. Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape (https://doi.org/10.1126/science.abe6230): the authors “describe four SARS-CoV-2–neutralizing single-domain antibodies, or VHHs, and combinations thereof that can disable spike function. This extends the growing list of reports on SARS-CoV-2 spike–specific single-domain antibodies that have been proposed as potential therapeutics for COVID-19 patients.”
Munitz A, Edry-Botzer L, Itan M, et al. Rapid seroconversion and persistent functional IgG antibodies in severe COVID-19 patients correlates with an IL-12p70 and IL-33 signature. Sci Rep 11, 3461 (2021). Full-text: https://doi.org/10.1038/s41598-021-83019-0
Ariel Munitz et al. describe a rapid, quantitative, accurate, and robust serological method to detect seroconversion upon SARS-CoV-2 infection and the neutralization potential of the detected antibodies. Their analysis of the cytokine profile in COVID-19 patients also revealed a unique correlation of an IL-12p70/IL33 and IgG seroconversion that correlated with disease severity.
Wang Z, Schmidt F, Weisblum Y, et al. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. Nature 2021, published 10 February. Full-text: https://www.nature.com/articles/s41586-021-03324-6
Michel Nussenzweig and colleagues tested samples from 14 and 6 people who had received the Moderna or the Pfizer-BioNTech vaccine, respectively. Activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin.
Skelly DT, Harding AC, Gilbert Jaramillo J, et al. Vaccine-induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of concern. Research Square 2021, posted 9 February, accessed 12 February. Full-text: https://www.researchsquare.com/article/rs-226857/v1?s=09
When testing antibody and T cell responses against B117, B1351 and a reference isolate (VIC001) representing the original circulating lineage B, Skelly et al. identified a reduction in antibody neutralization against the variants which was most evident in B1351. However, the majority of the T cell response was directed against epitopes conserved across all three strains. The reduction in antibody neutralization was less marked in post-boost vaccine-induced rather than in naturally-induced immune responses.
Liu C, Martins AJ, Lau WW, et al. Time-resolved Systems Immunology Reveals a Late Juncture Linked to Fatal COVID-19. Cell 2021, publised 10 February. Full-text: https://www.cell.com/cell/fulltext/S0092-8674(21)00168-9
John Tsang, Can Liu and colleagues assessed the cell surface protein phenotype, transcriptome, and T cell clonality of peripheral immune cells of COVID-19 patients over time. They revealed a network of cell type specific signatures linked to disease severity, dissected timing effects, and uncovered a late period during which the host immune response undergoes a striking divergence in patients with distinct disease severity and outcomes. The ‘disease severity network’ pointed to attenuated inflammation and an “exhaustion”-like gene expression state in CD56dimCD16hi NK cells as a primary positive correlate of disease severity.
Paper of the Day
Anderson EM, Goodwin EC, Verma A, et al. Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection. Cell 2021, published 9 February. Full-text: https://www.cell.com/cell/fulltext/S0092-8674(21)00160-4
The authors show that ~20% of humans possess non-neutralizing antibodies against SARS-CoV-2 prior to the COVID-19 pandemic. They measured antibodies in a unique cohort: individuals who had donated samples prior to the pandemic and who subsequently became infected with SARS-CoV-2. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but they were boosted upon SARS-CoV-2 infection.
Tan AT, Linster M, Tan CW, et al. Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients. Cell Rep. 2021 Jan 21:108728. PubMed: https://pubmed.gov/33516277. Full-text: https://doi.org/10.1016/j.celrep.2021.108728
Peak viral load is correlated with disease severity – and there is a positive relation between early detection of IFN-γ-secreting SARS-CoV-2-specific T cells and early control of infection. These are the key messages of a study that longitudinally tracked both viral loads and virus-specific T cells. Early antibody responses alone did not distinguish control of virus or disease severity.
Hoagland DA, Møller R, Uhl SA. Leveraging the antiviral type-I interferon system as a first line defense against SARS-CoV-2 pathogenicity. Immunity 2021, published 29 January. Full-text: https://www.cell.com/immunity/fulltext/S1074-7613(21)00040-6
A longitudinal hamster cohort revealed a wave of inflammation including a Type-I interferon (IFN-I) response that was evident in all tissues regardless of viral presence but was insufficient to prevent disease progression. Bolstering the antiviral response with intranasal administration of recombinant IFN-I reduced viral disease, prevented transmission, and lowered inflammation in vivo. The authors conclude that intranasal IFN-I might be an effective means of early treatment.
Valenzuela Nieto G, Jara R, Watterson D, et al. Potent neutralization of clinical isolates of SARS-CoV-2 D614 and G614 variants by a monomeric, sub-nanomolar affinity nanobody. Sci Rep 11, 3318 (2021). Full-text: https://www.nature.com/articles/s41598-021-82833-w
The authors describe a novel simple method for the selection of nanobodies from E. coli bacterial display libraries, resulting in the selection of 30 nanobodies. They demonstrate that the nanobody W25 can recognize full-length Spike and RBD protein by ELISA and therefore predict that it might be suitable as a diagnostic reagent.
Koutsakos M, Rowntree LC, Hensen L, et al. Integrated immune dynamics define correlates of COVID-19 severity and antibody responses. Cell Rep Med 2021, published 4 February. Full-text: https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00019-7
Katherine Kedzierska, Marios Koutsakos and colleagues provide a comprehensive map of longitudinal immunological responses in COVID-19 patients. ICU patients with severe COVID-19 displayed higher levels of soluble IL-6, IL-6R, IL-18, and hyperactivation of innate, adaptive and myeloid compartments than patients with moderate disease.
Ren X, Wen W, Fan X, et al. COVID-19 immune features revealed by a large-scale single cell transcriptome atlas. Cell 2021, published 3 February. Full-text: https://www.cell.com/cell/fulltext/S0092-8674(21)00148-3
Zemin Zhang, Xianwen Ren and colleagues applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1,46 million cells. The authors found SARS-CoV-2 RNAs in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within viral positive cells. Systemic up-regulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, might contribute to the cytokine storms observed in severe COVID-19.
Collier D, De Marco A, Ferreira I, et al. SARS-CoV-2 B.1.1.7 escape from mRNA vaccine-elicited neutralizing antibodies. medRxiv 2021, posted 2 February. Full-text: https://doi.org/10.1101/2021.01.19.21249840
Ravindra Gupta, Dami Collier and colleagues assess immune responses following vaccination with mRNA-based vaccine BNT162b2. They measured neutralising antibody responses following a single immunization using pseudoviruses expressing the wild type Spike protein or the 8 mutations found in the B117 Spike protein. The vaccine sera exhibited a broad range of neutralizing titers against the wild type pseudoviruses that were modestly reduced against B117. Introduction of the E484K mutation led to a more substantial loss of neutralizing activity by vaccine-elicited antibodies over that conferred by the B117mutations alone.
Sokal A, Chappert P, Barba-Spaeth G, et al. Maturation and persistence of the anti-SARS-CoV-2 memory B cell response. Cell 2021, published 2 February. Full-text: https://doi.org/10.1016/j.cell.2021.01.050
Excellent news from France: Matthieu Mahévas, Aurélien Sokal and colleagues longitudinally profiled memory B cells and found remarkable stability of the overall spike-specific memory B cell population up to 6 months after infection. Antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.
Bolouri H, Speake C, Skibinski D, et al. The COVID-19 immune landscape is dynamically and reversibly correlated with disease severity. J Clin Invest 2021, published 1 February. Full-text: https://www.jci.org/articles/view/143648
After assessing the immune landscape in longitudinal whole-blood specimens from 59 patients presenting with acute COVID-19, the authors found that the immune landscape in COVID-19 formed 3 dominant clusters, which correlate with disease severity. They identified coordinated immune alterations accompanying clinical improvement or decline that were also seen in patients who experienced an IL-6 pathway blockade.
Petter Brodin discusses the current understanding of the immunological determinants of COVID-19 disease presentation and severity and relate this to known immune system differences between young people and old and between men and women, as well as other factors associated with different disease presentations and severity.
Dong J, Zost SJ, Greaney AJ, et al. Genetic and structural basis for recognition of SARS-CoV-2 spike protein by a two-antibody cocktail. bioRxiv 2021, posted 28 January. Full-text: https://doi.org/10.1101/2021.01.27.428529
James Crowe, Jesse Bloom, Jinhui Dong and colleagues determined the structures of two human monoclonal antibodies COV2-2196 and COV2-2130, which form the basis of the investigational antibody cocktail AZD7442, in complex with the receptor binding domain (RBD) of SARS-CoV-2.
Paper of the Day
Rappazzo CG, Tse LV, Kaku CI, et al. Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody. Science. 2021 Jan 25:eabf4830. PubMed: https://pubmed.gov/33495307. Full-text: https://doi.org/10.1126/science.abf4830
Although SARS-CoV and SARS-CoV-2 share 76% amino acid identity in their S proteins, only a limited number of cross-neutralizing antibodies have been described to date. Here, Laura Walker, Garrett Rappazzo and colleagues describe broadly neutralizing antibodies (bnAbs) as an attractive opportunity for therapeutic drug engineering to prevent or mitigate future outbreaks of SARS-related CoVs. They demonstrate that bnAbs can provide broad protection in vivo.
Paper of the Day
Thomson E, Rosen LE, Shepherd JG, et al. Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity. Cell 2021, published 28 January. Full-text: https://doi.org/10.1016/j.cell.2021.01.037
Over the past months, the receptor-binding motif (RBM) mutation N439K has emerged independently in multiple SARS-CoV-2 lineages. N439K increases spike affinity for hACE2. Gyorgy Snell, Emma Thomson and colleagues show that the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the FDA, and reduces the activity of some polyclonal sera from persons recovered from infection.
Liu Z, VanBlargan LA, Bloyet LM, et al. Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization. Cell Host Microbe 2021, published 27 January. Full-text: https://doi.org/10.1016/j.chom.2021.01.014
Hard time ahead for anti-clonals. Sean Whelan, Zhuoming Liu and colleagues show that the mutation S477N confers resistance to neutralization by multiple monoclonal antibodies. Also E484K, the bad boy on the block (see yesterday’s presentation of the Wang paper (Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization) is less sensitive to neutralization by convalescent human sera.
The COVID-19 pandemic is revealing widely varying immune responses and diverse clinical outcomes in SARS-CoV-2 infection, raising questions about how antiviral responses are orchestrated, factors that influence the longevity of immunological memory, and approaches that mediate robust protection from viral infections.
Evidence increasingly indicates that male sex is a risk factor for more severe disease and death from COVID-19. Sex differences beyond sex organs are present across species and extend to physiological systems, including the immune system. Male sex in animals is more often associated with lower immune responses and higher susceptibility and/or vulnerability to infections. This is also generally the case in humans: male patients have higher viral loads for hepatitis B virus (HBV) and HIV.
Combes AJ, Courau T, Kuhn NF, et al. Global absence and targeting of protective immune states in severe COVID-19. Nature 2021, published 25 January. Full-text: https://doi.org/10.1038/s41586-021-03234-7
Examining the serum from severe patients, Alexis Combes et al. demonstrate that these patients uniquely produce antibodies that functionally block the production of the mild disease-associated ISG-expressing cells, by engaging conserved signaling circuits that dampen cellular responses to interferons.
Wauters E, Van Mol P, Garg AD et al. Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages. Cell Res (2021). Full-text: https://doi.org/10.1038/s41422-020-00455-9
Using scRNA-seq data derived from BAL, Els Wauters and colleagues from Leuven, Belgium, performed deep-immune profiling of the adaptive and innate immune cell landscape within the main locale of COVID-19 pathology. Briefly, their findings support a model wherein neutrophils execute their antiviral function in an immunologically ‘controlled’ fashion, regulated by T cells with good effector functions and paralleled by ‘orderly’ phagocytic disposal of expired cells by macrophages in mild disease. In contrast, in critical disease, T cells are less abundant and dysregulated, which coupled with hyperinflammatory monocytes facilitates excessive neutrophil-based inflammation.
Shaan Lakshmanappa Y, Elizaldi SR, Roh JW et al. SARS-CoV-2 induces robust germinal center CD4 T follicular helper cell responses in rhesus macaques. Nat Commun 12, 541 (2021). Full-text: https://doi.org/10.1038/s41467-020-20642-x
According to the authors, these animal experiments add to our understanding of immune responses to SARS-CoV-2 in three significant ways. First, they demonstrate that robust Th1–Tfh responses are observed following SARS-CoV-2 infection. Second, Tfh responses focused on S and N are seen within lymph nodes, circulate throughout the peripheral blood, potentially seeding the spleen. Third, they showed that acute antibody kinetics are characterized by induction of IgG, predominantly to S1 and of the IgG1 sub-class, indicative of early class switching. Taken together, these data demonstrate that productive Tfh responses are elicited following SARS-CoV-2 infection in healthy adult rhesus macaques.
Tan AT, Linster M, Tan CW, et al. Early induction of functional SARS-CoV-2 specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients. Cell Rep January 21, 2021. Full-text: https://doi.org/10.1016/j.celrep.2021.108728
This longitudinal immunological analysis in a small cohort from onset till outcome suggests that early induction of IFN-γ secreting SARS-CoV-2 specific T cells is present in patients who have mild disease and accelerated viral clearance. Detection of functional SARS-CoV-2 specific T cells may be of prognostic value.
Kusnadi A, Ramírez-Suástegui C, Fajardo V, et al. Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8+ T cells. Sci Immunol. 2021 Jan 21;6(55):eabe4782. PubMed: https://pubmed.gov/33478949. Full-text: https://doi.org/10.1126/sciimmunol.abe4782
This study, using single-cell transcriptome and TCR sequence analyses of > 87.000 in vitro activated virus-reactive CD8+ T cells and > 20.000 CD8+ T cells expressing activation markers ex vivo, from a total of 39 COVID-19 patients, gives important insights into CD8 T cell responses. Findings indicate that SARS-CoV-2-reactive CD8+ T cells from patients with severe COVID-19 displayed multiple features that support the generation of robust CD8+ T cell memory responses with pro-survival properties and a lack of “restrained function” via “exhaustion” features.
Gaebler C, Wang Z, Lorenzi JCC, et al. Evolution of antibody immunity to SARS-CoV-2. Nature (2021). Full-text: https://doi.org/10.1038/s41586-021-03207-w
After recovery from SARS-CoV-2 infection, people can make potent antibodies to SARS-CoV-2 that evolve in the months after infection. These antibodies may be evolving in response to residual viral antigen hidden in the gut.
Haynes WA, Kamath K, Lucas C, Shon J, Iwasaki A. Impact of B.1.1.7 variant mutations on antibody recognition of linear SARS-CoV-2 epitopes. medRxiv 2021, posted 8 January. Full-text: https://doi.org/10.1101/2021.01.06.20248960
The B.1.1.7 strain circulating within the UK has raised public concerns about potential for re-infection and vaccine efficacy due to possible evasion from antibody recognition. Here, Akiko Iwasaki, Winston Haynes and colleagues suggest that the mutations might not result in immune evasion for a large majority of COVID patients.
Cohen AA, Gnanapragasam PNP, Lee YE, et al. Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice. Science. 2021 Jan 12:eabf6840. PubMed: https://pubmed.gov/33436524. Full-text: https://doi.org/10.1126/science.abf6840
A single immunization with mosaic-RBD-nanoparticles provides a potential strategy to protect against SARS-CoV-2 and other emerging zoonotic coronaviruses. The authors confirm that multimerization of receptor-binding domains on nanoparticles enhances immunogenicity compared with soluble antigen.
Koenig PA, Das H, Liu H, et al. Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape. Science. 2021 Jan 12:eabe6230. PubMed: https://pubmed.gov/33436526. Full-text: https://doi.org/10.1126/science.abe6230
Nanobodies may represent a versatile and less costly alternative to conventional antibodies for passive immunization against SARS-CoV-2. They are efficiently produced in prokaryotic expression systems at low cost and exhibit favorable biophysical properties including high thermostability. Here, Paul-Albert König et al. from the University of Bonn, Germany, designed multivalent nanobody constructs based on epitope mapping data by SPR and X-ray crystallography, as well as extensive information on the conformation of spike:nanobody complexes determined by cryo-EM.
Lavine JS, Bjornstad ON, Antia R. Immunological characteristics govern the transition of COVID-19 to endemicity. Science. 2021 Jan 12:eabe6522. PubMed: https://pubmed.gov/33436525. Full-text: https://doi.org/10.1126/science.abe6522
In the future, SARS-CoV-2 may be no more virulent than the common cold. The question is when and what shall we do in the meantime. The authors conclusion: “Social distancing and an effective vaccine are critical for control during a virgin epidemic and the transition out of it, but once we enter the endemic phase, mass vaccination may no longer be necessary. The necessity for continual vaccination will depend on the age-dependence of the Infection Fatality Ratio (IFR). If primary infections of children are mild (CoV-1 and CoV-2), continued vaccination may not be needed as primary cases recede to mild childhood sniffles. If, on the other hand, primary infection is severe in children (as for MERS), then vaccination of children will need to be continued.”
Arce VM, Costoya JA. SARS-CoV-2 infection in K18-ACE2 transgenic mice replicates human pulmonary disease in COVID-19. Cell Mol Immunol (2021). Full-text: https://doi.org/10.1038/s41423-020-00616-1
Although several animal models of COVID-19 have been investigated, only a few (hamsters, ferrets, minks, cats, and non-human primates) have been found to be susceptible to the disease. Here, Victor Arce and José Costoya comment on a paper by Michael Diamond, Emma Winkler and colleagues that we presented on 29 August [Winkler ES, Bailey AL, Kafai NM, et al. SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat Immunol. 2020 Nov;21(11):1327-1335. PubMed: https://pubmed.gov/32839612. Full-text: https://doi.org/10.1038/s41590-020-0778-2]. The authors conclude that the severity of disease observed following SARS-CoV-2 infection in K18-hACE2 mice might provide a useful model in which to investigate pulmonary disease and test antiviral countermeasures in this species.
Chambers ES, Vukmanovic-Stejic M, Shih BB, et al. Recruitment of inflammatory monocytes by senescent fibroblasts inhibits antigen-specific tissue immunity during human aging. Nat Aging 1, 101–113 (2021). Full-text: https://doi.org/10.1038/s43587-020-00010-6
Senescent fibroblasts in the skin of older participants secrete an array of chemokines including CCL2 in response to tissue injury, such as that induced by injection of saline, VZV or air. Arne Akbar, Emma Chambers and colleagues show how this phenomenon can be blocked pharmacologically to boost adaptive immunity. See also the comment by Kasler H, Verdin E. How inflammaging diminishes adaptive immunity. Nat Aging 1, 24–25 (2021). Full-text: https://doi.org/10.1038/s43587-020-00021-3
Sette A, Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell 2021, published 12 January. Full-text: https://doi.org/10.1016/j.cell.2021.01.007
In this review, Alessandro Sette and Shane Crotty describe how CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to the control of SARS-CoV-2, in both non-hospitalized and hospitalized cases of COVID-19. The authors discuss the specific functions and kinetics of these adaptive immune responses, as well as their interplay with innate immunity and implications for COVID-19 vaccines and immune memory against re-infection.
Legros V, Denolly S, Vogrig M, et al. A longitudinal study of SARS-CoV-2-infected patients reveals a high correlation between neutralizing antibodies and COVID-19 severity. Cell Mol Immunol (2021). Full-text: https://doi.org/10.1038/s41423-020-00588-2
In a cohort of 140 SARS-CoV-2 individuals with confirmed SARS-CoV-2 infection, nAb titers correlated strongly with disease severity and with anti-spike IgG levels. Patients from intensive care units exhibited high nAb titers; conversely, patients with milder disease symptoms had heterogeneous nAb titers, and asymptomatic or exclusively outpatient patients had no or low nAbs. nAb activity in SARS-CoV-2-infected patients displayed a relatively rapid decline after recovery compared to individuals infected with other coronaviruses.
Zuniga M, Gomes C, Carsons SE, et al. Autoimmunity to the Lung Protective Phospholipid-Binding Protein Annexin A2 Predicts Mortality Among Hospitalized COVID-19 Patients. medRxiv 2021, posted on 4 January. Full-text: https://doi.org/10.1101/2020.12.28.20248807
Anti-Annexin A2 antibodies were elevated among hospitalized COVID-19 patients and these levels predicted mortality. This is the message of a pre-print paper by Ana Rodriguez, Marisol Zuniga and colleagues. The authors explain that inhibition of Annexin A2 induces systemic thrombosis, cell death, and non-cardiogenic pulmonary edema and that autoimmunity to Annexin A2 might explain key clinical findings of severe COVID-19. (Annexin A2 is a phospholipid-binding protein involved in fibrinolysis, cell membrane stabilization and repair, that ensures the integrity of the pulmonary microvasculature.)
Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 2021, published 6 January. Full-text: https://doi.org/10.1126/science.abf4063
After Year 1 of the SARS-CoV-2 pandemic, we realize that although millions of people were infected during spring 2020, there is no sizeable epidemic of re-infections. This observation suggests that SARS-CoV-2 infection might confer a solid immunity. Now, Shane Crotty, Alessandro Sette, Daniela Weiskopf, Jennifer Dan and colleagues publish in Science the pre-print paper we presented on 13 November. The authors analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 188 COVID-19 cases, including 43 cases at > 6 months post-infection. The result: Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months. These findings might suggest that after SARS-CoV-2 infection (or after vaccination), the vast majority of people could be protected from severe COVID-19 for years. Read also the NYTimes article by Mandavilli A. Immunity to the Coronavirus May Last Years, New Data Hint. The New York Times 2020, published 17 November. Full-text: https://www.nytimes.com/2020/11/17/health/coronavirus-immunity.html
Widge AT, Rouphael NG, Jackson LA, et al. Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination. N Engl J Med 2021; 384:80-82. Full-text: https://doi.org/10.1056/NEJMc2032195
Correlates of protection against SARS-CoV-2 infection in humans are not yet established. Here, Alicia Widge et al. describe immunogenicity data 119 days after the first vaccination in 34 healthy adult participants. Despite a slight expected decline in titers of binding and neutralizing antibodies, mRNA-1273 might have the potential to provide durable humoral immunity.
Röltgen K, Powell AE, Wirz OF, et al. Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome. Sci Immunol. 2020 Dec 7;5(54):eabe0240. PubMed: https://pubmed.gov/33288645. Full-text: https://doi.org/10.1126/sciimmunol.abe0240
Outpatients and asymptomatic individuals might have higher ratios of spike protein receptor-binding domain-specific IgG versus nucleoprotein-targeted IgG antibodies than hospitalized patients. This is the result of a study by Scott Boyd, Katharina Röltgen and colleagues who analyzed 983 longitudinal plasma samples from 79 hospitalized COVID-19 patients and 175 SARS-CoV-2-infected outpatients and asymptomatic individuals. Plasma antibody increases correlated with decreases in viral RNAemia, but antibody responses in acute illness were insufficient to predict inpatient outcomes.
Lumley SF, O’Donnell D, Stoesser NE, et al. Antibody Status and Incidence of SARS-CoV-2 Infection in Health Care Workers. N Engl J Med 2020, published 23 December. Full-text: https://doi.org/10.1056/NEJMoa2034545
Christmas 2020 – good news for people with SARS-CoV-2 antibodies. In this longitudinal cohort study, there were no symptomatic infections in 1265 workers with anti-spike antibodies. Two anti-spike–seropositive health care workers had a positive PCR test (0,13 per 10.000 days at risk), and both workers were asymptomatic when tested. The authors conclude that the presence of anti-spike or anti-nucleocapsid IgG antibodies are associated with a substantially reduced risk of SARS-CoV-2 reinfection in the ensuing 6 months.
Malone B, Simovski B, Moliné C, et al. Artificial intelligence predicts the immunogenic landscape of SARS-CoV-2 leading to universal blueprints for vaccine designs. Sci Rep 10, 22375 (2020). Full-text: https://doi.org/10.1038/s41598-020-78758-5
In order to effectively combat the SARS-CoV-2 pandemic, a vaccine will need to protect the vast majority of the human population and stimulate diverse T cell responses against multiple viral targets including, but not limited to, the S protein. Here, Travor Clancy, Brandon Malone and colleagues profiled the entire SARS-CoV-2 proteome across the most frequent 100 HLA-A, HLA-B and HLA-DR alleles in the human population and generated comprehensive epitope maps. They identified a subset of epitope hotspots that could be harnessed in a vaccine formulation to provide broad coverage across the global population.
Larsen MD, de Graaf EL, Sonneveld ME, et al. Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity. Science 2020, published 23 December. Full-text: https://doi.org/10.1126/science.abc8378
Afucosylated IgG (~6% of total IgG in humans) are specifically formed against enveloped viruses but generally not against other antigens. Here, Gestur Vidarsson, Mads Delbo Larsen and colleagues report that critically ill COVID-19 patients, but not those with mild symptoms, had high levels of afucosylated IgG antibodies against SARS-CoV-2, amplifying pro-inflammatory cytokine release and acute phase responses.
Jarjour NN, Masopust D, Jameson SC. T cell memory: Understanding COVID-19. Immunity 2020, published 19 December. Full-text: https://doi.org/10.1016/j.immuni.2020.12.009
In this Primer, Nicholas Jarjour, David Masopust and Stephen Jameson explain the fundamental features of T cell memory and their potential relevance for effective immunity to SARS-CoV-2.
Singh DK, Singh B, Ganatra SR. et al. Responses to acute infection with SARS-CoV-2 in the lungs of rhesus macaques, baboons and marmosets. Nat Microbiol December 18, 2020. Full-text: https://doi.org/10.1038/s41564-020-00841-4
Rhesus macaques, baboons and marmosets can all be infected with SARS-CoV-2 but show differential progression to COVID-19. Whereas older marmosets have a mild infection, macaques developed moderate progressive pneumonia that resolves, accompanied by a marked reduction in lung and nasal viral loads. Baboons have the most severe lung pathology, and the greatest viral load.
Yao C, Bora SA, Patimo T, et al. Cell type-specific immune dysregulation in severely ill COVID-19 patients. Cell Report December 16, 2020. Full-text: https://doi.org/10.1016/j.celrep.2020.108590
Changfu Yao and colleagues have added some evidence to the observation that although most immune cellular compartments have an expected hyper-inflammatory response in severe patients, several of their key pathways are dysfunctional. Moreover, immune imbalance in which dysregulation of both the innate and adaptive immune responses may be contributing to a more severe disease course. The key findings: monocyte antigen presentation pathway gene expression is lower in severe COVID-19, lymphocyte cytotoxicity pathways are reduced, and B cell activation is blunted. Interferon signaling is elevated in lymphocytes but diminished in monocytes.
Keller MD, Harris KM, Jensen-Wachspress MA, et al. SARS-CoV-2–specific T cells are rapidly expanded for therapeutic use and target conserved regions of the membrane protein. Blood December 17, 2020, 136 (25): 2905–2917. Full-text: https://doi.org/10.1182/blood.2020008488
In this report, Michael Keller and colleagues demonstrate a broadly specific T cell therapeutic targeting 3 structural proteins of SARS-CoV-2 that could be reliably expanded from the majority of convalescent donors. The authors believe that SARS-CoV-2 directed T cell immunotherapy targeting structural proteins (most importantly the membrane protein) should be feasible for the prevention or early treatment of SARS-CoV-2 infection in immunocompromised patients with blood disorders.
Duysburgh E, Mortgar L, Barbezange C, et al. Persistence of IgG response to SARS-CoV-2. Lancet Infect Dis December 17, 2020. Full-text: https://doi.org/10.1016/S1473-3099(20)30943-9
A rapid decline of SARS-CoV-2 IgG seropositivity or neutralizing capacity is unlikely: Among 74 (91%) HCW from Belgium who remained seropositive, median duration of antibody persistence (defined as the time between the day IgGs were last detected and the day of presumed onset of infection) is currently 168,5 (range 62–199) days. In total, 61 (82%) had neutralizing antibodies in their most recent IgG-positive serum sample.
Garcia-Beltran WF, Lam EC, Astudillo MG, et al. COVID-19 neutralizing antibodies predict disease severity and survival. Cell December 15, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.12.015
Wilfredo Garcia-Beltran from Boston and colleagues examined antibody responses in 113 COVID-19 patients and found that severe cases exhibited increased inflammatory markers, lymphopenia, pro-inflammatory cytokines, and high anti-RBD antibody levels. A new finding was that patient sera were also able to neutralize the recently emerged SARS-CoV-2 mutant D614G, suggesting cross-protection from re-infection by either strain. In contrast, SARS-CoV-2 sera lacked cross-neutralization to a highly homologous bat coronavirus, WIV1-CoV, that has not yet crossed the species barrier.
Ku MW, Bourgine M, Authié P. Intranasal Vaccination with a Lentiviral Vector Protects against SARS-CoV-2 in Preclinical Animal Models. Cell Host Microbe December 14, 2020. Full-text: https://doi.org/10.1016/j.chom.2020.12.010
Min-Wen Ku from Paris and colleagues generated a lentiviral vector (LV) that elicits neutralizing antibodies against the Spike glycoprotein of SARS-CoV-2. Eliciting an immune response in the respiratory tract through an intranasal boost results in > 3 log10 decrease in the lung viral load and reduces local inflammation. The vaccine also worked well in golden hamsters, designating intranasal immunization as a powerful approach against COVID-19.
Pairo-Castineira E, Clohisey S, Klaric L et al. Genetic mechanisms of critical illness in Covid-19. Nature (2020). Full-text: https://doi.org/10.1038/s41586-020-03065-y
Erola Pairo-Castineira and colleagues report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study (GWAS) in 2244 critically ill COVID-19 patients from 208 UK intensive care units (ICUs). They scanned each person’s genes, which contain the instructions for every biological process, including how to fight a virus. They have identified some genetic differences (odds ratio of the tested risk alleles were 1.2-1.9) between patients with severe COVID-19 and the general population, revealing “robust genetic signals relating to key host antiviral defense mechanisms, and mediators of inflammatory organ damage”.
Rha MS, Jeong HW, Ko JH, et al. PD-1-Expressing SARS-CoV-2-Specific CD8+ T Cells Are Not Exhausted, but Functional in Patients with COVID-19. Immunity December 10, 2020. Full-text: https://doi.org/10.1016/j.immuni.2020.12.002
Min-Seok Rha and collegues from Korea detected SARS-CoV-2-specific CD8+ T cells using MHC class I multimers and investigated their ex vivo phenotypes in peripheral blood mononuclear cells (PBMCs) from acute and convalescent COVID-19 patients. Notably, SARS-CoV-2-specific memory CD8+ T cells from convalescent patients exhibited a high proliferative capacity, but IFN-γ was produced by less than half of the SARS-CoV-2-specific memory CD8+ T cell population. The authors also demonstrated that PD-1-expressing SARS-CoV-2-specific CD8+ T cells from acute and convalescent patients were not exhausted, but activated and functional. PD-1 expression on CD8+ T cells likely reflects activation, rather than exhaustion, in COVID-19.
Jørgensen J, Holter M, Christensen JC, et al. Increased interleukin-6 and macrophage chemoattractant protein-1 are associated with respiratory failure in COVID-19. Sci Rep 10, 21697 (2020). Full-text: https://doi.org/10.1038/s41598-020-78710-7
For this Norwegian COVID-19 cohort study, plasma cytokine levels at admission and follow-up during the first ten days of hospitalization were related to disease severity. A broad network of pro-inflammatory cytokines was elevated in plasma, especially pronounced in severe cases. Although the authors “did not find convincing evidence of a true cytokine storm”, combinations of IL-6 and MCP-1 may be further explored as potential biomarkers in severe COVID-19 infection.
Zang R, Case JB, Yutuc E, et al. Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion. PNAS December 15, 2020 117 (50) 32105-32113; first published November 25, 2020. Full-text: https://doi.org/10.1073/pnas.2012197117
Cholesterol 25-hydroxylase (CH25H) is an interferon (IFN)-stimulated gene that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, Ruochen Zang from St. Louis and colleagues identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of cholesterol export. Data suggest a unifying model in which 25HC results in a redistribution of cholesterol and inhibits both endosomal entry and plasma membrane fusion, which potentially explains the CH25H inhibitory activity against wild-type SARS-CoV-2.
Chen Z, Ruan P, Wang L, Nie X, Ma X, Tan Y. T and B cell epitope analysis of SARS-CoV-2 S protein based on immunoinformatics and experimental research. J Cell Mol Med. 2020 Dec 15. PubMed: https://pubmed.gov/33325143 . Full-text: https://doi.org/10.1111/jcmm.16200
The authors used immunoinformatics to identify conservative B and T cell epitopes for S proteins of SARS-CoV-2, which might play roles in the initiation of SARS-CoV-2 infection. They identified the B cell and T cell peptide epitopes of S protein and their antigenicity, as well as the interaction between the peptide epitopes and human leucocyte antigen (HLA).
In November, two groups (Shrock 2020 and Ng 2020; we presented the papers on 30 September and 9 November) showed that individuals exposed and unexposed to SARS-CoV-2 have cross-reactive serum antibodies against the spike protein of SARS-CoV-2 and seasonal HCoVs. Jenna Guthmiller and Patrick Wilson discuss the studies more in depth. They conclude by highlighting the need for further research into how SARS-CoV-2 antibody responses are shaped by previous exposures to seasonal HCoVs and how this immunity can be harnessed to provide protection.
The papers cited above: 1) Ng KW, Faulkner N, Cornish GH, et al. Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. Science 06 Nov 2020. Full-text: https://doi.org/10.1126/science.abe1107 – 2) Shrock E Fujimura E, Kula T, et al. Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity. Science 29 Sep 2020. Full-text: https://doi.org/10.1126/science.abd4250
Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med 2020; 383:2255-2273. Full-text: https://doi.org/10.1056/NEJMra2026131
David Fajgenbaum and Carl June remind us that 2020 marks 10 years since the first description of a cytokine storm that developed after chimeric antigen receptor (CAR) T cell therapy and 27 years since the term was first used in the literature to describe the engraftment syndrome of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation. Follow them on their suspense-packed narrative. The 19-page review for your weekend.
Fu Y, Li Y, Guo E, et al. Dynamics and Correlation Among Viral Positivity, Seroconversion, and Disease Severity in COVID-19: A Retrospective Study. Ann Intern Med. 2020 Dec 8. PubMed: https://pubmed.gov/33284684. Full-text: https://doi.org/10.7326/M20-3337
A huge study on viral kinetics that may enrich our understanding of the various patterns of SARS-CoV-2 positivity and the disease course: In 2142 patients with laboratory-confirmed COVID-19, the viral positivity rate peaked within the first 3 days. The median duration of viral positivity was 24,0 days (95% CI, 18,9 to 29,1 days) in critically ill patients and 18,0 days (CI, 16,8 to 19,1 days) in non-critically ill patients. Being critically ill was an independent risk factor for longer viral positivity. In patients with laboratory-confirmed COVID-19, the IgM-positive rate was 19,3% in the first week, peaked in the fifth week (81,5%), and then decreased steadily to around 55% within 9 to 10 weeks. The IgG-positive rate was 44,6% in the first week, reached 93,3% in the fourth week, and then remained high.
Galani IE, Rovina N, Lampropoulou V, et al. Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison. Nat Immunol. 2020 Dec 4. PubMed: https://pubmed.gov/33277638. Full-text: https://doi.org/10.1038/s41590-020-00840-x
A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage. This brilliant work suggests that this paradigm might not apply for COVID-19. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients, Ioanna-Evdokia Galani from Athens, Greece and colleagues show here that IFN-λ and type I IFN production are both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. By comparison, in 16 patients with influenza, IFN-λ and type I IFN were induced earlier, robustly, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. These data point to an un-tuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure. Fantastic work (take a look at the beautiful figures) which is among the 10 most important COVID-19 immunology papers of the year.
Poston D, Weisblum Y, Wise H, et al. Absence of SARS-CoV-2 neutralizing activity in pre-pandemic sera from individuals with recent seasonal coronavirus infection. Clin Infect Dis. 2020 Dec 3:ciaa1803. PubMed: https://pubmed.gov/33270134. Full-text: https://doi.org/10.1093/cid/ciaa1803
Daniel Poston and colleagues measured neutralizing activity against SARS-CoV-2 in pre-pandemic sera from 37 Scottish patients with prior PCR-confirmed seasonal coronavirus infection. While neutralizing activity against seasonal coronaviruses was detected in nearly all sera, cross-reactive neutralizing activity against SARS-CoV-2 was undetectable. This data argues against a broad role for pre-existing protective humoral immunity against SARS-CoV-2.
Zheng J, Wang Y, Li K, Meyerholz DK, Allamargot C, Perlman S. SARS-CoV-2-induced immune activation and death of monocyte-derived human macrophages and dendritic cells. J Infect Dis. 2020 Dec 5:jiaa753. PubMed: https://pubmed.gov/33277988. Full-text: https://doi.org/10.1093/infdis/jiaa753
Infection of macrophages and dendritic cells potentially plays a major role in COVID-19 pathogenesis, even in the absence of productive infection. Jian Zheng and colleagues from Iowa demonstrate that SARS-CoV-2 infection of human monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs) was abortive but induced the production of multiple antiviral and pro-inflammatory cytokines. Despite the lack of efficient replication in MDMs, SARS-CoV-2 induced profound IFN-mediated cell death of host cells. Macrophage activation and death was not enhanced by exposure to low levels of convalescent plasma, suggesting that antibody-dependent enhancement of infection does not contribute to cell death.
Wajnberg A, Amanat F, Firpo A, et al. Robust neutralizing antibodies to SARS-CoV-2 infection persist for months. Science. 2020 Dec 4;370(6521):1227-1230. PubMed: https://pubmed.gov/33115920. Full-text: https://doi.org/10.1126/science.abd7728
Ania Wajnberg and colleagues used a cohort of 30.082 infected individuals with mild to moderate COVID-19 symptoms screened at Mount Sinai Health System in New York City to determine the robustness and longevity of the anti–SARS-CoV-2 antibody response. They found that neutralizing antibody titers against the SARS-CoV-2 spike protein persisted for at least 5 months after infection. The authors plan to follow this cohort over a longer period of time.
Singh H, Choudhari R, Nema V, Khan AA. ACE2 and TMPRSS2 polymorphisms in various diseases with special reference to its impact on COVID-19 disease. Microb Pathog. 2020 Dec 2:104621. PubMed: https://pubmed.gov/33278516. Full-text: https://doi.org/10.1016/j.micpath.2020.104621
There are diversities in distribution of ACE2 and TMPRSS2 polymorphisms among different populations. According to this systematic review, analyzing the genetic variants and expression of ACE2 and TMPRSS2 genes in a population may provide the genetic marker for susceptibility or resistance against the coronavirus infection. This might be useful for identifying susceptible population groups for targeted interventions and for making relevant public health policy decisions.
McMahan K, Yu J, Mercado NB, et al. Correlates of protection against SARS-CoV-2 in rhesus macaques. Nature 2020, published 4 December. Full-text: https://doi.org/10.1038/s41586-020-03041-6
Dan Barouch, Katherine McMahan and colleagues from Harvard show that adoptive transfer of purified IgG from convalescent macaques protects naïve recipient rhesus macaques against SARS-CoV-2 challenge in a dose dependent fashion; relatively low antibody titers were sufficient for protection against SARS-CoV-2 in rhesus macaques whereas higher antibody titers were required for therapy of SARS-CoV-2 infection in macaques. Depletion of CD8+ T cells in convalescent animals partially depletes the protective efficacy of natural immunity against SARS-CoV-2 re-challenge.
Starr TN, Greaney AJ, Addetia A, et al. Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. bioRxiv 2020, posted 1 December. Full-text: https://doi.org/10.1101/2020.11.30.405472
Jesse Bloom, Tyler Starr and colleagues from the Fred Hutchinson Cancer Research Center in Seattle, US, mapped SARS-CoV-2 mutation that could prevent binding by the three monoclonal antibodies LY-CoV016 (Eli Lilly; which is different from bamlanivimab [LY-CoV555]) and casirivimab and imdevimab (REGN-COV2). They identified a single amino-acid mutation that fully escapes the REGN-COV2 cocktail. Please note: these findings have not yet been peer reviewed.
Agarwal V, Venkatakrishnan AJ, Puranik A et al. Long-term SARS-CoV-2 RNA shedding and its temporal association to IgG seropositivity. Cell Death Discov. 6, 138 December 2, 2020. Full-text: https://doi.org/10.1038/s41420-020-00375-y
A retrospective analysis of 851 SARS-CoV-2-positive patients with at least two positive PCR tests. The mean lower bound of viral RNA shedding was 17,3 days (SD: 7,8), and the mean upper bound of viral RNA shedding from 668 patients transitioning to confirmed PCR-negative status was 22,7 days (SD: 11,8). Some seropositive patients actively shed viral RNA (14 of 90 patients).
Bacher P, Rosati E, Esser D, et al. Low avidity CD4+ T cell responses to SARS-CoV-2 in unexposed individuals and humans with severe COVID-19. Immunity November 26, 2020. Full-text: https://doi.org/10.1016/j.immuni.2020.11.016
Interesting work, arguing against a protective role for CCCoV (common cold coronavirus) reactive T cells in SARS-CoV-2 infection. Petra Bacher from UKSH (Kiel, Germany) and colleagues employed antigen-specific T cell enrichment to characterize SARS-CoV-2-specific T cells from 55 healthy donors and 56 COVID-19 patients including their avidity and clonality as well as their cross-reactivity to CCCoV and other viruses. First, pre-existing T cell memory was common in humans, correlated with the size of the CD4+ memory repertoire rather than with CCCoV-specific memory, and displayed only low functional avidity. Second, robust CD4+ T cell responses against CCCoV were prevalent in the population; however, T cells reacting to CCCoV were not present among SARS-CoV-2-specific T cells in COVID-19 patients. Third, in severe COVID-19 patients, SARS-CoV-2-specific CD4+ T cells also displayed low functional avidity and TCR clonality, although their frequencies increased with disease severity.
Salahudeen AA, Choi SS, Rustagi A et al. Progenitor identification and SARS-CoV-2 infection in human distal lung organoids. Nature November 24, 2020. Full-text: https://doi.org/10.1038/s41586-020-3014-1
The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. This work by Ameen A. Salahudeen, Shannon S. Choi and colleagues from Chicago helps to study these cells. The authors have established a long-term feeder-free, chemically defined culture of distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) cells. Their culture experiments identified unsuspected basal cell functional heterogeneity and established a facile in vitro organoid model for human distal lung infections including COVID-19-associated pneumonia.
Perreault J, Tremblay T, Fournier MJ, et al. Waning of SARS-CoV-2 RBD antibodies in longitudinal convalescent plasma samples within 4 months after symptom onset. Blood. 2020 Nov 26;136(22):2588-2591. PubMed: https://pubmed.gov/33001206. Full-text: https://ashpublications.org/blood/article/136/22/2588/463996/Waning-of-SARS-CoV-2-RBD-antibodies-in
Anti-RBD antibody response in 15 CCP donors who donated at least 4 times, during a time interval after symptom onset ranging from 33 to 77 days for the first donation to 66 to 114 days for the last donation. Interestingly, the decrease during a period of about 20 days (considering the mean and median of third and fourth quartiles, both of 76 and 95 days, respectively) was reminiscent of the plasma immunoglobulin G half-life of 21 days. This suggests that de novo synthesis of anti-RBD antibodies stopped between the third and fourth quartiles in all CCP donors.
Self WH, Tenforde MW, Stubblefield WB, et al. Decline in SARS-CoV-2 Antibodies After Mild Infection Among Frontline Health Care Personnel in a Multistate Hospital Network — 12 States, April–August 2020. MMWR Morb Mortal Wkly Rep 2020;69:1762–1766. Full-text: http://dx.doi.org/10.15585/mmwr.mm6947a2
Among 156 frontline health care personnel who had positive SARS-CoV-2 antibody test results in spring 2020, 94% experienced a decline at repeat testing approximately 60 days later, and 28% sero-reverted to below the threshold of positivity. A higher percentage of those with low baseline antibody levels sero-reverted (65%) than did those with high baseline titers (7%). These results suggest that a substantial proportion of persons infected with SARS-CoV-2 might have negative serologic test results in the months following infection.
Bowman ER, Cameron CMA,Avery A, et al. Levels of Soluble CD14 and Tumor Necrosis Factor Receptors 1 and 2 may be predictive of death in Severe Coronavirus Disease 2019 (COVID-19). J Inf Dis. Full-text: https://doi.org/10.1093/infdis/jiaa744
Emily Bowman and colleagues from Cleveland measured serum biomarkers in 14 uninfected individuals and in 44 individuals with mild, moderate, or critical COVID-19 disease. Levels of monocyte activation (sCD14 and FABP4) and inflammation (TNFR1 and 2) were increased in COVID-19 individuals, regardless of disease severity. Among patients with critical disease, individuals who recovered from COVID-19 had lower levels of TNFR1 and TNFR2 at hospital admission compared to the levels in patients with critical disease who ultimately died.
Perez-Potti, A., Lange, J. & Buggert, M. Deciphering the ins and outs of SARS-CoV-2-specific T cells. Nat Immunol 2020, published 26 November. Full-text: https://doi.org/10.1038/s41590-020-00838-5
Marcus Buggert, André Perez-Potti and Joshua Lange comment on the paper by Nelde A, Bilich T, Heitmann JS, et al. who characterized HLA-specific peptide targets from SARS-CoV-2 in convalescent patients and identify cross-reactive epitopes which were probably induced by common cold coronaviruses in non-infected individuals [SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition. Nat Immunol 2020, published 30 September. PubMed: https://pubmed.gov/32999467. Full-text: https://doi.org/10.1038/s41590-020-00808-x]. This was one of the first studies to indicate that a more polyclonal T cell response may be critical in protection against SARS-CoV-2.
Woolsey C, Borisevich V, Prasad AN, et al. Establishment of an African green monkey model for COVID-19 and protection against re-infection. Nat Immunol (2020). Full-text: https://doi.org/10.1038/s41590-020-00835-8
In this model, the authors demonstrate that African green monkeys (AGMs) mimic several aspects of human disease, including pronounced viral replication and pulmonary lesions. SARS-CoV-2 was detected in mucosal samples, including rectal swabs, as late as 15 days after exposure. Marked inflammation and coagulopathy in blood and tissues were prominent features. Antibody and cellular responses contributed to rapid clearance after re-challenge with an identical strain at 35 days after first exposure.
Omer SB, Yildirim I, Forman HP. Herd Immunity and Implications for SARS-CoV-2 Control. JAMA November 24, 2020; 324(20):2095-2096. Full-text: https://doi.org/10.1001/jama.2020.20892
Saad B. Omer and colleagues discuss herd immunity in the context of the COVID-19 pandemic and explain the herd immunity threshold as a function of transmissibility (R0), the role of an effective vaccine and vaccination program in sustaining herd immunity, and the risks of an infection-based herd immunity approach. Assuming that less than 10% of the population has been infected so far, with an infection-induced immunity lasting 2 to 3 years (duration unknown), infection-induced herd immunity is not realistic at this point to control the pandemic.
Rodda LB, Netland JH, Shehata L, et al. Functional SARS-CoV-2-specific immune memory persists after mild COVID-19. Cell November 23, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.11.029
Even mild COVID-19 elicits memory lymphocytes that persist and display functional hallmarks of antiviral immunity. Lauren Rodda found that three months after mildly symptomatic COVID-19, 15 recovered individuals had formed an expanded arsenal of SARS-CoV-2-specific immune memory B-cells (MBCs) that exhibited protective antiviral functions. Recovered individuals had increased neutralizing antibodies, IgG+ classical MBCs with BCRs that formed neutralizing antibodies, Th1 cytokine-producing CXCR5+ circulating T follicular helper(Tfh) cells and CXCR5- non-Tfh cells, proliferating CXCR3+ CD4+memory cells and IFN-γ-producing CD8+ T cells. These components of immune memory have all been associated with protection from other viruses in humans.
Prado-Vivar B, Becerra-Wong M, Guadalupe JJ, et al. A case of SARS-CoV-2 reinfection in Ecuador. Lancet November 23, 2020. Full-text: https://doi.org/10.1016/S1473-3099(20)30910-5
A 46-year-old man from Quito, Ecuador, presenting with a second infection, only 2 months after the first episode. Phylogenetic analysis revealed that the first infection variant belonged to clade 20A and lineage B1.p9, whereas the second infection variant belonged to clade 19B and lineage A.1.1. Of note, the second episode was more severe.
Karki ER, Sharma BR, Tuladhar S, et al. Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes. Cell November 18, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.11.025
More on the cytokine storm: Rajenda Karki and colleagues evaluated the role of pro-inflammatory cytokines that are highly upregulated in patients with COVID-19 in inducing inflammatory cell death, inflammation, tissue and organ damage, and mortality. They show that the specific combination of TNF-α and IFN-γ is critical for these processes. In mice, the combination of anti-TNF-α and anti-IFN-γ neutralizing antibodies protected against death in SARS-CoV-2 infection and models of sepsis, hemophagocytic lymphohistiocytosis (HLH), and cytokine shock.
Hekman RM, Hume AJ, Goel RK, et al. Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2. Molecular Cell November 18, 2020. Full-text: https://doi.org/10.1016/j.molcel.2020.11.028
SARS-CoV-2 infects alveolar epithelial type 2 cells (AT2s), leading to lung injury and impaired gas exchange. As AT2 injury is central to COVID-19 pathogenesis, there is an urgent need to delineate the mechanisms of SARS-CoV-2-driven lung pathology. Primary AT2s are difficult to maintain in culture, but human induced pluripotent stem cell-derived alveolar epithelial type 2 cells (iAT2s) have been developed and extensively characterized. Using these cells, Ryan Hekman and colleagues from Boston performed a quantitative phosphoproteomic survey, demonstrating diverse host responses to infection of alveolar epithelial cells and suggesting a dynamic disease signature that evolves as the virus disrupts host programs and rewires modules. Time course analysis revealed rapid remodeling of diverse host systems, including signaling, RNA processing, translation, metabolism, nuclear integrity, protein trafficking, and cytoskeletal-microtubule organization, leading to cell cycle arrest, genotoxic stress, and innate immunity.
Karlsson AC, Humbert M, Buggert M. The known unknowns of T cell immunity to COVID-19. Science Immunology 18 Nov 2020: Vol. 5, Issue 53, eabe8063. Full-text: https://doi.org/10.1126/sciimmunol.abe8063
In their brilliant perspective, Annika C. Karlsson and colleagues from Stockholm, Sweden summarize and speculate on a specific set of questions related to T cell immunity against respiratory viral infections, with a focus on COVID-19 severity, immunity, long-term consequences, and vaccination.
Cervia C, Nilsson J, Zurbuchen Y, et al. Systemic and mucosal antibody responses specific to SARS-CoV-2 during mild versus severe COVID-19. J Allergy Clin Immunol. 2020 Nov 19:S0091-6749(20)31623-7. Full-text: https://doi.org/10.1016/j.jaci.2020.10.040
Using immunoassays specific for SARS-CoV-2 spike proteins, Carlo Cervia and colleagues from Zurich, Switzerland determined SARS-CoV-2-specific IgA and IgG in sera and mucosal fluids of PCR positive patients and of negative HCWs. Serum IgA titers in mild COVID-19 cases were often transiently positive, whereas serum IgG titers remained negative or became positive 12-14 days after symptom onset. Conversely, patients with severe COVID-19 showed a highly significant increase of SARS-CoV-2-specific serum IgA and IgG titers after symptom onset. Interestingly, some HCWs with negative SARS-CoV-2-specific serum antibody titers showed SARS-CoV-2-specific IgA in mucosal fluids with virus-neutralizing capacity in some cases.
Bourdon M, Manet C, Montagutelli X. Host genetic susceptibility to viral infections: the role of type I interferon induction. Genes Immun (2020). https://doi.org/10.1038/s41435-020-00116-2
The innate immune response is the major front line of defense against viral infections. It involves hundreds of genes with antiviral properties whose expression is induced by type I interferons (IFNs) and are therefore called interferon-stimulated genes (ISGs). The authors review the role of the molecular partners of the type I IFNs induction pathway and their implication in the control of viral infections and of their complications. Be prepared: not all mechanisms are yet fully understood.
Meyerholz DK, Perlman S. Does common cold coronavirus infection protect against severe SARS-CoV-2 disease? J Clin Invest 2020, published 20 November. Full-text: https://doi.org/10.1172/JCI144807
Read this comment by David Meyerholz and Stanley Perlman on a paper we presented on 9 October [Sagar M, Reifler K, Rossi M, et al. Recent endemic coronavirus infection is associated with less severe COVID-19. J Clin Invest. 2020 Sep 30:143380. PubMed: https://pubmed.gov/32997649. Full-text: https://doi.org/10.1172/JCI143380] where Joseph Mizgerd, Manish Sagar and colleagues showed that individuals with a previously detected eCoV infection had less severe COVID-19 illness.
Yu X, Cragg MS. Engineered antibodies to combat viral threats. Nature 2020, published 18 November. Full-text: https://www.nature.com/articles/d41586-020-03196-2
A Nature News and Views article by Xiaojie Yu and Mark Cragg. As the COVID-19 pandemic rages globally, interest in antiviral treatments has never been higher. Antibodies are key defense components and engineering them to better exploit their natural functions might boost therapeutic options.
Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2 assessed for greater than six months after infection. bioRxiv 2020, posted 16 November. Full-text: https://doi.org/10.1101/2020.11.15.383323
As we approach the end of Year 1 of the SARS-CoV-2 pandemic, we realize that although millions of people were infected during spring 2020, there is now, 8 months later, no sizeable epidemic of re-infections. This observation suggests that SARS-CoV-2 infection might confer a solid immunity. Now, Shane Crotty, Alessandro Sette, Daniela Weiskopf, Jennifer Dan and colleagues analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 185 COVID-19 cases, including 41 cases at > 6 months post-infection. The result: Spike IgG was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months. These findings might suggest that after SARS-CoV-2 infection (or after vaccination), the vast majority of people could be protected against severe COVID-19 for years.
Read also the NYTimes article by Mandavilli A. Immunity to the Coronavirus May Last Years, New Data Hint. The New York Times 2020, published 17 November. Full-text: https://www.nytimes.com/2020/11/17/health/coronavirus-immunity.html
Samuel RM, Majd H, Richter MN, et al. Androgen Signaling Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men. Cell Stem Rep November 17, 2020. Full-text: https://doi.org/10.1016/j.stem.2020.11.009
Finasteride for COVID-19? Ryan M. Samuel and colleagues from San Francisco identified a link between male sex hormone signaling and regulation of the SARS-CoV-2 receptor ACE2 and co-receptor TMPRSS2, possibly explaining the higher complication rates in men. Target analysis of hit compounds revealed androgen signaling as a key modulator of ACE2 levels. Of note, treatment with anti-androgenic drugs such as finasteride reduced ACE2 expression and protected hESC-derived lung organoids against SARS-CoV-2 infection. Finally, clinical data on COVID-19 patients demonstrated that prostate diseases, which are linked to elevated androgen, are significant risk factors and genetic variants that increase androgen levels are associated with higher disease severity.
Li A, Ling Y, Song Z, et al. Early plasma IL-37 responses accompanied with low inflammatory cytokines correlate with benign clinical outcomes during SARS-CoV-2 infection. J Infect Dis. 2020 Nov 17:jiaa713. PubMed: https://pubmed.gov/33197260. Full-text: https://doi.org/10.1093/infdis/jiaa713
Ang Li and colleagues from Shanghai examined early responses of IL-37, a powerful anti-inflammatory cytokine, in 254 SARS-CoV-2-infected patients prior to any clinical intervention and determined its correlation with clinical prognosis. Higher early IL-37 responses correlated with earlier viral RNA negative conversion, chest CT image improvement and cough relief, consequently resulting in earlier hospital discharge. Further assays showed that higher IL-37 was associated with lower IL-6 and IL-8 and higher IFN-α, and facilitated biochemical homeostasis. Low IL-37 responses predicted severe clinical prognosis in combination with IL-8 and CRP. Moreover, IL-37 administration was able to attenuate lung inflammation and alleviate respiratory tissue damage in hACE2-transgenic mice infected with SARS-CoV-2.
Woldemeskel BA, Kwaa AK, Garliss CC, Laeyendecker O, Ray SC, Blankson JN. Healthy donor T cell responses to common cold coronaviruses and SARS-CoV-2. J Clin Invest. 2020 Nov 16:143120. PubMed: https://pubmed.gov/32966269. Full-text: https://doi.org/10.1172/JCI143120
Bezawit A. Woldemeskel and colleagues from Baltimore used the ELISPOT assay to characterize the T cell responses against peptide pools derived from the spike protein of 3 common cold coronaviruses and SARS-CoV-2 in 21 healthy donors seronegative for SARS-CoV-2. An in vitro expansion culture assay was also used to analyze memory T cell responses. Responses to the spike protein of the 3 common cold coronaviruses were found in many of the donors. T cell responses to SARS-CoV-2 spike and nucleocapsid proteins were present in only 1 participant and were potentially the result of cross-recognition by T cells specific for the common cold coronaviruses.
Knierman MD, Lannan MB, Spindler LJ, et al. The Human Leukocyte Antigen Class II Immunopeptidome of SARS-CoV-2 Spike Glycoprotein. Cell Rep November 13, 2020. Full-text: https://doi.org/10.1016/j.celrep.2020.108454
Using mass spectrometry, Michael D Knierman and colleagues from Lilly performed a precise and comprehensive immunopeptidomic investigation with SARS-CoV-2 spike glycoprotein. They identified 526 unique sequences from SARS-CoV-2 spike glycoprotein extracellular domain in a complex with HLA class II molecules on antigen presenting cells from a panel of healthy donors. The identified sequences spanned the entire spike protein and several sequences were isolated from a majority of the donors sampled, indicating promiscuous binding. This is good news, as both the depth and breadth of the HLA-II peptides indicate that mutational drift is not expected to dramatically alter the ability of an infected individual to mount a new B cell response.
Zhang J, Wu Q, Liu Z, et al. Spike-specific circulating T follicular helper cell and cross-neutralizing antibody responses in COVID-19-convalescent individuals. Nat Microbiol (2020). Full-text: https://doi.org/10.1038/s41564-020-00824-5
T follicular help (TFH) cells, a subset of T cells, have been identified as professional B helper T cells in past decades and are required for T-dependent antibody production. Convalescent individuals who experienced severe COVID-19 showed higher neutralizing antibody titers, a faster increase in lymphocyte counts and a higher frequency of CXCR3+ TFH cells compared with COVID-19-convalescent individuals who experienced non-severe disease. Circulating TFH cells were spike specific and functional, and the frequencies of CXCR3+ TFH cells were positively associated with neutralizing antibody titers in COVID-19-convalescent individuals.
Dayarathna S, Jeewandara C, Gomes L, et al. Similarities and differences between the ‘cytokine storms’ in acute dengue and COVID-19. Sci Rep 10, 19839 (2020). Full-text: https://doi.org/10.1038/s41598-020-76836-2
Severe COVID-19 and dengue hemorrhagic fever (DHF) are two diseases that can associate with an altered immune response to the infecting virus. In both infections, a cytokine storm is thought to play a role in disease pathogenesis. Shashika Dayarathna and colleagues from Sri Lanka found similarities between the cytokines that are elevated in early illness in those who progress to severe illness but also many differences. Those who developed severe pneumonia in COVID-19 had high levels of many inflammatory cytokines and chemokines but low IFN-γ levels. Patients who proceeded to develop DHF also had high cytokine and chemokine levels, but most strikingly very high IL-10 levels. Low IFN-γ response to SARS-CoV-2 and high levels of immunosuppressive cytokines such as IL-10 in both COVID-19 and dengue during early illness is likely to result in an altered antiviral response.
Shomuradova AS, Vagida MS, Sheetilov SA. SARS-CoV-2 epitopes are recognized by a public and diverse repertoire of human T cell receptors. Immunity November 13, 2020. Full-text: https://doi.org/10.1016/j.immuni.2020.11.004
Cellular and humoral immune response to SARS-CoV-2 were analyzed in 34 donors from Moscow who had recently recovered from COVID-19, as well as in two small control cohorts of healthy donors sampled before or during the pandemic. Some of the 14 healthy donors examined during the pandemic exhibited increased numbers of SARS-CoV-2-specific T cells, but no humoral response. It therefore seems possible that some people are protected by a pre-existing cross-reactive T cell response induced by other coronaviruses or had developed an asymptomatic infection that was cleared without the help of the humoral response. But can we believe this? The numbers were low and there is no doubt that his hypothesis needs to be validated in a larger cohort of donors.
Schulien I, Kemming J, Oberhardt V, et al. Characterization of pre-existing and induced SARS-CoV-2-specific CD8+ T cells. Nat Med (2020). Full-text: https://doi.org/10.1038/s41591-020-01143-2
Are differences in pre-existing and induced SARS-CoV-2-specific CD8+ T cell responses linked to different courses of infection? We don’t know yet. In particular, little is known about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8+ T cell responses during the natural course of SARS-CoV-2 infection. In this study, Robert Thimme, Maike Hofmann, Christoph Neumann-Haefelin and colleagues established experimental tools for high-resolution ex vivo analyses of SARS-CoV-2-specific CD8+ T cells. Find out what they discovered about heterogeneous and functionally competent cross-reactive and induced memory CD8+ T cell responses in cross-sectionally analyzed individuals with mild SARS-CoV-2 disease.
Tosif S, Neeland MR, Sutton P, et al. Immune responses to SARS-CoV-2 in three children of parents with symptomatic COVID-19. Nat Commun 11, 5703 (2020), published 11 November. https://doi.org/10.1038/s41467-020-19545-8
Children can mount an immune response to SARS-CoV-2 without virological confirmation of infection. This is the exciting result from a study by Shidan Tosif et al. who describe clinical features, virology, longitudinal cellular, and cytokine immune profile, SARS-CoV-2-specific serology and salivary antibody responses in a family of two parents with PCR-confirmed symptomatic SARS-CoV-2 infection and their three children, who tested repeatedly SARS-CoV-2 PCR-negative. These findings raise the possibility that immunity in children can prevent the establishment of SARS-CoV-2 infection.
Thomson EC, Rosen LE, Shepherd JG, et al. The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity. bioRxiv 2020, posted 5 November. Full-text: https://doi.org/10.1101/2020.11.04.355842
A widespread variant of SARS-CoV-2 which has been identified in 12 countries might have the potential to evade recently acquired immunity. That’s the result of a study by David Robertson, Gyorgy Snell, Emma Thomson and colleagues who examined the N439K mutation in the receptor binding motif (RBM) of the SARS-CoV-2 spike (S) protein. The authors found that the N439K mutation resulted in immune escape from a panel of neutralizing monoclonal antibodies (including some that are currently being developed for treatment of SARS-CoV-2 infection) as well as from polyclonal sera from a sizeable fraction of persons recovered from infection. The authors conclude that their findings might have consequences for the efficacy of emerging vaccines and antibody therapeutics.
Chakraborty S, Gonzalez J, Edwards K et al. Proinflammatory IgG Fc structures in patients with severe COVID-19. Nat Immunol 2020, November 9. Full-text: https://doi.org/10.1038/s41590-020-00828-7
Another (important) piece in the puzzle: Saborni Chakraborty and colleagues from Stanford show that specific pro-inflammatory antibody forms are elevated in more patients with severe COVID-19, in contrast to those with mild symptoms and seropositive children. The unique serologic signature is characterized by IgG3 and IgG1 with F0N0 glycoform modification and includes an increased likelihood of IgG1 with afucosylated Fc glycans. This Fc modification on SARS-CoV-2 IgGs enhanced interactions with the activating Fcγ receptor FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including interleukin-6 and tumor necrosis factor. This may explain why some patients develop severe COVID-19.
Ng KW, Faulkner N, Cornish GH, et al. Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. Science 06 Nov 2020. Full-text: https://doi.org/10.1126/science.abe1107
Using multiple independent assays (including flow cytometry-based assay for SARS-CoV-2-binding antibodies), the authors demonstrated the presence of pre-existing antibodies recognizing SARS-CoV-2 in at least some uninfected individuals. SARS-CoV-2 spike glycoprotein (S)-reactive antibodies were particularly prevalent in children and adolescents. They were predominantly of the IgG class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S-reactive IgG antibodies, targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period.
Angioni R, Sánchez-Rodríguez R, Munari F, et al. Age-severity matched cytokine profiling reveals specific signatures in Covid-19 patients. Cell Death Dis 11, 957 (2020). Full-text: https://doi.org/10.1038/s41419-020-03151-z
Roberta Angioni and colleagues analyzed the cytokine and leukocyte profile of COVID-19 patients at hospital admission and identified distinctive immunological signatures that characterize younger or older severe patients. They found that severe patients under the age of 60 did not show major leukocyte alterations and expressed high levels of IL-1RA, IL-6, CCL2, CXCL1, CXCL9, CXCL10, and EGF. In contrast, older patients expressed high levels of CXCL8, IL-10, IL-15, IL-27, and TNF-α, presented a significant reduction in the total T lymphocyte number and an increased expression of T cell exhaustion markers as compared to those younger.
Weisberg SP, Connors TJ, Zhu Y, et al. Distinct antibody responses to SARS-CoV-2 in children and adults across the COVID-19 clinical spectrum. Nat Immunol (2020). Full-text: https://doi.org/10.1038/s41590-020-00826-9
Children and adults have distinct immune responses after SARS-CoV-2 infection. Here, Donna Farber, Stuart Weisberg and colleagues present data from two adult (n=32) and two pediatric cohorts (n=47). They show that adult COVID-19 cohorts had anti-spike (S) IgG, IgM and IgA antibodies, as well as anti-nucleocapsid (N) IgG antibody, while children with and without MIS-C had reduced breadth of anti-SARS-CoV-2-specific antibodies, predominantly generating IgG antibodies specific for the S protein but not the N protein. The authors present possible explanations for these findings.
Tandon R, Mitra D, Sharma P. Effective screening of SARS-CoV-2 neutralizing antibodies in patient serum using lentivirus particles pseudotyped with SARS-CoV-2 spike glycoprotein. Sci Rep 10, 19076 (2020). Full-text: https://doi.org/10.1038/s41598-020-76135-w
Pseuodotyped particles have significant importance and use in virology as tools for studying the biology of highly pathogenic viruses in a lower biosafety environment. Here, Ritesh Tandon et al. report a third generation lentiviral pseudotyping system for SARS-CoV-2 (pLV-S) and its efficacy in detecting neutralizing antibody titers in convalescent patient serum. The authors conclude that these pseudoparticles could be utilized for screening of potential vaccine candidates as they represent SARS-CoV-2 Spike glycoprotein on their surface in its native confirmation.
Zohar T, Loos C, Fischinger S, et al. Compromised humoral functional evolution tracks with SARS-CoV-2 mortality. Cell 2020, pubished 3 November. Full-text: https://doi.org/10.1016/j.cell.2020.10.052
Both IgA and IgM evolve rapidly across all levels of disease severity, but rapid and potent IgG class switching is linked to survival. This is the key message of a paper by Galit Alter, Tomer Zohar and colleagues who analyzed the early evolution of the humoral response in 193 hospitalized individuals with moderate to severe COVID-19. The data highlight distinct humoral trajectories associated with resolution of SARS-CoV-2 infection.
Files JK, Boppana S, Perez MD, et al. Sustained cellular immune dysregulation in individuals recovering from SARS-CoV-2 infection. J Clin Invest. 2020 Oct 29:140491. PubMed: https://pubmed.gov/33119547. Full-text: https://doi.org/10.1172/JCI140491
A prolonged period of immune dysregulation may follow SARS-CoV-2, both in hospitalized and non-hospitalized patients. This is the result of a study by Nathaniel Erdman, Jacob Files and colleagues who analyzed samples and data from 46 hospitalized and 29 non-hospitalized patients as well as 20 controls. The authors also report that the dysregulation of T-cell activation and exhaustion markers in non-hospitalized individuals appears to be more pronounced in the elderly.
Stervbo U, Rahmann S, Roch T, et al. Epitope similarity cannot explain the pre-formed T cell immunity towards structural SARS-CoV-2 proteins. Sci Rep 10, 18995 (2020). Full-text: https://doi.org/10.1038/s41598-020-75972-z
Biobanked venous blood contains T cells reactive to SARS-CoV-2 S-protein even before the outbreak in Wuhan, suggesting that there is a preformed T cell memory towards structural proteins in individuals not exposed to SARS-CoV-2. Here, Ulrik Stervbo et al. utilize a combination of epitope prediction and similarity to common human pathogens to identify potential sources of the SARS-CoV-2 T cell memory. Their data suggests that the observed SARS-CoV-2 pre-formed immunity to structural proteins is not driven by near-identical epitopes.
Chen Y, Zuiani A, Fischinger S, and al. Quick COVID-19 Healers Sustain Anti-SARS-CoV-2 Antibody Production. Cell 2020, published 3 November. Full-text: https://doi.org/10.1016/j.cell.2020.10.051
After SARS-CoV-2 infection, some individuals maintain stable or increased SARS-CoV-2 IgG, displaying an immune phenotype that connects rapid symptom clearance to differential antibody durability dynamics. Those who sustain virus-specific IgG production might tend to have shorter disease courses despite similar distribution of initial anti-SARS-CoV-2 IgG levels, and their anti-S memory B cells harbor increased levels of somatic hypermutation (SHM) shortly after disease resolution. This is a result of an analysis by Duane Wesemann, Yuezhou Chen and colleagues who charted longitudinal antibody responses to SARS-CoV-2 in 76 subjects after symptomatic COVID-19 followed longitudinally to ∼100 days.
Custódio TF, Das H, Sheward DJ, et al. Selection, biophysical and structural analysis of synthetic nanobodies that effectively neutralize SARS-CoV-2. Nat Commun 11, 5588 (2020). Full-text: https://doi.org/10.1038
Traditional antibody production is hampered by long development times and costly production. Here, Christian Löw, Tânia Custódio and colleagues report the rapid isolation and characterization of nanobodies that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Several of the 85 binders isolated by the authors had low nanomolar affinities and efficient neutralization activity.
Khoury DS, Wheatley AK, Ramuta MD, et al. Measuring immunity to SARS-CoV-2 infection: comparing assays and animal models. Nat Rev Immunol (2020). Full-text: https://doi.org/10.1038/s41577-020-00471-1
Assays to measure naturally acquired immunity and test the efficacy of immune interventions are key to the development of novel prophylactic and therapeutic interventions. Here, Miles Davenport, David Khoury and colleagues analyze a selection of existing assays for measuring antibody-mediated virus neutralization and animal models of infection with SARS-CoV-2. Their message: identify what you want to measure and match these goals to your experimental design.
Bošnjak B, Stein SC, Willenzon S, et al. Low serum neutralizing anti-SARS-CoV-2 S antibody levels in mildly affected COVID-19 convalescent patients revealed by two different detection methods. Cell Mol Immunol (2020). Full-text: https://doi.org/10.1038/s41423-020-00573-9
Reinhold Förster, Berislav Bošnjak and colleagues performed a surrogate virus neutralization test (sVNT) and SARS-CoV-2 S protein-pseudotyped vesicular stomatitis virus (VSV) vector-based neutralization assay (pVNT) to assess the degree to which serum antibodies from coronavirus disease 2019 (COVID-19) convalescent patients interfere with the binding of SARS-CoV-2 S to ACE2. They analyzed 40 patients with mild SARS-CoV-2 infection, 10 patients with severe infection and 12 healthy controls. Both tests revealed neutralizing anti-SARS-CoV-2 S antibodies in the sera of approximately 90% of mildly and 100% of severely affected COVID-19 convalescent patients. Levels of neutralizing antibodies correlated with the duration and severity of clinical symptoms but not with patient age. The authors conclude that that sVNT is technically less complicated, cheaper, and much faster than pVNT, making it more suitable for the rapid screening of a large number of samples.
Meffre E, Iwasaki A. Interferon deficiency can lead to severe COVID. Nature 2020, published 2 November. Full-text: https://www.nature.com/articles/d41586-020-03070-1
In this News & Views articles, the authors highlight the possible key role for the signaling pathway mediated by type I interferon proteins in the development of severe COVID-19. The authors discuss the papers by Bastard et al. and Zhang et al. we presented on September 25:
Bastard P, Rosen LB, Zhang Q, et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science 2020, published 24 September. Full-text: https://science.sciencemag.org/content/early/2020/09/23/science.abd4585
Zhang Q, Bastard P, Liu Z, et al: Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 2020, published 24 September. Full-text: https://science.sciencemag.org/content/early/2020/09/23/science.abd4570
Gudbjartsson DF, Norddahl GL, Melsted P, et al. Humoral Immune Response to SARS-CoV-2 in Iceland. N Engl J Med 2020, published 1 September. Full-text: https://doi.org/10.1056/NEJMoa2026116
Yesterday the NEJM published a paper we presented on September 2. In this study by Kari Stefansson, Daniel Gudbjartsson and colleagues, over 90% of 1,215 qPCR-positive persons tested positive with two pan-Ig SARS-CoV-2 antibody assays and remained seropositive 120 days after diagnosis, with no decrease of antibody levels. Another piece of good news: the infection fatality risk in Iceland was 0.3%. See also the editorial by Galit Alter and Robert Seder: Alter G, Seder R: The Power of Antibody-Based Surveillance. N Engl J Med 2020, published 1 September. Full-text: https://doi.org/10.1056/NEJMe2028079.
Wajnberg A, Amanat F, Firpo A, et al. Robust neutralizing antibodies to SARS-CoV-2 infection persist for months. Science 2020, published 28 October. Full-text: https://doi.org/10.1126/science.abd7728
Assessing the antibody response to SARS-CoV-2 infection in mild and asymptomatic cases is of high importance since they constitute the majority of infections. Now, Ania Wajnberg, Florian Krammer, Carlos Cordon-Cardo and colleagues show that the vast majority of infected individuals with mild-to-moderate COVID-19 experience had robust IgG antibody responses against the viral spike protein. The authors from Icahn School of Medicine at Mount Sinai, New York, analyzed a dataset of 30,082 individuals. Titers were relatively stable for at least a period approximating 5 months Anti-spike binding titers correlated with neutralization of authentic SARS-CoV-2. The data suggests that more than 90% of seroconverters make detectible neutralizing antibody responses.
Fox A, Marino J, Amanat F, et al. Robust and specific secretory IgA against SARS-CoV-2 detected in human milk. iScience 2020, published 27 October. Full-text: https://doi.org/10.1016/j.isci.2020.101735
Rebecca Powell, Alisa Fox and colleagues report significant specific IgA reactivity to the full Spike, while 80% exhibited significant IgA and secretory (s)Ab binding to the receptor binding domain (RBD) in human milk samples from 8 COVID-19-recovered and 7 COVID-19-suspected donors. These data might indicate that a robust sIgA-dominant SARS-CoV-2 Ab response in human milk after infection should be expected in a significant majority of individuals. The authors also recommend further research to determine the potential for exploiting extracted milk sIgA for therapeutic use. How practical will that be?
Seow J, Graham C, Merrick B, et al. Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans. Nat Microbiol (2020). Full-text: https://doi.org/10.1038/s41564-020-00813-8
Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10–15 d after the onset of COVID-19 symptoms. But how long will antibody responses be maintained and will they provide protection from re-infection? To answer these questions, Katie Doores, Jeffrey Seow and colleagues collected sequential serum samples up to 94 d post-onset of symptoms from 65 individuals with SARS-CoV-2 infection. They show that the kinetics of the neutralizing antibody response to SARS-CoV-2 is typical of an acute viral infection where a peak response is detected 3–4 weeks post-infection, which then wanes. Their results suggest that for individuals who develop a low neutralizing antibody response (ID50 100–300), titers can return to baseline over a relatively short period, whereas those who develop a robust neutralizing antibody response maintain titers > 1,000 despite the initial decline. Must we already reconsider widespread serological testing and antibody protection against reinfection with SARS-CoV-2? The authors conclude that vaccine boosters might be required to provide long-lasting protection.
Yang OO, Ibarrondo FJ. Loss of Anti-SARS-CoV-2 Antibodies in Mild Covid-19. Reply. N Engl J Med. 2020 Oct 22;383(17):1697-1698. PubMed: https://pubmed.gov/32966713. Full-text: https://doi.org/10.1056/NEJMc2027051
Still a controversy about anti-SARS-CoV-2 antibody decay. Some groups found a marked decline while others obtained conflicting results that suggest stability over time. Several factors probably explain these apparent contradictions (heterogeneous populations studied but mainly different methods). Would you mind coming to an agreement, please? The authors here (see the second reply) believe they’re right (decay). They think that they have the better method. If so, this would be bad news by raising questions about the likelihood of natural herd immunity and whether a vaccine can give a more prolonged response.
Baang JH, Smith C, Mirabelli C, et al. Prolonged SARS-CoV-2 replication in an immunocompromised patient. J Infect Dis 2020, jiaa666. Full-text: https://doi.org/10.1093/infdis/jiaa666
Interesting case of “chronic COVID-19” in a patient with mantle cell lymphoma and associated B cell immunodeficiency. Viral cultures and sequence analysis demonstrate ongoing replication of infectious SARS-CoV-2 virus for at least 119 days. The patient had three admissions related to COVID-19 over a four-month period and was treated twice with remdesivir and convalescent plasma with resolution of symptoms. The patient’s lack of seroconversion and prolonged course illustrate the importance of humoral immunity in resolving SARS-CoV-2 infection. The authors hypothesize that antibody-mediated ablation of B cell precursors by mosunetuzumab and polatuzumab vedotin was primarily responsible for his prolonged viral shedding.
Youk J, Kim T, Evans KV. Three-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2. Cell Rep October 21, 2020. Full-text: https://doi.org/10.1016/j.stem.2020.10.004
The cellular response of human alveolar type 2 (hAT2) cells to SARS-CoV-2 remains elusive, due to difficulty in the long-term expansion of pure hAT2 cells. Jeonghwan Youk and colleagues now developed a technique for long-term, feeder-free human 3D alveolar type 2 cell cultures (h3ACs). According to the authors, SARS-CoV-2 infected h3ACs showed remarkable cellular and transcriptional changes far more clearly than other models, including h3BCs and 2D Vero cell lines, showing cellular tropism in the viral replication and transcription as well as the resultant reaction from the host cell.
Katsura H, Sontake V, Tata A, et al. Human lung stem cell-based alveolospheres provide insights into SARS-CoV-2 mediated interferon responses and pneumocyte dysfunction. Cell Rep October 21, 2020. Full-text: https://doi.org/10.1016/j.stem.2020.10.005
Hiroaki Katsura from Duke University, Durham, USA and colleagues present another new feeder-free, scalable, chemically-defined, and modular alveolosphere culture system for propagation and differentiation of human alveolar type 2 cells (AT2s/pneumocytes) derived from primary lung tissue. Cultured pneumocytes expressed the SARS-CoV-2 receptor ACE2 and could be infected with virus. Cells retained the cardinal features of AT2s, including the ability to self-renew, produce surfactants, and differentiate into AT1s. This model may offer a unique system for studying SARS-CoV-2 infection and developing effective therapies for COVID-19 and other respiratory diseases.
Ferretti AP, Kula T, Wang Y, et al. Unbiased screens show CD8+ T cells of COVID-19 patients recognize shared epitopes in SARS-CoV-2, most of which are not located in the Spike protein. Immunity, October 20, 2020. Full-text: https://doi.org/10.1016/j.immuni.2020.10.006
Which peptide sequences in SARS-CoV-2 are recognized by the memory CD8+ T cells of COVID-19 patients? Andrew P. Ferretti and colleagues found that CD8+ T cells predominantly recognized 3-8 shared epitopes for each HLA type studied. Of note, around ∼90% of shared epitopes were not located in the Spike protein, but in ORF1ab or the nucleocapsid protein. CD8+ T cells generally did not cross-react with epitopes in the four seasonal coronaviruses.
Overbaugh J. Understanding protection from SARS-CoV-2 by studying reinfection. Nat Med 2020, published 22 October. Full-text: https://doi.org/10.1038/s41591-020-1121-z
Can understanding the risk of SARS-CoV-2 reinfection provide an avenue to understanding the path to protection against SARS-CoV-2 for vaccine development? Julie Overbaugh argues that the study of reinfection is critical because if neutralizing antibody responses are robust in people who are re-infected, this would suggest that the vaccine concepts need to be diversified. This could include considering diverse antibody epitopes, both neutralizing and non-neutralizing, and optimizing the effector function of antibodies and enhancing cellular responses.
Dong J, Huang B, Wang B, et al. Development of humanized tri-specific nanobodies with potent neutralization for SARS-CoV-2. Sci Rep 10, 17806 (2020). Full-text: https://doi.org/10.1038/s41598-020-74761-y
Llamas against SARS-CoV2? In May, Djambo Dong et al. identified humanized VHHs that bind to S protein and block the S/ACE2 interaction (see article below; a VHH antibody [or nanobody] is the antigen binding fragment of heavy-chain-only antibodies). Now the authors use computer-aided design to construct multi-specific VHH antibodies fused to human IgG1 Fc. The resulting tri-specific VHH-Fc antibodies show potent S1 binding, S1/ACE2 blocking, and SARS-CoV-2 pseudovirus neutralization.
Dong J, Huang B, Jia Z, et al. Development of multi-specific humanized llama antibodies blocking SARS-CoV-2/ACE2 interaction with high affinity and avidity. Emerg Microbes Infect. 2020 Dec;9(1):1034-1036. PubMed: https://pubmed.gov/32403995. Full-text: https://doi.org/10.1080/22221751.2020.1768806
Schwarzkopf S, Krawczyk A, Knop D, Klump H, Heinold A, Heinemann FM, et al. Cellular immunity in COVID-19 convalescents with PCR-confirmed infection but with undetectable SARS-CoV-2–specific IgG. Emerg Infect Dis. 2021 Jan. Full-text: https://wwwnc.cdc.gov/eid/article/27/1/20-3772_article
Sina Schwarzkopf and colleagues from Essen University, Germany have investigated immune responses among a group of convalescent, potential blood donors in Germany who had PCR-confirmed SARS-CoV-2 infection. Sixty days after onset of symptoms, 13/78 (17%) study participants had borderline or negative results to an ELISA detecting IgG against the S1 protein. Cellular immunity toward any of the SARS-CoV-2 antigens was detectable in 7/9 (78%) participants who had a low antibody ratio < 1.
Perico L, Benigni A, Casiraghi F, et al. Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat Rev Nephrol (2020). Full-text: https://doi.org/10.1038/s41581-020-00357-4
Nice review on pathogenic mechanisms underlying SARS-CoV-2 infection and COVID-19, as well as on the critical role of the immunological hyper-response — characterized by widespread endothelial damage, complement-induced blood clotting and systemic microangiopathy — in disease exacerbation.
Liu B, Han J, Cheng X et al. Reduced numbers of T cells and B cells correlates with persistent SARS-CoV-2 presence in non-severe COVID-19 patients. Sci Rep 10, 17718 (2020). Full-text: https://doi.org/10.1038/s41598-020-73955-8
In total, 37 non-severe patients with persistent SARS-CoV-2 presence that were transferred to Zhongnan hospital of Wuhan were retrospectively recruited to the PP (persistently positive) group, which was further allocated to the PPP group (n = 19) and the PPN group (n = 18), according to their testing results after 7 days (N = negative). The PPP subgroup had markedly reduced B cells and T cells compared to the PPN group and healthy subjects. Finally, paired results of these lymphocyte subpopulations from 10 PPN patients demonstrated that the number of T cells and B cells significantly increased when the SARS-CoV-2 tests turned negative.
Leisman DE, Ronner L, Pinotti R, et al. Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Dis 2020, pubished 16 October. Full-text: https://doi.org/10.1016/S2213-2600(20)30404-5
Daniel Leisman and colleagues question the role of a cytokine storm in COVID-19-induced organ dysfunction after a systematic review and meta-analysis of 25 COVID-19 studies (n = 1245 patients) and four trials each in sepsis (n = 5320), cytokine release syndrome (n = 72), and acute respiratory distress syndrome unrelated to COVID-19 (n = 2767). Mean interleukin-6 concentrations were nearly 100 times higher in patients with cytokine release syndrome (3110.5 pg/mL), 27 times higher in patients with sepsis (983.6 pg/mL), and 12 times higher in patients with acute respiratory distress syndrome unrelated to COVID-19 (460 pg/mL). The authors conclude that alternative mechanisms of COVID-19-induced organ dysfunction are worth considering and that immune-activating treatments (i.e., interferons, IL-7, or checkpoint inhibition) might merit investigation.
Lee S, Channappanavar R, Kanneganti TD. Coronaviruses: Innate Immunity, Inflammasome Activation, Inflammatory Cell Death, and Cytokines. Trends Immunol 2020, published 15 October. Full-text: https://doi.org/10.1016/j.it.2020.10.005
The authors develop the current understanding of innate immune responses, inflammasome activation, inflammatory cell death pathways, and cytokine secretion during SARS-CoV, MERS-CoV, and SARS-CoV-2 infection. Your Sunday morning review.
Willyard C. How anti-ageing drugs could boost COVID vaccines in older people. Nature 2020, published 14 October. Full-text: https://www.nature.com/articles/d41586-020-02856-7
COVID-19 poses the greatest threat to older people, but vaccines often don’t work well in this group. Scientists hope drugs that rejuvenate the immune system will help. A Nature News Feature by Cassandra Willyard.
Poland GA, Ovsyannikova IG, Kennedy RB. SARS-CoV-2 immunity: review and applications to phase 3 vaccine candidates. Lancet 2020, published 13 October. Full-text: https://doi.org/10.1016/S0140-6736(20)32137-1
A mere 11 months ago, we didn’t know anything about SARS-CoV-2 and COVID-19. Now we are developing vaccines, antivirals, and monoclonal antibodies. In this review, the authors discuss what is known about human humoral and cellular immune responses to SARS-CoV-2 and relate this knowledge to the COVID-19 vaccines currently in phase 3 clinical trials. Will vaccines induce protective immunity? How long will this immunity maintained? Will we need multiple vaccine types for different populations (i.e., immune-immature infants, children, pregnant women, immunocompromised individuals, and immunosenescent individuals aged ≥65 years). Can unrelated vaccines (measles, mumps, and rubella vaccine and the Bacillus Calmette–Guérin vaccine) elicit trained innate immunity and confer protection against COVID-19? These are some of the questions you will explore with the authors.
Barnes CO, Jette CA, Abernathy ME, et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 2020, published 12 October. Full-text: https://doi.org/10.1038/s41586-020-2852-1
To determine structural correlates of SARS-CoV-2 neutralization, the authors solved 8 new structures of distinct COVID-19 human neutralizing antibodies (hNAbs) in complex with SARS-CoV-2 spike trimer or the receptor-binding domain (RBD). Structural comparisons allowed classification into several categories according to which part of the spike protein’s cell-attachment region they recognize. These categories might later provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects, suggesting combinations for clinical use, and providing insight into immune responses against SARS-CoV-2.
Tillett RL, Sevinsky JR, Hartley PD, et al. Genomic evidence for reinfection with SARS-CoV-2: a case study. Lancet Infect Dis 2020, published 12 October. Full-text: https://doi.org/10.1016/S1473-3099(20)30764-7
Mark Pandori, Richard Tillett and colleagues report a 25-year patient who had two positive SARS-CoV-2 tests, the first on April 18, 2020, and the second on June 5, 2020, separated by two negative tests done during follow-up in May, 2020. Their analysis indicates that the patient was infected by SARS-CoV-2 on two separate occasions by a genetically distinct virus. Intriguingly, the second infection was symptomatically more severe than the first. The authors recommend that all individuals, whether previously diagnosed with COVID-19 or not, should take identical precautions to avoid infection with SARS-CoV-2. We cross our fingers that this case is the exception rather than the rule.
Posten D, Weisblum Y, Wise H, et al. Absence of SARS-CoV-2 neutralizing activity in pre-pandemic sera from individuals with recent seasonal coronavirus infection. medRxiv 2020, published 11 October. Full-text: https://doi.org/10.1101/2020.10.08.20209650
Bad news from Rockefeller University. Paul Bieniasz, Daniel Poston and colleagues measured neutralizing activity against SARS-CoV-2 in pre-pandemic sera from patients with prior PCR-confirmed seasonal coronavirus infection. While neutralizing activity against seasonal coronaviruses was detected in nearly all sera, cross-reactive neutralizing activity against SARS-CoV-2 was undetectable. The authors conclude that while it is possible that there are rare instances of individuals possessing antibodies from prior seasonal HCoV infection may be able to also target SARS-CoV-2 S, their data would argue against a broad role for pre-existing protective humoral immunity against SARS-CoV-2. These findings have not yet been peer reviewed.
Hu F. Chen F, Ou Z, et al. A compromised specific humoral immune response against the SARS-CoV-2 receptor-binding domain is related to viral persistence and periodic shedding in the gastrointestinal tract. Cell Mol Immunol (2020). Full-text: https://doi.org/10.1038/s41423-020-00550-2
Do some people have lower levels of and slower generation of viral receptor-binding domain (RBD)-specific IgA and IgG antibodies and fail to create a robust protective humoral immune response? Which might result in SARS-CoV-2 persistence in the gastrointestinal tract and possibly in active viral shedding? That’s the hypothesis of Feng Li, Fengyu Hu and colleagues who report 21 patients who were readmitted for hospitalization after detection of SARS-CoV-2 after discharge. The authors detected SARS-CoV-2 in anal samples (15 of 21, 71.4%). Three patients had active viral replication in their gastrointestinal tracts but not in their respiratory tracts.
Sagar M, Reifler K, Rossi M, et al. Recent endemic coronavirus infection is associated with less severe COVID-19. J Clin Invest. 2020 Sep 30:143380. PubMed: https://pubmed.gov/32997649. Full-text: https://doi.org/10.1172/JCI143380
The four endemic coronaviruses (eCoV: HCoV-OC43, -HKU1, -NL63, and -229E), the most common etiologic agents for the seasonal “common cold”, share sequence homology with SARS-CoV-2. Here, Joseph Mizgerd, Manish Sagar and colleagues show that individuals with a previously detected eCoV infection had less severe COVID-19 illness. They report the analysis of 15,928 patients who had at least one CRP-PCR (comprehensive respiratory panel polymerase chain-reaction) test. A positive test was previously detected in 875 of these patients (termed eCoV+), and the remaining 15,053 individuals (classified as eCoV-) never had a documented eCoV infection. The authors suggest that pre-existing immune responses against endemic human coronaviruses can mitigate disease manifestations from SARS-CoV-2 infection.
(% of total)
|1679 (11.2)||133 (15.2)|
(% of tested)
|437 (26.0)||33 (24.8)|
(% of SARS-CoV-2+)
|231 (52.9)||21 (63.6)|
|Intensive care unit, no.
(% of hospitalized)
|65 (28.1)||1 (4.8)|
|Mechanical ventilation, no.
(% of hospitalized)
|38 (16.4)||0 (0)|
Lipsitch M, Grad YH, Sette A, Crotty S. Cross-reactive memory T cells and herd immunity to SARS-CoV-2. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-00460-4
It is not clear if cross-reactive T cell memory (which largely originates from previous exposure to circulating common cold coronaviruses) affects COVID-19 disease severity in SARS-CoV-2 infected individuals. In this Perspective article, the authors reflect on the immunological and epidemiological aspects and implications of pre-existing cross-reactive immune memory to SARS-CoV-2.
Meckiff BJ, Ramírez-Suástegui C, Fajardo V, et al. Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4+ T cells in COVID-19. Cell October 05, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.10.001
CD4+ T cells are essential for adaptive anti-viral immunity. However, due to the rarity of SARS-CoV-2-specific cells in the total CD4+ T cell populations, signals from these cells are likely to be masked by the relative abundance of other non-antigen specific CD4+ T cells. Benjamin J. Meckiff from La Jolla (USA) provides important insights into the gene expression patterns of SARS-CoV-2-reactive CD4+ T cells by performing single-cell transcriptomic analysis of > 100,000 viral antigen-reactive CD4+ T cells from 40 COVID-19 patients. They found remarkable heterogeneity in the nature of CD4+ T cell subsets that are reactive to SARS-CoV-2 and other respiratory viruses, and across individual patients with differing severity of COVID-19. In 18 hospitalized patients (compared to 22 non-hospitalized patients), proportions of cytotoxic follicular helper (TFH) cells and cytotoxic T helper cells (CD4-CTLs) responding to SARS-CoV-2 were increased, while the proportion of SARS-CoV-2-reactive regulatory T cells (TREG) were reduced. Importantly, in hospitalized COVID-19 patients, a strong cytotoxic TFH response was observed early in the illness which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional T helper (TH)1 and TH17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells.
Goldman JD, Wang K, Roltgen K, et al. Reinfection with SARS-CoV-2 and Failure of Humoral Immunity: a case report. medRxiv. 2020 Sep 25:2020.09.22.20192443. PubMed: https://pubmed.gov/32995830. Full-text: https://doi.org/10.1101/2020.09.22.20192443
The authors describe a care-home resident in their sixties with two distinct episodes of symptomatic COVID-19 separated by 144 days. After the second infection, the patient produced only low levels of antibodies which decreased over time. The authors hope to get near the point where we understand the correlates of humoral immunity required to prevent reinfection. Note: This paper has not yet been peer reviewed.
Prévost J, Gasser R, Beaudoin-Bussières G. Cross-sectional evaluation of humoral responses against SARS-CoV-2 Spike. Cell Rep Med 2020, September 29, 2020. Full-text: https://doi.org/10.1016/j.xcrm.2020.100126
Another cross-sectional study on 106 different SARS-CoV-2-infected individuals to evaluate humoral responses against SARS-CoV-2 Spike. The vast majority of infected individuals showed anti-Spike antibodies within 2 weeks after the onset of symptoms. While most individuals develop neutralizing antibodies within two weeks of infection, the level of neutralizing activity significantly decreased over time. Interestingly, anti-RBD IgM presented a stronger correlation with neutralization than IgG and IgA, suggesting that at least part of the neutralizing activity is mediated by IgM. However, it remains unclear whether this reduced level of neutralizing activity would remain sufficient to protect from re-infection.
Burki T. The online anti-vaccine movement in the age of COVID-19. Lancet Digit Health. 2020 Oct;2(10):e504-e505. PubMed: https://pubmed.gov/32984795. Full-text: https://doi.org/10.1016/S2589-7500(20)30227-2
About 31 million people follow anti-vaccine groups on Facebook, with 17 million people subscribing to similar accounts on YouTube. Within a decade, the anti-vaccination movement could overwhelm pro-vaccination voices online. If that came to pass, the consequences would stretch far beyond COVID-19. This article discusses some strategies.
Shrock E, Fujimura E, Kula T, et al. Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity. Science 29 Sep 2020. Full-text: https://doi.org/10.1126/science.abd4250
More on antibody response. This study provides deep serological profiling of 232 COVID-19 patients and 190 pre-COVID-19 era controls, revealing over 800 epitopes in the SARS-CoV-2 proteome, among them 10 epitopes likely recognized by neutralizing antibodies. Pre-existing antibodies in controls recognized SARS-CoV-2 ORF1, while only COVID-19 patients primarily recognized spike and nucleoprotein. A machine learning model predicted SARS-CoV-2 exposure history with 99% sensitivity and 98% specificity. Individuals with more severe COVID-19 exhibited stronger and broader SARS-CoV-2 responses, and weaker antibody responses to prior infections.
Anderson EJ, Rouphael NG, Widge AT, et al. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults. NEJM September 29, 2020. Full-text: https://doi.org/10.1056/NEJMoa2028436
It was high time: a Phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥ 71 years). After the second immunization, serum neutralizing activity was detected in all participants by multiple methods and appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. Adverse events included mostly mild-to-moderate local and systemic adverse events of short duration, which occurred predominantly after the second dose.
Schurink B, Roos E, Radonic T, et al. Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study. Lancet Microbe 2020, published 25 September. Full-text: https://doi.org/10.1016/S2666-5247(20)30144-0
The authors report the full body autopsy results of 21 patients at Amsterdam University Medical Centers (UMC), the Netherlands. In histological analyses of organs (sampled from nine to 21 patients per organ), an extensive inflammatory response was present in the lungs, heart, liver, kidneys, and brain. In the brain, extensive inflammation was detected, which was most pronounced in the olfactory bulbs and medulla oblongata. Their findings also suggest involvement of neutrophil extracellular traps
(NETs) in coagulopathy and prolonged activation of neutrophils in lethal COVID-19, or at least a delayed resolution of these NETs.
Nie J, Li Q, Wu J, et al. Quantification of SARS-CoV-2 neutralizing antibody by a pseudotyped virus-based assay. Nat Protoc 2020, published 25 September. Full-text: https://doi.org/10.1038/s41596-020-0394-5
The authors developed a pseudotyped virus-based neutralization assay against SARS-CoV-2 in biosafety level 2 facilities. The authors caution that experience in handling cells is needed before implementing this protocol.
Pierce CA, Preston-Hurlburt P, Dai Y, et al. Immune responses to SARS-CoV-2 infection in hospitalized pediatric and adult patients. Sci Transl Med. 2020 Sep 21:eabd5487. PubMed: https://pubmed.gov/32958614. Full-text: https://doi.org/10.1126/scitranslmed.abd5487
Compared to adults, pediatric patients have a shorter length of stay in hospital, a decreased requirement for mechanical ventilation and a lower mortality. Now Betsy Herold and Carl Pierce compared cytokine, humoral, and cellular immune responses in pediatric (children and youth, age < 24 years) (n = 65) and adult (n = 60) patients with COVID-19 at a metropolitan hospital system in New York City. Children had higher serum concentrations of IL-17A and IFN-γ which in adult patients decreased progressively with age. Read more about adult T cell responses, serum neutralizing antibody titers and antibody-dependent cellular phagocytosis.
Bastard P, Rosen LB, Zhang Q, et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science 2020, published 24 September. Full-text: https://science.sciencemag.org/content/early/2020/09/23/science.abd4585
In an outstanding paper, Jean-Laurent Casanova, Paul Bastard and colleagues highlight the crucial role of type I IFNs in protective immunity against SARS-CoV-2. The authors report an analysis of 987 patients with life-threatening COVID-19 pneumonia, 663 subjects with asymptomatic or benign SARS-CoV-2 infection and a third group of 1227 healthy volunteers. At least 10% of patients with life-threatening COVID-19 pneumonia had neutralizing auto-Abs against type I IFNs (IFN-ω: 13 patients; the 13 types of IFN-α: 36; both: 52) at the onset of critical disease.
Zhang Q, Bastard P, Liu Z, et al: Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 2020, published 24 September. Full-text: https://science.sciencemag.org/content/early/2020/09/23/science.abd4570
The title almost says it all: there are inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Jean-Laurent Casanova, Qian Zhang and colleagues report enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. The authors suggest that there may be mutations in other type I IFN-related genes in other patients with life-threatening COVID-19 pneumonia. They conclude that the administration of type I IFN might be of therapeutic benefit in selected patients, at least early in the course of SARS-CoV-2 infection.
Read also the comment by Meredith Wadman: Wadman M. Hidden immune weakness found in 14% of gravely ill COVID-19 patients. Science 2020, published 24 September. Full-text: https://www.sciencemag.org/news/2020/09/hidden-immune-weakness-found-14-gravely-ill-covid-19-patients
Huang J, Hume AJ, Abo KM, et al. SARS-CoV-2 Infection of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response. Cell Stem Cell September 18, 2020. Full-text: https://doi.org/10.1016/j.stem.2020.09.013
Jessie Huang and colleagues present an in vitro human model that simulates the initial apical infection of alveolar epithelium with SARS-CoV-2, using induced pluripotent stem cell-derived AT2s that have been adapted to air-liquid interface culture. Their model system reveals cell-intrinsic responses of a key lung target cell to SARS-CoV-2 infection and should facilitate drug development.
Larson D, Brodniak SL, Voegtly LJ, et al. A Case of Early Re-infection with SARS-CoV-2. Clin Infect Dis. 2020 Sep 19:ciaa1436. PubMed: https://pubmed.gov/32949240. Full-text: https://doi.org/10.1093/cid/ciaa1436
The next re-infection. A 42-year-old healthy male military healthcare provider became re-infected only 51 days after resolution of initial infection. Of note, his second infection was more severe, potentially due to immune enhancement, acquisition of a more pathogenic strain, or perhaps a greater inoculum of infection as the second exposure was from within household contacts.
Golinelli D, Boetto E, Maietti E, Fantini MP. The association between ABO blood group and SARS-CoV-2 infection: A meta-analysis. PLoS One 2020 Sep 18;15(9):e0239508. PubMed: https://pubmed.gov/32946531. Full-text: https://doi.org/10.1371/journal.pone.0239508
In this meta-analysis of 7 studies, the authors analyzed the odds of having each blood group among 7503 SARS-CoV-2 positive patients compared with 2,962,160 (!) controls. SARS-CoV-2 positive individuals were more likely to have blood group A (pooled OR 1.23, 95%CI: 1.09–1.40) and less likely to have blood group O (pooled OR = 0.77, 95%CI: 0.67–0.88).
Busch MH, Timmermans SAMEG, Nagy M, et al. Neutrophils and Contact Activation of Coagulation as Potential Drivers of Covid-19. Circulation. 2020 Sep 18. PubMed: https://pubmed.gov/32946302. Full-text: https://doi.org/10.1161/CIRCULATIONAHA.120.050656
Pieter van Paassen and colleagues from Maastricht, Netherlands have performed a comprehensive analysis on the intrinsic pathway of coagulation to characterize its role in COVID-19. By simultaneously studying potential triggers of the intrinsic pathway in 228 patients, the authors were able to identify neutrophils, neutrophil extracellular traps (NETs), and complement activation as potential drivers of this complex immuno-thrombotic disease. This indicates that hypercoagulability and thrombotic events are driven by NETosis, contact activation, and complement. The triangular relationship with its multiple amplifying feedback loops emphasizes therapeutic multiple-target strategies to effectively dampen the immuno-thrombotic response.
Peiris M, Leung GM. What can we expect from first-generation COVID-19 vaccines? Lancet September 21, 2020. Full-text: https://doi.org/10.1016/S0140-6736(20)31976-0
Not much. In their important comment, Malik Peiris and Gabriel M Leung suggest that we cannot assume COVID-19 vaccines, even if shown to be effective in reducing severity of disease, will reduce viral transmission comparably. The notion that COVID-19-vaccine-induced population immunity will allow a return to pre-COVID-19 “normalcy” might be based on illusory assumptions.
Saad-Roy M, Wagner CE, Baker RE, et al. Immune life history, vaccination, and the dynamics of SARS-CoV-2 over the next 5 years. Science 21 Sep 2020: eabd7343. Full-text: https://doi.org/10.1126/science.abd7343
Modelling different protective efficacies and durations of the adaptive immune response to SARS-CoV-2, as well as its interactions with vaccines and non-pharmaceutical interventions, this group from Princeton found that variations in the immune response to primary SARS-CoV-2 infections and a potential vaccine could lead to dramatically different immune landscapes and burdens of critically severe cases, ranging from sustained epidemics to, attention!, near elimination. According to these models, even with imperfect vaccine immunity and moderate vaccination rates, a vaccination may accelerate pandemic control.
Piccoli L, Park YJ, Tortorici MA, et al. Mapping neutralizing and immunodominant sites on the SARS-CoV-2 spike receptor-binding domain by structure-guided high-resolution serology. Cell 2020, published 16 September. Full-text: https://doi.org/10.1016/j.cell.2020.09.037
David Veesler, Luca Piccoli and colleagues provide an extensive analysis of Ab responses to SARS-CoV-2 S, 526 RBD (receptor-binding domain) and N in more than 600 SARS-CoV-2 infected individuals with different clinical outcomes. They found that the SARS-CoV-2 RBD is immunodominant, accounting for 90% of serum neutralizing activity and that RBD antibodies decline with a half-life of ∼50 days. They also identified two major receptor-binding motif antigenic sites. The authors are confident that their results “will guide the design of COVID-19 vaccines and therapeutics”.
Rydyznski Moderbacher C, Ramirez SI, Dan JM, et al. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell 2020, published 16 September. Full-text: https://doi.org/10.1016/j.cell.2020.09.038
Age is a disturbing risk factor in SARS-CoV-2 infection. Here, Shane Crotty, Alessandro Sette, Carolyn Rydyznski Moderbacher and colleagues present a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses. They confirm that the coordination of SARS-CoV-2 antigen-specific responses is disrupted in individuals > 65 years old. Scarcity of naive T cells was also associated with ageing and poor disease outcomes.
Sun Y, Kobe B, Qi J. Targeting multiple epitopes on the spike protein: a new hope for COVID-19 antibody therapy. Sig Transduct Target Ther 5, 208 (2020). https://doi.org/10.1038/s41392-020-00320-6
Do you remember our July 23 entry for Liu L, Wang P, Nair MS, et al. [Potent neutralizing antibodies directed to multiple epitopes on SARS-CoV-2 spike. Nature 2020, published 22 July. Full-text: https://doi.org/10.1038/s41586-020-2571-7]? Find now a detailed description of the paper. The authors conclude that the variety of potent neutralizing monoclonal antibodies against SARS-CoV-2 “inspires optimism that we will be able to find highly effective and safe candidates for clinical treatment of the COVID-19”. Effective mAb cocktail treatments on the horizon?
Jones D, Helmreich S. A history of herd immunity. Lancet 2020, published 19 September. Full-text: https://doi.org/10.1016/S0140-6736(20)31924-3
Do you remember the discussion about herd immunity in March 2020? And one of those who imprudently endorsed the notion who ended up needing intensive care? David Jones and Stefan Helmreich point out that “The language of herd immunity is part of the problem. A herd usually describes domesticated animals, especially livestock. Herd animals like cows, goats, or sheep are sacrificed for human consumption. Few humans want to be part of that kind of herd.” Follow them on voyage through history.
Huang M, Lu Q, Zhao H, et al. Temporal antibody responses to SARS-CoV-2 in patients of coronavirus disease 2019. Cell Discov 6, 64 (2020). https://doi.org/10.1038/s41421-020-00209-2
Wuxiang Guan, Min Huang and colleagues assessed the longitudinal clinical, laboratory, viral, and immunological data from 366 COVID patients. SARS-CoV-2-specific IgM and IgG antibody titer reached the peak levels at 3–4 weeks. The authors predict IgM to last for about two months while IgG titer might diminish 7 months after symptom onset. Patients with older age or severe disease achieved a higher IgG level than patients of younger age and mild disease.
Xi Y. Convalescent plasma therapy for COVID-19: a tried-and-true old strategy? Sig Transduct Target Ther 5, 203 (2020). https://doi.org/10.1038/s41392-020-00310-8
Yongzhi Xi discusses the benefits and challenges of convalescent plasma therapy. One major challenge is the antibody-dependent enhancement (ADE) of viral infection mediated by pre-existing enhancing, non-neutralizing, or sub-neutralizing levels of antibodies from the convalescent plasma administered.
Grant OC, Montgomery D, Ito K, Woods RJ. Analysis of the SARS-CoV-2 spike protein glycan shield reveals implications for immune recognition. Sci Rep 10, 14991 (2020). https://doi.org/10.1038/s41598-020-71748-7
Robert Woods, Oliver Grant and colleagues elucidate the role of glycans which might shield from antibody recognition up to 40% of the underlying protein surface of the S glycoprotein trimer. Could glycans alter the innate or adaptive immune response? And, given that glycan microheterogeneity varies between individuals, and depends on many factors, including age, underlying disease and ethnicity, is this a molecular basis for the observed differential susceptibilities among individuals to SARS-CoV-2 infection?
Edridge AWD, Kaczorowska J, Hoste ACR, et al. Seasonal coronavirus protective immunity is short-lasting. Nat Med (2020). https://doi.org/10.1038/s41591-020-1083-1
If you nurture the secret hope that SARS-CoV-2 immunity will be long-lasting, read this paper by Lia van der Hoek, Arthur Edridge and colleagues. They monitored healthy individuals for more than 35 years, measuring increases in antibodies to the structural coronavirus capsid protein for each seasonal coronavirus (HCoV-NL63, HCoV-229E, HCoV-OC43 and HCoV-HKU1). Reinfection with the same seasonal coronavirus occurred frequently by 12 months after infection.
Huang AT, Garcia-Carreras B, Hitchings MDT, et al. A systematic review of antibody mediated immunity to coronaviruses: kinetics, correlates of protection, and association with severity. Nat Commun 11, 4704 (2020). https://doi.org/10.1038/s41467-020-18450-4
Derek A. T. Cummings, Angkana Huang and colleagues review the scientific literature on antibody immunity to coronaviruses and propose 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. Your 12-page review for the weekend.
Greaney AJ, Starr TN, Gilchuk P, et al. Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition. bioRxiv 2020, posted 10 September. Full-text: https://doi.org/10.1101/2020.09.10.292078
The authors describe a mutational scanning method to map how all amino-acid mutations in the SARS-CoV-2 spike receptor-binding domain (RBD) could prevent binding by ten human antibodies. The complete escape maps might allow for the design of escape-resistant antibody cocktails–including cocktails of antibodies that compete for binding to the same surface of the RBD but have different escape mutations. A surprise finding: antibody cocktails do not have to target distinct regions of the RBD in order to resist viral escape. The paper has not yet been peer reviewed.
Schäfer R, Spohn G, Bechtel M, et al. Human Mesenchymal Stromal Cells are resistant to SARS-CoV-2 Infection under Steady State, Inflammatory Conditions and in the Presence of SARS-CoV-2 infected Cells. Stem Cell Rep September 11, 2020. Full-text: https://doi.org/10.1016/j.stemcr.2020.09.003
Mesenchymal Stem/Stromal Cells (MSC) may ameliorate pulmonary inflammation in ARDS and clinical trials assessing the potential of MSC for COVID-19 treatment are underway. Richard Schäfer and colleagues from Frankfurt show that MSC are resistant to SARS-CoV-2 infection. MSC carry ACE2 and TMPRSS2 only at very low levels on the cell surface and retain their immunomodulation potential supporting their potential applicability for COVID-19 treatment.
Habel JR, Nguyen TH, van de Sandt CE, et al. Suboptimal SARS-CoV-2−specific CD8+ T cell response associated with the prominent HLA-A*02:01 phenotype. PNAS September 10, 2020. Full-text: https://doi.org/10.1073/pnas.2015486117
Jennifer R. Habel and colleagues from Melbourne investigated circulating SARS-CoV-2−specific CD8 T cells from 18 COVID-19 patients. For two HLA-A*02:01 SARS-CoV-2−specific CD8 T cell epitopes, they found that, while ex vivo frequencies of responding T cells were approximately five-fold higher than for pre−COVID-19 samples, they were ∼10-fold lower than for influenza or EBV-specific memory CD8 T cells. Additionally, SARS-CoV-2−specific CD8 T cells recovered from convalescent COVID-19 patients had an atypically high prevalence of stem cell memory, central memory, and naïve phenotypes. This raises questions concerning the integrity of the epitope-specific CD8 T cell response in COVID-19.
Peng Y, Mentzer AJ, Liu G, et al. Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19. Nat Immunol 2020, published 7 September. Full-text: https://doi.org/10.1038/s41590-020-0782-6
Are SARS-CoV-2-specific CD8+ T cells protective? That’s one conclusion of the paper by Tao Dong, Yanchun Peng. After studying T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, the authors found that the proportion of the T cell response attributable to CD8+ (rather than CD4+) T cells was increased in mild cases. They also report a robust and diverse T cell response targeting multiple structural and non-structural regions of SARS-CoV-2 in most resolved cases, irrespective of whether the individual had mild or severe infection (see below, Swadling + Maini 2020). The authors conclude that the identification of non-spike dominant CD8+ T cell epitopes suggests the potential importance of including non-spike proteins such as NP, M and ORFs in future vaccine designs.
See also the comment by Leo Swadling and Mala Maini: [T cells in COVID-19 — united in diversity. Nat Immunol 2020, published 7 September. Full-text: https://doi.org/10.1038/s41590-020-0798-y] they insist that careful delineation of the frequency, specificity, functionality and durability of T cells during COVID-19 is vital to understanding how to use them as biomarkers and targets for immunotherapies or vaccines.
Li W, Schäfer A, Kulkarni SS, et al. High potency of a bivalent human VH domain in SARS-CoV-2 animal models. Cell September 04, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.09.007
Antibody domains and fragments such as VH (heavy chain variable domain, 15 kDa) are attractive antibody formats for candidate therapeutics. They may have better tissue penetration compared to full-sized antibodies. Wei Li and colleagues from Pittsburgh have isolated and screened several VH binders for their affinities, ACE2 competition and stabilities. One of those VHs, ab8, in an Fc (human IgG1, crystallizable fragment) fusion format, showed potent neutralization activity and specificity against SARS-CoV-2 both in vitro and in mice and hamsters, possibly enhanced by its relatively small size.
Cañete PF, Vinuesa CG. COVID-19 makes B cells forget, but T cells remember. Cell, September 04, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.09.013
Based on two papers recently published in Cell (see below, Sekine et al, Kaneko et al.), Pablo F. Cañete and Carola G. Vinuesa speculate in their editorial that although SARS-CoV-2 may blunt long-lived antibody responses, immune memory might still be achieved through virus-specific memory T cells.
Sekine T, Perez-Potti A, Rivera-Ballesteros O, et al. Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. Cell 2020, published 14 August. Full-text: https://www.cell.com/cell/fulltext/S0092-8674(20)31008-4 (see our presentation on 14 August).
Kaneko N, Kuo HH Boucau J, et al. Loss of Bcl-6-expressing T follicular helper cells and germinal centers in COVID-19. Cell August 19, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.08.025 (see our presentation on 20 August).
Nielsen SC, Yang F, Jackson KJ, et al. Human B cell clonal expansion and convergent antibody responses to SARS-CoV-2. Cell Host Microbe September 03, 2020. Full-text: https://doi.org/10.1016/j.chom.2020.09.002
Sandra C.A. Nielsen and colleagues from Stanford analyzed the evolution of the human antibody response to SARS-CoV-2 in detail and over time in 13 COVID-19 patients. They sequenced the immune globulin heavy chain (IGHVs) genes of the B cell antigen receptors (BCRs) and captured the hallmarks of clonal evolution, such as somatic hypermutation (SHM, a programmed process of mutation in the variable regions of immunoglobulin by which the immune system adapts to new foreign elements). After early recruitment of B cells expressing a limited subset of IGHV genes, immune response progresses to a robust polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA sub-classes with limited SHM in the initial weeks of infection. Antibody sequences across SARS-CoV-2 infected patients were convergent, highlighting stereotyped naïve responses to this virus. Notably, some patients had B cell clones expressing convergent IGH to other CoV RBD antibodies. These patients had the highest SARS-CoV RBD antibody IgG levels, suggesting that IGH sequencing data are able to predict the fine specificity of human serological response.
Chan KK, Dorosky D, Sharma P, et al. Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2. Science 04 Sep 2020: Vol. 369, Issue 6508, pp. 1261-1265. Full-text: https://doi.org/10.1126/science.abc0870
By using deep mutagenesis, Kui K. Chan and colleagues have identified mutations in angiotensin-converting enzyme 2 (ACE2, critical for binding of SARS-CoV-2) that increase spike binding across the interaction surface. Their mutational landscape provides a blueprint for understanding the specificity of the interaction between ACE2 and spike. Combining mutations gave ACE2 variants with high affinities that rival those of monoclonal antibodies and a stable dimeric variant showed potent SARS-CoV-2 and -1 neutralization in vitro. In addition, the similarity to the natural receptor may limit the possibility of viral escape.
Kox M, Waalders NJB, Kooistra EJ, Gerretsen J, Pickkers P. Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions. JAMA. 2020 Sep 3. PubMed: https://pubmed.gov/32880615. Full-text: https://doi.org/10.1001/jama.2020.17052
Time to rethink the “cytokine storm”? Matthijs Kox and colleagues from Nijmegen have compared 46 COVID-19 patients with ARDS admitted to their ICU, 66 with septic shock with or without ARDS, 30 out-of-hospital cardiac arrest and 62 patients with multiple trauma. Of note, most cytokine levels were significantly lower in COVID-19 than in septic shock and not higher than in OHCA and trauma patients, suggesting that COVID-19 may not be characterized by the cytokine storm.
Van Elslande J, Vermeersch P, Vandervoort K, et al. Symptomatic SARS-CoV-2 reinfection by a phylogenetically distinct strain. Clinical Infectious Diseases, September 5. Full-text: https://doi.org/10.1093/cid/ciaa1330
A handful of accounts of reinfection — people who recovered from COVID-19, only to test positive for the disease again later — has fed concerns that immunity might be short-lived. Jan Van Elslande and colleagues from Leuven, Belgium present another case. In this 51-year-old woman, re-infection occurred three months later and the illness was milder than the first episode.
Sattler A, Angermair S, Stockmann H, et al. SARS-CoV-2 specific T-cell responses and correlations with COVID-19 patient predisposition. J Clin Invest. 2020 Aug 24:140965. PubMed: https://pubmed.gov/32833687. Full-text: https://doi.org/10.1172/JCI140965
Are there individual factors that determine the successful (or unsuccessful) mounting of an immune response, deciding between life and death? Could altered T cell function put some patients at risk? Here Arne Sattler et al. analyze cellular responses to three viral proteins and suggest a link between individual patient predisposition with respect to age and comorbidity and impairment of CoV-2 specific Th1-type cellular immunity.
Chen X, Pan Z, Yue S, et al. Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19. Sig Transduct Target Ther 5, 180 (2020). Full-text: https://doi.org/10.1038/s41392-020-00301-9
High neutralizing antibody (NAb) capacity in severe cases, no NAbs in asymptomatic patients: In a cohort of 59 recovered patients with various disease severity, Xiangyu Chen and colleagues observed a positive correlation between serum neutralizing capacity and disease severity, revealing the tremendous heterogeneity of SARS-CoV-2-specific NAb responses. Their findings also suggest that the collection of plasma from COVID-19 recovered patients should be restricted to those with moderate to severe symptoms for passive antibody therapy.
Singh M, Bansal V, Feschotte C, et al. A single-cell RNA expression map of human coronavirus entry factors. Cell Reports. September 03, 2020. Full-text: https://doi.org/10.1016/j.celrep.2020.108175
Using single-cell transcriptomics across various healthy human tissues, Manvendra Singh and colleagues have profiled 28 SARS-CoV-2 and coronavirus-associated receptors and factors (SCARFs) that facilitate and/or restrict viral entry. Both pro- and anti-viral factors are highly expressed within the nasal epithelium, with potential age-dependent variation. The data provide a valuable resource for future studies of the basic biology and pathology of SARS-CoV-2 and other coronaviruses. However, the authors urge caution not to overinterpret their findings. The main problem is that SCARF expression within and between individuals is bound to be heavily modulated by genetic and environmental factors, including infection by SARS-CoV-2 and other pathogens.
DeKosky BJ. A molecular trap against COVID-19. Science 04 Sep 2020: Vol. 369, Issue 6508, pp. 1167-1168. Full-text: https://doi.org/10.1126/science.abe0010
The cell surface peptidase angiotensin-converting enzyme 2 (ACE2) is the primary receptor for the spike (S) fusion protein that facilitates cell entry of SARS-CoV-2. This vasopeptidase is expressed on the surface of epithelial cells in many tissues, including the lung, heart, blood vessels, kidneys, and gastrointestinal tract. Brandon J. DeKosky from the University of Kansas gives a great overview on ACE2-mediated viral entry, the growing understanding of ACE2 interaction and potential methods of blocking it.
Lee W, Ahn JH, Park HH et al. COVID-19-activated SREBP2 disturbs cholesterol biosynthesis and leads to cytokine storm. Sig Transduct Target Ther September 3, 2020, 5, 186. Full-text: https://doi.org/10.1038/s41392-020-00292-7
Sterol regulatory element binding proteins (SREBPs) regulate the gene expressions involved in lipid cholesterol biosynthesis. During recent years, it has become increasing clear that SREBPs are involved in immunity/inflammation and several studies have demonstrated the critical importance of SREBP pathway in preventing overproduction of proinflammatory cytokines from macrophages. Wonhwa Lee and colleagues describe here how SREBP-2 is activated by SARS-CoV-2 and show that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing a cytokine storm and lung damage in severe COVID-19 patients.
Gudbjartsson DF, Norddahl GL, Melsted P, et al. Humoral Immune Response to SARS-CoV-2 in Iceland. N Engl J Med 2020, published 1 September. Full-text: https://doi.org/10.1056/NEJMoa2026116
How long will people be protected from reinfection by SARS-CoV-2? Generally, many months, as may be expected from a coronavirus infection. In this study by Kari Stefansson, Daniel Gudbjartsson and colleagues, over 90% of 1,215 qPCR-positive persons tested positive with two pan-Ig SARS-CoV-2 antibody assays and remained seropositive 120 days after diagnosis, with no decrease of antibody levels. Another piece of good news: the infection fatality risk in Iceland was 0.3%. Less good news: only 0.9% of Icelanders were infected with SARS-CoV-2 indicating that the Icelandic population is vulnerable to a second wave of infection.
See also the editorial by Galit Alter and Robert Seder: Alter G, Seder R: The Power of Antibody-Based Surveillance. N Engl J Med 2020, published 1 September. Full-text: https://doi.org/10.1056/NEJMe2028079. In particular, they stress the utility of antibody assays as highly cost-effective alternatives to PCR testing for population-level surveillance, which is critical to the safe reopening of cities and schools.
Varadé J, Magadán S, González-Fernández Á. Human immunology and immunotherapy: main achievements and challenges. Cell Mol Immunol 2020, published 2 September. Full-text: https://doi.org/10.1038/s41423-020-00530-6
The review for your next sleepless night – 18 pages and 332 references. The trio Jezabel Varadé, Susana Magadán and África González-Fernández will take you on a trip to the past and the future of immunotherapy.
Thieme CJ, Anft M, Paniskaki K, et al. Robust T cell response towards spike, membrane, and nucleocapsid SARS-CoV-2 proteins is not associated with recovery in critical COVID-19 patients. Cell Reports Medicine 2020, published 29 August. Full-text: https://doi.org/10.1016/j.xcrm.2020.100092
Nina Babel, Constantin Thieme and colleagues performed a comprehensive characterization of the T cell response against S-, M- and N- SARS-CoV-2 proteins in patients with different COVID-19 severity and unexposed donors. Surprise: the T cell response of critical COVID-19 patients is robust and comparable or even superior to non-critical patients. The authors would thus disprove the hypothesis of insufficient SARS-CoV-2-reactive immunity in critical COVID-19. Expect some intense discussions.
Hunting for antibodies to combat COVID‑19. Biopharma dealmakers 2020, published 1 September. Full-text: https://www.nature.com/articles/d43747-020-01115-y
The development of highly successful monoclonal antibody-based therapies for cancer and immune disorders has created a wealth of expertise and manufacturing capabilities. Is there room for monoclonals for prevention or treatment of severe COVID-19 before the general availability of vaccines and efficient antiviral drugs? Find out how the ‘COVID-19 antibodysphere’ (Amgen, AstraZeneca, Vir, Regeneron, Lilly, Adagio) is building partnerships.
Xu C, Li, H, Flavell RA. A special collection of reviews on frontiers in immunology. Cell Res 2020, published 28 August. Full-text: https://doi.org/10.1038/s41422-020-00403-7
- Direct (tumor) and indirect (micro-environment) modifiers (Jedd Wolchok and colleagues)
- Future directions to reduce the risk of immune-related adverse events (irAEs; Vijay Kurchoo and colleagues)
- Alternative paths to target immune checkpoints in cancer (Chenqi Xu and colleagues)
- Antitumor roles of the cGAS-STING pathway (Zhejian Chen and colleagues)
- Immunometabolism (Hongbo Chi and colleagues)
- Interplay between immune signaling and metabolism (Richard Flavell and colleagues)
- Targeting metabolic intermediates and enzymes in inflammation (Eva Pålsson-McDermott and Luke O’Neill)
- Inflammasome activation (Thirumala-Devi Kanneganti and colleagues)
- ILC development/heterogeneity (Christoph Klose and David Artis)
- Microbiome-immunity crosstalk in the intestine and extra-intestinal organs (Eran Elinav and colleagues)
- Transcriptional and epigenetic basis of Treg cell development and function (Shimon Sakaguchi and Naganari Ohkura)
The papers in detail:
- Murciano-Goroff YR, Warner AB, Wolchok JD. The future of cancer immunotherapy: microenvironment-targeting combinations. Cell Res. 2020 Jun;30(6):507-519. PubMed: https://pubmed.gov/32467593. Full-text: https://doi.org/10.1038/s41422-020-0337-2
- Schnell A, Bod L, Madi A, Kuchroo VK. The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity. Cell Res. 2020 Apr;30(4):285-299. PubMed: https://pubmed.gov/31974523. Full-text: https://doi.org/10.1038/s41422-020-0277-x
- He X, Xu C. Immune checkpoint signaling and cancer immunotherapy. Cell Res. 2020 Aug;30(8):660-669. PubMed: https://pubmed.gov/32467592. Full-text: https://doi.org/10.1038/s41422-020-0343-4
- Yum S, Li M, Chen ZJ. Old dogs, new trick: classic cancer therapies activate cGAS. Cell Res. 2020 Aug;30(8):639-648. PubMed: https://pubmed.gov/32541866. Full-text: https://doi.org/10.1038/s41422-020-0346-1
- Saravia J, Raynor JL, Chapman NM, Lim SA, Chi H. Signaling networks in immunometabolism. Cell Res. 2020 Apr;30(4):328-342. PubMed: https://pubmed.gov/32203134. Full-text: https://doi.org/10.1038/s41422-020-0301-1
- Shyer JA, Flavell RA, Bailis W. Metabolic signaling in T cells. Cell Res. 2020 Aug;30(8):649-659. PubMed: https://pubmed.gov/32709897. Full-text: https://doi.org/10.1038/s41422-020-0379-5
- Pålsson-McDermott EM, O’Neill LAJ. Targeting immunometabolism as an anti-inflammatory strategy. Cell Res. 2020 Apr;30(4):300-314. PubMed: https://pubmed.gov/32132672. Full-text: https://doi.org/10.1038/s41422-020-0291-z
- Christgen S, Place DE, Kanneganti TD. Toward targeting inflammasomes: insights into their regulation and activation. Cell Res. 2020 Apr;30(4):315-327. PubMed: https://pubmed.gov/32152420. Full-text: https://doi.org/10.1038/s41422-020-0295-8
- Klose CSN, Artis D. Innate lymphoid cells control signaling circuits to regulate tissue-specific immunity. Cell Res. 2020 Jun;30(6):475-491. PubMed: https://pubmed.gov/32376911. Full-text: https://doi.org/10.1038/s41422-020-0323-8
- Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020 Jun;30(6):492-506. PubMed: https://pubmed.gov/32433595. Full-text: https://doi.org/10.1038/s41422-020-0332-7
- Ohkura N, Sakaguchi S. Transcriptional and epigenetic basis of Treg cell development and function: its genetic anomalies or variations in autoimmune diseases. Cell Res. 2020 Jun;30(6):465-474. PubMed: https://pubmed.gov/32367041. Full-text: https://doi.org/10.1038/s41422-020-0324-7
Cox RJ, Brokstad KA. Not just antibodies: B cells and T cells mediate immunity to COVID-19. Nat Rev Immunol. 2020 Aug 24:1-2. PubMed: https://pubmed.gov/32839569. Full-text: https://doi.org/10.1038/s41577-020-00436-4
Antibodies to SARS-CoV-2 may be maintained for only a few months, especially in patients with mild COVID-19. No antibodies, no protection? Relax and remember that memory B cells and T cells may be maintained even if there are no measurable levels of serum antibodies. Rebecca Cox and Karl Brokstad outline our current understanding of B cell and T cell immunity to SARS-CoV-2. Will this immunity last forever? Probably not, as has been shown this week by Kwok-Yung Yuen, Kelvin Kai-Wang To and colleagues: COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing). In this case, the first and the second SARS-CoV-2 episodes were just 142 days apart.
Takahashi T, Ellingson MK, Wong P, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature August 26, 2020. Full-text: https://doi.org/10.1038/s41586-020-2700-3
This in-depth analysis performed on 137 COVID-19 patients may provide an explanation for the world-wide observed sex biases (more severe courses and deaths among males). Takehiro Takahashi and colleagues revealed that male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. A poor T cell response negatively correlated with patients’ age and was associated with worse disease outcome in male patients, but not in female patients. Conversely, higher innate immune cytokines were associated with worse disease progression in female patients, but not in male patients.
Bruchez A, Sha K, Johnson J, et al. MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses. Science 27 Aug 2020. Full-text: https://doi.org/10.1126/science.abb3753
CIITA (the major histocompatibility class II transactivator) is a master regulator of the MHC class II genes which are critical for normal immune function. Anna Bruchez, Ky Sha and colleagues show how proteins such as CIITA are involved in host defense against a range of viruses. They also identified an additional function of these proteins beyond their roles in antigen presentation. CIITA induces resistance by activating expression of the p41 isoform of invariant chain CD74, which inhibits viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein. CD74 p41 can also block the endosomal entry pathway of coronaviruses, including SARS-CoV-2.
Fagiani F, Catanzaro M, Lanni C. Molecular features of IGHV3-53-encoded antibodies elicited by SARS-CoV-2. Sig Transduct Target Ther 5, 170 (2020). Full-text: https://doi.org/10.1038/s41392-020-00287-4
Francesca Fagiani, Michele Catanzaro and Cristina Lanni discuss in detail the paper by Yuan et al. we presented on July 14. Remember: Yuan and collaborators analyzed 294 anti-SARS-CoV-2 antibodies from COVID-19 patients and showed that the immunoglobulin heavy variable 3-53 (IGHV3-53) represents the most frequently used IGHV gene. They conclude that the characterization of these IGHV3-53 antibodies is a promising starting point for rational vaccine design.
Crooke SN, Ovsyannikova IG, Kennedy RB et al. Immunoinformatic identification of B cell and T cell epitopes in the SARS-CoV-2 proteome. Sci Rep 10, 14179 (2020). Published 25 August. Full-text: https://doi.org/10.1038/s41598-020-70864-8
Immunoinformatics for T cell and B cell epitopes? Here Gregory Poland, Stephen Crooke and colleagues used a series of open-source algorithms and webtools to analyze the proteome of SARS-CoV-2 and identify putative T cell and B cell epitopes. They identified 41 T cell epitopes (5 HLA class I, 36 HLA class II) and 6 B cell epitopes that could serve as promising targets for peptide-based vaccine development against this emerging global pathogen.
Ejemel M, Li Q, Hou S, et al. A cross-reactive human IgA monoclonal antibody blocks SARS-CoV-2 spike-ACE2 interaction. Nat Commun. 2020 Aug 21;11(1):4198. Full-text: https://doi.org/10.1038/s41467-020-18058-8
Pre- or post-exposure immunotherapies with neutralizing antibodies? Yang Wang, Monir Ejemel and colleagues describe a cross-reactive human IgA monoclonal antibody, termed MAb362, which binds to both SARS-CoV-1 and SARS-CoV-2 Spike proteins and competitively blocks ACE2 receptor binding. When converted to secretory IgA, MAb326 also neutralizes authentic SARS-CoV-2 virus. The authors suggest that such SARS-CoV-2 specific IgA antibodies might provide immunity against SARS-CoV-2 by inducing mucosal immunity within the respiratory system, a potentially critical feature of an effective vaccine.
Lu S, Zhao Y, Yu W, et al. Comparison of nonhuman primates identified the suitable model for COVID-19. Sig Transduct Target Ther 5, 157 (2020). Full-text: https://doi.org/10.1038/s41392-020-00269-6
Within 6 months after SARS-CoV-2 was first reported, five kinds of animals were developed into models to study COVID-19: the mouse, ferret, tree shrew, golden hamster, and a nonhuman primate (NHP) species. Now Xiaozhong Peng, Shuaiyao Lu and colleagues characterized SARS-CoV-2 infection in three NHP models of COVID-19: Old World monkeys Macaca mulatta (M. mulatta) and Macaca fascicularis (M. fascicularis) and New World monkeys Callithrix jacchus (C. jacchus). M. mulatta most closely recapitulated human-like conditions, including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues.
Bunders M, Altfeld M. Implications of sex differences in immunity for SARS-CoV-2 pathogenesis and design of therapeutic interventions. Immunity August 14, 2020. Full-text: https://doi.org/10.1016/j.immuni.2020.08.003
Women show stronger immune responses against pathogens and vaccines, but also in higher susceptibility to autoimmune diseases. But do sex differences in immunity contribute to better control of SARS-CoV-2 in women? In their elegant review, Madeleine Bunders and Marcus Altfeld summarize current knowledge on the basic biological pathways that underlie differences in immune responses between women and men.
Neidleman J, Luo X, Frouard J, et al. SARS-CoV-2-specific T cells exhibit phenotypic features of robust helper function, lack of terminal differentiation, and high proliferative potential. Cell Rep Med 2020, August 19. Full-text: https://doi.org/10.1016/j.xcrm.2020.100081
The phenotypes of SARS-CoV-2-specific T cells remain poorly defined. Jason Neidleman and colleagues conducted an in-depth phenotypic analysis of SARS-CoV-2-specific CD4+ and CD8+ T cells circulating in the bloodstream of nine individuals who had recently recovered from COVID-19. This was achieved by combining detection of specific T cells together with CyTOF, a mass spectrometry-based single-cell phenotyping method that uses antibodies conjugated to metal lanthanides to quantify expression levels of both surface and intracellular proteins. The main results: T cells were diverse, exhibited features different from antigen-specific T cells against CMV, included cells with both lymphoid and tissue homing potential, harbored phenotypic features of functional effector cells, and were long-lived and capable of homeostatic proliferation. The results suggest that long-lived and robust T cell immunity is generated following natural SARS-CoV-2 infection and support an important role for SARS-CoV-2-specific T cells in host control of COVID-19.
Kaneko N, Kuo HH Boucau J, et al. Loss of Bcl-6-expressing T follicular helper cells and germinal centers in COVID-19. Cell August 19, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.08.025
Examining postmortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection, Naoki Kaneko and colleagues from Ragon Institute (Massachusetts, USA) found a striking absence of lymph node and splenic germinal centers and Bcl-6 expressing B cells, defective Bcl-6+ T follicular helper cell generation and differentiation and dysregulated SARS-CoV-2 specific humoral immunity early in COVID-19 disease. According to the authors, the underlying basis for the loss of germinal centers is best explained by the striking failure of differentiation of Bcl-6+ T follicular helper cells likely because of dramatic changes in the extra-follicular cytokine milieu driven by TH1 cells and the aberrant local production of TNF-α in lymphoid organs. Their results provide a mechanistic explanation for the limited durability of humoral immunity and the less robust somatic hypermutation seen in this disease following natural infection.
Guervilly C, Burtey S, Sabatier F, et al. Circulating Endothelial Cells as a Marker of Endothelial Injury in Severe COVID -19. J Infect Dis 19 August 2020, jiaa528, https://doi.org/10.1093/infdis/jiaa528.
In this retrospective study, Christophe Guervilly and colleagues from Marseille measured circulating endothelial cells (CEC) in the blood of 99 patients with COVID-19. Patients in the intensive care units (ICU) had significantly higher CEC counts than non-ICU patients and the extent of endothelial injury was correlated with putative markers of disease severity and inflammatory cytokines. These data provide in vivo evidence that endothelial injury is a key feature of COVID-19.
Young BE, Fong SW Chan YH, et al. Effects of a major deletion in the SARS-CoV-2 genome on the severity of infection and the inflammatory response: an observational cohort study. Lancet 2020, published 18 August. Full-text: https://doi.org/10.1016/S0140-6736(20)31757-8
In January and February 2020, a SARS-CoV-2 variant with a 382-nucleotide deletion (Δ382) in the open reading frame 8 was detected in a cluster of cases in Singapore. Now Lisa Ng, Gavin Smith and colleagues compared the clinical outcomes and immune responses of patients infected with wild type and Δ382 SARS-CoV-2. Of 131 patients enrolled onto the study, 92 (70%) were infected with the wild type virus, ten (8%) had a mix of wild type and ∆382-variant viruses, and 29 (22%) had only the ∆382 variant. Their finding: development of hypoxia requiring supplemental oxygen was less frequent in the ∆382 variant group (0 of 29 patients) than in the wild type only group (26 [28%] of 92). They conclude that “further study of these variants could improve our understanding of SARS-CoV-2 virology and pathogenesis and could have implications for the development of treatments and vaccines.”
Addetia A, Crawford K, Dingens A, et al. Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with high attack rate. medRxiv 2020, posted 14 August. Full-text: https://doi.org/10.1101/2020.08.13.20173161
What are the immunological correlates of protection against SARS-CoV-2? The ongoing Phase III vaccine trials might provide an answer within months. In the meantime, Alexander Greninger and colleagues provide insights into the protective nature of neutralizing antibodies. Their data source? Shipping vessels, “particularly useful candidates for assessing protection from SARS-CoV-2 infection”. Here they report an outbreak of SARS-CoV-2 among 122 crewmembers with an attack rate greater than 85% – a fairly high percentage due to high population density and multiple contacts between people on ships. Preeminently, none of three individuals with pre-existing neutralizing antibodies were infected. (Their neutralizing titers [1:174, 1:161, 1:3082] were in the typical range of titers observed in humans who have been infected with SARS-CoV-2 within the previous few months.) These findings are consistent with data from animal models, in which the elicitation of high titers of neutralizing antibodies was protective against re-challenge with SARS-CoV-2. The paper has not yet been peer reviewed.
Laing AG, Lorenc A, del Molino del Barrio I, et al. A dynamic COVID-19 immune signature includes associations with poor prognosis. Nat Med 2020, published 17 August. Full-text: https://doi.org/10.1038/s41591-020-1038-6
Over the coming months, we will get a clearer view of 1) correlates of immunoprotection, such as virus-specific antibodies that limit disease and 2) correlates of immune dysregulation, such as cytokine over-production that may promote disease. Adrian Hayday, Manu Shankar-Hari and colleagues now explain that collectively, those correlates can compose a core disease-associated immune signature. They identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. One set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. The immune signature is provided as a large dataset supported by an online portal, www.immunophenotype.org,
Carter MJ, Fish M, Jennings A, et al. Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection. Nat Med 2020, published 18 August. Full-text: https://doi.org/10.1038/s41591-020-1054-6
Second article by Manu Shankar-Hari today. He, Shane Tibby and colleagues performed peripheral leukocyte phenotyping in 25 patients with pediatric multisystem inflammatory syndrome in children (MIS-C) temporally associated with SARS-CoV-2. Their data suggest that MIS-C is an immunopathogenic illness distinct from Kawasaki disease.
Gniffke EP, Harrington WE, Dambauskas N, et al. Plasma from recovered COVID-19 subjects inhibits spike protein binding to ACE2 in a microsphere-based inhibition assay. J Infect Dis August 15, 2020. Full-text: https://doi.org/10.1093/infdis/jiaa508
Edward Gniffke and colleagues from Seattle present a microsphere-based flow cytometry assay that quantifies the ability of plasma to inhibit the binding of spike protein to ACE2. This inhibition assay may be broadly useful in routine clinical evaluation of functional immunity in recovered patients (selecting the most potent post-convalescent plasma) and evaluating the functionality of anti-SARS2 antibodies produced in response to vaccines.
Zhang F, Gan R, Zhen Z, et al. Adaptive immune responses to SARS-CoV-2 infection in severe versus mild individuals. Sig Transduct Target Ther 5, 156 (2020). Full-text: https://doi.org/10.1038/s41392-020-00263-y
Zhiwei Huang and colleagues profiled adaptive immune cells of PBMCs from recovered COVID-19 patients with varying disease severity using single-cell RNA and TCR/BCR V(D)J sequencing. They observed multiple differences between severe patients (SPs) and mild/moderate patients (MPs) including TCR and BCR clonal expansion and diversity, isotype distribution of antibody sequences, V(D)J gene segments usage preference, and dysregulation of peripheral blood lymphocyte subsets. Higher levels of BCR clonal expansion and B-cell activation are present in the SP group, indicating that a more robust humoral immune response happens in severe infection. The authors conclude that SPs and MPs may experience different cellular and humoral immune responses, likely related to different degrees of disease severity.
Sekine T, Perez-Potti A, Rivera-Ballesteros O, et al. Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. Cell 2020, published 14 August. Full-text: https://www.cell.com/cell/fulltext/S0092-8674(20)31008-4
SARS-CoV-2-specific memory T cells will probably be critical for long-term immune protection. In this Cell paper, Marcus Buggert and colleagues mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19. They found that 1) acute phase SARS-CoV-2-specific T cells display an activated cytotoxic phenotype; 2) vs broad and polyfunctional SARS-CoV-2-specific T cell responses in convalescent phase; and 3) SARS-CoV-2-specific T cell responses are detectable even in seronegative individuals. The fact that many individuals with asymptomatic or mild COVID-19, after SARS-CoV-2 exposure or infection, generated highly durable and functionally replete memory T cell responses, not uncommonly even in the absence of detectable humoral responses, suggests that natural exposure or infection could prevent recurrent episodes of severe COVID-19.
Zhang J, Wang X, Xing X, et al. Single-cell landscape of immunological responses in patients with COVID-19. Nat Immunol 2020, published 12 August. Full-text: https://doi.org/10.1038/s41590-020-0762-x
Fu-Sheng Wang and colleagues profiled the immunological response landscape in 13 patients with COVID-19 at single-cell resolution, illustrating the dynamic nature of cellular responses during disease progression. First, patients with COVID-19 showed a concerted and strong IFN-α response, an overall acute inflammatory response and an enhanced migration ability. Second, broad immune activation was observed in patients with COVID-19, evidenced by increased proportions of activated T, pro T and plasma B cells. Third, the proportions of active state T cell clusters were significantly higher in patients with COVID-19 and with a preferential enrichment of effector T cell subsets, such as CD4+ effector-GNLY, CD8+ effector-GNLY and NKT CD160 cells in moderate patients and an NKT CD56 subset in severe patients. Finally, at the early phase of convalescence, the state of the immune system was not fully restored. How long will it take to achieve full immune recovery after COVID-19?
Grajales-Reyes GE, Colonna M. Interferon responses in viral pneumonias. Science 07 Aug 2020: Vol. 369, Issue 6504, pp. 626-627. Full-text: https://science.sciencemag.org/content/369/6504/626
IFNs are important cytokines of the innate and adaptive immune system and are classified into three main types: I (α or β), II (γ), and III (λ). This perspective summarizes the complexity of IFN responses in SARS-CoV-2 infection. Research is needed to establish whether IFN-λ and type I IFNs have similar effects or whether one is more beneficial or detrimental than the other. It should be conclusively established whether type I IFN responses are augmented in the lungs of COVID-19 patients in contrast to the suppressed type I IFN responses observed in the blood. Further research will be necessary to determine whether suppression of blood type I IFN in critically ill COVID-19 patients is due to the ability of SARS-CoV-2 proteins to interfere with IFN signaling.
Guo C, Li B, Ma H, et al. Single-cell analysis of two severe COVID-19 patients reveals a monocyte-associated and tocilizumab-responding cytokine storm. Nat Commun. 2020 Aug 6;11(1):3924. PubMed: https://pubmed.gov/32764665. Full-text: https://doi.org/10.1038/s41467-020-17834-w
In this study, Kun Qu and colleagues profiled the single-cell transcriptomes of 13,239 peripheral blood mononuclear cells (PBMCs) isolated prior to and following tocilizumab-induced remission. They identified a severe stage-specific monocyte subpopulation that contributed to the inflammatory cytokine storm in patients. Although tocilizumab treatment attenuated the inflammation, immune cells, including plasma B cells and CD8+ T cells, still exhibited robust humoral and cellular antiviral immune responses.
Cohen J. Designer antibodies could battle COVID-19 before vaccines arrive. Science 2020, published 4 August. Full-text: https://www.sciencemag.org/news/2020/08/designer-antibodies-could-battle-covid-19-vaccines-arrive
Science writer Jon Cohen describes how the competition is heating up to produce targeted monoclonal antibodies which could both prevent and treat COVID-19. Read about treatment and prevention trials, antibody cocktails and the role monoclonal antibodies might play even after the general availability of effective vaccines. Read also about the final problem of monoclonal antibodies: their cost, especially for the higher doses needed for treatment. Don’t expect monoclonals to be affordable globally. Rather, they might split the world into the haves and have-nots, like many previous drugs. That’s another reason why accessible vaccines are so important!
Hadjadj J, Yatim N, Barnabei L, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020 Aug 7;369(6504):718-724. PubMed: https://pubmed.gov/32661059. Full-text: https://doi.org/10.1126/science.abc6027
Interferons (IFNs) play an important role in the inhibition of viral replication. After performing an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity, Benjamin Terrier and colleagues observed a distinct phenotype in severe and critical patients. These patients had a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. The authors propose that type I IFN deficiency is a hallmark of severe COVID-19 and infer that severe COVID-19 patients might be relieved from the IFN deficiency through IFN administration and from exacerbated inflammation through anti-inflammatory therapies that target IL-6 or TNF-α.
See also the comment by Gary Grajales-Reyes and Marco Colonna. Interferon responses in viral pneumonias. Science 2020; 369: 626-627. Full-text: https://science.sciencemag.org/content/369/6504/626
Rodriguez, L, Pekkarinen, PT, Lakshmikanth, T, et al. Systems-level immunomonitoring from acute to recovery phase of severe COVID-19. Cell Rep Med 2020, published 5 August. Full-text: https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(20)30099-9
To treat hyperinflammation in severe COVID-19 we need to better understand which cells are involved, how they interact and which protein mediators they use to orchestrate their responses. To this end, Petter Brodin and colleagues followed 37 adult patients diagnosed with COVID-19 from the acute to the recovery phases of the disease and performed longitudinal systems-level blood immunomonitoring. They describe an IFNγ – eosinophil axis activated prior to lung hyperinflammation and changes in cell-cell coregulation during different stages of the disease.
Schulte-Schrepping J, Reusch N, Paclik D, et al. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell August 05, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.08.001
This German study revealed profound alterations in the myeloid cell compartment associated with severe COVID-19. By combining single-cell RNA-sequencing and single-cell proteomics of whole blood and peripheral blood mononuclear cells, Joachim Schultze and colleagues determined changes in immune cell composition and activation in mild versus severe COVID-19 cases (n = 109) over time. HLA-DRhiCD11chi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DRlo monocytes.
Silvin A, Chapuis N, Dunsmore G, et al. Elevated calprotectin and abnormal myeloid cell subsets discriminate severe from mild COVID-19. Published: August 05, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.08.002
Performing high dimensional flow cytometry and single cell RNA sequencing of COVID-19 patients, Eric Solary, Michaela Fontenay, Florent Ginhoux and colleagues found that severe COVID-19 was associated with a burst of circulating calprotectin that preceded cytokine release syndrome, low levels of non-classical monocytes in the peripheral blood, and an emergency myelopoiesis that releases immature and dysplastic myeloid cells with an immune suppressive phenotype. This work provides further rationale for the testing of several clinical strategies, including blocking emergency myelopoiesis.
Zhou R, Wang KK, Wong YC, et al. Acute SARS-CoV-2 infection impairs dendritic cell and T cell responses. Immunology August 03, 2020. Full-text: https://doi.org/10.1016/j.immuni.2020.07.026
More insights on T cell immunity. By investigating 17 acute and 24 convalescent patients, the authors found that acute infection resulted in broad immune cell reduction including T, NK, monocyte and dendritic cells (DC). DCs were significantly reduced with functional impairment. Neutralizing antibodies were rapidly and abundantly generated in patients, there were delayed receptor binding domain (RBD)- and nucleocapsid protein (NP)-specific T cell responses during the first 3 weeks post symptom onset. These findings provide evidence that impaired DCs, together with timely inverted strong antibody but weak CD8 T cell responses, may contribute to acute COVID-19 pathogenesis.
Mateus J, Grifoni A, Tarke A, et al. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science 2020, published 4 August. Full-text: https://science.sciencemag.org/content/early/2020/08/03/science.abd3871
SARS-CoV-2 reactive CD4+ T cells have been reported in unexposed individuals, suggesting pre-existing cross-reactive T cell memory in 20-50% of people (see, for example, SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19, presented here on 29 July). To investigate this exciting topic, Daniela Weiskopf, Alessandro Sette and colleagues utilized PBMC samples from subjects collected between March 2015 and March 2018. They demonstrate a range of pre-existing memory CD4+ T cells that are cross-reactive with comparable affinity to SARS-CoV-2 and the common cold coronaviruses HCoV-OC43, HCoV-229E, HCoV-NL63, or HCoV-HKU1. Based on these data, the authors find plausible to hypothesize that pre-existing cross-reactive HCoV CD4+ T cell memory could explain different COVID-19 clinical outcomes and influence epidemiological models of herd immunity. However, their last sentence includes a warning: it’s still highly speculative.
Atyeo C, Fischinger S, Zohar T, et al. Distinct early serological signatures track with SARS-CoV-2 survival. Immunity 2020, published 30 July. Abstract: https://www.cell.com/immunity/fulltext/S1074-7613(20)30327-7. Full-text: https://doi.org/10.1016/j.immuni.2020.07.020 | See also the graphical abstract: https://marlin-prod.literatumonline.com/cms/attachment/81258201-9c39-4b95-8a3d-bcb279d1e8c2/fx1.jpg
It still remains unclear why some individuals recover from infection while others rapidly progress and die. In order to investigate whether early SARS-CoV-2-specific humoral immune responses differ across individuals that ultimately recover or die from infection, Galit Alter, Helen Chu and colleagues profiled SARS-CoV-2–specific humoral responses on a small cohort of 22 hospitalized individuals and found that a combination of five SARS-CoV-2-specific antibody measurements were sufficient to distinguish individuals with different disease trajectories, including antibody measurements to S and N. In particular, spike–specific humoral responses were enriched among convalescent individuals, whereas functional antibody responses to the nucleocapsid were elevated in deceased individuals. This immunodominant S-specific antibody profile in convalescents was confirmed in a larger validation cohort. The authors suggest the potential of functional antigen-specific humoral immunity to guide patient care and vaccine development.
Lei X, Dong X, Ma R, et al. Activation and evasion of type I interferon responses by SARS-CoV-2. Nat Commun 11, 3810 (2020). Full-text: https://doi.org/10.1038/s41467-020-17665-9
The interplay and antagonism between SARS-CoV-2 and host innate immunity determine the clinical outcome of COVID-19. Now Jiang Wei and colleagues show that SARS-CoV-2 perturbs the host innate immune response both via its structural and nonstructural proteins. They reveal that SARS-CoV-2 induces an aberrant type I IFN response in cultured cells, with expressions of IFN-β and ISG56 being barely induced early during viral infection, and suggest that this delayed antiviral response might provide a window for virus replication. They also found that IFN-β treatment effectively blocks SARS-CoV-2 replication.
Braun J, Loyal L, Frentsch M, et al. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature 2020, published 29 July. Full-text: https://doi.org/10.1038/s41586-020-2598-9
Induction of SARS-CoV-2-specific CD4+ T cells is likely to be critical in the instruction of potentially protective antibody responses. Andreas Thiel, Leif-Erik Sander, Claudia Giesecke-Thiel and colleagues therefore investigated SARS-CoV-2 spike glycoprotein (S)-reactive CD4+ T cells in peripheral blood of patients with COVID-19 and SARS-CoV-2-unexposed healthy donors (HD). Surprise: they detected SARS-CoV-2 S-reactive CD4+ T cells in 83% of patients with COVID-19 but also in 35% of unexposed HD. These data raise the intriguing possibility that pre-SARS-CoV-2 S-reactive T cells represent cross-reactive clones, probably acquired during previous infections with endemic human coronaviruses (HCoVs) such as 229E and OC43. The biological role of such pre-existing S-cross-reactive CD4+ T cells in 35% of HD still remains unclear. However, assuming that these cells have a protective role in SARS-CoV-2 infection, they may contribute to divergent manifestations of COVID-19 and explain the resilience of children and young adults to symptomatic SARS-CoV-2 infection (more frequent social contacts than people from older age groups and thus a higher HCoV prevalence). This hypothesis remains to be validated in larger cohorts. The authors don’t forget to underline that the presence of S-cross-reactive T cells in a sizable fraction of the general population may have important implications for the design and analysis of upcoming COVID-19 vaccine trials.
Chen Z, John Wherry E. T cell responses in patients with COVID-19. Nat Rev Immunol 2020, published 29 July. Full-text: https://doi.org/10.1038/s41577-020-0402-6
Will T cells provide long-term protection from reinfection with SARS-CoV-2? Nobody knows yet. Now Zeyu Chen and E. John Wherry from Philadelphia review recent studies which have shed light on T cell responses to SARS-CoV-2 infection. Accumulating evidence supports a role for T cells in COVID-19 and probably in the immunological memory after SARS-CoV-2 infection. Multiple distinct patterns of T cell response may exist in different patients and the authors suggest that the possibility of distinct clinical approaches may one day be tailored to the particular immunotype of a specific patient.
Lucas C, Wong P, Klein J, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. 2020 Jul 27. PubMed: https://pubmed.gov/32717743. Full-text: https://doi.org/10.1038/s41586-020-2588-y
Akiko Iwasaki and colleagues serially analyzed the immune responses in 113 COVID-19 patients with moderate (non-ICU) and severe (ICU) disease. Following an early increase in cytokines, COVID-19 patients with moderate disease displayed a progressive reduction in type 1 (antiviral) and type 3 (antifungal) responses. In contrast, patients with severe disease maintained these elevated responses throughout the course of disease. Moreover, severe disease was accompanied by an increase in multiple type 2 (anti-helminths) effectors including, IL-5, IL-13, IgE and eosinophils. The authors identified four immune signatures, representing
- growth factors
- type 2/3 cytokines
- mixed type 1/2/3 cytokines
which correlated with three distinct disease trajectories in patients. These differences in the expression of inflammatory markers along disease progression between patients who exhibit moderate vs. severe COVID-19 symptoms may provide opportunities for targeted treatment.
Weisblum Y, Schmidt F, Zhang F, et al. Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. bioRxiv 2020, posted 22 July. Full-text: https://doi.org/10.1101/2020.07.21.214759 | Not yet peer reviewed.
Will SARS-CoV-2 adapt over time and evade neutralizing antibodies? Theodora Hatziioannou, Paul Bieniasz and colleagues at Rockefeller University made an animal virus produce the SARS-CoV-2 spike protein. When grown in the presence of neutralizing antibodies, functional SARS-CoV-2 spike protein variants with mutations in the receptor binding domain (RBD) and N-terminal domain that conferred resistance to monoclonal antibodies or convalescent plasma could be readily selected. Monoclonal antibodies, if one day used as treatment for COVID-19, will probably need to be designed as cocktails of multiple neutralizing antibodies which target distinct neutralizing epitopes.
Simon D, Tascilar K, Krönke G, et alPatients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion. Nat Commun 11, 3774 (2020). Full-text: https://doi.org/10.1038/s41467-020-17703-6
Might cytokine inhibitors be partially protective against the effects of SARS-CoV-2 infection? That’s what Georg Schett and colleagues from the University of Erlangen, Germany, are suggesting. They analyzed 534 patients who received continuous cytokine blockade for immune-mediated inflammatory diseases (IMIDs) of the joints, gut and skin (i.e., rheumatoid arthritis, spondyloarthritis, inflammatory bowel disease, psoriasis); 259 patients with IMIDs receiving no cytokine inhibition (n = 259); 285 health care professionals involved in the treatment of these patients; and 971 healthy controls from the same region. The authors conclude that patients with IMIDs receiving cytokine inhibitors may have a lower risk for SARS-CoV-2 infection than IMID patients not receiving such drugs or the general community.
|n||SARS-CoV-2 IgG+ (n)||SARS-CoV-2
|IMID*, no cytokine blockade||259||8||3.09%
|IMID*, continuous cytokine blockade||534||4||0.75%
* Immune-mediated inflammatory diseases of the joints, gut and skin (i.e., rheumatoid arthritis, spondyloarthritis, inflammatory bowel disease, psoriasis)
Yang L, Liu S, Liu J, et al. COVID-19: immunopathogenesis and Immunotherapeutics. Sig Transduct Target Ther 5, 128 (2020). Full-text: https://doi.org/10.1038/s41392-020-00243-2
Six pages and 79 references – the ideal weekend read. Zhang and colleagues try and elucidate the mechanisms underlying immune abnormalities in patients with COVID-19. In addition to using potent antiviral drugs (which are still beyond the horizon), the successful management of clinical COVID-19 will include enhancing anti-viral immunity and inhibiting systemic inflammation.
Hsieh CL, Goldsmith JA, Schaub M, et al. Structure-based design of prefusion-stabilized SARS-CoV-2 spikes. Science, 23 Jul 2020. Full-text: https://doi.org/10.1126/science.abd0826
High-yield production of a stabilized prefusion spike protein will accelerate the development of vaccines and serological diagnostics for SARS-CoV-2. After characterizing 100 structure-guided spike designs and 26 individual substitutions that increased protein yields and stability, the authors identified a promising variant, HexaPro, which contained four beneficial proline substitutions (F817P, A892P, A899P, A942P) as well as the two proline substitutions of previously described prefusion spikes. HexaPro had the ability to withstand heat stress, storage at room temperature, and three freeze-thaw cycles. The authors anticipate that “the high yield and enhanced stability of HexaPro should enable industrial production of subunit vaccines and could also improve DNA or mRNA-based vaccines by producing more antigen per nucleic acid molecule, thus improving efficacy at the same dose or maintaining efficacy at lower doses.”
Lv Z, Deng YQ, Ye Q, et al. Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody. Science 23 Jul 2020: eabc5881. Full-text: Full-text: https://doi.org/10.1126/science.abc5881
The authors report a humanized monoclonal antibody, H014, which neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nanomolar level by engaging the S receptor binding domain. In the hACE2 mouse model, H014 reduced SARS-CoV-2 titers in the infected lungs and prevented pulmonary pathology. H014 seems to prevent attachment of SARS-CoV-2 to its host cell receptors. The authors are hopeful that antibody-based therapeutic interventions might play a key role in the treatment of COVID-19.
Horton R. Offline: Preparing for a vaccine against COVID-19. Lancet, July 25, 2020. Full-text: https://doi.org/10.1016/S0140-6736(20)31636-6
The British ChAdOx1 nCoV-19, the Chinese adenovirus type-5-vector vaccine and the American mRNA-1273 “give great encouragement to the view” that a vaccine can be produced within the next 18 months. But there are reasons for anxiety. Richard Horton takes you on a 3-minute tour.
Liu L, Wang P, Nair MS, et al. Potent neutralizing antibodies directed to multiple epitopes on SARS-CoV-2 spike. Nature (2020). Published: 22 July. Full-text: https://doi.org/10.1038/s41586-020-2571-7
A group of researchers including Yaoxing Huang, Lawrence Shapiro and David D. Ho report the isolation of 61 SARS-CoV-2-neutralizing monoclonal antibodies from 5 infected patients hospitalized with severe disease. Among these are 19 antibodies that potently neutralized the authentic SARS-CoV-2 in vitro, 9 of which exhibited exquisite potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng/mL. The list of findings grows. A must-read!
(David H. Ho will remind senior scientists of studies published in the 90’s about HIV and AIDS (see pubmed.gov/10341272, pubmed.gov/10577640, pubmed.gov/11018071, pubmed.gov/15781098, pubmed.gov/16890836, among several hundred other publications). In 2001, he was presented with the Presidential Citizens Medal by President Clinton.)
Li J, Guo M, Tian X et al. Virus-host interactome and proteomic survey of PBMCs from COVID-19 patients reveal potential virulence factors influencing SARS-CoV-2 pathogenesis. Cell Med, published July 21, 2020. Full-text: https://doi.org/10.1016/j.medj.2020.07.002
- Genome-wide screens identify 58 binary interactions between 29 SARS-CoV-2 proteins
- Virus-host interactome identifies 286 host targets for SARS-CoV-2 proteins
- Quantitative analysis depicts the overall proteome signature in COVID-19 PBMCs
- Nsp10 targets NKRF to facilitate IL-8 induction
Zhu L, Yang P, Zhao Y, et al. Single-cell sequencing of peripheral blood mononuclear cells reveals distinct immune response landscapes of COVID-19 and influenza patients. Immunity, published July 19, 2020. Web: https://www.cell.com/immunity/fulltext/S1074-7613(20)30316-2. Full-text: https://doi.org/10.1016/j.immuni.2020.07.009
The authors report the single-cell transcriptional landscape of longitudinally collected peripheral blood mononuclear cells (PBMCs) in both COVID-19 and influenza A virus (IAV)-infected patients. COVID-19 (STAT1 and IRF3) and IAV (STAT3 and NFκB) activate distinct signaling.
Fischer B, Knabbe C, Vollmer T. SARS-CoV-2 IgG seroprevalence in blood donors located in three different federal states, Germany, March to June 2020. Euro Surveill. 2020;25(28), published 16 July 2020. Full-text: https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.28.2001285
Bad news for German herd immunity. In 3,186 regular blood donors in three German federal states, the seroprevalence of IgG SARS-CoV-2 antibodies was 0.91% overall, ranging from 0.66% in Hesse to 1.22% in Lower-Saxony. 99% of Germans have no specific immunity against SARS-CoV-2 infection.
Li Q, Wu J, Nie J, et al. The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity. Cell July 17, 2020 Full-text: https://doi.org/10.1016/j.cell.2020.07.012
This work may be of high relevance for antibody and vaccine development. The authors investigated 80 variants and 26 glycosylation site modifications of the spike protein of SARS-CoV-2 for the infectivity and reactivity to a panel of neutralizing antibodies and sera from convalescent patients. D614G, along with several variants containing both D614G and another amino acid change, were significantly more infectious. Most variants and the majority of glycosylation deletions were less infectious. However, some variants and N234Q glycosylation were markedly resistant to neutralizing antibodies.
Codo AC, Davanzo GG, de Brito Monteiro L, et al. Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis dependent axis. Cell Metabolism July 17, 2020. Full-text: https://doi.org/10.1016/j.cmet.2020.07.007
Why diabetes is bad (if uncontrolled). Elevated glucose levels directly induce viral replication and pro-inflammatory cytokine expression. Glycolytic flux is required for CoV-2 replication. Virus-induced mtROS production stabilizes HIF-1α, which in turn upregulates glycolytic genes and IL-1β expression. These data may explain why uncontrolled diabetes is a risk factor for severe COVID-19. The mtROS/HIF-1α/glycolysis-axis could be a treatment target.
Sariol A, Perlman S. Lessons for COVID-19 immunity from other coronavirus infections. Immunity July 14, 2020. Full-text: https://doi.org/10.1016/j.immuni.2020.07.005
In this comprehensive review, these two researchers describe the immune responses to other coronaviruses and discuss their relevance to the SARS-CoV-2 immune response. They also address crucial questions for COVID-19 immunity.
Hadjadj J, Yatim N, Barnabei L. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 13 Jul 2020. Full-text: https://doi.org/10.1126/science.abc6027
Not the first, but the largest study to date, analyzing the integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. The picture is clearer now: SARS-CoV-2 infection is characterized by an absence of circulating IFN-β with all disease-severity grades. In addition, most severe COVID-19 patients display impaired IFN-α production that is associated with lower viral clearance and an exacerbated inflammatory response. Inflammation is partially driven by the transcriptional factor NF-κB and characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling.
Ovsyannikova IG, Haralambieva IH, Crooke SN, Poland GA, Kennedy RB. The role of host genetics in the immune response to SARS-CoV-2 and COVID-19 susceptibility and severity. Immunol Rev. 2020 Jul 13. PubMed: https://pubmed.gov/32658335 . Full-text: https://doi.org/10.1111/imr.12897
Individuals in the population harbor single nucleotide polymorphisms (SNPs) across a variety of genes (eg, ACE2, TMPRSS2, HLA, CD147, MIF, IFNG, IL6) that have been implicated in the pathology and immunology of SARS-CoV-2 and other pathogenic coronaviruses. This well-written review gives an overview on current knowledge on host factors involved in coronavirus infections and proposes a large research agenda.
Yuan M, Liu H, Wu NC, et al. Structural basis of a shared antibody response to SARS-CoV-2. Science 13 Jul 2020. Full-text: https://doi.org/10.1126/science.abd2321
Among 294 anti-SARS-CoV-2 antibodies, IGHV3-53 was the most frequently used IGHV gene for targeting the receptor-binding domain (RBD) of the spike protein. Co-crystal structures of two IGHV3-53 neutralizing antibodies with RBD revealed that the germline-encoded residues dominate recognition of the ACE2 binding site. These IGHV3-53 antibodies show minimal affinity for maturation and high potency, which is promising for vaccine design.
Lee JS, Park S, Jeong W, et al. Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19. Science Immunology 10 Jul 2020: Vol. 5, Issue 49. Full-text: https://doi.org/10.1126/sciimmunol.abd1554
Delayed IFN-I response contributes to pathological inflammation whereas early IFN-I response controls viral replication. The authors performed single-cell RNA-seq using tens of thousands of peripheral blood mononuclear cells (PBMCs) obtained from 4 healthy donors, 8 patients with mild or severe COVID-19, and 5 patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly up-regulation of the TNF/IL-1β-driven inflammatory response as compared to severe influenza. The IFN-I response might contribute to the hyper-inflammatory response by potentiating TNF/IL-1β-driven inflammation in severe progression of COVID-19.
Zost SJ, Gilchuk P, Chen RE et al. Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein. Nat Med Jul 10, 2020. Full-text: https://doi.org/10.1038/s41591-020-0998-x
Using a rapid antibody discovery platform, the authors isolated hundreds of human monoclonal antibodies (mAbs) against the SARS-CoV-2 spike protein. Antibodies could be grouped into five binding patterns on the basis of domain recognition and cross-reactivity. There were 178 mAbs that recognized the RBD domain and 43 that recognized the NTD domain. Most of the neutralizing antibodies (67/70) mapped to the RBD, revealing the RBD to be the principal site of vulnerability for SARS-CoV-2 neutralization.
O’Callaghan KP, Blatz AM, Offit PA. Developing a SARS-CoV-2 Vaccine at Warp Speed. JAMA, July 6, 2020. Full-text: https://doi.org/10.1001/jama.2020.12190
In this Viewpoint, the authors describe the the five currently leading vaccine candidates, all of which are aimed at inducing antibodies directed against the receptor-binding domain of the surface spike S protein of SARS-CoV-2. These vaccine candidates are messenger RNA-based (Moderna, Pfizer), recombinant vesicular stomatitis virus vectored (MSD) and adenovirus replication-defective vectored (Johnson & Johnson, AstraZeneca). All 5 candidates are undergoing rigorous investigation of their safety profile, including unintended adverse events.
Case JB, Rothlauf PW, Chen RE, et al. Neutralizing antibody and soluble ACE2 inhibition of a replication-competent VSV-SARS-CoV-2 and a clinical isolate of SARS-CoV-2. Cell Host Microbe July 01, 2020. Full-text: https://doi.org/10.1016/j.chom.2020.06.021
Using an infectious molecular clone of vesicular stomatitis virus (VSV), researchers replaced the glycoprotein gene (G) with the spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and developed a high-throughput imaging-based neutralization assay at biosafety level 2. This provides a tool for testing inhibitors of SARS-CoV-2 mediated entry under reduced biosafety containment.
Dieterle EM, Haslwater D, Bortz RH, et al. A replication-competent vesicular stomatitis virus for studies of SARS-CoV-2 spike-mediated cell entry and its inhibition. Cell July 01, 2020. Full-text: https://doi.org/10.1016/j.chom.2020.06.020
Same direction. This group from the Albert Einstein College in New York have also generated a highly infectious recombinant VSV bearing the SARS-CoV-2 spike glycoprotein S as its sole entry glycoprotein and show that this recombinant virus, rVSV-SARS-CoV-2 S, closely resembles SARS-CoV-2 in its entry-related properties. Another step towards robust, scalable, and readily deployable surrogate viral assays to screen antiviral humoral responses, define correlates of immune protection, and down-select candidate antivirals.
Deng W, Bao L, Liu J, et al. Primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques. Science 02 Jul 2020. Full-text: https://doi.org/10.1126/science.abc5343
Four rhesus macaques were re-challenged intratracheally with the same dose of the SARS-CoV-2 strain at 28 days post-initial challenge with the identical SARS-CoV-2 strain. Animals did not show detectable viral dissemination, clinical manifestations of viral disease, or histopathological changes. Comparing the humoral and cellular immunity between primary infection and rechallenge revealed notably enhanced neutralizing antibody and immune responses.
Cohen Jذ. The line is forming for a COVID-19 vaccine. Who should be at the front? Science Mag 2020, June 29. Full-text: https://www.sciencemag.org/news/2020/06/line-forming-covid-19-vaccine-who-should-be-front
Even if the optimists are right and a COVID-19 vaccine is approved for widespread use as early as this fall, it is likely to be in short supply at first. This article summarizes WHO’s and CDC’s plans to deal with this problem. For the US, a top tier includes 12 million people referred to as “critical health care and other workers,” with the first doses going to a subset of these people who are the “highest risk medical, national security, and other essential workers”. Tiers two and three would include 110 million people who also work in health care and other essential jobs, or are in these groups: 65 and older, living in long-term care facilities, or those with medical conditions known to increase the risk of developing severe COVID-19. And then everyone else.
Sokolowska M, Lukasik Z, Agache I, et al. Immunology of COVID-19: mechanisms, clinical outcome, diagnostics and perspectives – a report of the European Academy of Allergy and Clinical Immunology (EAACI). Allergy. 2020 Jun 25. PubMed: https://pubmed.gov/32584441. Full-text: https://doi.org/10.1111/all.14462
Experts in basic and clinical immunology have joined forces to provide a consensus report on the basic molecular and immune mechanisms associated with susceptibility, clinical presentations and severity of COVID-19. This report summarizes current immunological data, including the differences between adequate innate and adaptive immune response in mild disease and the deep immune dysfunction in the more severe multi-organ disease.
Song JW, Lam SM, Fan X, et al. Omics-driven systems interrogation of metabolic dysregulation in COVID-19 pathogenesis. Cell Metabolism June 24, 2020. Full-text: https://doi.org/10.1016/j.cmet.2020.06.016
To date, the largest quantitative repository on the plasma lipidome and metabolome distinctly associated with COVID-19. Evaluation of metabolic pathway alterations based on differential correlation network analyses, highlighting two lipid modules possibly implicated in COVID-19 pathogenesis.
Tong M, Jiang Y, Xia D, et al. Elevated Serum Endothelial Cell Adhesion Molecules Expression in COVID-19 Patients. J Inf Dis, 25 June 2020. Full-text: https://doi.org/10.1093/infdis/jiaa349
A small but important retrospective study of 39 COVID-19 patients and 32 control participants, examining the expression of endothelial cell adhesion molecules by enzyme-linked immunosorbent assays (ELISA). Serum levels of fractalkine, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and vascular adhesion protein-1 were elevated in mild patients, elevated dramatically in severe cases, while decreased in the convalescence phase. The increased expression may contribute to coagulation dysfunction.
Barnes CO, West Jr AP, Huey-Tubman KE. Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies. Cell June 23, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.06.025
Incredible work, providing a glimpse (67 pages!) into diverse antibody responses in neutralizing plasmas from donors who recovered from COVID-19. Polyclonal plasma IgGs exhibited different degrees of cross-reactive binding between S proteins from SARS-CoV-2, SARS-CoV, and MERS-CoV and showed that the plasma IgGs also included non-cross-reactive antibodies against common cold virus RBDs. By mapping SARS-CoV-2 S epitopes targeted by convalescent plasma IgGs, the authors not only observed the expected targeting of the S protein RBD, but also discovered an S1A epitope outside of the RBD, which may represent an alternative binding site for neutralizing antibodies.
Yang D, Chu H, Hou Y, et al. Attenuated interferon and pro-inflammatory response in SARS-CoV-2-infected human dendritic cells is associated with viral antagonism of STAT1 phosphorylation. J Infect Dis. 2020 Jun 21:jiaa356. PubMed: https://pubmed.gov/32563187. Full-text: https://doi.org/10.1093/infdis/jiaa356
Some novel insights into pathogenesis: Dendritic cells (DCs) and macrophages are sentinel cells for innate and adaptive immunity. The authors demonstrate that these cells were permissive to SARS-CoV-2 infection but did not support productive virus replication. SARS-CoV-2 launched an attenuated interferon response in both cell types and an attenuated immune response in DCs. The latter was associated with viral antagonism of STAT1 phosphorylation (STAT1 plays a critical role in the innate immune response in the clearance of SARS-CoV).
Major J, Crotta S, Llorian M, et al. Type I and III interferons disrupt lung epithelial repair during recovery from viral infection. Science. 2020 Jun 11:eabc2061. PubMed: https://pubmed.gov/32527928. Full-text: https://doi.org/10.1126/science.abc2061 ll (Outstanding)
Key message: Interferon may be helpful during early infection and harmful at later stages. IFN-λ mainly signals in epithelia, inducing localized antiviral immunity, and has a key role in the reduction of epithelial proliferation and differentiation during lung repair. In animal and cell experiments, the authors show that IFN-induced p53 directly reduces epithelial proliferation and differentiation, increasing disease severity and susceptibility to bacterial superinfections. Excessive or prolonged IFN production may aggravate viral infection by impairing lung epithelial regeneration.
Broggi A, Ghosh S, Sposito B, et al. Type III interferons disrupt the lung epithelial barrier upon viral recognition. Science 11 Jun 2020. Full-text: https://DOI.ORG/10.1126/science.abc3545 l (Important)
Same direction as above: Detrimental activities of IFN-λ only occur upon chronic exposure and in the presence of tissue damage. In mice, IFN-λ produced by lung dendritic cells in response to a synthetic viral RNA-induced barrier damage, causing susceptibility to lethal bacterial superinfections.
Hassan AO, Case JB, Winkler ES, et al. A SARS-CoV-2 infection model in mice demonstrates protection by neutralizing antibodies. Cell 2020, June 10. Full-text: https://doi.org/10.1016/j.cell.2020.06.011
Most mice are not readily infected by SARS-CoV-2 because of species-specific differences in their ACE2 receptors. US researchers transduced replication-defective adenoviruses encoding human ACE2 via intranasal administration into BALB/c mice and established receptor expression in lung tissues. hACE2-transduced mice were productively infected with SARS-CoV-2, and this resulted in high viral titers in the lung and lung pathology. Neutralizing mAbs protect from SARS-CoV-2 induced lung infection, and inflammation. This accessible mouse model will expedite the testing and deployment of therapeutics and vaccines.
Sun J, Zhuang, Zheng J, et al. Generation of a Broadly Useful Model for COVID-19 Pathogenesis Vaccination, and Treatment. Cell 2020, June 10. Full-text: https://doi.org/10.1016/j.cell.2020.06.010
Another murine model, but from China. After exogenous delivery of human ACE2 with a replication-deficient adenovirus, Ad5-hACE2-sensitized mice developed pneumonia and high-titer virus replication in lungs. Type I interferon, T cells and, most importantly, signal transducer and activator of transcription 1 (STAT1) were critical for virus clearance and disease resolution. This murine model of broad and immediate utility will help to investigate COVID-19 pathogenesis, and to evaluate new therapies and vaccines.
Wilk AJ, Rustagi A, Zhao NQ, et al. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat Med. 2020 Jun 8. PubMed: https://pubmed.gov/32514174. Full-text: https://doi.org/10.1038/s41591-020-0944-y l (Important)
Using single-cell RNA sequencing, the authors profiled peripheral blood mononuclear cells from seven patients hospitalized for COVID-19 and six healthy controls. The cell atlas of the peripheral immune response to severe COVID-19 included a heterogeneous interferon-stimulated gene signature, HLA class II down-regulation and a developing neutrophil population that appeared closely related to plasmablasts appearing in patients with acute respiratory failure requiring mechanical ventilation. Of note, peripheral monocytes and lymphocytes did not express substantial amounts of pro-inflammatory cytokines.
Suthar MS, Zimmerman MG, Kauffman RC, et al. Rapid generation of neutralizing antibody responses in COVID-19 patients. Cell Rep Med June 05, 2020. Full-text: https://doi.org/10.1016/j.xcrm.2020.100040
A robust humoral immune response occurs early during severe or moderate COVID-19 infections: in this cross-sectional study of 44 hospitalized COVID-19 patients, receptor-binding domain (RBD)-specific IgG responses became detectable in all patients 6 days after PCR confirmation. Neutralizing antibody titers were detectable in 40/44 cases, mostly by 20 days of symptom onset. Of note, RBD-specific IgG titers seemed to correlate with the neutralizing potency, indicating that RBD-specific IgG titers could be used as a surrogate of neutralization activity against SARS-CoV-2 infection.
Seydoux E, Homad LJ, MacCamy AJ, et al. Analysis of a SARS-CoV-2 infected individual reveals development of potent neutralizing antibodies to distinct epitopes with limited somatic mutation. Immunity June 05, 2020. Full-text: https://doi.org/10.1016/j.immuni.2020.06.001
The authors isolated B cells specific for the SARS-CoV-2 envelope glycoprotein spike (S) from a COVID-19-infected subject. Main findings: The 45 S-specific monoclonal antibodies generated had undergone minimal somatic mutation, with limited clonal expansion. Most anti-S antibodies that were generated in this patient during the first weeks of COVID-19 infection were non-neutralizing and targeted epitopes outside the RBD. Neutralizing antibodies targeting the interaction of the S protein with ACE2 were minimally mutated.
Gutierrez L, Beckford J, Alachkar H. Deciphering the TCR repertoire to solve the COVID-19 mystery. Trends Pharmacol Sci. June 03, 2020. Full-text: https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(20)30130-9
Outstanding article on unresolved questions. Why do some patients develop severe disease, while others do not; and what roles do genetic variabilities play in the individual immune response to this viral infection? The authors discuss the critical role T cells play in the orchestration of the antiviral response underlying the pathogenesis of COVID-19.
Subbarao K, Mahanty S. Respiratory Virus Infections: Understanding COVID-19. Immunity. 2020 May 20:S1074-7613(20)30212-0. PubMed: https://pubmed.gov/32497522. Full-text: https://doi.org/10.1016/j.immuni.2020.05.004
Nice review about the immune response to respiratory viruses. What happens when the virus reaches the respiratory mucosa? What are the consequences of infection in the host?
Bojkova D, Klann K, Koch B et al. Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature 2020, May 14. https://doi.org/10.1038/s41586-020-2332-7
The authors describe a SARS-CoV-2 cell infection system to determine changes in host-cell pathways upon infection, resulting from host-cell (antiviral) responses or viral effector proteins, and assess some potential inhibitors.
Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020 May 28;181(5):1036-1045.e9. PubMed: https://pubmed.gov/32416070. Full-text: https://doi.org/10.1016/j.cell.2020.04.026 ll (Outstanding)
Incredible in-depth analysis of host response to SARS-CoV-2 and other human respiratory viruses in cell lines, primary cell cultures, ferrets, and COVID-19 patients. Data consistently revealed a unique and inappropriate inflammatory response to SARS-CoV-2 which is imbalanced with regard to controlling virus replication versus activation of the adaptive immune response. It is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. The authors propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19. Given this dynamic, treatments for COVID-19 have less to do with the IFN response and more to do with controlling inflammation.
Grifoni A, Weiskopf D, Ramirez SI, et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell. 2020 Jun 25;181(7):1489-1501.e15. PubMed: https://pubmed.gov/32473127. Full-text: https://doi.org/10.1016/j.cell.2020.05.015 ll (Outstanding)
Cellular response is a major knowledge gap. This important study identified circulating SARS-CoV-2−specific CD8 and CD4 T cells in around 70 and 100% of 20 COVID-19 convalescent patients, respectively. CD4 T cell responses to the spike protein were robust and correlated with the magnitude of IgG titers. Of note, the authors detected SARS-CoV-2−reactive CD4 T cells in 40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating seasonal coronaviruses and SARS-CoV-2.
Bordoni V, Sacchi A, Cimini E, et al. An inflammatory profile correlates with decreased frequency of cytotoxic cells in COVID-19. Clin Infect Dis. 2020 May 1. PubMed: https://pubmed.gov/32407466. Full-text: https://doi.org/10.1093/cid/ciaa577
The increase in inflammatory mediators is correlated with a reduction of innate and adaptive cytotoxic antiviral function. Authors found a lower perforin+ NK cell number in 7 intensive care unit (ICU) patients compared to 41 non-ICU patients, suggesting an impairment of the immune cytotoxic arm as a pathogenic mechanism.
Vabret N, Britton GJ, Gruber C, et al. Immunology of COVID-19: Current State of the Science. Immunity. 2020 Jun 16;52(6):910-941. PubMed: https://pubmed.gov/32505227. Full-text: https://doi.org/10.1016/j.immuni.2020.05.002 ll (Outstanding)
Brilliant review on the current knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death.
Ni L, Ye F, Cheng ML, et al. Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals. Immunity 2020, May 03. Full-text: https://www.cell.com/action/showPdf?pii=S1074-7613%2820%2930181-3 l (Important)
SARS-CoV-2-specific humoral and cellular immunity was characterized in 14 recovered patients. Of these, 13 displayed serum neutralizing activities in a pseudotype entry assay. Notably, there was a strong correlation between neutralization antibody titers and the numbers of virus-specific T cells. These findings suggest that both B and T cells participate in immune-mediated protection.