+++ Immunology +++

* * * Next update: 24 November. In the meantime, find the global updates at 7 Days. * * *

19 November

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

18 November

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.

17 November

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.

 

16 September

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.

 

15 September

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.

 

14 November

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.

 

12 November

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.

 

11 November

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 proinflammatory 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.

 

Figure 1. SARS-CoV-2 antibodies in patients with COVID-19 and in undiagnosed children. a, Anti-RBD IgM, IgA and IgG titers in patients with COVID-19 who required treatment in the ICU (red; n = 21), hospitalization but no ICU (floor; yellow; n = 22) or treatment on an outpatient basis (light blue; n = 18), and seropositive children (peds; dark blue; n = 16). OD, optical density. b, Anti-RBD AUC for the four patient… | Continue reading at https://doi.org/10.1038/s41590-020-00828-7. Reproduced with permission.

 

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 preexisting 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 the younger.

 

5 November

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.

 

4 November

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.

 

3 November

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

 

29 October

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.

 

27 October

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 reinfection? 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.

 

25 October

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 more prolonged responses.

 

24 October

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.

 

23 October

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.

22 October

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 reinfected, 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.

 

20 October

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 used 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.

 

19 October

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 PPP group (n = 19) and PPN group (n = 18), according to their testing results after 7 days (N = negative). PPP subgroup had markedly reduced B cells and T cells compared to 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.

 

17 October

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.

 

14 October

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.

 

13 October

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.

 

11 October

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.

 

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

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.

 

  eCoV- eCoV+
SARS-CoV-2 tested
(% of total)
1679 (11.2) 133 (15.2)
SARS-CoV-2+, no.

(% of tested)

437 (26.0) 33 (24.8)
Hospitalized, no.

(% 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)

 

8 October

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.

 

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