Immunology & Vaccines
ProMed (International Society for Infectious Diseases). Undiagnosed pneumonia – China (HU): RFI. Archive Number: 20191230.6864153. Full-text: https://promedmail.org/promed-post/?id=6864153 ll
This email is the first message that alerted the world to what was to become the worst health crisis in 100 years.
Stebbing J, Phelan A, Griffin I, et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020 Apr;20(4):400-402. PubMed: https://pubmed.gov/32113509. Full-text: https://doi.org/10.1016/S1473-3099(20)30132-8
Guo L, Ren L, Yang S, et al. Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19). Clin Infect Dis. 2020 Mar 21. PubMed: https://pubmed.gov/32198501. Fulltext: https://doi.org/10.1093/cid/ciaa310
To KK, Tsang OT, Leung WS, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis. 2020 Mar 23. PubMed: https://pubmed.gov/32213337. Fulltext: https://doi.org/10.1016/S1473-3099(20)30196-1 l (Important)
Lurie N, Saville M, Hatchett R, Halton J. Developing Covid-19 Vaccines at Pandemic Speed. NEJM March 30, 2020. Full-text: https://doi.org/10.1056/NEJMp2005630
Excellent review on vaccine development. Outlook on new platforms for RNA and DNA vaccines that can be made quickly because they require no culture or fermentation, instead using synthetic processes. Hope and despair.
Le TT, Andreadakis Z, Kumar A, et al. The COVID-19 vaccine development landscape. Nature reviews drug discovery. 09 April 2020. Full-text: https://www.nature.com/articles/d41573-020-00073-5
Brief data-driven overview by seven experts. The conclusion is that efforts are unprecedented in terms of scale and speed and that there is an indication that a vaccine could be available by early 2021. As of 8 April 2020, the global vaccine landscape includes 115 candidates, of which the 5 most advanced candidates have already moved into clinical development, including mRNA-1273 from Moderna, Ad5-nCoV from CanSino Biologicals, INO-4800 from Inovio, LV-SMENP-DC and pathogen-specific aAPC from Shenzhen Geno-Immune Medical Institute. The race is on!
Rockx B, Kuiken T, Herfst S, et al. Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model. Science 17 Apr 2020: eabb7314. Full text: https://science.sciencemag.org/content/early/2020/04/16/science.abb7314 l (Important)
This animal study was performed to understand the pathogenesis, showing SARS-CoV-2-infected macaques provide a new model to test therapeutic strategies. Virus was excreted from nose and throat in the absence of clinical signs, and detected in type I and II pneumocytes in foci of diffuse alveolar damage and in ciliated epithelial cells of nasal, bronchial, and bronchiolar mucosae. In SARS-CoV infection, lung lesions were typically more severe, while they were milder in MERS-CoV infection, where virus was detected mainly in type II pneumocytes.
Tay MZ, Poh CM, Rénia L et al. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-0311-8. Full-text: https://www.nature.com/articles/s41577-020-0311-8#citeas
A brilliant overview of the pathophysiology of SARS-CoV-2 infection. How SARS-CoV-2 interacts with the immune system, how dysfunctional immune responses contribute to disease progression and how they could be treated.
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.
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.
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.
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.
Zhu FC, Li YH, Guan XH, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet. 2020 Jun 13;395(10240):1845-1854. PubMed: https://pubmed.gov/32450106. Full-text: https://doi.org/10.1016/S0140-6736(20)31208-3 l (Important)
Open-label Phase I trial of an Ad5 vectored COVID-19 vaccine, using the full-length spike glycoprotein. A total of 108 healthy adults aged between 18 and 60 years from Wuhan, China, were given three different doses. ELISA antibodies and neutralising antibodies increased significantly and peaked 28 days post-vaccination. Specific T cell response peaked at day 14 post-vaccination. Follow-up is still short and the authors are going to follow up the vaccine recipients for at least 6 months, so more data will be obtained. Of note, adverse events were relatively frequent, encompassing pain at injection sites (54%), fever (46%), fatigue (44%) and headache (39%). Phase II studies are underway.
Shen B, Yi X, Sun Y, et al. Proteomic and Metabolomic Characterization of COVID-19 Patient Sera. Cell May 27, 2020. Full-text: https://www.sciencedirect.com/science/article/pii/S0092867420306279
Molecular insights into the pathogenesis of SARS-CoV-2 infection. Authors applied proteomic and metabolomic technologies to analyze the proteome and metabolome of sera from COVID-19 patients and several control groups. Pathway analyses and network enrichment analyses of the 93 differentially expressed proteins showed that 50 of these proteins belong to three major pathways, namely activation of the complement system, macrophage function and platelet degranulation. It was found that 80 significantly changed metabolites were also involved in the three biological processes revealed in the proteomic analysis.
Park A, Iwasaki A. Type I and Type III Interferons – Induction, Signaling, Evasion, and Application to Combat COVID-19. Cell Host Microbe. 2020 Jun 10;27(6):870-878. PubMed: https://pubmed.gov/32464097. Full-text: https://doi.org/10.1016/j.chom.2020.05.008 l (Important)
The interferon (IFN) response constitutes the major first line of defense against viruses. This complex host defense strategy can, with accurate understanding of its biology, be translated into safe and effective antiviral therapies. In their comprehensive review, authors describe the recent progress in our understanding of both type I and type III IFN-mediated innate antiviral responses against human coronaviruses and discuss the potential use of IFNs as a treatment strategy.
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?
Wang H, Zhang Y, Huang B, et al. Development of an inactivated vaccine candidate, BBIBP-CorV, with potent protection against SARS-CoV-2. Cell 2020, June 06. Full-text: https://doi.org/10.1016/j.cell.2020.06.008
Will this be the first vaccine? Compared with the adenovirus-vectored and the DNA vaccine, inactivated vaccine development and production is a conventional and mature technology (main pro: large amounts of vaccine doses can be easily manufactured, main con: safety issues, including an antibody-dependent worsening of the infection). BBIBP-CorV, an inactivated SARS-CoV-2 vaccine, induced high levels of neutralizing antibody in several animal models, including 8 rhesus macaques, protecting them against SARS-CoV-2 infection. There was no observable antibody-dependent infection enhancement or immunopathological exacerbation. A Phase I clinical trial of BBIBP-CorV is currently in progress and a Phase II clinical trial has recently been initiated.
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.
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.
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.
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.
Fuller DH, Berglund P. Amplifying RNA Vaccine Development. NEJM, June 18, 2020. N Engl J Med 2020; 382:2469-2471. Full-text: https://doi.org/10.1056/NEJMcibr2009737
Recent interest in messenger RNA (mRNA) vaccines has been fueled by methods that increase mRNA stability and protein production and improve delivery. The mRNA vaccines do not need to enter the nucleus to express the antigen. Avoidance of the risk of integration into the host genome is thus considered a comparative advantage. The authors describe new techniques in this field. The most promising seems to be a strategy that is based on two RNA vectors — one retaining the replicase-encoding gene and the other encoding the antigen.
Huo J, Zhao Y, Ren J, et al. Neutralisation of SARS-CoV-2 by destruction of the prefusion Spike. Cell Host Microbe June 19, 2020. Full-text: https://doi.org/10.1016/j.chom.2020.06.010
The monoclonal antibody CR3022 tightly binds the receptor binding domain (RBD) and neutralizes SARS-CoV-2. The highly conserved, structure-stabilising, CR3022 epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. The mechanism of neutralisation is new and was not seen before for coronaviruses, suggesting that the CR3022 epitope should be a major target for therapeutic 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).
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.
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.
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.
Cohen J. 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.
Dai L, Zheng T, Xu K, et al. A universal design of betacoronavirus vaccines against COVID-19, MERS and SARS. Cell June 28, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.06.035
The CoV spike receptor-binding domain (RBD) is an attractive vaccine target but is undermined by limited immunogenicity. The authors identified a dimeric form of MERS-CoV RBD that overcomes this limitation and significantly increased the immunogenicity. The RBD-dimer significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MERS-CoV infection. This can be a generalizable strategy for beta-CoV vaccine design.
Bouhaddou M, Memon D, Meyer B, et al. The Global Phosphorylation Landscape of SARS-CoV-2 Infection. Cell. 2020 Jun 28:S0092-8674(20)30811-4. PubMed: https://pubmed.gov/32645325. Full-text: https://doi.org/10.1016/j.cell.2020.06.034 ll (Outstanding)
Nothing to do next weekend? Then read this incredible work of 66 pages (> 400 references!). In brief: proteomics approaches that globally quantify changes in protein abundance and phosphorylation represent a powerful tool to elucidate mechanisms of viral pathogenesis by providing a snapshot of how cellular pathways and processes are rewired upon infection. Using a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, the 78 (!) authors present the global phosphorylation and protein abundance landscape of SARS-CoV-2 infection, map phosphorylation changes to disrupted kinases and pathways, and use these profiles to find drugs with the potential to treat SARS-CoV-2 infection. In total, 87 compounds (10 FDA-approved drugs) were identified.
Schultheiß C, Paschold L, Simnica D, et al. Next Generation Sequencing of T and B cell receptor repertoires from COVID-19 patients showed signatures associated with severity of disease. Cell June 29, 2020. Full-text: https://doi.org/10.1016/j.immuni.2020.06.024 l (Important)
Insights on adaptive immunity. The authors analyzed COVID-19 patients with active, severe infection (n=20) or after recovery of mild disease (n=19) and created a repository of currently > 14 million B and T cell receptor (BCR, TCR) sequences from the blood of these patients. The B cell response showed converging IGHV3-driven BCR clusters closely associated with SARS-CoV-2 antibodies. The T cell pools of patients with active disease were considerably diminished and showed shifts towards CD4+ and expanded Treg cells. Clonality and skewing of TCR repertoires was associated with interferon type I and III responses and early CD4+ and CD8+ T cell activation.
Deming ME, Michael NL, Robb M, et al. Accelerating Development of SARS-CoV-2 Vaccines — The Role for Controlled Human Infection Models. NEJM July 1, 2020. Full-text: https://doi.org/10.1056/NEJMp2020076. Full-text: https://www.nejm.org/doi/full/10.1056/NEJMp2020076
The authors review practical considerations relevant to the development of a SARS-CoV-2 controlled human infection models (CHIMs) and the prerequisites for using such a model. Large, randomized, controlled trials of SARS-CoV-2 vaccines are still the most efficient, generalizable, and scientifically robust path to establishing vaccine efficacy. However, SARS-CoV-2 CHIM development might be able to accelerate the development of later rounds of vaccine candidates.
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.
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.
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.
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.
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.
Yan 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.
Today, 15 July 2020, there will be no Top 10, but the Top 1,000:
COVID Reference Top 10 – Daily Science (390 pages, download)
Here we publish in a single PDF our daily Top 10 papers we have presented ever since COVID Reference’s first edition on 29 March 2020. There is no secret to our procedure: the daily scanning of the literature helps us to stay afloat in the never-ending waves of new publications about SARS-CoV-2 and COVID-19. Many papers discussed in the Top 10 will eventually make it into subsequent editions of COVID Reference.
We dedicate this book to our students. May this selection of approx. 1,000 fine articles and full-text links deepen their understanding of the new coronavirus and prepare them for the challenges ahead.
Stay with us for the next thousand Top 10 papers.
All the best,
Christian Hoffmann & Bernd Sebastian Kamps
Find 22 outstanding papers at https://covidreference.com/outstanding-papers.
- P. S.
We have also updated the Transmission chapter in order to reflect the latest WHO statement on aerosol transmission:
“There have been reported outbreaks of COVID-19 in some closed settings, such as restaurants, nightclubs, places of worship or places of work where people may be shouting, talking, or singing. In these outbreaks, aerosol transmission, particularly in these indoor locations where there are crowded and inadequately ventilated spaces where infected persons spend long periods of time with others, cannot be ruled out.”
Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA Vaccine against SARS-CoV-2 – Preliminary Report. N Engl J Med. 2020 Jul 14. PubMed: https://pubmed.gov/32663912. Full-text: https://doi.org/10.1056/NEJMoa2022483
This study conducted in Washington and Atlanta evaluated the candidate vaccine mRNA-1273 that encodes the stabilized prefusion SARS-CoV-2 spike protein. In a Phase I open label trial, 45 healthy adults received two vaccinations, 28 days apart, at three different doses. Antibody responses were higher with a higher dose and further increased after the second vaccination, leading to serum-neutralizing activity in all participants. Values were similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in > 50% included fatigue, chills, headache, myalgia, and pain at the injection site.
Arnold C. How computational immunology changed the face of COVID-19 vaccine development. Nat Med. 2020 Jul 15. PubMed: https://pubmed.gov/32669667. Full-text: https://doi.org/10.1038/d41591-020-00027-9
After more than two decades of work, computational immunology now enables the development of a candidate vaccine in just a few hours. However, no in silico analysis, no matter how high-quality the input and how exacting the computational algorithms, will ever be a substitute for experimental data.
Mathew D, Giles JR, Baxter AE, et al. Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science 2020 Jul 15. PubMed: https://pubmed.gov/32669297. Full-text: https://doi.org/10.1126/science.abc8511
Patients differ: Analysing 125 COVID-19 patients, the authors identified three “immunotypes” associated with poorer clinical trajectories versus improving health. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses reaching > 30% of circulating B cells. However, another subgroup had lymphocyte activation comparable to uninfected subjects. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. This study provides a compendium of immune response data and also an integrated framework as a “map” for connecting immune features to disease. By localizing patients on an immune topology map built on this dataset, we can begin to infer which types of therapeutic interventions may be most useful in specific patients.
Le Bert N, Tan AT, Kunasegaran K, et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature. 2020 Jul 15. PubMed: https://pubmed.gov/32668444. Full-text: https://doi.org/10.1038/s41586-020-2550-z
Is there a natural immunity? In this study, T cell responses to structural (nucleocapsid protein, NP) and non-structural (NSP-7 and NSP13 of ORF1) regions of SARS-CoV-2 were analyzed in 36 COVID-19 convalescents. In all of them, CD4 and CD8 T cells recognizing multiple regions of the NP protein were found. Surprisingly, the authors also frequently detected SARS-CoV-2 specific T cells in 37 individuals with no history of SARS, COVID-19 or contact with SARS/COVID-19 patients. These T cells exhibited a different pattern of immunodominance, frequently targeting the ORF-1-coded proteins NSP7 and 13 as well as the NP structural protein. Epitope characterization of NSP7-specific T cells showed recognition of protein fragments with low homology to “common cold” human coronaviruses but conserved amongst animal betacoronaviruses. Thus, infection with betacoronaviruses induces multispecific and long-lasting T cell immunity to the structural protein NP.
Lynch KL, Whitman JD, Lacanienta NP, et al. Magnitude and kinetics of anti-SARS-CoV-2 antibody responses and their relationship to disease severity. Clin Infect Dis. 2020 Jul 14. PubMed: https://pubmed.gov/32663256 . Full-text: https://doi.org/10.1093/cid/ciaa979
Using a high-throughput quantitative IgM and IgG assay that detects antibodies to the spike protein receptor binding domain and nucleocapsid protein, the authors evaluated antibody kinetics and correlation between magnitude of the response and disease severity in a total of 533 sera from 94 acute and 59 COVID-19 patients. Compared to those with milder disease, peak measurements were significantly higher for patients admitted to the ICU for all time intervals between 6 and 20 days for IgM, and all intervals after 5 days for IgG.
Akbar AN, Gilroy DW. Aging immunity may exacerbate COVID-19. Science 17 Jul 2020: Vol. 369, Issue 6501, pp. 256-257. Full-text: https://doi.org/10.1126/science.abb0762
Brief and nice overview on how “inflammaging”, a common denominator of age-associated frailty, may contribute to the severe COVID-19 course in older people. One hypothesis is that preexisting inflammatory cells, including senescent populations and adipocytes, create the inflammaging phenotype that amplifies subsequent inflammatory events. Nevertheless, high amounts of inflammation alone do not explain the devastating tissue destruction and it may be that age-associated changes in T cells have a role in the immunopathology.
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 proinflammatory 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 targeted.
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.
This is a kind request to everyone in the scientific community who is currently working on scientific papers on COVID-19, brooding over introductions. It is no longer necessary to emphasize that the “COVID-19 pandemic has to date caused >7 million infections resulting in over 400,000 deaths” and that “following infection with SARS-CoV2, COVID-19 patients can experience mild or even asymptomatic disease, or can present with severe disease requiring hospitalization and mechanical ventilation.” (Science, July 15). And, please, don’t start your paper or your abstract with the COVID-19 pandemic as “a major threat to global health for which there are limited medical countermeasures” (Nature, July 15). More brand-new findings? “The severe acute respiratory syndrome coronavirus 2 emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine” (NEJM, July 15).
Are you kiddin’? We know it. We all know it! We all know it all! On July 16th, Pubmed.gov listed more than 31,000 COVID-19 papers. Almost every paper is (fortunately) freely accessible. We are faced with dozens of important scientific papers every day and our time is limited. So get down to business, folks. Straight to the point, no elaborations. Save yourself cumbersome or scrambled introductions.
Rob Camp, Christian Hoffmann, Bernd Sebastian Kamps
Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet, 20 July 2020. Full-text: https://www.thelancet.com/lancet/article/s0140-6736(20)31604-4
Andrew Pollard and colleagues report their phase 1/2 randomized trial of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein. Study participants received either ChAdOx1 nCoV-19 (n=543) or a meningococcal conjugate vaccine (MenACWY) as control (n=534). In ChAdOx1 vaccinees, T-cell responses peaked on day 14, anti-spike IgG responses rose by day 28, and neutralizing antibody responses against SARS-CoV-2 were detected in >90% (find more details in the paper, especially about results after a booster dose). Adverse events such as fatigue, headache, and local tenderness occurred commonly. There were no serious adverse events.
Zhu FC, Guan XH, Li YH, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet, 20 July 2020. Full-text: https://www.thelancet.com/lancet/article/s0140-6736(20)31605-6
Wei Chen and colleagues report results from a randomized phase 2 trial of an Ad5-vectored COVID-19 vaccine from a single center in Wuhan. More than 90% of participants had T-cell responses, seroconversion of binding antibody occurred in more than 96%, and neutralizing antibodies were shown in about 85%. The authors found that compared with the younger population, older people had a significantly lower immune response, but higher tolerability, to the Ad5-vectored COVID-19 vaccine. In a phase 2b trial, an additional dose might therefore be needed to induce a better immune response in the older population. Adverse events such as fever, fatigue, headache, or local site pain were comparable to the ChAdOx1 study above.
Bar-Zeev N, Moss WJ. Encouraging results from phase 1/2 COVID-19 vaccine trials. Lancet, 20 July 2020. Full-text: https://www.thelancet.com/lancet/article/s0140-6736(20)31611-1
A comment on the two papers above as well as a list of questions to be addressed by the coming phase 3 trials:
- Will a single dose be sufficient in older adults, or is a booster dose required?
- Does longevity of response or rates of waning differ with a two-dose regimen, and does longevity of clinical protection require cell-mediated responses?
- Are there host-specific differences in immunogenicity by age, sex, or ethnicity?
- Do T-cell responses correlate with protection irrespective of humoral titers?
- Are there specific adverse events in pregnant women?
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. COVID19 (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-Co-2 infection.
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 more findings goes on. A must-read!
David H. Ho will remind senior scientists of studies published in the 90ies about HIV and AIDS (see pubmed.gov/10341272, pubmed.gov/10577640, pubmed.gov/11018071, pubmed.gov/15781098, pubmed.gov/16890836, among several hundred 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
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 a key role for 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-vectored 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.
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.
Today, revise what you have studied over the past months and find a summary of articles about clinical manifestations, comorbidities and severe COVID-19 since the beginning:
Simon, D., Tascilar, K., Krönke, G. et al. Patients 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)
Zhang NN, Li XF, Deng YQ. A thermostable mRNA vaccine against COVID-19. Cell 2020, ublished: July 23. Abstract: https://www.cell.com/cell/fulltext/S0092-8674(20)30932-6. Full-text: https://doi.org/10.1016/j.cell.2020.07.024
The authors describe the development of a LNP-encapsulated mRNA vaccine (termed “ARCoV”) which targets the RBD of SARS-CoV-2. The vaccine induces neutralizing antibodies and T-cell immunity in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse adapted strain. Phase 1.
Graham SP, McLean RK, Spencer AJ et al. Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19. npj Vaccines 5, 69 (2020). Full-text: https://doi.org/10.1038/s41541-020-00221-3
Simon P. Graham, Teresa Lambe and colleagues compare the immunogenicity of one or two doses of ChAdOx1 nCoV-19 in both mice and pigs. Whilst a single dose induced antigen-specific antibody and T cells responses, a booster immunization enhanced antibody responses, particularly in pigs, with a significant increase in SARS-CoV-2 neutralizing titers. See also the ChAdOx1 phase 1/2 randomized trial of a chimpanzee adenovirus-vectored vaccine (nCoV-19) published a week ago: https://covidreference.com/top-10-july-20.
Martin C, Lowery D. mRNA vaccines: intellectual property landscape. Nat Rev Drug Discov 2020, 27 July. Full-text: https://www.nature.com/articles/d41573-020-00119-8
Cecilia Martin and Drew Lowery generate an intellectual property landscape surrounding mRNA vaccine development. Overall filing activity aims at protecting methods to improve mRNA delivery efficiency as well as pharmacological modifications to reduce mRNA instability and innate immunogenicity. Moderna, CureVac, BioNTech and GSK own nearly half of the mRNA vaccine patent applications.
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 of 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 the 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.
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.
Corbett KS, Flynn B, Foulds KE, et al. Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. N Engl J Med 2020, published 28 July. Full-text: https://doi.org/10.1056/NEJMoa2024671
Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. For this important vaccine trial, Barney S. Graham, Robert A. Seder and colleagues divided 12 female and 12 male Indian-origin rhesus macaques into groups of three and vaccinated them intramuscularly at week 0 and at week 4 with either 10 or 100 μg of mRNA-1273 or placebo. At week 8 (4 weeks after the second vaccination), all animals were challenged with SARS-CoV-2. mRNA-1273 induced antibody levels exceeding those found in human convalescent-phase serum. Vaccination also induced type 1 helper T-cell (Th1)–biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses.
No viral replication was detectable in the nose of any of the eight animals in the 100-μg dose group by day 2 after challenge (8 weeks after the first vaccination). The ability to limit viral replication in both the lower and the upper airways will have important implications for vaccine-induced prevention of both SARS-CoV-2 disease and transmission.
Liu G, Carter B, Bricken T, Jain S, Viard M, Carrington M, Gifford DK. Computationally Optimized SARS-CoV-2 MHC Class I and II Vaccine Formulations Predicted to Target Human Haplotype Distributions. Cell Systems 2020, published 27 July. Full-text: https://www.cell.com/cell-systems/fulltext/S2405-4712(20)30238-6
Do you want to optimize peptide vaccine formulations for SARS-CoV-2? David K. Gifford and colleagues from the MIT now give you a combinatorial machine learning method. They also encourage the early publication of vaccine designs to enable collaboration and rapid progress toward safe and effective vaccines for COVID-19. Consequently, they provide an open-source implementation of their design methods (OptiVax), vaccine evaluation tool (EvalVax), as well as the data used in their design efforts: https://github.com/gifford-lab/optivax.
van Doremalen N, Lambe T, Spencer A, et al. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature 2020, published 30 July. Full-text: https://doi.org/10.1038/s41586-020-2608-y
Good news first or bad news first? The good news: Vincent Munster, Sarah Gilbert and colleagues showed that vaccination with the adenovirus-vectored ChAdOx1 vaccine (see also the July 20 Top 10) induced a balanced Th1/Th2 humoral and cellular immune response in rhesus macaques. The authors observed a significantly reduced viral load in bronchoalveolar lavage fluid and lower respiratory tract tissue, and no pneumonia was observed in vaccinated animals. The bad news (for prevention policies in general and for anti-vaxxers in particular): there was no difference in nasal shedding between vaccinated and control animals. Back to the good news: there was no evidence of immune-enhanced disease following viral challenge in vaccinated animals.
For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Hanneke Schuitemaker, Dan Barouch and colleagues developed a series of adenovirus serotype 26 (Ad26) vectors encoding different variants of the SARS-CoV-2 spike (S) protein and showed the immunogenicity and protective efficacy of a single dose of Ad26 vector-based vaccines in 52 rhesus macaques. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs following SARS-CoV-2 challenge.
Yang J, Wang W, Chen Z et al. A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity. Nature 2020, published 29 July. Full-text: https://doi.org/10.1038/s41586-020-2599-8
The authors show that a recombinant vaccine comprising residues 319-545 of the Spike protein receptor-binding domain (S-RBD) can induce a potent functional antibody response in mice, rabbits and non-human primates as early as 7 or 14 days after a single dose injection. Antibodies shared common binding epitopes from infected patients, neutralizing activity was strong, and a simple adjuvant like Alum could further enhance the immune response. Even one dose of the vaccine generated viral neutralizing activity. The vaccine protected non-human primates from live SARS-CoV-2 challenge 28 days after the first vaccination.
Rubin EJ, Baden LR, Morrissey S. New SARS-CoV-2 Vaccine Results. N Engl J Med 2020; 383:e57. Access: https://www.nejm.org/doi/full/10.1056/NEJMe2026514
Audio interview (19:56) with Peter Piot who talks about his own experience with COVID-19, as well as recent developments in SARS-CoV-2 vaccines.
Newton-Cheh C, Zlotoff DA, Hung J, Rupasov A, Crowley JC, and Funamoto M. Case 24-2020: A 44-Year-Old Woman with Chest Pain, Dyspnea, and Shock. N Engl J Med 2020; 383:475-484, published 30 July. Full-text: https://doi.org/10.1056/NEJMcpc2004975
Eight days before admission — and 3 days after her husband had begun to have fatigue, a nonproductive cough, and a fever — the patient started to have chills, a sore throat, a nonproductive cough, and myalgias.
Sharma A, Eisen JE, Shepard JAO, Bernheim A, and Little BP. Case 25-2020: A 47-Year-Old Woman with a Lung Mass. N Engl J Med 2020, published 29 July.. Full-text: https://doi.org/10.1056/NEJMcpc2004977
The patient had been well until 2 months before this evaluation, when intermittent nonproductive cough and wheezing developed. She had no fever, chills, or shortness of breath. Two days before this evaluation, the cough worsened in frequency and severity and new shortness of breath developed.
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.
Gu H, Chen Q, Yang G, et al. Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy. Science 2020 Jul 30:eabc4730. PubMed: https://pubmed.gov/32732280. Full-text: https://doi.org/10.1126/science.abc4730
First, adapt a clinical isolate of SARS-CoV-2 by serial passaging in the respiratory tract of aged BALB/c mice. When the mouse-adapted strain shows increased infectivity in mouse lung after 6 passages, leading to interstitial pneumonia and inflammatory responses following intranasal inoculation, sequence the virus genome and look for adaptive mutations which might be associated with the increased virulence. That’s what Yusen Zhou, Cheng-Feng Qin, Shihui Sun, Shibo Jiang and colleagues did. They found an N501Y mutation located at the receptor binding domain (RBD) of the spike protein. They also showed the protective efficacy of a recombinant RBD vaccine candidate. They conclude that this MASCp6 could be of value in evaluating vaccines and antivirals against SARS-CoV-2.
Matheson NJ, Lehner PJ. How does SARS-CoV-2 cause COVID-19? Science 2020; 369:510-511. Full-text: https://doi.org/10.1126/science.abc6156
If you still have doubts about how SARS-CoV-2 enters human cells, read these two pages by Nicholas J. Matheson and Paul J. Lehner from Cambridge, UK. Find out what is so special about ACE2, what might cause the clinical deterioration that leads to severe systemic COVID-19 and how SARS-CoV-2 and our adaptive immune system, either antibodies or T cells, play together. The authors point out how essential it is to identify individuals with early SARS-CoV-2 infection who are at high risk of progression to severe disease. They recommend that treatment with future antiviral drugs should not be delayed until patients are hospitalized with severe lung injury.
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.
Ramlall V, Thangaraj PM, Meydan C et al. Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection. Nat Med, published 3 August. Full-text: https://www.nature.com/articles/s41591-020-1021-2
Mortality of severe COVID-19 is driven by viral replication and comorbidities that influence immune-mediated pathology. As the complement system is a critical defense against pathogens that, when dysregulated, can contribute to inflammation-mediated pathologies, Sagi Shapira, Nicholas Tatonetti and colleagues explored the role of complement or coagulatory function in SARS-CoV-2 infection and clinical outcome. In a retrospective observational study of 11,116 patients who presented to New York-Presbyterian/Columbia University Irving Medical Center with suspected SARS-CoV-2 infection, they found that history of macular degeneration (a proxy for complement activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) are risk factors for morbidity and mortality in SARS-CoV-2-infected patients. Moreover, patients with AMD succumbed to disease more rapidly than others. The authors also found that transcriptional profiling of nasopharyngeal swabs from 650 control and SARS-CoV-2-infected patients demonstrate that infection results in robust engagement and activation of complement and coagulation pathways.
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.
Zhang B, Chu H, Han S et al. SARS-CoV-2 infects human neural progenitor cells and brain organoids. Cell Res 2020, published 4 August. Full-text: https://doi.org/10.1038/s41422-020-0390-x
Jian-Dong Huang and colleagues assessed SARS-CoV-2 infection in induced pluripotent stem cells (iPSCs)-derived human neural progenitor cells (hNPCs), neurospheres, and brain organoids. They detected extensive viral protein expression and infectious viral particles in neurospheres and brain organoids infected with SARS-CoV-2, suggesting that SARS-CoV-2 can productively infect the human brain. In particular, they demonstrated that SARS-CoV-2 could also target the neuronal progenitor cell populations. Chronic or long-term consequences of SARS-CoV-2 infection in the CNS should be closely monitored.
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.
Corbett KS, Edwards DK, Leist SR et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 2020, published 5 August. Full-text: https://doi.org/10.1038/s41586-020-2622-0
Barney Graham, Andrea Carfi and colleagues show that mRNA-1273, a vaccine currently tested in Phase 3 trials, protects mice against SARS-CoV-2 infection in the lungs and noses without evidence of immunopathology. The vaccine induced both potent neutralizing antibody responses to wild-type (D614) and D614G mutant2 SARS-CoV-2 and CD8 T cell responses. The authors are prolific – a week ago, they evaluated the same vaccine in non-human primates and published their paper in the N Engl J Med (see Corbett et al., Top 10 July 29). Read also the last paragraph of this week’s paper where Corbett et al. describe a new paradigm for rapid vaccine development.
See also a Nat Biomed Eng editorial: Fast-and-fit vaccines. Published 10 August 2020. Full-text: https://doi.org/10.1038/s41551-020-00605-9
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.
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
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.
Zhu N, Wang W, Liu Z, et al. Morphogenesis and cytopathic effect of SARS-CoV-2 infection in human airway epithelial cells. Nat Commun 11, 3910 (2020). https://doi.org/10.1038/s41467-020-17796-z
Totura A, Livingston V, Frick O, Dyer D, Nichols D, Nalca A. Small particle aerosol exposure of African green monkeys to MERS-CoV as a model for highly pathogenic coronavirus infection. Emerg Infect Dis 2020. Published August 2020. Full-text: https://doi.org/10.3201/eid2612.201664
For the initial development of a MERS-CoV primate model, Allison Totura and colleagues exposed 12 African green monkeys to 103, 104, or 105 PFU target doses of aerosolized MERS-CoV. Clinical disease signs that replicated human cases of MERS were observed in all groups but were most pronounced in the group that received the highest dose of MERS-CoV. It would be interesting to investigate if a dose-dependent increase of respiratory disease signs can be replicated in a SARS-CoV-2 animal model.
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.
Dagotto G, Yu J, Barouch DH. Approaches and Challenges in SARS-CoV-2 Vaccine Development. Cell Host Microbe 2020, published 10 August. Full-text: https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(20)30455-8
Progress in SARS-CoV-2 vaccine development to date has been faster than for any other pathogen in history. In this perspective, Dan Barouch, Gabriel Dagotto and Jingyou Yu discuss three topics that are critical for SARS-CoV-2 vaccine development:
- Antigen selection and engineering
- Pre-clinical challenge studies in non-human primate models
- Immune correlates of protection
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?
Arunachalam PS, Wimmers F, Mok CKP, Perera RAPM, et al. Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science 2020, published 11 August. Full-text: http://doi.org/10.1126/science.abc6261
There is something wrong with our innate immune system responding to SARS-CoV-2. Bali Pulendran and colleagues analyzed immune responses in 76 COVID-19 patients and 69 healthy individuals and found a spatial dichotomy in the innate immune response, characterized by suppression of peripheral innate immunity, in the face of proinflammatory responses reported in the lung. In PBMCs of COVID-19 patients, there was reduced expression of HLA-DR and pro-inflammatory cytokines by myeloid cells, and impaired mTOR signaling and IFN-α production by plasmacytoid DCs. In contrast, there were enhanced plasma levels of inflammatory mediators, including EN-RAGE (S100A12, a biomarker of pulmonary injury), TNFSF14, and oncostatin-M. The authors suggest that these three molecules and their receptors could represent attractive therapeutic targets.
See also the Stanford Press News, 11 August: Study reveals immune-system deviations in severe COVID-19 cases.
Mulligan MJ, Lyke KE, Kitchin N, et al. Phase 1/2 study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 2020, published 12 August. Full-text: https://doi.org/10.1038/s41586-020-2639-4
Mark Mulligan, Kirsten Lyke, Nicholas Kitchin, Judith Absalon and colleagues report the safety, tolerability, and immunogenicity data from an ongoing study among 45 healthy adults, randomized to receive 2 doses, separated by 21 days, of 10 µg, 30 µg, or 100 µg of BNT162b1. BNT162b1, developed by BioNTech and Pfizer, is a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD). A clear dose-level response in elicited neutralizing titers was observed after doses 1 and 2 with a particularly steep dose response between the 10 μg and 30 μg dose levels. Geometric mean neutralizing titers reached 1.9- to 4.6-fold that of a panel of COVID-19 convalescent human sera at least 14 days after a positive SARS-CoV-2 PCR. The clinical testing of BNT162b1 is taking place in the context of a broader, ongoing COVID-19 vaccine development program by both companies. That program includes the clinical testing of three additional vaccine candidates, including candidates encoding the full-length spike.
Brest P, Refae S, Mograbi B, et al. Host polymorphisms may impact SARS-CoV-2 infectivity. Trends Genetics August 10, 2020. Full-text: https://doi.org/10.1016/j.tig.2020.08.003
In their comment, the authors support the hypothesis of genetic influence on individual susceptibility to COVID-19 infection. Germinal polymorphisms may regulate the expression of the SARS-CoV-2 cellular target itself and proteases controlling the process of its shedding or, conversely, its internalization.
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 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.
Xia S, Duan K, Zhang Y, et al. Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. JAMA 2020, published 13 August. Full-text: https://doi.org/10.1001/jama.2020.15543
An Pan, Xiaoming Yang and colleagues provide the first interim safety, tolerability, and immune response results for a β-propiolactone–inactivated whole-virus vaccine adjuvanted in 0.5 mg of aluminum hydroxide. The incidence rate of adverse reactions in the current study (15.0% among all participants) was not significantly different between the vaccine groups and the active control (alum) groups; it was also lower compared with results of other SARS-CoV-2 candidate vaccines. The neutralizing antibody response suggested that the inactivated vaccine may effectively induce antibody production, but the optimal interval between injections and times of booster injections of the inactivated vaccine remains unclear. In the discussion, find more about ADE and VAERD. See also the comment by Mark Mulligan: An Inactivated Virus Candidate Vaccine to Prevent COVID-19. JAMA 2020, published 13 August 13. Full-text: https://doi.org/10.1001/jama.2020.15539
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.
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.
Hachim A, Kavian N, Cohen CA et al. ORF8 and ORF3b antibodies are accurate serological markers of early and late SARS-CoV-2 infection. Nat Immunol 2020, published 17 August. Full-text: https://doi.org/10.1038/s41590-020-0773-7
A broader landscape of antibody responses to a range of viral proteins may help in detecting the immunogenicity of SARS-CoV-2 infection and understanding pathogenesis and immunity. Sophie Valkenburg, Niloufar Kavian, Asmaa Hachim and colleagues used the luciferase immunoprecipitation system (LIPS) assay to assess the antibody responses to a panel of 15 SARS-CoV-2 antigens; four structural proteins (S, N, M and E), three S subunits (S1, S2 and S2′), the seven available ORFs (ORF3a, ORF3b, ORF6, ORF7a, ORF7b, ORF8 and ORF10) and one relevant NSP within ORF1ab (NSP1). Their data suggest that the combinational use of ORF3b, ORF8 and N may be a high-performing marker of infection at early and late time points.
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.
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.”
Iadecola C, Anrather J, Kamel H. Effects of COVID-19 on the nervous system. Cell 2020, published 19 August. Full-text: https://www.cell.com/cell/fulltext/S0092-8674(20)31070-9
Many hospitalized COVID-19 patients exhibit neurological manifestations, ranging from headache and loss of smell, to confusion and disabling strokes. The disease might also take a toll on the nervous system in the long term. Follow Costantino Iadecola, Josef Anrather and Hooman Kamel in this appraisal of the potential for neurotropism and mechanisms of neuropathogenesis of SARS-CoV-2.
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.
Hassan AP, Kafai NM, Dmitriev IP. A single-dose intranasal ChAd vaccine protects upper and lower respiratory tracts against SARS-CoV-2. Cell August 19, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.08.026
In their animal experiments on mice expressing the ACE receptor, Ahmed Hassan and colleagues from St. Louis, US show the protective activity of a chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized Spike protein. Of note, intramuscular dosing induced robust systemic humoral and cell-mediated immune responses but did not confer sterilizing immunity. In contrast, a single intranasal dose induced high levels of neutralizing antibodies, promoted systemic and mucosal IgA and T cell responses, and virtually completely prevented SARS-CoV-2 infection in both the upper and lower respiratory tracts.
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 in which 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 monkey Callithrix jacchus (C. jacchus). M. mulatta most closely recapitulated human-like conditions, including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues.
Johansen MD, Irving A, Montagutelli X, et al. Animal and translational models of SARS-CoV-2 infection and COVID-19. Mucosal Immunol. 2020 Aug 20:1-15. PubMed: https://pubmed.gov/32820248. Full-text: https://doi.org/10.1038/s41385-020-00340-z
Elucidating the mechanisms of pathogenesis will enable the identification of the most effective therapies. Head-to-head comparison of existing drugs, testing of safety, and the development of new and targeted preventions and treatments is most efficiently achieved using representative animal models of primary infection with validation of findings in primary human cells and tissues. Philip Hansbro, Matt Johansen and colleagues explore and discuss the diverse animal, cell and tissue models that are being used and developed. A 10-page read with 246 references for your next weekend.
Feng L, Wang Q, Shan C, et al. An adenovirus-vectored COVID-19 vaccine confers protection from SARS-COV-2 challenge in rhesus macaques. Nat Commun 11, 4207 (2020). Full-text: https://doi.org/10.1038/s41467-020-18077-5
Ling Chen, Liqiang Feng and colleagues report the generation of a replication-incompetent recombinant serotype 5 adenovirus, Ad5-S-nb2, which elicited systemic S-specific antibody and cell-mediated immune (CMI) responses in mice and rhesus macaques both after intramuscular injection and intranasal inoculation. At 30 days after a single vaccination with Ad5-S-nb2, macaques were protected against SARS-CoV-2 challenge.
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.
Diagram of peptide identification workflow illustrating the algorithms used and filtering criterion applied to refine peptide selection. Reproduced with permission.
Price WN 2nd, Rai AK, Minssen T. Knowledge transfer for large-scale vaccine manufacturing. Science. 2020 Aug 21;369(6506):912-914. PubMed: https://pubmed.gov/32792464. Full-text: https://doi.org/10.1126/science.abc9588
Identifying an effective SARS-CoV-2 vaccine and prove its safety in huge clinical trials is only the first step. The next step is not less challenging: manufacturing vaccines at enormous scale. In this Policy Forum, law school scholars Nicholson Price, Arti Rai and Timo Minssen explain that fast manufacturing will require not only physical capacity but also access to knowledge not contained in patents or in other public disclosures. Follow the authors on a path through the jungle of licenses, know-how transfer, hostage taking and manufacturing secrecy, and discover why large biopharmaceutical firms are now willing to share information that they might previously have viewed as providing competitive advantage.
Callaway E. The unequal scramble for coronavirus vaccines — by the numbers. Nature 2020, published 24 August. Full-text: https://www.nature.com/articles/d41586-020-02450-x
Will SARS-CoV-2 vaccines be only for the rich? Ellen Callaway shows how wealthy countries have struck deals to buy more than two billion doses of coronavirus vaccine. Find out that the UK is the world’s highest per-capita buyer, with 340 million purchased: around 5 doses for each citizen. And read more about COVAX, spearheaded by Gavi, a Geneva-based funder of vaccines for low-income countries, along with CEPI and the World Health Organization. It aims to secure 2 billion vaccine doses. One billion are for 92 low- and middle-income countries and economies (LMICS), which encompass half the world’s population.
Most of the vaccines will be manufactured in Europe and in the US. Reproduced with permission.
To KK, Hung IF, Ip JD, et al. COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing. Clinical Infectious Diseases, 25 August 2020, ciaa1275. Full-text: https://doi.org/10.1093/cid/ciaa1275
The first case of re-infection? During recent weeks, there has been probably no other case report gaining so much media attraction as this 33-year old gentleman residing in Hong Kong. By the end of March, a mildly symptomatic SARS-Cov-2 infection was confirmed by a positive posterior oropharyngeal saliva PCR on March 26, 2020. On August 15, 142 days later, the patient returned to Hong Kong from Spain via the United Kingdom and was tested positive by SARS-CoV-2 RT-PCR on the posterior oropharyngeal saliva taken for entry screening at the Hong Kong airport. Of note, the patient remained asymptomatic during the second episode but had elevated CRP, relatively high viral load with gradual decline, and seroconversion of SARS-CoV-2 IgG during the second episode, suggesting that this was a genuine episode of acute infection. Viral genomes from first and second episodes belonged to different clades/lineages. Kelvin Kai-Wang To and his colleagues discuss several implications of this case.
Damas J, Hughes GM, Keough KC, et al. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates. PNAS August 21, 2020 Full-text: https://doi.org/10.1073/pnas.2010146117
Joana Damas and colleagues utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. A large number of mammals were identified that can potentially be infected by SARS-CoV-2 via their ACE2 proteins. Species with the highest risk for SARS-CoV-2 infection were wildlife and endangered species. However, the authors urge caution not to overinterpret their predictions, given the limited infectivity data for the species studied.
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 concluded that the characterization of these IGHV3-53 antibodies was a promising starting point for rational vaccine design.
Faginani et al. Figure 1. Representation of “reverse vaccinology 2.0” theory: focus on the molecular features of IGHV3-53-encoded antibodies. Monoclonal antibodies are obtained from seropositive subjects, isolated and structurally characterized. Based on the molecular features, a structure-based immunogen is designed and then tested in appropriate animal models. Reproduced with permission.
Slaoui M, Hepburn M. Developing Safe and Effective Covid Vaccines — Operation Warp Speed’s Strategy and Approach. N Engl J Med 2020, published 26 August. Full-text: https://doi.org/10.1056/NEJMp2027405
What is OWS and what does it do? Moncef Slaoui and Matthew Hepburn from Operation Warp Speed explain the forces behind a national vaccine strategy. The players: Pfizer and BioNTech, AstraZeneca and Oxford University, Janssen, Moderna, Janssen, Novavax, Sanofi/GSK. Will they succeed in this unprecedented endeavor?