Publications by authors named "Yoshihiro Kawaoka"

571 Publications

Hypergraph models of biological networks to identify genes critical to pathogenic viral response.

BMC Bioinformatics 2021 May 29;22(1):287. Epub 2021 May 29.

Computing and Analytics Division, Pacific Northwest National Laboratory, Seattle, WA, USA.

Background: Representing biological networks as graphs is a powerful approach to reveal underlying patterns, signatures, and critical components from high-throughput biomolecular data. However, graphs do not natively capture the multi-way relationships present among genes and proteins in biological systems. Hypergraphs are generalizations of graphs that naturally model multi-way relationships and have shown promise in modeling systems such as protein complexes and metabolic reactions. In this paper we seek to understand how hypergraphs can more faithfully identify, and potentially predict, important genes based on complex relationships inferred from genomic expression data sets.

Results: We compiled a novel data set of transcriptional host response to pathogenic viral infections and formulated relationships between genes as a hypergraph where hyperedges represent significantly perturbed genes, and vertices represent individual biological samples with specific experimental conditions. We find that hypergraph betweenness centrality is a superior method for identification of genes important to viral response when compared with graph centrality.

Conclusions: Our results demonstrate the utility of using hypergraphs to represent complex biological systems and highlight central important responses in common to a variety of highly pathogenic viruses.
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http://dx.doi.org/10.1186/s12859-021-04197-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164482PMC
May 2021

Profiling B cell immunodominance after SARS-CoV-2 infection reveals antibody evolution to non-neutralizing viral targets.

Immunity 2021 06 6;54(6):1290-1303.e7. Epub 2021 May 6.

Department of Medicine, Washington University School of Medicine, St Louis, MO 63130, USA.

Dissecting the evolution of memory B cells (MBCs) against SARS-CoV-2 is critical for understanding antibody recall upon secondary exposure. Here, we used single-cell sequencing to profile SARS-CoV-2-reactive B cells in 38 COVID-19 patients. Using oligo-tagged antigen baits, we isolated B cells specific to the SARS-CoV-2 spike, nucleoprotein (NP), open reading frame 8 (ORF8), and endemic human coronavirus (HCoV) spike proteins. SARS-CoV-2 spike-specific cells were enriched in the memory compartment of acutely infected and convalescent patients several months post symptom onset. With severe acute infection, substantial populations of endemic HCoV-reactive antibody-secreting cells were identified and possessed highly mutated variable genes, signifying preexisting immunity. Finally, MBCs exhibited pronounced maturation to NP and ORF8 over time, especially in older patients. Monoclonal antibodies against these targets were non-neutralizing and non-protective in vivo. These findings reveal antibody adaptation to non-neutralizing intracellular antigens during infection, emphasizing the importance of vaccination for inducing neutralizing spike-specific MBCs.
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http://dx.doi.org/10.1016/j.immuni.2021.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101792PMC
June 2021

Multivalent nanoparticle-based vaccines protect hamsters against SARS-CoV-2 after a single immunization.

Commun Biol 2021 05 19;4(1):597. Epub 2021 May 19.

School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA.

The COVID-19 pandemic continues to wreak havoc as worldwide SARS-CoV-2 infection, hospitalization, and death rates climb unabated. Effective vaccines remain the most promising approach to counter SARS-CoV-2. Yet, while promising results are emerging from COVID-19 vaccine trials, the need for multiple doses and the challenges associated with the widespread distribution and administration of vaccines remain concerns. Here, we engineered the coat protein of the MS2 bacteriophage and generated nanoparticles displaying multiple copies of the SARS-CoV-2 spike (S) protein. The use of these nanoparticles as vaccines generated high neutralizing antibody titers and protected Syrian hamsters from a challenge with SARS-CoV-2 after a single immunization with no infectious virus detected in the lungs. This nanoparticle-based vaccine platform thus provides protection after a single immunization and may be broadly applicable for protecting against SARS-CoV-2 and future pathogens with pandemic potential.
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http://dx.doi.org/10.1038/s42003-021-02128-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134492PMC
May 2021

Macrocyclic peptides exhibit antiviral effects against influenza virus HA and prevent pneumonia in animal models.

Nat Commun 2021 05 11;12(1):2654. Epub 2021 May 11.

Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.

Most anti-influenza drugs currently used, such as oseltamivir and zanamivir, inhibit the enzymatic activity of neuraminidase. However, neuraminidase inhibitor-resistant viruses have already been identified from various influenza virus isolates. Here, we report the development of a class of macrocyclic peptides that bind the influenza viral envelope protein hemagglutinin, named iHA. Of 28 iHAs examined, iHA-24 and iHA-100 have inhibitory effects on the in vitro replication of a wide range of Group 1 influenza viruses. In particular, iHA-100 bifunctionally inhibits hemagglutinin-mediated adsorption and membrane fusion through binding to the stalk domain of hemagglutinin. Moreover, iHA-100 shows powerful efficacy in inhibiting the growth of highly pathogenic influenza viruses and preventing severe pneumonia at later stages of infection in mouse and non-human primate cynomolgus macaque models. This study shows the potential for developing cyclic peptides that can be produced more efficiently than antibodies and have multiple functions as next-generation, mid-sized biomolecules.
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http://dx.doi.org/10.1038/s41467-021-22964-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113231PMC
May 2021

CCR2 Regulates Vaccine-Induced Mucosal T-Cell Memory to Influenza A Virus.

J Virol 2021 May 5. Epub 2021 May 5.

Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, 53706, WI, USA

Elicitation of lung tissue-resident memory CD8 T cells (Ts) is a goal of T-cell based vaccines against respiratory viral pathogens, such as influenza A virus (IAV). Chemokine receptor 2 (CCR2)-dependent monocyte trafficking plays an essential role in the establishment of CD8 Ts in lungs of IAV-infected mice. Here, we used a combination adjuvant-based subunit vaccine strategy that evokes multifaceted (T1/T17/T1/T17) IAV nucleoprotein-specific lung Ts, to determine whether CCR2 and monocyte infiltration are essential for vaccine-induced T development and protective immunity to IAV in lungs. Following intranasal vaccination, neutrophils, monocytes, conventional DCs and monocyte-derived dendritic cells internalized and processed vaccine antigen in lungs. We found that Basic Leucine Zipper ATF-Like Transcription Factor 3 (BATF-3)-dependent DCs were essential for eliciting T cell responses, but CCR2 deficiency enhanced the differentiation of CD127/KLRG-1, OX40CD62L and mucosally imprinted CD69CD103 effector and memory CD8 T cells in lungs and airways of vaccinated mice. Mechanistically, increased development of lung Ts, induced by CCR2 deficiency was linked to dampened expression of T-bet, but not altered TCF-1 levels or T cell receptor signaling in CD8 T cells. T1/T17 functional programming, parenchymal localization of CD8/CD4 effector and memory T cells, recall T cell responses and protective immunity to a lethal IAV infection were unaffected in CCR2-deficient mice. Taken together, we identified a negative regulatory role for CCR2 and monocyte trafficking in mucosal imprinting and differentiation of vaccine-induced Ts. Mechanistic insights from this study may aid the development of T-cell-based vaccines against respiratory viral pathogens including IAV and SARS-CoV-2.While antibody-based immunity to influenza A virus (IAV) is type and sub-type specific, lung and airway-resident memory T cells that recognize conserved epitopes in the internal viral proteins are known to provide heterosubtypic immunity. Hence, broadly protective IAV vaccines need to elicit robust T-cell memory in the respiratory tract. We have developed a combination adjuvant-based IAV nucleoprotein vaccine that elicits strong CD4 and CD8 T cell memory in lungs and protects against H1N1 and H5N1 strains of IAV. In this study, we examined the mechanisms that control vaccine-induced protective memory T cells in the respiratory tract. We found that trafficking of monocytes into lungs might limit the development of anti-viral lung-resident memory T cells, following intranasal vaccination. These findings suggested that strategies that limit monocyte infiltration can potentiate vaccine-induced frontline T-cell immunity to respiratory viruses, such as IAV and SARS-CoV-2.
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http://dx.doi.org/10.1128/JVI.00530-21DOI Listing
May 2021

Antigenic differences between equine influenza virus vaccine strains and Florida sublineage clade 1 strains isolated in Europe in 2019.

Vet J 2021 Jun 14;272:105674. Epub 2021 Apr 14.

Virology Unit, Irish Equine Centre, Naas, Co. Kildare, W91 RH93 Johnstown, Ireland.

From late 2018 to 2019, equine influenza virus (EIV) strains of Florida sublineage clade 1 (Fc1), which had until then been circulating mainly in the United States, suddenly spread across Europe causing many outbreaks, and Florida sublineage clade 2 (Fc2) strains, which had been circulating mainly in Europe, have not been detected in Europe since 2018. Since 2010, the World Organisation for Animal Health (OIE) has recommended that EIV vaccines contain an Fc1 strain that is like A/equine/South Africa/4/2003 or A/equine/Ohio/2003. Accordingly, Japanese vaccines contain A/equine/Ibaraki/1/2007 as the Fc1 strain. To evaluate the effectiveness of these vaccines against the Fc1 strains detected in Europe in 2019, we performed virus neutralization tests using horse antisera. Challenge viruses used were Irish strain A/equine/Tipperary/1/2019 and two recombinant viruses generated by reverse genetics. Recombinant viruses possessing hemagglutinin (HA) and neuraminidase (NA) derived from A/equine/Tipperary/1/2019 (rA/equine/Tipperary/1/2019) or British strain A/equine/Essex/1/2019 (rA/equine/Essex/1/2019) were generated. Equine antisera against A/equine/South Africa/2003 and A/equine/Ibaraki/2007 were produced by experimental infection. Antibody titers against A/equine/Tipperary/1/2019, rA/equine/Tipperary/1/2019, and rA/equine/Essex/1/2019 were 2.5- to 6.3-fold lower than those against the homologous vaccine strains A/equine/South Africa/4/2003 or A/equine/Ibaraki/2007. These results suggest that the ongoing evolution of the Fc1 viruses may impact on antigenicity and although antibodies against current vaccine strains neutralize the 2019 strains, ongoing surveillance is essential for optimum choice of candidate vaccine strains.
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http://dx.doi.org/10.1016/j.tvjl.2021.105674DOI Listing
June 2021

Accuracy of rapid antigen detection test for nasopharyngeal swab specimens and saliva samples in comparison with RT-PCR and viral culture for SARS-CoV-2 detection.

J Infect Chemother 2021 Jul 17;27(7):1058-1062. Epub 2021 Apr 17.

Department of Laboratory Medicine, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo, Japan.

Introduction: Rapid antigen detection (RAD) tests are convenient tools for detecting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in clinics, and testing using saliva samples could decrease the risk of infection during sample collection. This study aimed to assess the accuracy of the SARS-CoV-2 RAD for testing of nasopharyngeal swab specimens and saliva samples in comparison with the RT-PCR tests and viral culture for detecting viable virus.

Methods: One hundred seventeen nasopharyngeal swab specimens and 73 saliva samples with positive results on RT-PCR were used. Residual samples were assayed using a commercially available RAD test immediately, and its positivity was determined at various time points during the clinical course. The concordance between 54 nasopharyngeal swab samples and saliva samples that were collected simultaneously was determined. Viral culture was performed on 117 samples and compared with the results of the RAD test.

Results: The positive rate of RAD test using saliva samples was low throughout the clinical course. Poor concordance was observed between nasopharyngeal swab specimens and saliva samples (75.9%, kappa coefficient 0.310). However, a substantially high concordance between the RAD test and viral culture was observed in both nasopharyngeal swab specimens (86.8%, kappa coefficient 0.680) and saliva samples (95.1%, kappa coefficient 0.643).

Conclusions: The sensitivity of the SARS-CoV-2 RAD test was insufficient, particularly for saliva samples. However, a substantially high concordance with viral culture suggests its potential utility as an auxiliary test for estimating SARS-CoV-2 viability.
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http://dx.doi.org/10.1016/j.jiac.2021.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052479PMC
July 2021

A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus.

Immunity 2021 Apr;54(4):815-828.e5

Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA. Electronic address:

Protective Ebola virus (EBOV) antibodies have neutralizing activity and induction of antibody constant domain (Fc)-mediated innate immune effector functions. Efforts to enhance Fc effector functionality often focus on maximizing antibody-dependent cellular cytotoxicity, yet distinct combinations of functions could be critical for antibody-mediated protection. As neutralizing antibodies have been cloned from EBOV disease survivors, we sought to identify survivor Fc effector profiles to help guide Fc optimization strategies. Survivors developed a range of functional antibody responses, and we therefore applied a rapid, high-throughput Fc engineering platform to define the most protective profiles. We generated a library of Fc variants with identical antigen-binding fragments (Fabs) from an EBOV neutralizing antibody. Fc variants with antibody-mediated complement deposition and moderate natural killer (NK) cell activity demonstrated complete protective activity in a stringent in vivo mouse model. Our findings highlight the importance of specific effector functions in antibody-mediated protection, and the experimental platform presents a generalizable resource for identifying correlates of immunity to guide therapeutic antibody design.
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http://dx.doi.org/10.1016/j.immuni.2021.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111768PMC
April 2021

CCR2 Regulates Vaccine-Induced Mucosal T-Cell Memory to Influenza A Virus.

bioRxiv 2021 Mar 25. Epub 2021 Mar 25.

Elicitation of lung tissue-resident memory CD8 T cells (T s) is a goal of T-cell based vaccines against respiratory viral pathogens such as influenza A virus (IAV). Chemokine receptor 2 (CCR2)-dependent monocyte trafficking plays an essential role in the establishment of CD8 T s in lungs of IAV-infected mice. Here, we used a combination adjuvant-based subunit vaccine strategy that evokes multifaceted (T 1/T 17/T 1/T 17) IAV nucleoprotein-specific lung T s, to determine whether CCR2 and monocyte infiltration are essential for vaccine-induced T development and protective immunity to IAV in lungs. Following intranasal vaccination, neutrophils, monocytes, conventional dendrtitic cells (DCs) and monocyte-derived DCs internalized and processed vaccine antigen in lungs. We also found that Basic Leucine Zipper ATF-Like Transcription Factor 3 (BATF-3)-dependent DCs were essential for eliciting T cell responses, but CCR2 deficiency enhanced the differentiation of CD127 /KLRG-1 , OX40 CD62L and mucosally imprinted CD69 CD103 effector and memory CD8 T cells in lungs and airways of vaccinated mice. Mechanistically, increased development of lung T s, induced by CCR2 deficiency was linked to dampened expression of T-bet, but not altered TCF-1 levels or T cell receptor signaling in CD8 T cells. T1/T17 functional programming, parenchymal localization of CD8/CD4 effector and memory T cells, recall T cell responses and protective immunity to a lethal IAV infection were unaffected in CCR2-deficient mice. Taken together, we identified a negative regulatory role for CCR2 and monocyte trafficking in mucosal imprinting and differentiation of vaccine-induced T s. Mechanistic insights from this study may aid the development of T-cell-based vaccines against respiratory viral pathogens including IAV and SARS-CoV-2.

Importance: While antibody-based immunity to influenza A virus (IAV) is type and sub-type specific, lung and airway-resident memory T cells that recognize conserved epitopes in the internal viral proteins are known to provide heterosubtypic immunity. Hence, broadly protective IAV vaccines need to elicit robust T-cell memory in the respiratory tract. We have developed a combination adjuvant-based IAV nucleoprotein vaccine that elicits strong CD4 and CD8 T cell memory in lungs and protects against H1N1 and H5N1 strains of IAV. In this study, we examined the mechanisms that control vaccine-induced protective memory T cells in the respiratory tract. We found that trafficking of monocytes into lungs might limit the development of anti-viral lung-resident memory T cells, following intranasal vaccination. These findings suggested that strategies that limit monocyte infiltration can potentiate vaccine-induced frontline T-cell immunity to respiratory viruses such as IAV and SARS-CoV-2.
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http://dx.doi.org/10.1101/2021.03.24.436901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010722PMC
March 2021

Increased risk of rhinovirus infection in children during the coronavirus disease-19 pandemic.

Influenza Other Respir Viruses 2021 07 14;15(4):488-494. Epub 2021 Mar 14.

Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

Background: Coronavirus disease (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected in Japan in January 2020 and has spread throughout the country. Previous studies have reported that viral interference among influenza virus, rhinovirus, and other respiratory viruses can affect viral infections at the host and population level.

Methods: To investigate the impact of COVID-19 on influenza and other respiratory virus infections, we analyzed clinical specimens collected from 2244 patients in Japan with respiratory diseases between January 2018 and September 2020.

Results: The frequency of influenza and other respiratory viruses (coxsackievirus A and B; echovirus; enterovirus; human coronavirus 229E, HKU1, NL63, and OC43; human metapneumovirus; human parainfluenza virus 1, 2, 3, and 4; human parechovirus; human respiratory syncytial virus; human adenovirus; human bocavirus; human parvovirus B19; herpes simplex virus type 1; and varicella-zoster virus) was appreciably reduced among all patients during the COVID-19 pandemic except for that of rhinovirus in children younger than 10 years, which was appreciably increased. COVID-19 has not spread among this age group, suggesting an increased risk of rhinovirus infection in children.

Conclusions: Rhinovirus infections should be continuously monitored to understand their increased risk during the COVID-19 pandemic and viral interference with SARS-CoV-2.
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http://dx.doi.org/10.1111/irv.12854DOI Listing
July 2021

Longitudinal antibody repertoire in "mild" versus "severe" COVID-19 patients reveals immune markers associated with disease severity and resolution.

Sci Adv 2021 03 5;7(10). Epub 2021 Mar 5.

Division of Viral Products, Center for Biologics Evaluation and Research (CBER), FDA, Silver Spring, MD 20871, USA.

Limited knowledge exists on immune markers associated with disease severity or recovery in patients with coronavirus disease 2019 (COVID-19). Here, we elucidated longitudinal evolution of SARS-CoV-2 antibody repertoire in patients with acute COVID-19. Differential kinetics was observed for immunoglobulin M (IgM)/IgG/IgA epitope diversity, antibody binding, and affinity maturation in "severe" versus "mild" COVID-19 patients. IgG profile demonstrated immunodominant antigenic sequences encompassing fusion peptide and receptor binding domain (RBD) in patients with mild COVID-19 who recovered early compared with "fatal" COVID-19 patients. In patients with severe COVID-19, high-titer IgA were observed, primarily against RBD, especially in patients who succumbed to SARS-CoV-2 infection. The patients with mild COVID-19 showed marked increase in antibody affinity maturation to prefusion SARS-CoV-2 spike that associated with faster recovery from COVID-19. This study revealed antibody markers associated with disease severity and resolution of clinical disease that could inform development and evaluation of effective immune-based countermeasures against COVID-19.
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http://dx.doi.org/10.1126/sciadv.abf2467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935365PMC
March 2021

Transmission of SARS-CoV-2 in domestic cats imposes a narrow bottleneck.

PLoS Pathog 2021 02 26;17(2):e1009373. Epub 2021 Feb 26.

Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

The evolutionary mechanisms by which SARS-CoV-2 viruses adapt to mammalian hosts and, potentially, undergo antigenic evolution depend on the ways genetic variation is generated and selected within and between individual hosts. Using domestic cats as a model, we show that SARS-CoV-2 consensus sequences remain largely unchanged over time within hosts, while dynamic sub-consensus diversity reveals processes of genetic drift and weak purifying selection. We further identify a notable variant at amino acid position 655 in Spike (H655Y), which was previously shown to confer escape from human monoclonal antibodies. This variant arises rapidly and persists at intermediate frequencies in index cats. It also becomes fixed following transmission in two of three pairs. These dynamics suggest this site may be under positive selection in this system and illustrate how a variant can quickly arise and become fixed in parallel across multiple transmission pairs. Transmission of SARS-CoV-2 in cats involved a narrow bottleneck, with new infections founded by fewer than ten viruses. In RNA virus evolution, stochastic processes like narrow transmission bottlenecks and genetic drift typically act to constrain the overall pace of adaptive evolution. Our data suggest that here, positive selection in index cats followed by a narrow transmission bottleneck may have instead accelerated the fixation of S H655Y, a potentially beneficial SARS-CoV-2 variant. Overall, our study suggests species- and context-specific adaptations are likely to continue to emerge. This underscores the importance of continued genomic surveillance for new SARS-CoV-2 variants as well as heightened scrutiny for signatures of SARS-CoV-2 positive selection in humans and mammalian model systems.
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http://dx.doi.org/10.1371/journal.ppat.1009373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946358PMC
February 2021

Antibody titers against SARS-CoV-2 decline, but do not disappear for several months.

EClinicalMedicine 2021 Feb 11;32:100734. Epub 2021 Feb 11.

Department of Hematology and Clinical Immunology, Yokohama City University School of Medicine, Japan.

Background: To develop an effective vaccine against a novel viral pathogen, it is important to understand the longitudinal antibody responses against its first infection. Here we performed a longitudinal study of antibody responses against SARS-CoV-2 in symptomatic patients.

Methods: Sequential blood samples were collected from 39 individuals at various timepoints between 0 and 154 days after onset. IgG or IgM titers to the receptor binding domain (RBD) of the S protein, the ectodomain of the S protein, and the N protein were determined by using an ELISA. Neutralizing antibody titers were measured by using a plaque reduction assay.

Findings: The IgG titers to the RBD of the S protein, the ectodomain of the S protein, and the N protein peaked at about 20 days after onset, gradually decreased thereafter, and were maintained for several months after onset. Extrapolation modeling analysis suggested that the IgG antibodies were maintained for this amount of time because the rate of reduction slowed after 30 days post-onset. IgM titers to the RBD decreased rapidly and disappeared in some individuals after 90 days post-onset. All patients, except one, possessed neutralizing antibodies against authentic SARS-CoV-2, which they retained at 90 days after onset. The highest antibody titers in patients with severe infections were higher than those in patients with mild or moderate infections, but the decrease in antibody titer in the severe infection cohort was more remarkable than that in the mild or moderate infection cohort.

Interpretation: Although the number of patients is limited, our results show that the antibody response against the first SARS-CoV-2 infection in symptomatic patients is typical of that observed in an acute viral infection.

Funding: The Japan Agency for Medical Research and Development and the National Institutes of Allergy and Infectious Diseases.
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http://dx.doi.org/10.1016/j.eclinm.2021.100734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877219PMC
February 2021

Plasticity of the Influenza Virus H5 HA Protein.

mBio 2021 02 9;12(1). Epub 2021 Feb 9.

Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA

Since the emergence of highly pathogenic avian influenza viruses of the H5 subtype, the major viral antigen, hemagglutinin (HA), has undergone constant evolution, resulting in numerous genetic and antigenic (sub)clades. To explore the consequences of amino acid changes at sites that may affect the antigenicity of H5 viruses, we simultaneously mutated 17 amino acid positions of an H5 HA by using a synthetic gene library that, theoretically, encodes all combinations of the 20 amino acids at the 17 positions. All 251 mutant viruses sequenced possessed ≥13 amino acid substitutions in HA, demonstrating that the targeted sites can accommodate a substantial number of mutations. Selection with ferret sera raised against H5 viruses of different clades resulted in the isolation of 39 genotypes. Further analysis of seven variants demonstrated that they were antigenically different from the parental virus and replicated efficiently in mammalian cells. Our data demonstrate the substantial plasticity of the influenza virus H5 HA protein, which may lead to novel antigenic variants. The HA protein of influenza A viruses is the major viral antigen. In this study, we simultaneously introduced mutations at 17 amino acid positions of an H5 HA expected to affect antigenicity. Viruses with ≥13 amino acid changes in HA were viable, and some had altered antigenic properties. H5 HA can therefore accommodate many mutations in regions that affect antigenicity. The substantial plasticity of H5 HA may facilitate the emergence of novel antigenic variants.
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http://dx.doi.org/10.1128/mBio.03324-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885105PMC
February 2021

Development and deployment of COVID-19 vaccines for those most vulnerable.

Sci Transl Med 2021 02;13(579)

Human Vaccines Project, New York, NY 10119, USA.

Development of safe and effective COVID-19 vaccines is a global priority and the best hope for ending the COVID-19 pandemic. Remarkably, in less than 1 year, vaccines have been developed and shown to be efficacious and are already being deployed worldwide. Yet, many challenges remain. Immune senescence and comorbidities in aging populations and immune dysregulation in populations living in low-resource settings may impede vaccine effectiveness. Distribution of vaccines among these populations where vaccine access is historically low remains challenging. In this Review, we address these challenges and provide strategies for ensuring that vaccines are developed and deployed for those most vulnerable.
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http://dx.doi.org/10.1126/scitranslmed.abd1525DOI Listing
February 2021

Growth properties and immunogenicity of a virus generated by reverse genetics for an inactivated equine influenza vaccine.

Equine Vet J 2021 Feb 1. Epub 2021 Feb 1.

Molecular Biology Division, Equine Research Institute, Japan Racing Association, Tochigi, Japan.

Background: Keeping vaccine strains up to date is the key to controlling equine influenza (EI). Viruses generated by reverse genetics (RG) are likely to be effective for quickly updating a vaccine strain.

Objectives: To evaluate the growth properties of an RG virus in embryonated chicken eggs, and to evaluate antibody responses to a formalin-inactivated vaccine derived from the RG virus in Thoroughbred horses.

Study Design: In vitro and in vivo experiments.

Methods: Wild-type (WT) viruses (A/equine/Ibaraki/1/2007) or RG viruses (consisting of haemagglutinin [HA] and neuraminidase genes derived from A/equine/Ibaraki/1/2007 and the six other genes derived from high-growth A/Puerto Rico/8/34) were inoculated into embryonated chicken eggs, and the allantoic fluids were harvested at every 24 hours after inoculation. WT and RG viruses were inactivated by formalin for vaccine use. Ten unvaccinated yearlings (five each for WT or RG vaccine) received the first two doses of a primary vaccination course 4 weeks apart followed by their third dose 12 weeks later. Twenty vaccinated adult horses (10 each for WT or RG vaccine) received a single dose of a booster vaccination.

Results: The RG virus had high growth properties in embryonated chicken eggs. Unvaccinated yearlings responded poorly to the first vaccination, especially those that received the RG vaccine, but mounted better responses to the second and the third vaccinations, and maintained relatively high haemagglutination inhibition (HI) titres up to 28 weeks after the first vaccination. Vaccinated adult horses did not respond remarkably to the booster vaccination, but no horses showed titres below their pre-booster values even at 12 weeks after vaccination. The RG virus elicited immunogenicity in horses adequate for vaccine use.

Main Limitations: No virus challenge study was performed.

Conclusions: The RG viruses are useful as an EI vaccine strain, and quick updates of an EI vaccine strain can be achieved by using RG techniques.
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http://dx.doi.org/10.1111/evj.13431DOI Listing
February 2021

Protective Immunity and Persistent Lung Sequelae in Domestic Cats after SARS-CoV-2 Infection.

Emerg Infect Dis 2021 02;27(2):660-663

Severe acute respiratory syndrome coronavirus 2 readily transmits between domestic cats. We found that domestic cats that recover from an initial infection might be protected from reinfection. However, we found long-term persistence of inflammation and other lung lesions after infection, despite a lack of clinical symptoms and limited viral replication in the lungs.
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http://dx.doi.org/10.3201/eid2702.203884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853591PMC
February 2021

SARS-CoV-2 Infection Severity Is Linked to Superior Humoral Immunity against the Spike.

mBio 2021 01 19;12(1). Epub 2021 Jan 19.

Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, Illinois, USA

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a global pandemic. The antigen specificity of the antibody response mounted against this novel virus is not understood in detail. Here, we report that subjects with a more severe SARS-CoV-2 infection exhibit a larger antibody response against the spike and nucleocapsid protein and epitope spreading to subdominant viral antigens, such as open reading frame 8 and nonstructural proteins. Subjects with a greater antibody response mounted a larger memory B cell response against the spike, but not the nucleocapsid protein. Additionally, we revealed that antibodies against the spike are still capable of binding the D614G spike mutant and cross-react with the SARS-CoV-1 receptor binding domain. Together, this study reveals that subjects with a more severe SARS-CoV-2 infection exhibit a greater overall antibody response to the spike and nucleocapsid protein and a larger memory B cell response against the spike. With the ongoing pandemic, it is critical to understand how natural immunity against SARS-CoV-2 and COVID-19 develops. We have identified that subjects with more severe COVID-19 disease mount a more robust and neutralizing antibody response against SARS-CoV-2 spike protein. Subjects who mounted a larger response against the spike also mounted antibody responses against other viral antigens, including the nucleocapsid protein and ORF8. Additionally, this study reveals that subjects with more severe disease mount a larger memory B cell response against the spike. These data suggest that subjects with more severe COVID-19 disease are likely better protected from reinfection with SARS-CoV-2.
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http://dx.doi.org/10.1128/mBio.02940-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845638PMC
January 2021

Fever, Diarrhea, and Severe Disease Correlate with High Persistent Antibody Levels against SARS-CoV-2.

medRxiv 2021 Jan 6. Epub 2021 Jan 6.

Lasting immunity will be critical for overcoming the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, factors that drive the development of high titers of anti-SARS-CoV-2 antibodies and how long those antibodies persist remain unclear. Our objective was to comprehensively evaluate anti-SARS-CoV-2 antibodies in a clinically diverse COVID-19 convalescent cohort at defined time points to determine if anti-SARS-CoV-2 antibodies persist and to identify clinical and demographic factors that correlate with high titers. Using a novel multiplex assay to quantify IgG against four SARS-CoV-2 antigens, a receptor binding domain-angiotensin converting enzyme 2 inhibition assay, and a SARS-CoV-2 neutralization assay, we found that 98% of COVID-19 convalescent subjects had anti-SARS-CoV-2 antibodies five weeks after symptom resolution (n=113). Further, antibody levels did not decline three months after symptom resolution (n=79). As expected, greater disease severity, older age, male sex, obesity, and higher Charlson Comorbidity Index score correlated with increased anti-SARS-CoV-2 antibody levels. We demonstrated for the first time that COVID-19 symptoms, namely fever, abdominal pain, diarrhea and low appetite, correlated consistently with higher anti-SARS-CoV-2 antibody levels. Our results provide new insights into the development and persistence of anti-SARS-CoV-2 antibodies.
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http://dx.doi.org/10.1101/2021.01.05.21249240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805469PMC
January 2021

A single dose of a vesicular stomatitis virus-based influenza vaccine confers rapid protection against H5 viruses from different clades.

NPJ Vaccines 2020 Jan 10;5(1). Epub 2020 Jan 10.

Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.

The avian influenza virus outbreak in 1997 highlighted the potential of the highly pathogenic H5N1 virus to cause severe disease in humans. Therefore, effective vaccines against H5N1 viruses are needed to counter the potential threat of a global pandemic. We have previously developed a fast-acting and efficacious vaccine against Ebola virus (EBOV) using the vesicular stomatitis virus (VSV) platform. In this study, we generated recombinant VSV-based H5N1 influenza virus vectors to demonstrate the feasibility of this platform for a fast-acting pan-H5 influenza virus vaccine. We chose multiple approaches regarding antigen design and genome location to define a more optimized vaccine approach. After the VSV-based H5N1 influenza virus constructs were recovered and characterized in vitro, mice were vaccinated by a single dose or prime/boost regimen followed by challenge with a lethal dose of the homologous H5 clade 1 virus. We found that a single dose of VSV vectors expressing full-length hemagglutinin (HAfl) were sufficient to provide 100% protection. The vaccine vectors were fast-acting as demonstrated by uniform protection when administered 3 days prior to lethal challenge. Moreover, single vaccination induced cross-protective H5-specific antibodies and protected mice against lethal challenge with various H5 clade 2 viruses, highlighting the potential of the VSV-based HAfl as a pan-H5 influenza virus emergency vaccine.
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http://dx.doi.org/10.1038/s41541-019-0155-zDOI Listing
January 2020

Novel modulators of p53-signaling encoded by unknown genes of emerging viruses.

PLoS Pathog 2021 01 7;17(1):e1009033. Epub 2021 Jan 7.

Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

The p53 transcription factor plays a key role both in cancer and in the cell-intrinsic response to infections. The ORFEOME project hypothesized that novel p53-virus interactions reside in hitherto uncharacterized, unknown, or hypothetical open reading frames (orfs) of human viruses. Hence, 172 orfs of unknown function from the emerging viruses SARS-Coronavirus, MERS-Coronavirus, influenza, Ebola, Zika (ZIKV), Chikungunya and Kaposi Sarcoma-associated herpesvirus (KSHV) were de novo synthesized, validated and tested in a functional screen of p53 signaling. This screen revealed novel mechanisms of p53 virus interactions and two viral proteins KSHV orf10 and ZIKV NS2A binding to p53. Originally identified as the target of small DNA tumor viruses, these experiments reinforce the notion that all viruses, including RNA viruses, interfere with p53 functions. These results validate this resource for analogous systems biology approaches to identify functional properties of uncharacterized viral proteins, long non-coding RNAs and micro RNAs.
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http://dx.doi.org/10.1371/journal.ppat.1009033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790267PMC
January 2021

Emergence of SARS-CoV-2 and its outlook.

Glob Health Med 2020 Feb;2(1):1-2

Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported at the end of 2019 in China. By the end of February 2020, the virus has spread worldwide through continuous human-to-human transmission via contact and droplet infection, demonstrating the ease with which emerging viruses disperse globally through the mass transport system. Here, we summarize our knowledge of other coronaviruses that have infected humans in comparison with SARS-CoV-2.
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http://dx.doi.org/10.35772/ghm.2020.01009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731098PMC
February 2020

Comparison of Rapid Antigen Tests for COVID-19.

Viruses 2020 12 10;12(12). Epub 2020 Dec 10.

Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.

Reverse transcription-quantitative PCR (RT-qPCR)-based tests are widely used to diagnose coronavirus disease 2019 (COVID-19). As a result that these tests cannot be done in local clinics where RT-qPCR testing capability is lacking, rapid antigen tests (RATs) for COVID-19 based on lateral flow immunoassays are used for rapid diagnosis. However, their sensitivity compared with each other and with RT-qPCR and infectious virus isolation has not been examined. Here, we compared the sensitivity among four RATs by using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolates and several types of COVID-19 patient specimens and compared their sensitivity with that of RT-qPCR and infectious virus isolation. Although the RATs read the samples containing large amounts of virus as positive, even the most sensitive RAT read the samples containing small amounts of virus as negative. Moreover, all RATs tested failed to detect viral antigens in several specimens from which the virus was isolated. The current RATs will likely miss some COVID-19 patients who are shedding infectious SARS-CoV-2.
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http://dx.doi.org/10.3390/v12121420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764512PMC
December 2020

Transmission of SARS-CoV-2 in domestic cats imposes a narrow bottleneck.

bioRxiv 2020 Nov 17. Epub 2020 Nov 17.

Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, United States of America.

The evolutionary mechanisms by which SARS-CoV-2 viruses adapt to mammalian hosts and, potentially, escape human immunity depend on the ways genetic variation is generated and selected within and between individual hosts. Using domestic cats as a model, we show that SARS-CoV-2 consensus sequences remain largely unchanged over time within hosts, but dynamic sub-consensus diversity reveals processes of genetic drift and weak purifying selection. Transmission bottlenecks in this system appear narrow, with new infections being founded by fewer than ten viruses. We identify a notable variant at amino acid position 655 in Spike (H655Y) which arises rapidly in index cats and becomes fixed following transmission in two of three pairs, suggesting this site may be under positive selection in feline hosts. We speculate that narrow transmission bottlenecks and the lack of pervasive positive selection combine to constrain the pace of ongoing SARS-CoV-2 adaptive evolution in mammalian hosts.
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http://dx.doi.org/10.1101/2020.11.16.384917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685321PMC
November 2020

SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo.

Science 2020 12 12;370(6523):1464-1468. Epub 2020 Nov 12.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

The spike aspartic acid-614 to glycine (D614G) substitution is prevalent in global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains, but its effects on viral pathogenesis and transmissibility remain unclear. We engineered a SARS-CoV-2 variant containing this substitution. The variant exhibits more efficient infection, replication, and competitive fitness in primary human airway epithelial cells but maintains similar morphology and in vitro neutralization properties, compared with the ancestral wild-type virus. Infection of human angiotensin-converting enzyme 2 (ACE2) transgenic mice and Syrian hamsters with both viruses resulted in similar viral titers in respiratory tissues and pulmonary disease. However, the D614G variant transmits significantly faster and displayed increased competitive fitness than the wild-type virus in hamsters. These data show that the D614G substitution enhances SARS-CoV-2 infectivity, competitive fitness, and transmission in primary human cells and animal models.
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http://dx.doi.org/10.1126/science.abe8499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775736PMC
December 2020

Revealing fine-scale spatiotemporal differences in SARS-CoV-2 introduction and spread.

Nat Commun 2020 11 3;11(1):5558. Epub 2020 Nov 3.

Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA.

Evidence-based public health approaches that minimize the introduction and spread of new SARS-CoV-2 transmission clusters are urgently needed in the United States and other countries struggling with expanding epidemics. Here we analyze 247 full-genome SARS-CoV-2 sequences from two nearby communities in Wisconsin, USA, and find surprisingly distinct patterns of viral spread. Dane County had the 12 known introduction of SARS-CoV-2 in the United States, but this did not lead to descendant community spread. Instead, the Dane County outbreak was seeded by multiple later introductions, followed by limited community spread. In contrast, relatively few introductions in Milwaukee County led to extensive community spread. We present evidence for reduced viral spread in both counties following the statewide "Safer at Home" order, which went into effect 25 March 2020. Our results suggest patterns of SARS-CoV-2 transmission may vary substantially even in nearby communities. Understanding these local patterns will enable better targeting of public health interventions.
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http://dx.doi.org/10.1038/s41467-020-19346-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609670PMC
November 2020

Effectiveness of Face Masks in Preventing Airborne Transmission of SARS-CoV-2.

mSphere 2020 10 21;5(5). Epub 2020 Oct 21.

Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan

Guidelines from the CDC and the WHO recommend the wearing of face masks to prevent the spread of coronavirus (CoV) disease 2019 (COVID-19); however, the protective efficiency of such masks against airborne transmission of infectious severe acute respiratory syndrome CoV-2 (SARS-CoV-2) droplets/aerosols is unknown. Here, we developed an airborne transmission simulator of infectious SARS-CoV-2-containing droplets/aerosols produced by human respiration and coughs and assessed the transmissibility of the infectious droplets/aerosols and the ability of various types of face masks to block the transmission. We found that cotton masks, surgical masks, and N95 masks all have a protective effect with respect to the transmission of infective droplets/aerosols of SARS-CoV-2 and that the protective efficiency was higher when masks were worn by a virus spreader. Importantly, medical masks (surgical masks and even N95 masks) were not able to completely block the transmission of virus droplets/aerosols even when completely sealed. Our data will help medical workers understand the proper use and performance of masks and determine whether they need additional equipment to protect themselves from infected patients. Airborne simulation experiments showed that cotton masks, surgical masks, and N95 masks provide some protection from the transmission of infective SARS-CoV-2 droplets/aerosols; however, medical masks (surgical masks and even N95 masks) could not completely block the transmission of virus droplets/aerosols even when sealed.
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http://dx.doi.org/10.1128/mSphere.00637-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580955PMC
October 2020

HER2-mediated enhancement of Ebola virus entry.

PLoS Pathog 2020 10 14;16(10):e1008900. Epub 2020 Oct 14.

Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

Multiple cell surface molecules including TAM receptors (TYRO3, AXL, and MERTK), a family of tyrosine kinase receptors, can serve as attachment receptors for Ebola virus (EBOV) entry into cells. The interaction of these receptors with EBOV particles is believed to trigger the initial internalization events that lead to macropinocytosis. However, the details of how these interactions lead to EBOV internalization have yet to be elucidated. Here, we screened receptor tyrosine kinase (RTK) inhibitors for anti-EBOV activity by using our previously established biologically contained Ebola virus that lacks the VP30 gene (EBOVΔVP30) and identified several RTKs, including human epidermal growth factor receptor 2 (HER2), as potential targets of anti-EBOV inhibitors and as novel host factors that have a role in EBOV infection. Of these identified RTKs, it was only HER2 whose knockdown by siRNAs impaired EBOVΔVP30-induced AKT1 phosphorylation, an event that is required for AKT1 activation and subsequent macropinocytosis. Stable expression of HER2 resulted in constitutive activation of AKT1, resulting in the enhancement of EBOVΔVP30 growth, EBOV GP-mediated entry, and macropinocytosis. Moreover, we found that HER2 interacts with the TAM receptors, and in particular forms a complex with TYRO3 and EBOVΔVP30 particles on the cell surface. Interestingly, HER2 was required for EBOVΔVP30-induced TYRO3 and AKT1 activation, but the other TAM receptors (TYRO3 and MERTK) were not essential for EBOVΔVP30-induced HER2 and AKT1 activation. Our findings demonstrate that HER2 plays an important role in EBOV entry and provide novel insights for the development of therapeutics against the virus.
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http://dx.doi.org/10.1371/journal.ppat.1008900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556532PMC
October 2020

SARS-CoV-2 D614G Variant Exhibits Enhanced Replication and Earlier Transmission .

bioRxiv 2020 Sep 29. Epub 2020 Sep 29.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

The D614G substitution in the S protein is most prevalent SARS-CoV-2 strain circulating globally, but its effects in viral pathogenesis and transmission remain unclear. We engineered SARS-CoV-2 variants harboring the D614G substitution with or without nanoluciferase. The D614G variant replicates more efficiency in primary human proximal airway epithelial cells and is more fit than wildtype (WT) virus in competition studies. With similar morphology to the WT virion, the D614G virus is also more sensitive to SARS-CoV-2 neutralizing antibodies. Infection of human ACE2 transgenic mice and Syrian hamsters with the WT or D614G viruses produced similar titers in respiratory tissue and pulmonary disease. However, the D614G variant exhibited significantly faster droplet transmission between hamsters than the WT virus, early after infection. Our study demonstrated the SARS-CoV2 D614G substitution enhances infectivity, replication fitness, and early transmission.
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http://dx.doi.org/10.1101/2020.09.28.317685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536872PMC
September 2020

Distinct B cell subsets give rise to antigen-specific antibody responses against SARS-CoV-2.

Res Sq 2020 Sep 25. Epub 2020 Sep 25.

Discovery of durable memory B cell (MBC) subsets against neutralizing viral epitopes is critical for determining immune correlates of protection from SARS-CoV-2 infection. Here, we identified functionally distinct SARS-CoV-2-reactive B cell subsets by profiling the repertoire of convalescent COVID-19 patients using a high-throughput B cell sorting and sequencing platform. Utilizing barcoded SARS-CoV-2 antigen baits, we isolated thousands of B cells that segregated into discrete functional subsets specific for the spike, nucleocapsid protein (NP), and open reading frame (ORF) proteins 7a and 8. Spike-specific B cells were enriched in canonical MBC clusters, and monoclonal antibodies (mAbs) from these cells were potently neutralizing. By contrast, B cells specific to ORF8 and NP were enriched in naïve and innate-like clusters, and mAbs against these targets were exclusively non-neutralizing. Finally, we identified that B cell specificity, subset distribution, and affinity maturation were impacted by clinical features such as age, sex, and symptom duration. Together, our data provide a comprehensive tool for evaluating B cell immunity to SARS-CoV-2 infection or vaccination and highlight the complexity of the human B cell response to SARS-CoV-2.
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http://dx.doi.org/10.21203/rs.3.rs-80476/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523131PMC
September 2020