Evolution of Antibody Immunity to SARS-CoV-2

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with development of variable levels of antibodies with neutralizing activity that can protect against infection in animal models. Antibody levels decrease with time, but the nature and quality of the memory B cells that would be called upon to produce antibodies upon re-infection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection. We find that IgM, and IgG anti-SARS-CoV-2 spike protein receptor binding domain (RBD) antibody titers decrease significantly with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by five-fold in pseudotype virus assays. In contrast, the number of RBD-specific memory B cells is unchanged. Memory B cells display clonal turnover after 6.2 months, and the antibodies they express have greater somatic hypermutation, increased potency and resistance to RBD mutations, indicative of continued evolution of the humoral response. Analysis of intestinal biopsies obtained from asymptomatic individuals 4 months after coronavirus disease-2019 (COVID-19) onset, using immunofluorescence, or polymerase chain reaction, revealed persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 volunteers. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

To date severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected nearly 100 million individuals resulting in over two million deaths. Many vaccines are being deployed to prevent coronavirus disease-2019 (COVID-19) including two novel mRNA-based vaccines. These vaccines elicit neutralizing antibodies and appear to be safe and effective, but the precise nature of the elicited antibodies is not known. Here we report on the antibody and memory B cell responses in a cohort of 20 volunteers who received either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines. Consistent with prior reports, 8 weeks after the second vaccine injection volunteers showed high levels of IgM, and IgG anti-SARS-CoV-2 spike protein (S), receptor binding domain (RBD) binding titers. Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection. However, activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin. Consistent with these findings, vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes epitopes in common with mAbs isolated from infected donors. Structural analyses of mAbs complexed with S trimer suggest that vaccine- and virus-encoded S adopts similar conformations to induce equivalent anti-RBD antibodies. However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations. Notably, the same mutations were selected when recombinant vesicular stomatitis virus (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs. Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates

Zika virus (ZIKV) causes severe neurologic complications and fetal aberrations. Vaccine development is hindered by potential safety concerns due to antibody cross-reactivity with dengue virus and the possibility of disease enhancement. In contrast, passive administration of anti-ZIKV antibodies engineered to prevent enhancement may be safe and effective. Here, we report on human monoclonal antibody Z021, a potent neutralizer that recognizes an epitope on the lateral ridge of the envelope domain III (EDIII) of ZIKV and is protective against ZIKV in mice. When administered to macaques undergoing a high-dose ZIKV challenge, a single anti-EDIII antibody selected for resistant variants. Co-administration of two antibodies, Z004 and Z021, which target distinct sites on EDIII, was associated with a delay and a 3- to 4-log decrease in peak viremia. Moreover, the combination of these antibodies engineered to avoid enhancement prevented viral escape due to mutation in macaques, a natural host for ZIKV

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates

Summary: Zika virus (ZIKV) causes severe neurologic complications and fetal aberrations. Vaccine development is hindered by potential safety concerns due to antibody cross-reactivity with dengue virus and the possibility of disease enhancement. In contrast, passive administration of anti-ZIKV antibodies engineered to prevent enhancement may be safe and effective. Here, we report on human monoclonal antibody Z021, a potent neutralizer that recognizes an epitope on the lateral ridge of the envelope domain III (EDIII) of ZIKV and is protective against ZIKV in mice. When administered to macaques undergoing a high-dose ZIKV challenge, a single anti-EDIII antibody selected for resistant variants. Co-administration of two antibodies, Z004 and Z021, which target distinct sites on EDIII, was associated with a delay and a 3- to 4-log decrease in peak viremia. Moreover, the combination of these antibodies engineered to avoid enhancement prevented viral escape due to mutation in macaques, a natural host for ZIKV. : Passive administration of anti-Zika human monoclonal antibodies could be an efficacious and safe alternative to vaccines for at-risk populations. Keeffe et al. show that administration of a combination of two monoclonal antibodies to macaques followed by high-dose intravenous Zika challenge reduces viremia and prevents the emergence of viral escape mutations. Keywords: flavivirus, antibodies, crystal structure, escape, macaques, prophylaxis, protection, epitope, antibody dependent enhancemen

Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and Mexico.

Antibodies to Zika virus (ZIKV) can be protective. To examine the antibody response in individuals who develop high titers of anti-ZIKV antibodies, we screened cohorts in Brazil and Mexico for ZIKV envelope domain III (ZEDIII) binding and neutralization. We find that serologic reactivity to dengue 1 virus (DENV1) EDIII before ZIKV exposure is associated with increased ZIKV neutralizing titers after exposure. Antibody cloning shows that donors with high ZIKV neutralizing antibody titers have expanded clones of memory B cells that express the same immunoglobulin VH3-23/VK1-5 genes. These recurring antibodies cross-react with DENV1, but not other flaviviruses, neutralize both DENV1 and ZIKV, and protect mice against ZIKV challenge. Structural analyses reveal the mechanism of recognition of the ZEDIII lateral ridge by VH3-23/VK1-5 antibodies. Serologic testing shows that antibodies to this region correlate with serum neutralizing activity to ZIKV. Thus, high neutralizing responses to ZIKV are associated with pre-existing reactivity to DENV1 in humans

Risk of Zika microcephaly correlates with features of maternal antibodies

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2019-10-10T12:26:15Z No. of bitstreams: 1 Robbiani F D ...Risk.pdf: 2296966 bytes, checksum: 5e47aca9208f3f35c969fd82960279f4 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2019-10-10T13:32:42Z (GMT) No. of bitstreams: 1 Robbiani F D ...Risk.pdf: 2296966 bytes, checksum: 5e47aca9208f3f35c969fd82960279f4 (MD5)Made available in DSpace on 2019-10-10T13:32:42Z (GMT). No. of bitstreams: 1 Robbiani F D ...Risk.pdf: 2296966 bytes, checksum: 5e47aca9208f3f35c969fd82960279f4 (MD5) Previous issue date: 2019-01-07National Institutes of Health grants 5R01AI121207, R01TW009504, and R25TW009338 to A.I. Ko; National Institutes of Health pilot awards U19AI111825 and UL1TR001866 to D.F. Robbiani; National Institutes of Health grants R01AI037526, UM1AI100663, U19AI111825, UL1TR001866, and P01AI138938 to M.C. Nussenzweig; National Institutes of Health grants R01AI124690 and U19AI057229 (Cooperative Center for Human Immunology pilot project); The Rockefeller University Development Office and anonymous donors (to C.M. Rice); Fundação de Amparo `a Pesquisa do Estado da Bahia grant PET0021/2016 (to M.G. Reis); National Institutes of Health grant R21AI129479-Supplement (to K.K.A. Van Rompay) and the National Institutes of Health Office of Research Infrastructure Programs/OD (P51OD011107 to the CNPRC); the United States Food and Drug Administration contract HHSF223201610542P (to L.L. Coffey); National Institutes of Health grants R01AI100989 and R01AI133976 (to L. Rajagopal and K.M. Adams Waldorf); and National Institutes of Health grants AI083019 and AI104002 (to M. Gale Jr.) and grant P51OD010425 to the WaNPRC (to K.M. Adams Waldorf, J. Tisoncik-Go, and M. Gale Jr.). Studies at WNPRC were supported by DHHS/PHS/National Institutes of Health grant R01Al116382-01A1 (to D.H. O’Connor), in part by the National Institutes of Health Office of Research Infrastructure Programs/OD (grant P51OD011106) awarded toWNPRC, at a facility constructed in part with support from Research Facilities Improvement Programgrants RR15459-01 and RR020141-01; and National Institutes of Health core and pilot grant P51 OD011092 and grants R21-HD091032 and R01-HD08633 (to ONPRC). P.F.C. Vasconcelos was supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (projects 303999/2016-0, 439971/20016-0, and 440405/2016-5) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Zika fast-track).The Rockefeller University. Laboratory of Molecular Immunology. New York, NY, USA.The Rockefeller University. Laboratory of Molecular Immunology. New York, NY, USA / Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven / Universidade Federal da Bahia. Faculdade de Medicina. Instituto da Saúde Coletiva. Salvador, BA, Brasil.Fudan University. School of Basic Medical Sciences. Shanghai Medical College. Key Laboratory of Medical Molecular Virology. Shanghai, China.The Rockefeller University. Laboratory of Molecular Immunology. New York, NY, USA.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil / Universidade Federal de São Paulo. São Paulo, SP, Brasil.Universidade Federal da Bahia. Faculdade de Medicina. Instituto da Saúde Coletiva. Salvador, BA, Brasil.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Universidade Federal da Bahia. Faculdade de Medicina. Instituto da Saúde Coletiva. Salvador, BA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.The Rockefeller University. Laboratory of Molecular Immunology. New York, NY.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.The Rockefeller University. Laboratory of Molecular Immunology. New York, NY, USA.Universidade Federal de São Paulo. São Paulo, SP, Brasil.Hospital Santo Amaro. Salvador, BA, Brasil.Hospital Santo Amaro. Salvador, BA, Brasil.Hospital Santo Amaro. Salvador, BA, Brasil.Hospital Aliança. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven / Universidade Federal da Bahia. Faculdade de Medicina. Instituto da Saúde Coletiva. Salvador, BA, Brasil.University of California. California National Primate Research Center. Davis, Davis, CA, USA.University of California. School of Veterinary Medicine. Department of Pathology, Microbiology, and Immunology. Davis, Davis, CA, USA.Washington National Primate Research Center. Seattle, WA, USA / University of Washington. Center for Innate Immunity and Immune Disease. Seattle, WA, USA / University of Washington. Department of Immunology. Seattle, WA, USA.Washington National Primate Research Center. Seattle, WA / University of Washington. Center for Innate Immunity and Immune Disease. Seattle, WA, USA / University of Washington. Department of Immunology. Seattle, WA, USA / University of Washington. Department of Global Health. Seattle, WA, USA.University of Washington. Department of Global Health. Seattle, WA, USA / University of Washington. Department of Pediatrics. Seattle, WA, USA / Seattle Children’s Research Institute. Center for Global Infectious Disease Research. Seattle, WA, USA.Washington National Primate Research Center. Seattle, WA, USA / University of Washington. Center for Innate Immunity and Immune Disease. Seattle, WA, USA / University of Washington. Department of Global Health. Seattle, WA, USA / University of Washington. Department of Obstetrics and Gynecology. Seattle, WA, USA.University of Wisconsin-Madison. Department of Pathology and Laboratory Medicine. Madison, WI, USA.University of Wisconsin-Madison. Wisconsin National Primate Research Center. Madison, WI, USA.University of Wisconsin-Madison. Wisconsin National Primate Research Center. Madison, WI, USA.University of Wisconsin-Madison. Department of Pathology and Laboratory Medicine. Madison, WI, USA.Oregon National Primate Research Center. Division of Reproductive and Developmental Sciences. Beaverton, OR, USA.Oregon National Primate Research Center. Division of Pathobiology and Immunology. Beaverton, OR, USA / Oregon Health and Science University. Vaccine and Gene Therapy Institute. Portland, OR, USA.Oregon Health and Science University. Vaccine and Gene Therapy Institute. Portland, OR, USA.Oregon National Primate Research Center. Pathology Services Unit, Division of Comparative Medicine. Beaverton, OR, USA.Oregon National Primate Research Center. Division of Pathobiology and Immunology. Beaverton, OR, USA.Oregon National Primate Research Center. Division of Reproductive and Developmental Sciences. Beaverton, OR, USA.Oregon National Primate Research Center. Division of Reproductive and Developmental Sciences. Beaverton, OR, USA / Oregon Health and Science University. Department of Obstetrics and Gynecology. Portland, OR, USA.Oregon National Primate Research Center. Division of Reproductive and Developmental Sciences. Beaverton, OR, USA.Oregon National Primate Research Center. Division of Pathobiology and Immunology. Beaverton, OR, USA / Oregon Health and Science University. Vaccine and Gene Therapy Institute. Portland, OR, USA.Oregon National Primate Research Center. Division of Pathobiology and Immunology. Beaverton, OR, USA / Oregon Health and Science University. Vaccine and Gene Therapy Institute. Portland, OR, USA.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.Universidade Federal da Bahia. Faculdade de Medicina. Instituto da Saúde Coletiva. Salvador, BA, Brasil.University of California. California National Primate Research Center. Davis, Davis, CA, USA / University of California. School of Veterinary Medicine. Department of Pathology, Microbiology, and Immunology. Davis, Davis, CA, USA.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven, USA.The Rockefeller University. Laboratory of Molecular Immunology. New York, NY, USA / The Rockefeller University. Howard Hughes Medical Institute. New York, NY, USA.Zika virus (ZIKV) infection during pregnancy causes congenital abnormalities, including microcephaly. However, rates vary widely, and the contributing risk factors remain unclear. We examined the serum antibody response to ZIKV and other flaviviruses in Brazilian women giving birth during the 2015-2016 outbreak. Infected pregnancies with intermediate or higher ZIKV antibody enhancement titers were at increased risk to give birth to microcephalic infants compared with those with lower titers (P < 0.0001). Similarly, analysis of ZIKV-infected pregnant macaques revealed that fetal brain damage was more frequent in mothers with higher enhancement titers. Thus, features of the maternal antibodies are associated with and may contribute to the genesis of ZIKV-associated microcephaly