A detailed understanding of the molecular features of the neutralizing epitopes developed by viral escape mutants is important for predicting and developing vaccines or therapeutic antibodies against continuously emerging SARS-CoV-2 variants. Here, we report three human monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during first wave of pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, but poorly neutralized Beta and completely failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these three mAbs in complex with trimeric spike protein showed that all three mAbs are involved in bivalent spike binding with two mAbs targeting class-1 and one targeting class-4 Receptor Binding Domain (RBD) epitope. Comparison of immunogenetic makeup, structure, and function of these three mAbs with our recently reported class-3 RBD binding mAb that potently neutralized all SARS-CoV-2 variants revealed precise antibody footprint, specific molecular interactions associated with the most potent multi-variant binding / neutralization efficacy. This knowledge has timely significance for understanding how a combination of certain mutations affect the binding or neutralization of an antibody and thus have implications for predicting structural features of emerging SARS-CoV-2 escape variants and to develop vaccines or therapeutic antibodies against these.Funding Information: This research was supported by the Indian Council of Medical Research VIR/COVID-19/02/2020/ECD-1 (A.C.). S.K. is supported through DBT/Wellcome Trust India Alliance Early Career Fellowship grant IA/E/18/1/504307. Both E.A.O and A.P are supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health (under award numbers 75N92019P00328, U54EB015408, and U54EB027690) as part of the Rapid Acceleration of Diagnostics (RADx) initiative. A.P. is 17 also supported through CCHI grant 5U19 AI14237-04 (subaward 000520244-SP008-SC014). Both K.N. and E.S.R. are supported through Dengue Translational Research Consortia National Biopharma Mission BT/NBM099/02/18 (A.C.). K.G. was supported through DBT grant BT/PR30260/MED/15/194/2018 (A.C, K.M). C.W.D. is supported through the National Institute of Allergy and Infectious Diseases (NIAID) U19 AI142790, Consortium for Immunotherapeutics against Emerging Viral Threats. Work done in M.S.S. lab was funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under HHSN272201400004C (NIAID Centers of Excellence for Influenza Research and Surveillance, CEIRS). This work was supported in part by grants (NIH P51OD011132 and NIH/NIAID CEIRR under contract 75N93021C00017 to Emory University) from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) and by intramural funding from the NIAID. This work was also supported in part by the Emory Executive Vice President for Health Affairs Synergy Fund award, COVID-Catalyst-I3 Funds from the Woodruff Health Sciences Center and Emory School of Medicine, the Pediatric Research Alliance Center for Childhood Infections and Vaccines and Children’s Healthcare of Atlanta, and Woodruff Health Sciences Center 2020 COVID-19 CURE Award.Declaration of Interests: The International Centre for Genetic Engineering and Biotechnology, New Delhi, India, Emory Vaccine Center, Emory University, Atlanta, USA, Indian Council of Medical Research, India and Department of Biotechnology, India have filed a provisional patent application on human monoclonal antibodies mentioned in this study on which A.C., S.K., M.K.K., and A.S. are inventors (Indian patent 202111052088). N.C., H.V., A.S.N., and J.D.R. are co-inventors on a pending patent related to SARS-CoV-2 WT, Delta and Omicron spike protein structures and ACE2 Interactions from BoAb assay technology filed by Emory University (US Patent Application No. 63/265,361, Filed on 14 December 2021). M.S.S. has previously served as a consultant for Moderna and Ocugen. J.D.R. is a Co-founder and Consultant for Cambium Medical Technologies. J.D.R. is a Consultant for Secure Transfusion Services. All other authors declare no competing interests.
As SARS-CoV-2 becomes endemic, it is critical to understand immunity following early-life infection. We evaluated humoral responses to SARS-CoV-2 in 23 infants/young children. Antibody responses to SARS-CoV-2 spike antigens peaked approximately 30 days after infection and were maintained up to 500 days with little apparent decay. While the magnitude of humoral responses was similar to an adult cohort recovered from mild/moderate COVID-19, both binding and neutralization titers to WT SARS-CoV-2 were more durable in infants/young children, with spike and RBD IgG antibody half-life nearly 4X as long as in adults. IgG subtype analysis revealed that while IgG1 formed the majority of the response in both groups, IgG3 was more common in adults and IgG2 in infants/young children. These findings raise important questions regarding differential regulation of humoral immunity in infants/young children and adults and could have broad implications for the timing of vaccination and booster strategies in this age group.
Individuals who are immunocompromised, including patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia (NHL/CLL), often mount ineffective antibody responses after SARS-CoV-2 vaccination 1-3 and remain at a high risk of severe Several monoclonal antibodies against the SARS-CoV-2 spike protein have been developed for prophylaxis or treatment against infection.5 AZD7442 is a combination of 2 such antibodies (tixagevimab and cilgavimab) with a half-life of ~90 days. 6It received emergency use authorization (EUA) for use as preexposure prophylaxis in patients who are immunocompromised based on the PROVENT trial, which showed a reduced risk of symptomatic infection among patients deemed at risk of inadequate vaccine response or increased viral exposure.7 However, only 7.2% of the participants had cancer, and 3.2% received immunosuppressive therapy.Importantly, PROVENT was conducted before the emergence of the B.1.1.529(Omicron) variant. Uing purified antibodies and/or pseudoviruses, some studies showed that many antibody formulations developed against the original SARS-CoV-2, including AZD7442, lost significant in vitro activity against Omicron variants.8 Additionally, sera from patients who received AZD7442 blocked the binding between the wild-type spike receptor binding domain (RBD) and plates coated with its receptor ACE2 but had minimal efficacy at blocking the binding between Omicron BA.1 RBD and ACE2.9 Reduced efficacy against Omicron variants was observed in patients treated with half-dose AZD7442, 10 and ~10% of AZD7442-treated kidney transplant recipients developed COVID-19 afterwards, with 35.9% of them requiring hospitalization.11 Although these reports raise concerns that AZD7442 has limited efficacy against Omicron variants, the neutralizing activity of full dose AZD7442 against live, contemporary Omicron variants after administration to patients who are immunocompromised remains unknown.We measured the antibody binding and neutralizing activities of plasma from AZD7442-treated patients with NHL/CLL for several live SARS-CoV-2 variants, including Omicron BA.2.75, BA.5, BQ.1.1,and XBB, which are currently in circulation.Adult patients with NHL/CLL at the Winship Cancer Institute of Emory University who received AZD7442 in accordance with the EUA fact sheet were enrolled in this prospective observational study approved by the institutional review board of Emory University.As such, patients received either a dose of 150 mg of each antibody followed by a repeat dose within 3 months or a single dose of 300 mg of each antibody.Blood was drawn after providing written informed consent, and antibody binding and live virus neutralization activities were measured as described previously 1,12 and in the supplemental Material.
Abstract When should vaccines to evolving pathogens such as SARS-CoV-2 be updated? Our computational models address this focusing on updating SARS-CoV-2 vaccines to the currently circulating Omicron variant. Current studies typically compare the antibody titers to the new variant following a single dose of the original-vaccine versus the updated-vaccine in previously immunized individuals. These studies find that the updated-vaccine does not induce higher titers to the vaccine-variant compared with the original-vaccine, suggesting that updating may not be needed. Our models recapitulate this observation but suggest that vaccination with the updated-vaccine generates qualitatively different humoral immunity, a small fraction of which is specific for unique epitopes to the new variant. Our simulations suggest that these new variant-specific responses could dominate following subsequent vaccination or infection with either the currently circulating or future variants. We suggest a two-dose strategy for determining if the vaccine needs updating and for vaccinating high-risk individuals.
Abstract This study reports that most patients with NSCLC had a significant increase in the nAb response to the currently circulating Omicron variants after bivalent booster vaccination and had Ab titers comparable to healthy participants. Interestingly, though the durability of the nAb response persisted in most of the healthy participants, patients with NSCLC had significantly reduced nAb titers after 4–6 months of vaccination. Our data highlight the importance of COVID-19 bivalent booster vaccination as the standard of care for patients with NSCLC given the evolution of new variants of concern.
Significance Influenza viruses typically cause a higher disease burden in children and the elderly, who have weaker immune systems. During the 2013–2014 influenza season, H1N1 viruses caused an unusually high level of disease in middle-aged adults. Here, we show that recent H1N1 strains possess a mutation that allows viruses to avoid immune responses elicited in middle-aged adults. We show that current vaccine strains elicit immune responses that are predicted to be less effective in some middle-aged adults. We suggest that new viral strains should be incorporated into seasonal influenza vaccines so that proper immunity is elicited in all humans, regardless of age and pre-exposure histories.
Currently, vaccines for SARS-CoV-2 and influenza viruses are updated if the new vaccine induces higher antibody-titers to circulating variants than current vaccines. This approach does not account for complex dynamics of how prior immunity skews recall responses to the updated vaccine. We: (i) use computational models to mechanistically dissect how prior immunity influences recall responses; (ii) explore how this affects the rules for evaluating and deploying updated vaccines; and (iii) apply this to SARS-CoV-2. Our analysis of existing data suggests that there is a strong benefit to updating the current SARS-CoV-2 vaccines to match the currently circulating variants. We propose a general two-dose strategy for determining if vaccines need updating as well as for vaccinating high-risk individuals. Finally, we directly validate our model by reanalysis of earlier human H5N1 influenza vaccine studies.
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