MacCamy, A. J. | Search bioRxiv

bioRxiv2021

Characterization of a vaccine-elicited human antibody with sequence homology to VRC01-class antibodies that binds the C1C2 gp120 domain

Broadly HIV-1 neutralizing VRC01-class antibodies bind the CD4-binding site of the HIV-1 envelope (Env) and contain VH1-2*02-derived heavy chains paired with light chains expressing five amino acid long CDRL3s. Their unmutated forms do not recognize Env or neutralize HIV-1. The lack of elicitation of VRC01-class antibodies in human clinical trials could potentially be due to the absence of activation of the corresponding naive B cells by the vaccine Env immunogens. To address this point directly, we examined Env-specific BCR sequences from participants in the HVTN 100 clinical trial. Of all the sequences analyzed only one displayed sequence homology to VRC01-class antibodies, but the corresponding antibody (FH1) recognized the C1C2 gp120 domain. For FH1 to switch epitope recognition to the CD4-binding site, alterations in both the CDRH3 and CDRL3 were necessary. Our findings support the use of specifically designed immunogens to activate VRC01-class B cells in future human vaccine trials.

immunology↗

bioRxiv2020

Characterization of neutralizing antibodies from a SARS-CoV-2 infected individual

B cells specific for the SARS-CoV-2 S envelope glycoprotein spike were isolated from a COVID-19-infected subject using a stabilized spike-derived ectodomain (S2P) twenty-one days post-infection. Forty-four S2P-specific monoclonal antibodies were generated, three of which bound to the receptor binding domain (RBD). The antibodies were minimally mutated from germline and were derived from different B cell lineages. Only two antibodies displayed neutralizing activity against SARS-CoV-2 pseudo-virus. The most potent antibody bound the RBD in a manner that prevented binding to the ACE2 receptor, while the other bound outside the RBD. Our study indicates that the majority of antibodies against the viral envelope spike that were generated during the first weeks of COVID-19 infection are non-neutralizing and target epitopes outside the RBD. Antibodies that disrupt the SARS-CoV-2 spike-ACE2 interaction can potently neutralize the virus without undergoing extensive maturation. Such antibodies have potential preventive/therapeutic potential and can serve as templates for vaccine-design. IN BRIEFSARS-CoV-2 infection leads to expansion of diverse B cells clones against the viral spike glycoprotein (S). The antibodies bind S with high affinity despite being minimally mutated. Thus, the development of neutralizing antibody responses by vaccination will require the activation of certain naive B cells without requiring extensive somatic mutation. HighlightsO_LIAnalysis of early B cell response to SARS-CoV-2 spike protein C_LIO_LIMost antibodies target non-neutralizing epitopes C_LIO_LIPotent neutralizing mAb blocks the interaction of the S protein with ACE2 C_LIO_LINeutralizing antibodies are minimally mutated C_LI

immunology↗