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

Gray, M. D.; Feng, J.; Weidle, C. E.; Cohen, K. W.; Ballweber-Fleming, L.; MacCamy, A. J.; Huynh, C. N.; Trichka, J. J.; Montefiori, D.; Ferrari, G.; Pancera, M.; McElrath, M. J.; Stamatatos, L.

doi:10.1101/2021.08.21.457217

bioRxiv · 10.1101/2021.08.21.457217

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

Gray, M. D.·Feng, J.·Weidle, C. E.·Cohen, K. W.·Ballweber-Fleming, L.·MacCamy, A. J.·Huynh, C. N.·Trichka, J. J.·Montefiori, D.·Ferrari, G.·Pancera, M.·McElrath, M. J.·Stamatatos, L.

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Abstract

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.

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Gray, M. D., Feng, J., Weidle, C. E., Cohen, K. W., Ballweber-Fleming, L., MacCamy, A. J., Huynh, C. N., Trichka, J. J., Montefiori, D., Ferrari, G., Pancera, M., McElrath, M. J., Stamatatos, L.. 2021-08-23. Characterization of a vaccine-elicited human antibody with sequence homology to VRC01-class antibodies that binds the C1C2 gp120 domain. https://doi.org/10.1101/2021.08.21.457217

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