Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates

He, W.; Ou, T.; Skamangas, N.; Bailey, C.; Bronkema, N.; Guo, Y.; Yin, Y.; Kobzarenko, V.; Zhang, X.; Pan, A.; Liu, X.; Allwardt, A.; Mitra, D.; Quinlan, B.; Sanders, R.; Choe, H.; Farzan, M.

doi:10.1101/2022.11.07.515497

bioRxiv · 10.1101/2022.11.07.515497

Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates

He, W.·Ou, T.·Skamangas, N.·Bailey, C.·Bronkema, N.·Guo, Y.·Yin, Y.·Kobzarenko, V.·Zhang, X.·Pan, A.·Liu, X.·Allwardt, A.·Mitra, D.·Quinlan, B.·Sanders, R.·Choe, H.·Farzan, M.

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Abstract

V2-glycan/apex broadly neutralizing antibodies (bnAbs) recognize a closed quaternary epitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessary to elicit apex antibodies and useful to guide maturation of other bnAb classes. To compare antigens designed to maintain this conformation, apex-specific responses were monitored in mice engrafted with a diverse repertoire of B cells expressing the HCDR3 of the apex bnAb VRC26.25. Engineered B cells affinity matured, guiding improvement of VRC26.25 itself. We found that soluble Env (SOSIP) variants differed significantly in their ability to raise anti-apex responses. A transmembrane SOSIP (SOSIP-TM) delivered as an mRNA-lipid nanoparticle elicited more potent neutralizing responses than multimerized SOSIP proteins. Importantly, SOSIP-TM elicited neutralizing sera from B cells engineered with the predicted VRC26.25-HCDR3 progenitor, which also affinity matured. Our data show that HCDR3-edited B cells facilitate efficient in vivo comparisons of Env antigens and highlight the potential of an HCDR3-focused vaccine approach.

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He, W., Ou, T., Skamangas, N., Bailey, C., Bronkema, N., Guo, Y., Yin, Y., Kobzarenko, V., Zhang, X., Pan, A., Liu, X., Allwardt, A., Mitra, D., Quinlan, B., Sanders, R., Choe, H., Farzan, M.. 2022-11-07. Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates. https://doi.org/10.1101/2022.11.07.515497

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