Guiding the maturation of anti-CD4-BS bnAbs through sequential heterologous Env immunization

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PROJECT SUMMARY An effective HIV-1 vaccine will be one that elicits diverse anti-viral immune responses, including broadly neutralizing antibodies (bnAbs). We are focused on the elicitation of anti-CD4-binding site (CD4-BS) bnAbs, including VRC01-class bnAbs, through a guided immunization approach with specifically designed Env-derived protein immunogens. We previously reported on the design of a clade C Env-derived immunogen that activates naïve B cells expressing the bnAb precursors of VRC01-class antibodies in vivo. We also reported on the design of a second immunogen derived from a clade B Env that, when administered as a 1st boost, increases the maturation of the emerging VRC01 B cell responses. Our current proposal is based on our very recent observations that a 2nd booster immunization with a cocktail of stabilized soluble trimeric Envs (SOSIPs) drives the maturation of these VRC01 B cells closer to their full maturation, so that the elicited antibodies display vastly improved cross-neutralizing potentials against certain heterologous, tier 2 viruses as compared to the antibodies elicited after the 1st boost. However, this maturation process is still incomplete, and the antibodies elicited by the 2nd boost do not display the same breath of neutralization as the fully matured human VRC01- class antibodies isolated from HIV+ subjects. We expect, and propose to validate experimentally, that their maturation will be completed with additional immunizations with this cocktail of stabilized Env trimers (SOSIPs), or a specific subset of these SOSIPs. An important aspect of our proposal is that we will compare how the maturation of the VRC01 B cell and antibody responses may be affected by the way the immunogens are presented to the immune system. Specifically, we will compare the type and rates of somatic mutation- accumulation and the quality of the corresponding antibodies, when the immunogens are administered as adjuvanted recombinant proteins or expressed in vivo by a self-amplifying platform (saRNA). Another important aspect of our proposal is that we will not limit our work to well-controlled knock-in mice, but transgenic mice that express human VH/VL genes, as well. Because the B cell repertoire of these mice better reflect that of humans, we expect that our optimized immunization schema will not only activate a broader range of VRC01-class antibodies than it does in the knock-in mouse models, but that additional classes of anti- CD4-BS antibody responses will also be elicited.