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Principal Investigator: Leonidas Stamatatos
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2023
Award: $589,260
Funding agency: National Institute of Allergy and Infectious Diseases
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.
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