Background
HIV continues to be a major global public health issue with ~39.9 million people living with it at the end of 2023 (WHO). An effective vaccine is therefore needed, that can elicit diverse immune responses including broadly neutralizing antibodies (bnAbs). One such class of bnAbs that recognize the CD4-binding site on the HIV-1 Env are the VRC01-class of antibodies. They are derived from the pairing of VH1-2*02 antibody heavy chains with 5-amino acid long CDRL3 expressing light chains and have been isolated from several people living with HIV-1. They not only prevent infection of humanized mice by HIV-1 and of non-human primates by S(H)IV, but also prevented HIV-1 acquisition from susceptible viruses in two phase 3 clinical trials (HVTN 703/704). Hence, VRC01-class antibody elicitation is expected to be essential for an effective HIV-1 vaccine.
Methods
We sequentially administered three different Env-derived immunogens in a transgenic mouse model (engineered by the Fred Alt group). Post final immunization, Env+ CD4-BS+ B cells were isolated from spleens of immunized animals and their VH/VL genes sequenced. Selected VH/VL pairs were generated as IgGs, and their binding and neutralizing properties were determined.
Results
The elicited antibodies showed accumulated somatic mutations present in human VRC01-class bnAbs and several of them neutralized >30% of heterologous tier 2 viruses. Here, for the first time, we report on ‘prime-boost’ immunization regimens that lead to accelerated development of VRC01-class antibodies capable of neutralizing diverse heterologous, tier 2 HIV-1 viruses.
Conclusions
Our study based on the ‘germline-targeting’ vaccination approach, identifies an immunization strategy that rapidly guides the maturation of VRC01-class antibodies towards their cross-neutralizing forms. These efforts will inform the development of phase 1 clinical trials that are focused on the elicitation of broadly neutralizing HIV-1 antibody responses.
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