Vrc01-class Precursor Frequency in an African Population is Influenced by Ighv1-2 Allelic Composition and Not Malaria Exposure

The study highlights that genetic diversity, rather than malaria exposure, influences the frequency of VRC01-class bnAb precursors in Kenyan adults, suggesting the need for participant genotyping in vaccine trials.

Summary and findings

This study measured the frequencies of CD4 binding site-targeting VRC01-class broadly neutralizing antibody (bnAb) precursors in 60 healthy Kenyan adults. The study found that the overall frequency of these precursors was similar to that reported in North American populations, influenced by IGHV1-2 allelic composition rather than malaria exposure. Four new allelic variants of the IGHV1-2 gene were identified.

Abstract

<title>Abstract</title> <p>Recent innovations in vaccine design have reignited optimism about the feasibility of developing a safe and effective HIV vaccine. For instance, germline-targeting (GT) immunogens have been designed to selectively expand naïve B cell precursors with broadly neutraliing antibodies (bnAbs)-associated germline-encoded features, thereby priming them for structure-guided maturation. The frequencies and affinities of these precursors in the populations targeted for vaccination are critical to the success of GT vaccine strategies, but limited information is currently available across different geographies and demographics. We set up a study to characterise CD4 binding site-targeting VRC01-class bnAb precursor frequencies in 60 healthy Kenyan adults with varied levels of prior exposure to malaria. Naïve VRC01-class bnAb precursors were detected using the germline-targeting eOD-GT8 immunogen. The overall frequency of these precursors was similar to that reported in North American populations, with IGHV1-2 allelic composition rather than prior long-term exposure to malaria impacting the precursor frequency estimates. Our findings also revealed four new allelic variants of the IGHV1-2 gene that are not currently included in the immunogenetic reference database. Notably, a novel IGHV1-2 allele (IGHV1-2*06_S5416) demonstrated the ability to engage eOD-GT8, unlike the reference *06 allele. Overall, our results support the development of GT vaccines to induce VRC01-class bnAbs in this population and reiterate the need for participant genotyping in GT vaccine trials, particularly in African populations where genetic diversity is high yet understudied.</p>

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