Characterisation of bnAb precursors and assessment of the B cell repertoires in health and in people living with HIV to inform Germline Targeting vaccine design

Germline-targeting (GT) vaccine strategies offer a promising approach to HIV vaccine design by engaging naïve B cell precursors and guiding their maturation into broadly neutralising antibodies (bnAbs) capable of countering HIV diversity. However, the success of GT vaccines depends on the presence, frequency, and binding affinity of bnAb precursor B cells, factors which are influenced in part by immunoglobulin genetic diversity, which is largely understudied in African populations.

This study aims to (1) characterise the general antibody repertoire in health and HIV infection, (2) examine the CD4 binding site (CD4bs)-specific B cell repertoire to determine whether natural HIV exposure alters the precursor compartment, and (3) evaluate the functional maturity of responses primed by natural infection.

The study utilises samples from a cohort of adults in relatively good health and a cohort of people living with HIV (PLWH) prior to the initiation of antiretroviral therapy (ART).The study expects to find diverse immunoglobulin gene repertoires, including novel alleles in naïve B cells, with some VRC01-class precursor B cells present, though at lower frequencies. Natural infection is anticipated to prime CD4bs bnAb precursors and, over time, expand clonotypes, hence pushing responses towards bnAbs and offering potential for boosting these B cells using vaccines.

Evaluating the immunogenetic landscape and the presence of VRC01-class bnAb precursors in African populations determines the feasibility and adaptability of GT vaccine strategies for HIV in this region. Findings from this work will inform the rational design of HIV vaccines that are safe, effective, and universally protective, tailored to genetically diverse populations.