An early life multivalent immunization strategy for induction of neutralization breadth

ABSTRACT In 2023, adolescents and young people accounted for approximately 25% of new HIV infections globally. The period after weaning but before sexual debut represents a window of relatively low HIV acquisition risk, providing an opportune time for administering a multi-dose vaccine regimen to elicit protective immunity prior to adolescence. The success of a protective HIV vaccine will rely on the induction of broadly neutralizing antibodies (bnAbs). Given the potential for rapid bnAb development in children living with HIV, vaccines targeting B cell evolution towards bnAbs may be more effective in early life. Germline-targeting immunization strategies have shown great potential by using a series of priming, shaping, and polishing immunogens to activate bnAb precursor B cells and guide them towards potent and broad neutralization. While these priming immunogens effectively engage bnAb precursors, identifying appropriate strategies to drive bnAb evolution remains a challenge. The overall goal of this project is to identify an optimal prime-boost strategy to guide antibody maturation towards neutralization breadth in the setting of immune maturation. We hypothesize that an early life HIV immunization strategy incorporating multivalent HIV env immunogens will drive efficient priming and maturation of B cell responses towards neutralization breadth. Our hypothesis will be investigated under the following aims: 1) Compare sequential versus simultaneous administration of germ-line targeting immunogens for induction of CD4bs and V2 apex bnAb precursors; 2) Determine whether a multivalent prime- boost strategy will better drive the development and maturation of bnAb lineages towards neutralization breadth.; and 3) Define the evolution of vaccine-elicited B cell responses and mAbs following immunization with bnAb B cell lineage designed immunogens through a structure-to-sequence approach. The proposed studies will help establish a prime-boost regimen to evolve bnAb B cell lineages throughout early childhood towards neutralization breadth prior to adolescence. These studies will establish early life as an optimal time for beginning a sequential HIV immunization strategy and inform the next phase of bnAb germline-targeting immunization strategies for evaluation in preclinical and human clinical trials.