Fusion Peptide Priming and Trimer Boosting Strategies for HIV Vaccine Development in Guinea Pigs 2308606

Abstract

Inducing broadly neutralizing antibodies (bnAb) is a central challenge in HIV vaccine development. The HIV envelope (Env) fusion peptide (FP) is a highly conserved bnAb epitope, yet is inefficiently targeted by antibodies elicited by experimental vaccines. Here, we test how Env trimer design and dosing strategies shape the magnitude and specificity of antibody responses by pairing FP priming with boosts using native-like Env trimers. Escalating-dose (ED) immunization regimens are a recently described approach to deliver antigens over a prolonged period, resulting in sustained increased antigen stability in the lymph node and germinal-center activity, improved immune kinetics, and enhanced recruitment and selection of targeted B-cell populations. The impact of ED regimens on boosting HIV-1 FP-specific responses has not been explored. Here, guinea pigs (n = 5 per group) were primed with FP-rTTHC followed by boosts with prefusion trimers from clade A (BG505), clade C (ConC), or a Triple-Tandem-Trimer (three trimeric units of ConC, linked one after another: ConC-DS-14ln-TTT), delivered either as bolus injections or ED regimens. All strategies elicited strong Env-specific responses, but the quality of these responses varied among immunogen designs. Bolus boosts using BG505 or ConC generated the most robust FP-specific recall responses, but neutralization levels ultimately converged across regimens. However, the TTT trimer expanded reactivity to non-FP epitopes, suggesting broader epitope engagement during boosting. Notably, cross-reactive BG505-binding antibodies appeared as early as week 6 after two FP primes, highlighting rapid activation of FP-targeting B cells. These findings clarify how trimer architecture and dosing influence the trajectory of epitope targeting, strengthening the case for FP priming as a powerful method for engaging a vulnerable HIV Env epitope and demonstrating that the TTT platform may serve as an effective boost to epitopes beyond FP. N/A Vaccines and Immunotherapy (VAC)