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Lingshu Wang

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Open access Jul 2026

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

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)

Shreyanshu Ray, Cheng Cheng, K. McKee et al. · Journal of Immunology · 0 citations

Open access Aug 2026

Potent type-specific de novo antibodies complement broadly reactive imprinted antibodies in immune responses to SARS-CoV-2 variants

For rapidly mutating viruses such as influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), immune memory recalled by antigenically drifted variants primarily comprises antibodies that cross-react to the priming strain rather than de novo elicited responses, a phenomenon termed original antigenic sin or immune imprinting. The composition and functionality of de novo responses elicited by variant exposures remain unclear. Here we isolated and characterized hundreds of recall and de novo neutralizing monoclonal antibodies after sequential exposures to SARS-CoV-2 variants in ancestral-imprinted humans. De novo variant type-specific antibodies used different V(D)J genes that were closer to germline sequence, potently neutralized future variants and targeted distinct receptor binding domain epitopes compared to ancestral cross-reactive (recall) antibodies. Nevertheless, neutralizing responses to the updated 2024–2025 booster were predominantly ancestral cross-reactive. These results reveal the distinct contributions of recall and de novo antibodies to a balanced immune response and underscore the benefit of updated booster vaccines, which augment both subsets. Updated SARS-CoV-2 boosters broaden humoral immunity by recalling cross-reactive antibodies and eliciting new less cross-reactive Omicron type-specific antibodies that target distinct RBD epitopes and more potently neutralize recent variants.

T. Johnston, S. Li, M. Painter et al. · Nature Immunology · 2 citations