Immune Monitoring Reveals Fusion Peptide Priming to Imprint Cross-Clade HIV-Neutralizing Responses with a Characteristic Early B Cell Signature
Cheng Cheng, Hongying Duan, Kai Xu, Gwo‐Yu Chuang, Angela R. Corrigan, Hui Geng, Sijy O’Dell, Li Ou, Michael Chambers, Anita Changela, Xuejun Chen, Kathryn E. Foulds, Edward K. Sarfo, Alexander J. Jafari, Kurt R. Hill, Rui Kong, Kevin Liu, John Paul Todd, Yaroslav Tsybovsky, Raffaello Verardi, Shuishu Wang, Yiran Wang, Winston Wu, Tongqing Zhou, Frank Arnold, Nicole A. Doria-Rose, Richard A. Koup, Adrian B. McDermott, Diana G. Scorpio, Michael Worobey, Lawrence Shapiro, John R. Mascola, Peter D. Kwong
Abstract
The HIV fusion peptide (FP) is a promising vaccine target. FP-directed monoclonal antibodies from vaccinated macaques have been identified that neutralize up to ∼60% of HIV strains; these vaccinations, however, have involved ∼1 year with an extended neutralization-eclipse phase without measurable serum neutralization. Here, in 32 macaques, we test seven vaccination regimens, each comprising multiple immunizations of FP-carrier conjugates and HIV envelope (Env) trimers. Comparisons of vaccine regimens reveal FP-carrier conjugates to imprint cross-clade neutralizing responses and a cocktail of FP conjugate and Env trimer to elicit the earliest broad responses. We identify a signature, appearing as early as week 6 and involving the frequency of B cells recognizing both FP and Env trimer, predictive of vaccine-elicited breadth ∼1 year later. Immune monitoring of B cells in response to vaccination can thus enable vaccine insights even in the absence of serum neutralization, here identifying FP imprinting, cocktail approach, and early signature as means to improve FP-directed vaccine responses.