Escalating dose priming increases VRC01-class B-cell precursors and leads to robust cross-strain serum neutralization in a stringent mouse model

Authors

• KT Nguyen
• X Chen
• S Charaf
• S O'Dell
• M Choe
• AS Olia
• M Suleiman
• S Luo
• C Cheng
• T Zhou
• PD Kwong
• NA Doria-Rose
• FW Alt
• JR Mascola
• TC Pierson

Abstract

To generate protective immunity against HIV-1, eliciting broad and potent neutralizing antibodies (bnAbs) is paramount. One prevalent strategy in HIV-1 vaccine development involves promoting VRC01-class bnAbs that target the HIV-1 envelope CD4 binding site (CD4bs) with high breadth and potency.

We have shown that a sequential immunization strategy elicits VRC01-class bnAbs in a lenient mouse model expressing diverse human VRC01-class precursors in 25% of memory B-cells. Here, we investigate whether these vaccine regimens similarly promote VRC01-class bnAbs in a more stringent mouse model expressing VRC01-class precursors at 0.0002%, comparable to humans, and seek methods to further improve these regimens. We immunized these mice with various prime and boost regimens and discovered that 1) sequential immunization still elicits CD4bs-specific cross-strain serum neutralization, albeit with a lower response rate than in the lenient VRC01 mouse model; and 2) Mut49 60mer—a glycan masking mutant of the engineered gp120 outer-domain eOD-GT8—and a gp120 core nanoparticle C13.4.1-Ferritin were the best priming and first boost immunogens, respectively, for maintaining CD4bs-directed responses. We also evaluated whether escalating dose (ED) priming could enhance VRC01-class antibody responses and lead to robust serum neutralization against various HIV trimers. Indeed, adjusting the administration of the first two immunogens in the sequential regimens from a bolus to ED significantly increased CD4bs-specific serum binding and neutralization titers.

Overall, our optimized sequential immunization regimens in combination with ED priming generated robust CD4bs-specific cross-strain serum neutralization in a stringent mouse model with naturally occurring levels of VRC01-class B-cell precursors.

Scientific Focus Area: Virology

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