Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site.

Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)–specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers. Editor's summary: HIV vaccine efforts include developing immunogens that induce broadly neutralizing antibodies (bnAbs). Two studies highlight advances in inducing VRC01-class bnAbs that bind to the conserved CD4 binding site (CD4bs) epitope of the HIV envelope (Env). Caniels et al. used structure-based design to optimize a trimeric HIV Env antigen called BG505 SOSIP GT1.1 (GT1.1). Adult nonhuman primates (NHPs) immunized with GT1.1 produced antibodies that neutralized fully glycosylated viruses by specifically binding to the CD4bs. Nelson et al. evaluated GT1.1 in infant NHPs compared with a predecessor immunogen, BG505 SOSIP. Both immunogens induced neutralizing antibodies against autologous viruses, but only infants primed with GT1.1 generated VRC01-like CD4bs bnAb precursors upon boosting with BG505 SOSIP. These findings indicate that trimeric germline-targeting immunogens can elicit neutralizing antibodies toward conserved HIV Env epitopes. (See accompanying Research Article by Nelson et al. and accompanying Focus by Amara.) —Christiana Fogg [ABSTRACT FROM AUTHOR]