Immunization with germ line–targeting SOSIP trimers elicits broadly neutralizing antibody precursors in infant macaques.

Adolescents are a growing population of people living with HIV. The period between weaning and sexual debut presents a low-risk window for HIV acquisition, making early childhood an ideal time for implementing an immunization regimen. Because the elicitation of broadly neutralizing antibodies (bnAbs) is critical for an effective HIV vaccine, our goal was to assess the ability of a bnAb B cell lineage–designed HIV envelope SOSIP (protein stabilized by a disulfide bond between gp120-gp41—named "SOS"—and an isoleucine-to-proline point mutation—named "IP"—at residue 559) to induce precursor CD4 binding site (CD4bs)–targeting bnAbs in early life. Infant rhesus macaques received either a BG505 SOSIP, based on the infant BG505 transmitted/founder virus, or the CD4bs germ line–targeting BG505 SOSIP GT1.1 (n = 5 per group). Although both strategies induced durable, high-magnitude plasma autologous virus neutralization responses, only GT1.1-immunized infants (n = 3 of 5) exhibited VRC01-like CD4bs bnAb precursor development. Thus, a multidose immunization regimen with bnAb lineage–designed SOSIPs shows promise for inducing early B cell responses with the potential to mature into protective HIV bnAbs before sexual debut. 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 neutralize 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 germ line–targeting immunogens can elicit neutralizing antibodies toward conserved HIV Env epitopes. (See accompanying Research Article by Caniels et al. and accompanying Focus by Amara.) —Christiana Fogg [ABSTRACT FROM AUTHOR]