Background:
An HIV vaccine that induces protective, broadly-neutralizing antibodies (bnAbs) prior to sexual debut is critical to eliminate the ~410,000 new infections annually that occur among youth aged 15 to 24 years worldwide, and provide lifelong immunity. Recent work has established that HIV-infected children develop bnAbs earlier and at a higher frequency than adults, suggesting that the infant immune landscape may be more amenable to the induction of bnAb B cell lineages by vaccination than that of adults. The goal of this study was to assess the ability of bnAb germline-targeting BG505 SOSIP trimers to induce precursor bnAb responses in early life.
Methods:
Infant (n=5) and juvenile (n=4) rhesus macaques (RMs) received 3 immunizations of the germline-targeting BG505 GT1.1 SOSIP trimer (50mg) with the 3M-052-SE adjuvant 6 weeks apart. All RMs were then boosted 12 weeks later with the wildtype BG505.664 SOSIP trimer 3 times in 6-month intervals. Vaccine elicited antibody responses were monitored through 1.5 years.
Results:
BG505 GT1.1 SOSIP trimer immunization induced consistently higher magnitude vaccine antigen-specific IgG responses after each immunization in infants compared to juvenile RMs. BG505 SOSIP immunization also induced similar plasma tier 2 autologous virus neutralization responses in both age groups, which were maintained through 1.5 years. Notably, by week 80 three GT1.1 SOSIP-immunized infants exhibited a plasma neutralization signature reflective of CD4 binding site-specific (CD4bs) bnAb precursor development, while none of the juvenile RMs had developed this response. Electron-microscopy based epitope mapping of polyclonal plasma confirmed the presence of CD4bs-targeting antibodies in the majority of immunized infant RMs.
Conclusions:
Our data demonstrates that sequential immunization of infant RMs with germline-targeting and wildtype BG505 SOSIP trimers can induce high serum neutralizing antibody titers and CD4bs bnAb precursors, while these responses were not detectable in vaccinated juvenile RMs. Our results support observations in human studies suggesting that the infant immune environment is better suited for induction of plasma HIV bnAb responses.