Background
HIV is a highly mutable virus, therefore a vaccine that induces protective, broadly-neutralizing antibodies (bnAbs) before sexual debut is critical to eliminate the ~410,000 new infections annually among adolescents worldwide. Recent work has established that children living with HIV develop bnAbs earlier and at a higher frequency than adults. In this study we compared the ability of a CD4 binding site (CD4bs) germline-targeting SOSIP trimer immunization strategy to induce precursor bnAbs in infant and juvenile rhesus macaques (RMs).
Methods
Infant (n=5) and juvenile (n=4) 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 BG505.664 WT SOSIP trimer 3 times in 6-month intervals. After an over one-year follow-up, all animals received two boosts with a mosaic Clade B SOSIP nanoparticle. Vaccine-elicited antibody responses were monitored through 2.5 years after the 1st vaccination.
Results
BG505 GT1.1 SOSIP trimer immunization consistently induced higher magnitude vaccine-specific IgG binding in infants compared to juvenile RMs yet, plasma autologous tier 1 and 2 neutralization responses were similar between the groups. Additionally, analysis of circulating B cells at week 14 showed that the infants had higher frequencies of BG505 GT1.1-specific B cells than the juveniles following the last BG505 GT1.1 prime. Plasma nsEMPEM revealed 4 infants developed CD4bs targeting antibodies compared to 3 juveniles. Similarly 3 of 5 GT1.1 SOSIP-immunized infants exhibited a plasma neutralization signature indicating CD4bs bnAb precursor development, compared to only 1 of 4 juvenile RMs. Interestingly in the RMs, higher tier 1 neutralization titers showed a trend in predicting the likelihood of an animal to develop bnAb precursors. Following the nanoparticle boost, an additional infant developed the CD4bs precursor bnAb signature, while this response was not maintained in the one juvenile. Nanoparticle boosting also improved the breadth of heterologous neutralization in 4 out of the 5 infants and 2 out of the 4 juveniles.
Conclusions
Our data indicates that sequential immunization with germline-targeting BG505 SOSIP trimers may elicit CD4bs bnAb precursors more frequently in infants compared to juveniles. Our results highlight the potential for an HIV immunization strategy in early life to induce protective bnAb responses and can inform future human pediatric clinical trials.