A broadly cross-reactive neutralizing antibody response is necessary to prevent infection from diverse strains of HIV. Induction of such broadly neutralizing antibodies by vaccination has been challenging but current approaches can induce autologous neutralizing antibodies (nAbs) in various animal models. Here we tested if vaccine-induced nAbs alone or in combination with cellular immune responses can protect rhesus macaques (RMs) against intravaginal challenges with the autologous strain of virus representative of circulating HIV-1 strains.
We immunized three groups of RMs as follows: group 1 with a trimeric HIV envelope protein (BG505 SOSIP.664) adjuvanted with the TLR7/8 ligand 3M-052, alone to induce nAbs; group 2 with a heterologous viral vector regimen expressing SIVmac239 Gag to induce tissue-resident memory CD8 T cells (TRMs, which traffic to and reside in mucosal tissues), as well as with BG505 SOSIP.664/3M-052 as in group 1; and group 3 as controls with 3M-052 alone. One month after the final protein vaccination, we challenged the animals weekly, in total 10 times, with SHIV-BG505 via the intravaginal route to measure vaccine-induced protection. We then identified immune correlates of protection. Finally, vaginal tissues were isolated from four protected animals from group 2 following necropsy, and were stimulated ex vivo with cognate Gag peptides to reactivate TRMs. The impact of TRM activation was analyzed by CITE-seq single-cell RNA sequencing to identify a possible mechanism(s) by which the TRMs enhanced protection.
The protein and HVV immunizations were immunogenic as measured by high autologous nAb titers and Gag-specific T cell responses, respectively. Following 10 weekly vaginal challenges with SHIV-BG505, protection was observed in both immunization groups: 53.3% and 66.7% in groups 1 and 2, respectively. A nAb titer above ~300 represented the primary correlate of protection in group 1 animals. Surprisingly, in group 2, nAb response was not the primary correlate. A majority of the protected animals had nAb titers <300 suggesting that the TRMs reduced the nAb threshold associated with protection. Furthermore, protection observed in group 2 was durable as these animals resisted six additional challenges five months later with the same virus. Ex vivo restimulation of TRMs in vaginal tissues revealed rapid induction of local antiviral immunity.
TRMs can reduce nAb threshold and provide durable protection against HIV.