Vaccine-induced protection from homologous Tier 2 simian-human immunodeficiency virus challenge in nonhuman primates

Abstract

55Passive administration of HIV neutralizing antibodies (nAbs) can protect macaques from 56 hard-to-neutralize (Tier 2) chimeric simian-human immunodeficiency virus (SHIV) 57 challenge. However, conditions for nAb-mediated protection following vaccination have 58 not been established. Here, we selected groups of 6 rhesus macaques with either high 59 or low serum nAb titers from a total of 78 animals immunized with recombinant native-like 60 (SOSIP) Env trimers from the BG505 HIV isolate. Repeat intrarectal challenge with 61 homologous Tier 2 SHIVBG505 led to rapid infection in unimmunized and low-titer animals. 62In contrast, high-titer animals demonstrated protection that was gradually lost as nAb 63 titers waned over weeks to months. From these results, we determined that an autologous 64 serum ID50 nAb titer of ~1:500 was required to afford over 90% protection from medium-65 dose SHIV infection. We further identified autologous nAb titers, but not ADCC or T cell 66 activity, as strong correlates of protection. These results provide proof-of-concept that 67Env protein-based vaccination strategies can protect against hard-to-neutralize SHIV 68 challenge in rhesus macaques by inducing Tier 2 nAbs, provided appropriate neutralizing 69 titers can be reached and maintained. 70 71

Mapping Polyclonal Antibody Responses in Non-human Primates Vaccinated with HIV Env Trimer Subunit Vaccines

“…In the low-titer NHP group, 2/6 animals became infected after the first challenge, and 4/6 after the second. Finally, in the high-titer NHP group, 1/6 animals became infected after the first challenge, 1/6 after the sixth, 1/6 after the tenth, 1/6 after the twelfth, and 2/6 never became infected (Pauthner et al, 2019).…”

“…The SHIV BG505 virus challenge study enrolled 12 immunized and 6 naive control animals (Pauthner et al, 2019). As previously described, the challenge virus contained a S375Y mutation that confers replication capacity in rhesus macaques and results in AIDS-like pathology (Pauthner et al, 2019). Animals received up to 12 intrarectal challenges at weekly intervals with a break after 6 challenges for those animals not infected early.…”

“…Pauthner et al (2017) recently reported success in eliciting protective tier-2 virus neutralization responses by BG505 SOSOP.664 immunization in rhesus macaques. Immunized non-human primates (NHPs) were grouped into ''high-titer'' or ''low-titer'' animals, defined in the Pauthner et al (2017Pauthner et al ( , 2019 studies, depending on the ability of their serum antibodies to neutralize BG505 pseudo-virus. Both groups, matched with non-immunized controls, were then repetitively challenged with a chimeric SHIV expressing the autologous BG505 Env (SHIV BG505 ) (Pauthner et al, 2019).…”

“…Immunized non-human primates (NHPs) were grouped into ''high-titer'' or ''low-titer'' animals, defined in the Pauthner et al (2017Pauthner et al ( , 2019 studies, depending on the ability of their serum antibodies to neutralize BG505 pseudo-virus. Both groups, matched with non-immunized controls, were then repetitively challenged with a chimeric SHIV expressing the autologous BG505 Env (SHIV BG505 ) (Pauthner et al, 2019). Because the variable levels of both neutralization titers and protection from challenge observed in these macaques may hold important clues as to the potentially productive and unproductive immune system paths that may be evoked by the native-like SOSIP trimer, we decided to perform an analysis of epitopes recognized in the animals from these groups, and to compare them with the antibody response elicited following infection of nonimmunized animals.…”

“…Here, we report EMPEM analysis of NHP polyclonal responses to BG505-based immunogens described in the Pauthner et al (2017Pauthner et al ( , 2019 studies. We found that high-titer animals recognized a greater diversity of epitopes than lower-titer animals.…”