A clade C HIV-1 vaccine protects against heterologous SHIV infection by modulating IgG glycosylation and T helper response in macaques.

The rising global HIV-1 burden urgently requires vaccines capable of providing heterologous protection. Here, we developed a clade C HIV-1 vaccine consisting of priming with modified vaccinia Ankara (MVA) and boosting with cyclically permuted trimeric gp120 (CycP-gp120) protein, delivered either orally using a needle-free injector or through parenteral injection. We tested protective efficacy of the vaccine against intrarectal challenges with a pathogenic heterologous clade C SHIV infection in rhesus macaques. Both routes of vaccination induced a strong envelope-specific IgG in serum and rectal secretions directed against V1V2 scaffolds from a global panel of viruses with polyfunctional activities. Envelope-specific IgG showed lower fucosylation compared with total IgG at baseline, and most of the vaccine-induced proliferating blood CD4⁺ T cells did not express CCR5 and α4β7, markers associated with HIV target cells. After SHIV challenge, both routes of vaccination conferred significant and equivalent protection, with 40% of animals remaining uninfected at the end of six weekly repeated challenges with an estimated efficacy of 68% per exposure. Induction of envelope-specific IgG correlated positively with G1FB glycosylation, and G2S2F glycosylation correlated negatively with protection. Vaccine-induced TNF-α⁺ IFN-γ⁺ CD8⁺ T cells and TNF-α⁺ CD4⁺ T cells expressing low levels of CCR5 in the rectum at prechallenge were associated with decreased risk of SHIV acquisition. These results demonstrate that the clade C MVA/CycP-gp120 vaccine provides heterologous protection against a tier2 SHIV rectal challenge by inducing a polyfunctional antibody response with distinct Fc glycosylation profile, as well as cytotoxic CD8 T cell response and CCR5-negative T helper response in the rectum. A clade C HIV-1 vaccine: Clade C HIV-1 infections are responsible for a large proportion of global HIV-1 burden, and a vaccine is urgently required. Sahoo et al. created a clade C HIV-1 vaccination regimen that they tested in rhesus macaques, consisting of priming with modified vaccinia Ankara (MVA) and boosting with cyclically permuted trimeric gp120 (CycP-gp120). To assess delivery methods, vaccines were administered by parenteral injection or oral administration using a needle-free injector. Both routes of MVA/CycP-gp120 administration provided equivalent protection against mucosal SHIV infection. Reduced risk of infection correlated with distinct env-specific IgG Fc glycosylation profiles, as well as with vaccine-induced TNF-α⁺ IFN-γ⁺ CD8⁺ T cells and TNF-α⁺ CCR5^lo CD4⁺ T cells. These findings demonstrate that the MVA/CycP-gp120 immunization regimen provides significant protection against heterologous SHIV infection. [ABSTRACT FROM AUTHOR]