Immunogenicity and protection mediated by dmLT and alum adjuvants for an HIV-1 vaccine

The development of an effective HIV-1 vaccine is of paramount importance to global health. Here, we compared the influence of two adjuvants, <i>Escherichia coli</i> double-mutant heat-labile toxin (dmLT) and alum, on the protective immunity induced by a cyclically permuted trimeric HIV-1 envelope gp120 protein (CycP-gp120) boost. Two groups of rhesus macaques received two modified vaccinia Ankara (MVA)/SHIV C.1086 primes followed by a CycP-gp120 protein boost adjuvanted with either dmLT (n = 9) or alum (n = 10). A group of unvaccinated macaques (n = 8) served as controls. All animals were intrarectally challenged with heterologous SHIV.CH505.375H.dCT weekly for 7 weeks. Following the challenge, dmLT-adjuvanted animals showed significant protection with a vaccine efficacy of 60.8% per exposure (<i>p</i> = 0.0246). Alum-adjuvanted animals did not show significant protection (<i>p</i> = 0.1575). Both adjuvants induced comparable envelope-specific binding antibody in serum and rectal secretions with broad V1V2 scaffold-binding specificity. IL-6 plasma concentration correlated positively with V1V2 scaffold-binding and increased after vaccination with both adjuvants. With respect to CD4 T cells, dmLT induced higher frequencies of proliferating central memory (T_CM) and ICOS⁺ cells in blood compared to alum. However, these proliferating CD4 T_CM cells showed a decrease in the proportion of gut-homing receptor α4β7-expressing cells in the dmLT group compared to the alum group at week 2 post-protein boost. The V1V2 scaffold-specific IgG, proliferating T_CM and ICOS⁺ CD4 T-cell frequencies, and plasma IL-6 concentration associated positively with protection. These data demonstrate that the vaccine adjuvants dmLT and alum differentially modulate protective helper T-cell responses induced by the CycP-gp120 protein, highlighting the importance of an appropriate adjuvant for eliciting a protective immune response against HIV-1.