Optimizing parallel induction of HIV type 1-specific antibody and T-cell responses by multicomponent subunit vaccines.
Clutton G., Carpov A., Parks CL., Dean HJ., Montefiori DC., Hanke T.
OBJECTIVES: Protection against HIV type 1 (HIV-1) infection/AIDS will likely require concerted actions of protective CD8(+) killer T cells and protective antibodies. The challenges in inducing such effectors by active immunization are such that the T-cell and antibody vaccine components require separate development. Here, a rational attempt is taken to combine two separately optimized heterologous regimens into a single T-cell-inducing and antibody-inducing vaccination schedule with minimal induction of unprotective Env-specific T cells. DESIGN: Clade A BG505 Env-derived uncleaved gp140 (BG505u) and conserved region tHIVc immunogens were utilized and presented to the immune system using non-replicating simian (chimpanzee) adenovirus ChAdV-63 (C) and poxvirus-modified vaccinia virus Ankara MVA (M). In addition, purified BG505 gp120 (P) was used for antibody induction. METHODS: BALB/c mice were vaccinated to elicit Env antibodies alone using ChAdV63.BG505u. MVA.BG505u and BG505 gp120 in regimens CMP, CPP and PPP, and in combination with the ChAdV63.tHIVc and MVA.tHIVc components in regimens CMP+CMM, CPP+CMM and PPP+CMM. Antibody and T-cell responses to BG505 Env and conserved regions of the HIV-1 proteome were determined. RESULTS: Although all three regimens delivering BG505 Env induced similar levels of antibodies, BG505-specific T cells were induced in the CMP>CPP>PPP hierarchy, which was maintained during coinduction of tHIVc-specific T cells. Adjuvanted BG505 PPP decreased induction of tHIVc-specific T cells and tHIVc T-cell induction decreased induction of BG505 Ab. As expected, the antibodies that were induced neutralized tier 1 HIV-1 strains. CONCLUSION: These results inform designs of initial human studies combining separately optimized T-cell and B-cell HIV-1 vaccines into a single regimen.