HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial

BACKGROUND. Vector prime-boost immunization strategies induce strong cellular and humoral immune responses. We examined the priming dose and administration order of heterologous vectors in HIV Vaccine Trials Network 078 (HVTN 078), a randomized, double-blind phase Ib clinical trial to evaluate the safety and immunogenicity of heterologous prime-boost regimens, with a New York vaccinia HIV clade B (NYVAC-B) vaccine and a recombinant adenovirus 5-vectored (rAd5-vectored) vaccine. METHODS. NYVAC-B included HIV-1 clade B Gag-Pol-Nef and gp120, while rAd5 included HIV-1 clade B Gag-Pol and clades A, B, and C gp140. Eighty Ad5-seronegative subjects were randomized to receive 2 x NYVAC-B followed by 1 x 10(10) PFU rAd5 (NYVAC/Ad5(hi)); 1 x 10(8) PFU rAd5 followed by 2 x NYVAC-B (Ad5(lo)/NYVAC); 1 x 10(9) PFU rAd5 followed by 2 x NYVAC-B (Ad5(med)/NYVAC); 1 x 10(10) PFU rAd5 followed by 2 x NYVAC-B (Ad5(hi)/NYVAC); or placebo. Immune responses were assessed 2 weeks after the final vaccination. Intracellular cytokine staining measured T cells producing IFN-gamma and/or IL-2; cross-clade and epitope-specific binding antibodies were determined; and neutralizing antibodies (nAbs) were assessed with 6 tier 1 viruses. RESULTS. CD4(+) T cell response rates ranged from 42.9% to 93.3%. NYVAC/AdS(hi) response rates (P <= 0.01) and magnitudes (P <= 0.03) were significantly lower than those of other groups. CD18(+) T cell response rates ranged from 65.5 % to 85.7%. NYVAC/Ad5(hi) magnitudes were significantly lower than those of other groups (P <= 0.04). IgG response rates to the group M consensus gp140 were 89.7% for NYVAC/Ad5(hi) and 21.4%, 84.6%, and 100% for Ad5(lo)/NYVAC, Ad5(med)/NYVAC, and Ad5(hi)/NYVAC, respectively, and were similar for other vaccine proteins. Overall nAb responses were low, but aggregate, responses appeared stronger for Ad5(med)/NYVAC and Ad5(hi)/NYVAC than for NYVAC/AdS5(hi.) CONCLUSIONS. rAd5 prime followed by NYVAC boost is superior to the reverse regimen for both vaccine-induced cellular and humoral immune responses. Higher Ad5 priming doses significantly increased binding and nAbs. These data provide a basis for optimizing the design of future clinical trials testing vector-based heterologous prime-boost strategies.