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 × NYVAC-B followed by 1 × 10 10 PFU rAd5 (NYVAC/Ad5 hi ); 1 × 10 8 PFU rAd5 followed by 2 × NYVAC-B (Ad5 lo /NYVAC); 1 × 10 9 PFU rAd5 followed by 2 × NYVAC-B (Ad5 med /NYVAC); 1 × 10 10 PFU rAd5 followed by 2 × 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-γ 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/Ad5 hi response rates (P ≤ 0.01) and magnitudes (P ≤ 0.03) were significantly lower than those of other groups. CD8+ 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/Ad5 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.TRIAL REGISTRATION. ClinicalTrials.gov NCT00961883.FUNDING. NIAID, NIH UM1AI068618, AI068635, AI068614, and AI069443.
Montefiori et al.: rAd5/NYVAC-B is superior to NYVAC-B/rAd5 and is dependent on rAd5 dose for neutralizing antibody responses against HIV-1. Retrovirology 2012 9(Suppl 2):P132.
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