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

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Abstract

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 × 10¹⁰ PFU rAd5 (NYVAC/Ad5_hi); 1 × 10⁸ PFU rAd5 followed by 2 × NYVAC-B (Ad5_lo/NYVAC); 1 × 10⁹ PFU rAd5 followed by 2 × NYVAC-B (Ad5_med/NYVAC); 1 × 10¹⁰ 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.

Authors

Pierre-Alexandre Bart, Yunda Huang, Shelly T. Karuna, Samuel Chappuis, Julien Gaillard, Nidhi Kochar, Xiaoying Shen, Mary A. Allen, Song Ding, John Hural, Hua-Xin Liao, Barton F. Haynes, Barney S. Graham, Peter B. Gilbert, M. Juliana McElrath, David C. Montefiori, Georgia D. Tomaras, Giuseppe Pantaleo, Nicole Frahm