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

• Published in: The Journal of clinical investigation 2014-11, Vol.124 (11), p.4843-4856
• Main Authors: Bart, Pierre-Alexandre, Huang, Yunda, Karuna, Shelly T, Chappuis, Samuel, Gaillard, Julien, Kochar, Nidhi, Shen, Xiaoying, Allen, Mary A, Ding, Song, Hural, John, Liao, Hua-Xin, Haynes, Barton F, Graham, Barney S, Gilbert, Peter B, McElrath, M Juliana, Montefiori, David C, Tomaras, Georgia D, Pantaleo, Giuseppe, Frahm, Nicole
• Format: Article
• Language: English
• Subjects: Adenovirus; Adenoviruses; Adult; AIDS vaccines; AIDS Vaccines - immunology; Antibodies, Viral - blood; Antigens; Biomedical research; Cells, Cultured; Clinical Medicine; Clinical trials; Deoxyribonucleic acid; DNA; Double-Blind Method; Female; Health aspects; HIV Infections - prevention & control; HIV-1 - immunology; Human immunodeficiency virus 1; Humans; Immune response; Immune system; Immunity, Cellular; Immunity, Humoral; Immunization, Secondary; Immunoglobulin G - blood; Male; Physiological aspects; Protein Binding; Response rates; Studies; T cells; Vaccination; Vaccines; Young Adult
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI75894

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/Ad5hi); 1 × 108 PFU rAd5 followed by 2 × NYVAC-B (Ad5lo/NYVAC); 1 × 109 PFU rAd5 followed by 2 × NYVAC-B (Ad5med/NYVAC); 1 × 1010 PFU rAd5 followed by 2 × NYVAC-B (Ad5hi/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/Ad5hi 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/Ad5hi 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/Ad5hi and 21.4%, 84.6%, and 100% for Ad5lo/NYVAC, Ad5med/NYVAC, and Ad5hi/NYVAC, respectively, and were similar for other vaccine proteins. Overall nAb responses were low, but aggregate responses appeared stronger for Ad5med/NYVAC and Ad5hi/NYVAC than for NYVAC/Ad5hi. 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.