title: HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial.
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/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.
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Bart
authors.forename: Yunda
authors.initials: Y
authors.lastname: Huang
authors.forename: Shelly T
authors.initials: ST
authors.lastname: Karuna
authors.forename: Samuel
authors.initials: S
authors.lastname: Chappuis
authors.forename: Julien
authors.initials: J
authors.lastname: Gaillard
authors.forename: Nidhi
authors.initials: N
authors.lastname: Kochar
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Shen
authors.forename: Mary A
authors.initials: MA
authors.lastname: Allen
authors.forename: Song
authors.initials: S
authors.lastname: Ding
authors.forename: John
authors.initials: J
authors.lastname: Hural
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Barney S
authors.initials: BS
authors.lastname: Graham
authors.forename: Peter B
authors.initials: PB
authors.lastname: Gilbert
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pantaleo
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D002478:Cells, Cultured; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007117:Immunization, Secondary; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D011485:Protein Binding; D014611:Vaccination; D055815:Young Adult
chemical_list: D016915:AIDS Vaccines; D000914:Antibodies, Viral; D007074:Immunoglobulin G