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 × 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.

Head-to-Head Comparison of Poxvirus NYVAC and ALVAC Vectors Expressing Identical HIV-1 Clade C Immunogens in Prime-Boost Combination with Env Protein in Nonhuman Primates

“…Furthermore, a DNA-C prime (two plasmid vectors)/NYVAC-C (vP2010; old single-component) boost immunization protocol tested in a phase I clinical trial (EV02) resulted in significantly enhanced HIV-1-specific T-and B-cell immune responses (25), though again with an Env antigen-specific bias that was polyfunctional and long-lasting (13). In another recent human clinical trial (HVTN078), NYVAC was used in combination with an adenovirus 5 (Ad5)-based HIV vaccine, and it was shown that NYVAC was a potent boosting component (23). A similar NYVAC-based HIV/AIDS therapeutic vaccine candidate expressing Env and Gag-Pol-Nef HIV-1 antigens from clade B (NYVAC-B) has been evaluated in HIV-1-infected patients on antiretroviral therapy in a phase I clinical trial (Theravac-01).…”

“…In particular, recombinant NYVAC vectors expressing HIV-1 Env, Gag, Pol, and Nef antigens from clade B or C elicited strong, broad, and polyfunctional T-cell immune responses in mice, nonhuman primates, and humans, together with varied levels of humoral re-sponses against HIV-1 gp120 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)). An additional feature is that the current NYVAC vectors preferentially trigger CD4 ϩ T-cell responses (13,14,24,25) in both humans and macaques, inferring immunologically the recruitment of stronger B-cell responses than ALVAC-based vectors.…”

Distinct Roles of Vaccinia Virus NF-κB Inhibitor Proteins A52, B15, and K7 in the Immune Response

“…The attenuated poxvirus strain NYVAC (New York vaccinia virus) has been used as a vaccine vector in HIV clinical trials (3,4). Studies in nonhuman primates showed that NYVAC expressing Env and/or the Gag-Pol-Nef (GPN) clade C HIV antigens elicited a balanced CD4/CD8 T cell response (5) or robust T cell immunity (6).…”

HIV/AIDS Vaccine Candidates Based on Replication-Competent Recombinant Poxvirus NYVAC-C-KC Expressing Trimeric gp140 and Gag-Derived Virus-Like Particles or Lacking the Viral Molecule B19 That Inhibits Type I Interferon Activate Relevant HIV-1-Specific B and T Cell Immune Functions in Nonhuman Primates

“…Clinical trials with homologous NYVAC vectors expressing HIV-1 antigens (gp120 Env and the polyprotein Gag-Pol-Nef) have shown a limited immunogenicity profile with a preference for CD4 ϩ T cell activation, which was markedly enhanced when priming was performed with a DNA vector expressing the same HIV-1 antigens (29)(30)(31)(32)(33). Thus, in order to optimize the immunization protocol with NYVAC vectors expressing HIV-1 antigens, various approaches in NHPs have been evaluated, either comparing NYVAC to ALVAC (13) or combining NYVAC with DNA vectors (10), peptides (22), and dendritic cell targets (28), which have all demonstrated promising results.…”