A Phase I Double Blind, Placebo-Controlled, Randomized Study of a Multigenic HIV-1 Adenovirus Subtype 35 Vector Vaccine in Healthy Uninfected Adults

Abstract

BackgroundWe conducted a phase I, randomized, double-blind, placebo-controlled trial to assess the safety and immunogenicity of escalating doses of two recombinant replication defective adenovirus serotype 35 (Ad35) vectors containing gag, reverse transcriptase, integrase and nef (Ad35-GRIN) and env (Ad35-ENV), both derived from HIV-1 subtype A isolates. The trial enrolled 56 healthy HIV-uninfected adults.MethodsAd35-GRIN/ENV (Ad35-GRIN and Ad35-ENV mixed in the same vial in equal proportions) or Ad35-GRIN was administered intramuscularly at 0 and 6 months. Participants were randomized to receive either vaccine or placebo (10/4 per group, respectively) within one of four dosage groups: Ad35-GRIN/ENV 2×109 (A), 2×1010 (B), 2×1011 (C), or Ad35-GRIN 1×1010 (D) viral particles.ResultsNo vaccine-related serious adverse event was reported. Reactogenicity events reported were dose-dependent, mostly mild or moderate, some severe in Group C volunteers, all transient and resolving spontaneously. IFN-γ ELISPOT responses to any vaccine antigen were detected in 50, 56, 70 and 90% after the first vaccination, and in 75, 100, 88 and 86% of Groups A–D vaccine recipients after the second vaccination, respectively. The median spot forming cells (SFC) per 106 PBMC to any antigen was 78–139 across Groups A–C and 158–174 in Group D, after each of the vaccinations with a maximum of 2991 SFC. Four to five HIV proteins were commonly recognized across all the groups and over multiple timepoints. CD4+ and CD8+ T-cell responses were polyfunctional. Env antibodies were detected in all Group A–C vaccinees and Gag antibodies in most vaccinees after the second immunization. Ad35 neutralizing titers remained low after the second vaccination.Conclusion/SignificanceAd35-GRIN/ENV reactogenicity was dose-related. HIV-specific cellular and humoral responses were seen in the majority of volunteers immunized with Ad35-GRIN/ENV or Ad35-GRIN and increased after the second vaccination. T-cell responses were broad and polyfunctional.Trial RegistrationClinicalTrials.gov NCT00851383

Clade A HIV-1 Gag-Specific T Cell Responses Are Frequent but Do Not Correlate with Viral Loads in a Cohort of Treatment-Naïve HIV-Infected Individuals Living in Guinea-Bissau

“…The present political instability in Guinea-Bissau has prevented us from testing the peptide pool in HIV-negative subjects to rule out nonspecific reactivity. However, although the standard operating procedure and geographical location differed from those of the present study, an absence of reactivity was recently demonstrated elsewhere for naïve HIV-negative individuals (7). This is the first report of HIV-1-specific T cell responses from Guinea-Bissau.…”

“…(i) The sequence covering the overlapping Gag peptide pool is incorporated into a prophylactic HIV vaccine candidate currently being tested in clinical trials in East Africa (7). The high degree of reactivity in this geographically distinct population may indicate the potential of testing such a vaccine in regions outside East Africa.…”

Progress in HIV vaccine development

“…120,121 Ad26 and Ad35 studies have shown potential in phase I/II human vaccine trials. [122][123][124][125] A recent randomized, double-blind, placebo-controlled trial in 218 healthy adults using Ad26. EnvA.01 and Ad35.Env vectors in both homologous and heterologous combinations elicited humoral and cellular immune responses in nearly all participants.…”

Neutralizing antibodies against adenovirus type 2 in normal and HIV-1-infected subjects: Implications for use of Ad2 vectors in vaccines

“…13,14 The seroprevalence rates and titers of NAbs directed against Ad2 have previously been reported in the Belgian population (n D 100) using traditional replication inhibition with a plaque assay, and in the Philadelphian population (n D 40) with neutralization assays, using rAd and the SEAP reporter gene. 15,20 Here, we developed a quantitative neutralization assay using rAd2 and the EGFP reporter gene.…”

“…[10][11][12] The development of vectors based on other rAd serotypes with lower seroprevalence than Ad5, such as Ad35 and Ad26, has shown promise in human trials. 13,14 The functions of most Ad2 and Ad5 proteins (from adenoviral species C) are similar and these are currently the most widely investigated adenoviruses. Several Ad2-vectored candidate vaccines have been developed in China, but the seroprevalence rates and titers of NAbs to Ad2 among healthy and HIV-positive individuals in China are unclear.…”