Safety and Immunogenicity of the MRKAd5 gag HIV Type 1 Vaccine in a Worldwide Phase 1 Study of Healthy Adults

Abstract

The safety and immunogenicity of the MRK adenovirus type 5 (Ad5) HIV-1 clade B gag vaccine was assessed in an international Phase I trial. Three-hundred and sixty healthy HIV-uninfected adults were enrolled on five continents. Subjects received placebo or 1 × 10⁹ or 1 × 10¹⁰ viral particles (vp) per dose of the MRKAd5 HIV-1 gag vaccine at day 1, week 4, and week 26. Immunogenicity was evaluated using an IFN-γ ELISPOT gag 15-mer assay with positive responses defined as ≥55 SFC/10⁶ PBMCs and ≥4-fold over mock control. The vaccine was well tolerated. The most common adverse events were injection site reactions, headache, pyrexia, diarrhea, fatigue, and myalgia. At week 30, geometric mean ELISPOT responses were 24, 114, and 226 SFC/10⁶ PBMCs in the placebo, 1 × 10⁹ vp/dose, and 1 × 10¹⁰ vp/dose groups, respectively. Overall, responses to 1 × 10¹⁰ vp were 85% and 68% in subjects with low (≤200) and high (>200) baseline Ad5 titers, respectively. The MRKAd5 HIV-1 gag vaccine was immunogenic in diverse geographic regions. Gag ELISPOT responses were greater in the 1 × 10¹⁰ vp/dose groups than in the 1 × 10⁹ vp/dose groups. Data from this first international study indicate that adenovirus-vectored vaccines are well tolerated and may be immunogenic in subjects from regions with high prevalence of preexisting Ad5 immunity.

FIG. 1.

Subject accounting. A total of 32 vaccinated subjects (30 in the vaccine groups and two in the placebo group) were excluded from the primary immunogenicity analysis. Reasons for exclusion are provided.

FIG. 2.

MRKAd5 gag ELISPOT response (SFC/106 PBMC) versus baseline anti-Ad5 antibody titer by dose level (all regions pooled). The figure demonstrates a significant decline in ELISPOT with increasing Ad5 titer at the 1 × 10⁹ dose, but not at the 1 × 10¹⁰ dose. Filled circles (•) indicate participants who were ELISPOT positive or seroresponders. Open circles (○) indicate participants who were ELISPOT negative or nonresponders.

FIG. 3.

Gag ELISPOT response over time by dose level and baseline anti-Ad5 antibody strata (all regions pooled): critical time points only with confidence intervals. Antibody titers persisted through week 78 at levels near that achieved at week 30.