Safety and immunogenicity of the Merck adenovirus serotype 5 (MRKAd5) and MRKAd6 human immunodeficiency virus type 1 trigene vaccines alone and in combination in healthy adults

Abstract

Preexisting immunity to adenovirus serotype 5 (Ad5) diminishes immune responses to vaccines using Ad5 as a vector. Alternate Ad serotypes as vaccine vectors might overcome Ad5-specific neutralizing antibodies and enhance immune responses in populations with a high prevalence of Ad5 immunity. To test this hypothesis, healthy human immunodeficiency virus (HIV)-seronegative adults were enrolled in a blinded, randomized, dose-escalating, placebo-controlled study. In part A, subjects with baseline Ad6 titers of < or = 18 received the Merck Ad6 (MRKAd6) HIV type 1 (HIV-1) trigene vaccine at weeks 0, 4, and 26. In part B, subjects stratified by Ad5 titers (< or = 200 or >200) and Ad6 titers (< or = 18 or >18) received the MRKAd5-plus-MRKAd6 (MRKAd5+6) HIV-1 trigene vaccine at weeks 0, 4, and 26. Immunogenicity was assessed by an enzyme-linked immunospot (ELISPOT) assay at week 30. No serious adverse events occurred. MRKAd6 trigene vaccine recipients responded more often to Nef than to Gag or Pol. In part A, ELISPOT response rates to > or = 2 vaccine antigens were 14%, 63%, and 71% at 10(9), 10(10), and 10(11) viral genomes (vg)/dose, respectively. All responders had positive Nef-specific ELISPOT results. In part B, Nef-ELISPOT response rates at 10(10) vg/dose of the MRKAd5+6 trigene vaccine were 50% in the low-Ad5/low-Ad6 stratum (n = 8), 78% in the low-Ad5/high-Ad6 stratum (n = 9), 75% in the high-Ad5/low-Ad6 stratum (n = 8), and 44% in the high-Ad5/high-Ad6 stratum (n = 9). The MRKAd6 and MRKAd5+6 trigene vaccines elicited dose-dependent responses predominantly to Nef and were generally well tolerated, indicating that Ad6 should be considered a candidate vector for future vaccines. Although small sample sizes limit the conclusions that can be drawn from this exploratory study, combining two Ad vectors may be a useful vaccine strategy for circumventing isolated immunity to a single Ad serotype.

FIG. 1.

MRKAd5 and MRKAd6 trigene vaccine constructs. The HIV nef-gag/pol expression cassette (lower diagram) was added to both the MRKAd5 and MRKAd6 vectors. ITR_L, inverted terminal repeat (left); ITR_R, inverted terminal repeat (right); BGH, bovine growth hormone; pA, polyadenylation signal sequence; SV40, simian virus 40.

FIG. 2.

Study schema. The Safety Evaluation Committee (SEC) examined adverse-event reports from completed stages where indicated before subjects were vaccinated in later stages. For stages IIB and IIIB, randomization was stratified by high versus low titers of neutralizing antibodies against Ad5 (≤200 versus >200) and by high versus low titers of neutralizing antibodies against Ad6 (≤18 versus >18) at baseline (1).

FIG. 3.

Subject accounting. (A) Stages IA, IIA, and IIIA; (B) stages IIB and IIIB. (Stage IB, which only used the Ad5 vector, is not displayed for clarity.)