Human Immunodeficiency Virus Type 1 Vaccine Development: Recent Advances in the Cytotoxic T-Lymphocyte Platform “Spotty Business”

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Abstract
The discontinuation of the Merck recombinant adenovirus type 5 (rAd5) phase II proof-of-concept STEP study is undoubtedly a significant setback for the field of HIV vaccine development. In the study, a trivalent, three-vector rAd5 (Gag, Pol, Nef) vaccine was tested in two cohorts of 1,500 individuals at high risk for HIV infection. The vaccine was scheduled for three immunizations of 1.5 × 1010 viral genomes of each rAd5 vector encoding Gag, Pol, or Nef administered on day 1, month 1, and month 6. There are concerns that preexisting vector serology can mute the effectiveness of a CTL vaccine approach. Accordingly, the first cohort was made up of 1,500 individuals with low levels of preexisting antibodies against Ad5, with titers of ≤1:200, while the second cohort of 1,500 included participants with anti-Ad5 titers of greater than 1:200. However, the STEP study was prematurely stopped by the data- and safety-monitoring board because it was clear that even in the cohort with low titers of preexisting antibodies against Ad5, there was no evidence of efficacy. Table 1 summarizes the results from the cohort with titers of ≤1:200, comparing the rates of infection and viral loads of the vaccinated versus placebo groups. This was the best-response group in earlier clinical studies, eliciting CTL responses in over 60% of vaccinees. As shown in Table 1, in the subset of individuals that received at least two immunizations, there was a trend toward more HIV infections in the rAd5-vaccinated (19/672) group than in those in the placebo (11/691) group. The difference in viral loads 12 to 18 weeks postacquisition of the infection between the vaccinated and placebo groups (40,000 versus 37,000 copies per ml, respectively) were not statistically significant. Since this rAd5 trivalent vaccine did not prevent infection or decrease viral replication in vaccinated individuals, the implications for CTL-based vaccines remain unclear, except that future studies should test hypotheses and concepts that are not identical to the Merck approach. Furthermore, this study draws a line in the sand in that the following CTL-based approach should induce higher levels of CTL responses and induce a different immune phenotype. The inclusion of different antigens or prime-boost strategies in future studies with defined immune endpoints will be important. We will consider many of these in the following sections.

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