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A large phase IIB clinical trial of an HIV-1 vaccine was halted last week after an interim analysis revealed that the vaccine was ineffective. The vaccine included three recombinant adenovirus serotype 5 (rAd5) vectors expressing HIV-1 gag, pol, and nef. Unlike traditional vaccines, which are designed to generate antibody responses, this vaccine was intended to elicit HIV-1–specific cellular immune responses, in which CD8 T cells would become programmed to recognize and kill HIV-1–infected cells. In previous, smaller trials, the vaccine generated such responses in the majority of recipients and was well tolerated.
In the present trial (called the STEP study), approximately 3000 uninfected adults who were at high risk for acquiring HIV-1 infection were randomized to receive three doses of vaccine or placebo during a 6-month period. The trial took place in North and South America, the Caribbean, and Australia and was cosponsored by the vaccine manufacturer (Merck) and the HIV Vaccine Trials Network.
After an average follow-up of 13 months, a planned interim analysis was conducted among approximately 1500 participants who were expected to have the best responses because of low levels of preexisting immunity to adenovirus 5. However, the vaccine failed to prevent HIV-1 infection in these individuals and also did not reduce viral load in those who became infected. Rates of HIV-1 acquisition were 3.2% in the vaccine group (24 of 741) and 2.8% in the placebo group (21 of 762). Mean viral loads 8 to 12 weeks after diagnosis were 40,000 copies/mL in the vaccine group and 37,000 copies/mL in the placebo group. Given these results, vaccination and enrollment have been discontinued in the STEP study and also in three other studies: a phase II trial (called the Phambili trial) of the same vaccine in South Africa and two additional phase I trials.
Vaccination and enrollment are discontinued in phase II trials of Merck’s investigational HIV vaccine candidate [press release]. Whitehouse Station, N.J., and Seattle: Merck and HIV Vaccine Trials Network; Sep 21, 2007. Available at: http://www.hvtn.org/pdf/FINAL_HIV_Vaccine_Press_Release.pdf. Accessed Sep 27, 2007.
Comment
The failure of this HIV-1 vaccine candidate certainly represents a major disappointment for the field and has generated questions about whether it may reflect a “concept failure” of T-cell–based vaccines in general. Such a conclusion could be premature, however, given that next-generation vaccine candidates have already been shown to elicit more potent cellular immune responses with enhanced breadth, quality, and protective efficacy as compared with rAd5 vectors in nonhuman primates. Moreover, the continued development of T-cell–based vaccines is important, because no immunogens have been constructed to date that induce broadly reactive neutralizing antibodies.
Data from follow-up analyses in this study will contribute substantially to the design of future vaccine candidates. Important issues to explore include the extent to which secondary immune responses developed in vaccinees following infection and the degree of genetic distance between the vaccine antigens and the infecting viruses.
Overall, the disappointing results from the STEP study highlight the enormous scientific challenge associated with developing a safe and effective HIV-1 vaccine. The need for such a vaccine remains unquestioned, however, and the failure of this particular vaccine candidate should not deter researchers from continuing to work toward this important goal.