117 30 Years of HIV Vaccine Research

Soon after HIV was discovered as the cause of AIDS in 1983–1984, there was an expectation that a preventive vaccine would be rapidly developed. The first HIV vaccine paradigm was aimed at inducing neutralizing antibodies, with numerous recombinant envelope proteins tested in clinical trials. It came to an end in 2003, with the negative results from the VaxGen trials in North America and Thailand. The second paradigm aimed at inducing CD8(+) T-cell responses, and it led to the development of DNA vaccines and of live-recombinant viral vectors, especially poxviruses and adenoviruses (Ad). The concept was tested in the STEP and Phambili trials, using an Ad5 vector. The trials were stopped in 2007, after an interim review of STEP showed that the vaccine failed to prevent HIV infection or to decrease virus load in vaccinated volunteers who became infected, and even enhanced HIV acquisition in a subpopulation of vaccinated individuals. The current wave of vaccine development is attempting to induce more complex immune responses and exploring novel approaches. The RV 144 trial in Thailand, which assessed the protective efficacy of a prime-boost protocol using a canarypox vectors followed by gp120 boosts, showed 31.2% efficacy in preventing HIV acquisition and presumptive immune correlates have been identified. The field is now exploring new leads that include the rational design of novel immunogens based on epitopes recognized by broadly neutralizing antibodies, live replication-competent vectors and the role of potentially protective non-neutralizing antibodies.