LETTERS to the EDITOR

AIDS vaccine therapy: phase I trial

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. In trying to achieve that goal, three successive scientific paradigms have been explored: induction of neutralizing antibodies, induction of cell mediated immunity, and exploration of combination approaches and novel concepts. Although major progress has been made in understanding the scientific basis for HIV vaccine development, efficacy trials have been critical in moving the field forward. In 2009, the field was reinvigorated with the modest results obtained from the RV144 trial conducted in Thailand. Here, we review those vaccine development efforts, with an emphasis on events that occurred during the earlier years. The goal is to provide younger generations of scientists with information and inspiration to continue the search for an HIV vaccine.

Current therapeutic vaccine trials in major chronic diseases including AIDS, cancer, allergy and autoimmunity, target antigenic pathogens but not the pathogenic stromal cytokines which can be major sources of histopathologic processes. Considering that the limited efficacy of these vaccines has been ascribed to local pathogen-induced cytokine dysfunction, we propose to antagonize pathogenic cytokine(s) by high affinity neutralizing auto-Abs triggered by specific anti-cytokine vaccines. As anticipated by theoretical considerations, animal experiments and initial clinical trials showed that anti-cytokine immunization was safe, well tolerated and triggered transient high titers Abs neutralizing pathogenic cytokines but, in contrast to conventional vaccines, no relevant cellular response was observed. Advantages of active versus passive anti-cytokine Ab therapy, particularly for long-term treatments, as those required in AIDS, cancer, allergy and autoimmunity include greater ease of maintaining high Ab titers, lack of anti-antibody responses and low cost.

To evaluate individual genes responsible for virulence of vaccinia virus, a shuttle vector containing a viral fusion fragment from a deletion mutant (Z-19) was constructed. The vector also included a β-galactosidase cassette which contained the LacZ under the control of the vaccinia late promoter p11 to screen recombinants. The gene in question was reinserted into the attenuated mutant by homologous recombination. The vaccinia growth factor and the vaccinia complement-binding protein genes were inserted into this shuttle vector and transferred by recombination into Z-19. The presence of the inserted gene was examined by Southern hybridization and its expression by Northern blot hybridization. The virulence of the recombinants was investigated by inoculation into mice. Results indicate that the recombinants contained and expressed the inserted gene. Although virulence was recovered, it did not reach the level of the wild-type, either when the recombinant viruses were inoculated alone or in combination. Construction of the shuttle vector allows reintroduction of genes into Z-19 which is completely attenuated in vivo and could be useful as a vaccine vector.

HIV infection is accompanied by a vigorous immune response to the virus consisting of humoral and cellular elements that effectively neutralize virus infectivity and lyse infected cells when analyzed in cell culture models. However, this immune response shows no evidence of being able to eliminate the infection. The inability to clear this infection places HIV in a category of viruses for which vaccines have yet to be successfully developed. Indeed, effective vaccines have emerged only for viruses where natural immunity is part of the pathogenic process; it is such immunity that became the guiding principle for the development of the respective vaccines. It follows that the unique features of HIV infection and pathogenesis are issues to consider carefully in formulating vaccine strategies, particularly those that relate to its susceptibility to immune attack on the one hand, and its mechanisms of immune escape on the other.

This chapter describes the progress in the development of a human immunodeficiency virus (HIV) vaccine. It focuses principally on HIV, ranging from the properties of the virus that are most relevant for vaccine development to experimental trials of candidate HIV vaccines in chimpanzees and in humans. Present and future vaccine strategies as well as the application of vaccines as therapeutic measures are also considered. Over the past several years, substantial progress has been made in the quest for a vaccine against AIDS. This stems in large measure from a better understanding of the basic features of HIV but has been punctuated by successful feasibility studies of experimental vaccines in animal models. These developments have provided the impetus for the biomedical research establishment to pursue a vaccine against HIV as a legitimate target goal. Because the number of effective neutralization and cytotoxic T lymphocyte (CTL) targets is low in the case of HIV, this provides the virus with a considerable survival advantage with respect to the host immune defense, given its ability to escape both humoral and cellular mechanisms under immune pressure. The use of live vectors that are both effective and safe alone or in combination with other forms of immunization appears to hold great promise against HIV disease and may become a reasonable facsimile for whole HIV preparations that are precluded from use because of safety considerations.