application): This application was submitted by Dr. Ronald C. Desrosiers in response to RFA AI-93-04 and proposes establishment of a National Cooperative Vaccine Development Group for AIDS (NCVDG). The proposed studies are centered around a radical but promising strategy for the development of a vaccine against HIV: the construction of a live-attenuated, multiply-deleted HIV-1 vaccine for prevention of infection and disease, using modern recombinant DNA technology to delete large regions of genetic information from the virus. Preliminary studies using the SIV/rhesus monkey model indicate that a singly-deleted variant missing the nef gene is both safe and highly effective. Major advantages of a live- attenuated, multiply-deleted HIV-1 vaccine for AIDS include very low cost of production, worldwide availability, and the likelihood that this will be the most effective vaccine that can be made. In the proposed studies, optimal combinations of deletions that balance safety and potency will be identified, immunological components responsible for protection will be examined, and a variety of safety and efficacy issues will be addressed. The proposal is divided into 3 Projects plus an Administrative and Scientific Core. PROJECT I (Desrosiers) deals with construction of multiply-deleted SIV and HIV-1 variants, characterization of their biological properties in vitro, and evaluation of their safety and efficacy in the rhesus macaque and chimpanzee models. PROJECT II (Walker) focuses on defining the cellular immune responses to live- attenuated vaccines, emphasizing CTL activity. PROJECT III (Wyand) is designed to test safety and efficacy under increasingly rigorous challenge conditions and various immunization schemes. The Core will provide administrative support and scientific services, including assistance in preparing and storing virus stocks, purifying virus, preparing ELISA plates, quality control and performing neutralization assays.
