This application is in response to RFA-NIH-NIAID-87-AI-21, a request for National Cooperative Vaccine Development Groups for the Acquired Immunodeficiency Syndrome (AIDS). We have brought together a critical mass of four scientists within Stanford Medical Center with past interactions who each propose individual efforts aimed at HIV vaccination. The projects will systematically examine neutralizing epitopes on HIV and express HIV antigens in prokaryotic and eukaryotic expression vectors, and constitute creative approaches to all of the goals set out in the RFA: (i) whole HIV vaccine, (ii) subunit vaccine, (iii) recombinant DNA produced antigens, (iv) synthetic vaccines, and (v) use of viral vectors. Project I (Dr. Harry Greenberg) will isolate HIV neutralizing monoclonal antibodies, use these antibodies to define neutralizing epitopes and devise neutralizing epitope specific blocking ELISAs to define the neutralizing antibody response in humans and animals. Project II (Dr. William Robinson) will utilize synthetic peptides to define protective epitopes on HIV proteins and use them in prokaryotic expression systems. Project III (Dr. Bruce Stocker) will introduce protective HIV epitopes into salmonella vaccine strains fused to flagellar or other bacterial proteins and test these in animals as a live attenuated recombinant bacterial vaccine vector. Project IV (Dr. Edward Mocarski) will introduce HIV protein and particulate (defective virus) antigens into cytomegalovirus expression vectors to produce high levels of protein in mammalian cells and to test recombinant CMV as a live virus vaccine vector in animals. The overall goals of the Program Project will be accomplished by the integration of information from these four projects, with the monoclonal antibody and synthetic peptide work together providing critical understanding of HIV neutralizing epitopes, with prokaryotic and eukaryotic vaccine vectors systems providing useful and practical approaches towards vaccination of humans and with assays that will enable quantitation of the neutralizing immune response in animals or humans without the need for inectious HIV. The work proposed describes new approaches and strategies for HIV vaccine development entirely of a preclinical nature, relying on the ability to raise HIV neutralizing antibody or induce a cellular response in vaccinated animals as indicators of protective immunity. In the future, vaccines developed through this Program Project will be readily tested in humans.
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