The overall objective of this project is the design and development of a novel class of human immunodeficiency virus (HIV) vaccines that are synthetic, peptide-based, containing multiple-antigen, carrier-free, and with built-in adjuvant. Such a novel synthetic vaccine is aimed at improving the problems of conjugation, carrier, and adjuvant found in synthetic vaccines. THe proposed design will contain multiple peptide antigens related to HIV such as T helper-inducing determinants and B-cell determinants as well as an adjuvant, all attaching to a small, dendritic branching lysyl core known as the multiple antigen peptide (MAP) system developed recently in our laboratory. Furthermore, the peptide antigens and the lysyl core will be arranged precisely as a single unit and synthesized in a chemically unambiguous manner. In addition, the MAP system contains a high density of peptide antigens on the outer surface (>90% of the total molecular weight) and only a small scaffolding lysyl core (<10% of the molecular weight). These distinct features also serve to overcome the impediment of the carrier problem in the design of peptide-based vaccines. Moreover, the simplicity of the design also provides modifications and developments to enhance both the immunogenicity and long term stability for human vaccines. Finally, fatty acid, liposome-forming or membrane-anchoring moiety conjugated to the MAPs are proposed as suitable models to alleviate the use of adjuvants. Thus, the long term goal of this project is the design and development of a chemical-defined, self-sufficient, multiple-antigen, carrierless, and peptide-based vaccine suitable for humans and protective against human immunodeficiency virus. Although we have demonstrated that the MAP system provides an excellent prototype model in eliciting immunological responses in animals, much of the potentials of the MAP system has yet to be defined. Our immediate goals are (1) to optimize the design of the MAP models, namely; the size, arrangement, stoichiometric relationship of outer peptide antigens and the small branching lysyl core, using selected and known peptide epitopes of the envelop proteins of the human immunodeficiency virus, (2) to incorporate adjuvants in MAPs, and (3) to test and evaluate the efficacy of these models in animals.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (SRC (36))
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Rockefeller University
Other Domestic Higher Education
New York
United States
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Tam, J P; Lu, Y A; Liu, C F et al. (1995) Peptide synthesis using unprotected peptides through orthogonal coupling methods. Proc Natl Acad Sci U S A 92:12485-9
Spetzler, J C; Tam, J P (1995) Unprotected peptides as building blocks for branched peptides and peptide dendrimers. Int J Pept Protein Res 45:78-85
Tam, J P; Spetzler, J C (1995) Chemoselective approaches to the preparation of peptide dendrimers and branched artificial proteins using unprotected peptides as building blocks. Biomed Pept Proteins Nucleic Acids 1:123-32
Spetzler, J C; Rao, C; Tam, J P (1994) A novel strategy for the synthesis of the cysteine-rich protective antigen of the malaria merozoite surface protein (MSP-1). Knowledge-based strategy for disulfide formation. Int J Pept Protein Res 43:351-8
Liu, C F; Tam, J P (1994) Peptide segment ligation strategy without use of protecting groups. Proc Natl Acad Sci U S A 91:6584-8
Vanage, G R; Jaiswal, Y K; Lu, Y A et al. (1994) Immunization with synthetic peptide segments of a sperm protein impair fertility in rats. Res Commun Chem Pathol Pharmacol 84:3-15
Nardelli, B; Haser, P B; Tam, J P (1994) Oral administration of an antigenic synthetic lipopeptide (MAP-P3C) evokes salivary antibodies and systemic humoral and cellular responses. Vaccine 12:1335-9
Huang, W; Nardelli, B; Tam, J P (1994) Lipophilic multiple antigen peptide system for peptide immunogen and synthetic vaccine. Mol Immunol 31:1191-9
Nardelli, B; Tam, J P (1993) Cellular immune responses induced by in vivo priming with a lipid-conjugated multimeric antigen peptide. Immunology 79:355-61
Nonacs, R; Humborg, C; Tam, J P et al. (1992) Mechanisms of mouse spleen dendritic cell function in the generation of influenza-specific, cytolytic T lymphocytes. J Exp Med 176:519-29

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