title: A totally synthetic polyoxime malaria vaccine containing Plasmodium falciparum B cell and universal T cell epitopes elicits immune responses in volunteers of diverse HLA types.
abstract: This open-labeled phase I study provides the first demonstration of the immunogenicity of a precisely defined synthetic polyoxime malaria vaccine in volunteers of diverse HLA types. The polyoxime, designated (T1BT(*))(4)-P3C, was constructed by chemoselective ligation, via oxime bonds, of a tetrabranched core with a peptide module containing B cell epitopes and a universal T cell epitope of the Plasmodium falciparum circumsporozoite protein. The triepitope polyoxime malaria vaccine was immunogenic in the absence of any exogenous adjuvant, using instead a core modified with the lipopeptide P3C as an endogenous adjuvant. This totally synthetic vaccine formulation can be characterized by mass spectroscopy, thus enabling the reproducible production of precisely defined vaccines for human use. The majority of the polyoxime-immunized volunteers (7/10) developed high levels of anti-repeat Abs that reacted with the native circumsporozoite on P. falciparum sporozoites. In addition, these seven volunteers all developed T cells specific for the universal epitope, termed T(*), which was originally defined using CD4(+) T cells from protected volunteers immunized with irradiated P. falciparum sporozoites. The excellent correlation of T(*)-specific cellular responses with high anti-repeat Ab titers suggests that the T(*) epitope functioned as a universal Th cell epitope, as predicted by previous peptide/HLA binding assays and by immunogenicity studies in mice of diverse H-2 haplotypes. The current phase I trial suggests that polyoximes may prove useful for the development of highly immunogenic, multicomponent synthetic vaccines for malaria, as well as for other pathogens.
authors: Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, NY 10010, USA. Elizabeth.Nardin@med.nyu.edu
authors: E H
authors: EH
authors: Nardin
authors: J M
authors: JM
authors: Calvo-Calle
authors: G A
authors: GA
authors: Oliveira
authors: R S
authors: RS
authors: Nussenzweig
authors: M
authors: M
authors: Schneider
authors: J M
authors: JM
authors: Tiercy
authors: L
authors: L
authors: Loutan
authors: D
authors: D
authors: Hochstrasser
authors: K
authors: K
authors: Rose
mesh_terms: D000328:Adult; D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis; D000918:Antibody Specificity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D018985:Epitopes, B-Lymphocyte / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006683:HLA-DQ Antigens / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007700:Kinetics; D008213:Lymphocyte Activation; D017780:Malaria Vaccines / Q000009:adverse effects / Q000276:immunology*; D008297:Male; D010091:Oximes / Q000009:adverse effects / Q000276:immunology*; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000009:adverse effects / Q000276:immunology*
chemical_list: C419396:(T1BT)4-P3C polyoxime vaccine; D000913:Antibodies, Protozoan; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D007132:Immunoglobulin Isotypes; D007376:Interleukin-2; D017780:Malaria Vaccines; D010091:Oximes; D015800:Protozoan Proteins; D014614:Vaccines, Synthetic; C041595:circumsporozoite protein, Protozoan