The major merozoite surface antigen (gp195) of P. falciparum and its analogues in several other Plasmodia induces a protective immune response in simian and murine hosts and is a prime candidate for a blood-stage malaria vaccine. Yeast recombinant gp195-based polypeptides are being developed as vaccine antigens. The efficacy of such vaccines is dependent on their ability to induce the appropriate antigen-specific B cells and to efficiently stimulate T cells which serve as helper/inducer cells in the antibody response or in antibody-independent immune responses.
The specific aims of this project are (1) to define B cell recognition sites involved in the antibody responses to gp195 and gp195-related polypeptides and to determine whether H-2-linked immune response (Ir) genes control responsiveness to these recognition sites, (2) to define T cell recognition sites, study their regulation by Ir genes, and determine the surface phenotype of T cells induced by gp195 and recombinant gp195-related polypeptides and synthetic peptides, (3) to generate gp195-specific T cell lines and characterize their fine specificity and function (T helper activity, production of gamma interferon), and (4) to relate B cell and T cell recognition sites to variable, conserved, or group- specific regions of gp195 molecules. B cell recognition sites will be defined by immunization of mice with parasite-purified gp195 and gp195-related polypeptides and evaluation of serum antibody specificity by an ELISA assay. T cell recognition sites will be similarly defined using the antigen-induced proliferation assay or antigen-specific T helper cell assays. Antigens to be used for specificity analyses are (1) the homologous parasite-purified gp195: (2) a heterologous parasite-purified gp195 differing in group specific regions from the homologous protein; (3) recombinant gp195-related polypeptides corresponding to different fragments of the complete gp195 protein; and (4) synthetic peptides corresponding to variable repeat regions and to potential immuno- dominant B cell or T cell epitopes predicted by appropriate computer algorithms. The possible influence of Ir genes on responsiveness to B cell and T cell recognition sites will be studied by comparing the B cell and T cell recognition sites utilized by mice differing only at H-2 linked Ir genes. The characterization of T cell and B cell recognition sites as variable, conserved or group-specific is particularly relevant to vaccine design and will be accomplished by comparing antigen specificity for the homologous versus the heterologous gp195 protein.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI027130-02
Application #
3454899
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1989-07-01
Project End
1994-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Hawaii
Department
Type
Schools of Medicine
DUNS #
121911077
City
Honolulu
State
HI
Country
United States
Zip Code
96822