Protective B and T-cell epitopes on malarial circumsporozoite (CS) proteins have been identified. However, many attempts to use these determinants in subunit vaccines have not been successful. The twin goals of this project are, first, to define the properties of immune responses against CS peptides which mediate protection, and, secondly, to develop a rationale and practical procedures for producing malaria vaccines which stimulate such responses. Our approach is based on the combined expertise of investigators with experience in malaria research and the properties of immunogens and adjuvants which selectively stimulate cell mediated immunity or particular isotypes of IgG antibody. We will start with a formulation that has been shown to induce protective antibodies. The P berghei repeat peptide, (DPPPPNAN)2, will be conjugated to tetanus toxoid and injected into mice. The fine specificity of the protective epitopes will be mapped. The peptide will then be conjugated to Salmonella flagella and BSA and formulated with nonionic block copolymer adjuvants, detoxified Ra LPS and other materials in order to produce immunogens which are expected to induce antisera which are predominantly IGG1, IgG2a or IgG2b isotype. We will characterize the antisera in terms of concentration, avidity, isotype and specificity for the peptide and surface of the parasite. Protective effects will be tested by challenging mice with live sporozoites. The immunogens and formulations will be modified according to the results of ongoing experiments in an effort to refine understanding of the properties of protective antibody. Once the properties of protective antibody are known, further studies will evaluate additional parameters such as duration of response, memory and boostability using components potentially usable in man. CS protein derived T-cell determinants (helper and proliferative) will be included in vaccine constructs in an effort to facilitate such boosting. Next, attempts will be made to induce specific protective CTL to CS epitopes using lipid-modified peptides according to recently developed procedures. Using knowledge of the protective efficacy of antibody and CTL and the means to modulate and direct immunogenicity, we will attempt to develop constructs and formulations that contain multiple determinants and elicit optimal protection. We will investigate applicability of the findings in other species of malaria, especially P yoelii in rodents. Finally, we will correlate in vitro assays of immunity, such as IFA, CSP, ISI and CTL with in vivo protective capability in order to identify in vitro correlates of protective immunity for use by other vaccine developers.
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| Reed, R C; Verhuel, A F; Hunter, R L et al. (1997) Rapid onset of malaria-induced mortality by immunizations with lipo-peptides: an experimental model to study deleterious immune responses and immunopathology in malaria. Vaccine 15:65-70 |
| Reed, R C; Louis-Wileman, V; Cosmai, E V et al. (1997) Multiple antigen constructs (MACs): induction of sterile immunity against sporozoite stage of rodent malaria parasites, Plasmodium berghei and Plasmodium yoelii. Vaccine 15:482-8 |
| Jennings, V M; Actor, J K; Lal, A A et al. (1997) Cytokine profile suggesting that murine cerebral malaria is an encephalitis. Infect Immun 65:4883-7 |
| Reed, R C; Louis-Wileman, V; Wells, R L et al. (1996) Re-investigation of the circumsporozoite protein-based induction of sterile immunity against Plasmodium berghei infection. Vaccine 14:828-36 |
