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Prime-Boost Immunization Against Malaria
Summary: Dr. Hill is working on the development of a vaccine against malaria.
A large variety of approaches to developing an effective malaria vaccine are under investigation worldwide. Pre-erythrocytic vaccines have recently shown particular promise. A protein-adjuvant vaccine encoding the circumsporozoite protein RTS,S/AS02 has shown substantial but short-term efficacy in a Gambian field trial. Heterologous prime-boost immunization focuses on maximizing effector T cell responses against the liver-stage parasite. In animal models of malaria, we have found prime-boost immunization using two viral vectors (fowlpox-MVA or adenovirus-MVA) to be more immunogenic and protective than DNA-MVA regimes.
In a series of Phase I and IIa clinical trials of this approach, three different candidate malaria vaccines (plasmid DNA, modified vaccinia virus Ankara [MVA], and fowlpox strain 9) have been administered in various combinations to more than 400 individuals in Oxford, The Gambia, and Kenya. The vaccines each encode either a polyepitope string fused to the whole Plasmodium falciparum TRAP antigen or the entire circumsporozoite antigen. When delivered with MVA as the boosting vaccine, heterologous prime-boost immunization regimes with these vaccines induced exceptionally high frequencies of interferon-gamma (IFN-gamma)–secreting antigen-specific CD4+ and CD8+ T cell responses. Responses declined over time but were re-boostable at one year with a single MVA immunization. These vaccination regimens have been safe and well tolerated without any serious adverse vaccine-related events. Vaccination induced repeatable partial and complete protection against heterologous strain sporozoite challenge in some volunteers, with the best regimes inducing on average a greater than 85 percent reduction in liver parasite burden. Further potential improvements to this vaccination approach, using a six-antigen polyprotein as an insert, and antibody-inducing and blood-stage antigen components are under development. DNA-based vaccines used in prime-boost regimes are safe and immunogenic and have repeatable quantifiable efficacy against malaria in humans.
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