Malaria parasites, stained with fluorescent markers, growing in red blood cells. Malaria kills over ...
Traditional vaccines are made from killed or inactivated pathogens and only a very small number of subunit vaccines derived from pathogen components have been licensed. However, the availability of full sequences of the genomes of most infectious pathogens and of new viral vectors now make possible a new generation of vectored vaccines that will address not only difficult global diseases such as HIV, malaria and tuberculosis but also the immunotherapy of viral infections and cancer.
We have developed numerous improved adenoviral vectors that generate very powerful antibody and T cell responses when used in optimised immunisation regimes. Some of these are of chimpanzee origin and avoid the problem of widespread immunity to human adenoviruses. Others express novel adjuvants in addition to a pathogen gene, enhancing further the potency of these novel vaccines. Clinical trials are in progress of several of these new approaches targeting the most virulent malaria parasite Plasmodium falciparum.
The DPhil project will involve generation of vaccines comprising newly available vectors and a series of promising vaccine candidate antigens from the P. falciparum genome. These will be tested in malaria models for safety, immunogenicity and efficacy. The functional activity of the induced immune responses will be assessed both by growth inhibition assays and by polyfunctional flow cytometry. The most promising candidates will progress towards clinical trials at the vaccine centre in Oxford.
Both subject specific and generic training in research skills will be provided. Specific training will be available in molecular biology, vector construction, virology, immunization techniques, a large variety of immunoassays (ELIspot, ELISA, flow cytometry assays), parasitology, statistical analysis of data and experimental design. The research group is large and includes students, post-docs, clinical fellows, research nurses, clinical triallists, project managers, field researchers, and biomanufacturing experts, spanning activities in vaccinology and human genetics, thereby providing exposure to a broad range of research and development activities in the biomedical sciences.
Tropical Medicine & Global Health and Immunology & Infectious Disease
Project reference number: 165
| Name | Department | Institution | Country | |
|---|---|---|---|---|
| Prof Adrian VS Hill | Jenner Institute | Oxford University | UK | adrian.hill@well.ox.ac.uk |
2011. Vaccines against malaria. Philos. Trans. R. Soc. Lond., B, Biol. Sci., 366 (1579), pp. 2806-14. Read abstract | Read more
There is no licenced vaccine against any human parasitic disease and Plasmodium falciparum malaria, a major cause of infectious mortality, presents a great challenge to vaccine developers. This has led to the assessment of a wide variety of approaches to malaria vaccine design and development, assisted by the availability of a safe challenge model for small-scale efficacy testing of vaccine candidates. Malaria vaccine development has been at the forefront of assessing many new vaccine technologies including novel adjuvants, vectored prime-boost regimes and the concept of community vaccination to block malaria transmission. Most current vaccine candidates target a single stage of the parasite's life cycle and vaccines against the early pre-erythrocytic stages have shown most success. A protein in adjuvant vaccine, working through antibodies against sporozoites, and viral vector vaccines targeting the intracellular liver-stage parasite with cellular immunity show partial efficacy in humans, and the anti-sporozoite vaccine is currently in phase III trials. However, a more effective malaria vaccine suitable for widespread cost-effective deployment is likely to require a multi-component vaccine targeting more than one life cycle stage. The most attractive near-term approach to develop such a product is to combine existing partially effective pre-erythrocytic vaccine candidates. Hide abstract
2011. CD8+ T effector memory cells protect against liver-stage malaria. J. Immunol., 187 (3), pp. 1347-57. Read abstract | Read more
Identification of correlates of protection for infectious diseases including malaria is a major challenge and has become one of the main obstacles in developing effective vaccines. We investigated protection against liver-stage malaria conferred by vaccination with adenoviral (Ad) and modified vaccinia Ankara (MVA) vectors expressing pre-erythrocytic malaria Ags. By classifying CD8(+) T cells into effector, effector memory (T(EM)), and central memory subsets using CD62L and CD127 markers, we found striking differences in T cell memory generation. Although MVA induced accelerated central memory T cell generation, which could be efficiently boosted by subsequent Ad administration, it failed to protect against malaria. In contrast, Ad vectors, which permit persistent Ag delivery, elicit a prolonged effector T cell and T(EM) response that requires long intervals for an efficient boost. A preferential T(EM) phenotype was maintained in liver, blood, and spleen after Ad/MVA prime-boost regimens, and animals were protected against malaria sporozoite challenge. Blood CD8(+) T(EM) cells correlated with protection against malaria liver-stage infection, assessed by estimation of number of parasites emerging from the liver into the blood. The protective ability of Ag-specific T(EM) cells was confirmed by transfer experiments into naive recipient mice. Thus, we identify persistent CD8 T(EM) populations as essential for vaccine-induced pre-erythrocytic protection against malaria, a finding that has important implications for vaccine design. Hide abstract
2009. Expression of tak1 and tram induces synergistic pro-inflammatory signalling and adjuvants DNA vaccines. Vaccine, 27 (41), pp. 5589-98. Read abstract | Read more
Improving vaccine immunogenicity remains a major challenge in the fight against developing country diseases like malaria and AIDS. We describe a novel strategy to identify new DNA vaccine adjuvants. We have screened components of the Toll-like receptor signalling pathways for their ability to activate pro-inflammatory target genes in transient transfection assays and assessed in vivo adjuvant activity by expressing the activators from the DNA backbone of vaccines. We find that a robust increase in the immune response necessitates co-expression of two activators. Accordingly, the combination of tak1 and tram elicits synergistic reporter activation in transient transfection assays. In a mouse model this combination, but not the individual molecules, induced approximately twofold increases in CD8+ T-cell immune responses. These results indicate that optimal immunogenicity may require activation of distinct innate immune signalling pathways. Thus this strategy offers a novel route to the discovery of a new generation of adjuvants. Hide abstract