Vaccines against pre-erythrocytic malaria and outbreak pathogens
Infectious diseases remain a significant cause of global mortality. Vaccines against endemic diseases such as malaria or outbreak pathogens like Ebola virus could have significant public health impact. Understanding immune responses induced by natural infection and vaccination is crucial to the vaccine development process and this is the main focus of my group.
The Jenner Institute has a number of malaria vaccines in development, including the sporozoite stage vaccine R21 and the liver-stage vaccines ChAd63 ME-TRAP and MVA ME-TRAP. These vaccines are currently being tested in Phase I and II clinical trials in the UK and partner sites in Africa, including Burkina Faso and Kenya. In Oxford, we test the efficacy of new malaria vaccines using a human challenge model where we infect volunteers with malaria and monitor them closely to detect the development of parasites before curing the infection with drugs. More than 1500 human participants have now been safely infected in this way and so we are able to identify at an early stage of the vaccine development process whether or not a new vaccine is likely to be successful.
One aim of my research is to define vaccine-induced immunological parameters that correlate with protection from malaria. Using samples from our vaccinated volunteers we can study responses using methods such as ELISPOT, flow cytometry and transcriptional profiling for T cells. We also undertake in-depth assessment of antibody responses including IgG titre, avidity, B cell sequencing, antibody neutralisation and functional assays characterising interactions between antibodies and parasites. By combining data from these different assays and analysing how these different measures relate to protection against malaria, I have been able to define the function and phenotype of T cells that are associated with protection in our human challenge model.
The Jenner Institute is also developing vaccines against emerging and outbreak pathogens including Ebola, MERS, influenza, Lassa and Nipah. We undertake similar detailed immunophenotyping of vaccine-induced T cell and antibody responses of samples from our clinical trials of these vaccines.
Another area of my research focusses on why vaccines sometimes work less well than we expect. Interactions between different cell populations can inhibit immunity as can exposure to malaria and other viral infections. We employ a systematic approach combining many different immune phenotypes to develop a deep understanding of the interaction between factors affecting immune responses. We can then feed this information back through the vaccine development process to improve the immunogenicity of our vaccines for future trials or optimise dosing and routes of administration to improve vaccine efficacy.
Finally, a new program of work is underway to look at the role of the human gut microbiome in the development of immune responses to vaccines. The gut microbiome undergoes significant changes in composition and function during early life at the time when many vaccines are given. We aim to determine if there is the composition of intestinal microbiota affects the immune response to the R21 malaria vaccine.
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