Clinical Evaluation of "Prime-Target" Immunisation

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Malaria is one of the biggest causes of morbidity and mortality in many developing countries. There are hundreds of millions of clinical cases each year and about half a million deaths. Malaria is caused by a protozoan parasite, a type of microbe for which vaccine development has proved very difficult. This parasite has a complex multi-stage life cycle, is transmitted by Anopheles mosquitoes, has thousands of potential antigens that might be relevant to designing a vaccine, and exposure to malaria itself can cause immunosuppression.Nonetheless, some approaches to vaccine development are now showing promise. Here we build on many years of research and development of new viral vectors vaccines in the UK and elsewhere to assess a new approach to targeting the malaria parasite during its clinically silent early stage in the human liver. We propose to assess the feasibility of developing a malaria vaccine using a new "prime-target" immunisation approach that involves targeting white blood cells with the capacity to kill malaria parasites, so-called CD8+ killer T cells, to the liver by a novel vaccination strategy. Instead of just inducing circulating killer T cells in the blood, using a standard intramuscular immunisation, and hoping that they can find parasites in the liver and kill them, the approach to be tried here is to use sequential immunisations by different administration routes to target killer T cells to malaria-infected liver cells.We have found that the efficacy of leading liver-stage malaria vaccine candidates in mice can be enhanced with this approach from 0-30% efficacy to 100%. To achieve this high vaccine efficacy we administer a booster vaccination with a recombinant viral vector, e.g. a recombinant adenovirus vaccine, by a route that leads to antigen expression predominantly in the liver. This is best achieved by an intravenous immunization. We have found that this "prime and target" approach, even with repeated use of the same vaccine vector, increased substantially the number of so-called "tissue resident memory T cells" that remain in the liver and can be very effective in providing protection in that organ. The numbers of these cells correlated with improved vaccine-induced protection suggesting that they are causally related to the better vaccine efficacy.We propose here to undertake the first clinical trial of the efficacy of this approach in humans using, for the first time, two liver-stage-specific malaria antigens in the vaccine. Small-scale safety assessments are underway this year, with the clinical data showing a good safety profile so far, and we here propose to assess efficacy of the new approach in 2018 using a standard controlled human malaria infection (CHMI) protocol. We and others use such an infection model to evaluate vaccine performance safely and efficiently and we have undertaken safely twenty such CHMI trials in UK volunteers. We believe that this work could lead to the identification and development of a cost-effective high efficacy malaria vaccine that could be used quite widely to help prevent disease and death caused by malaria, also and facilitate its eventual elimination from many areas. The new prime-target immunisation approach, if it works in humans, may also provide an effective general means of targeting cellular immunity to the liver and so might also be useful in making new vaccines against other liver infections such as those caused by the hepatitis B and C viruses.