A. Olotu, Ifakara Health Institute - Immune responses in malaria-exposed children immunised with a new generation blood-stage malaria vaccine.

Scientists have discovered a protein called Pf reticulocyte-binding protein homolog 5 (PfRH5) which has shown promising results as a candidate malaria vaccine in studies conducted in monkeys and humans living in areas where there is no malaria. The safety and the ability of this vaccine to produce protective antibody responses in adults, young children and infants residing in areas with malaria is unknown.

The ARL candidate will conduct a clinical trial and use standard laboratory techniques to determine if this vaccine is safe and well-tolerated in adults, young children and infants and to find out if it can produce antibodies capable of killing parasites growing in red blood cells in laboratory tests. The study will recruit volunteers residing in a low malaria transmission area in Bagamoyo, Tanzania.

The study will provide new knowledge with regard to the potential for PfRH5 protein to be included in a malaria vaccine and inform decisions to conduct larger field trials to evaluate efficacy. The results will also identify whether there is scope to further improve this vaccine before conducting bigger trials in the field.

Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is a new generation and highly promising blood-stage malaria vaccine antigen. Preclinical and early clinical data show the antigen elicits functional antibodies against merozoites in non-human primates and malaria-naïve UK adults in contrast to those elicited by natural malaria exposure. The safety and capability of PfRH5 immunisation to induce functional immune responses in adults, young children and infants residing in malaria endemic countries is unknown.

Using an age de-escalation dose-escalation randomised double-blind controlled trial, and established immunological techniques, the ARL candidate will establish the safe and well-tolerated dose of PfRH5 in adults, young children and infants and characterise the magnitude, quality and longevity of immune responses following immunization by a heterologous prime-boost approach with chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) expressing PfRH5. The study will recruit volunteers from low malaria transmission areas in Bagamoyo, Tanzania.

The study will provide new knowledge with regard to the potential for PfRH5 as a malaria vaccine and inform decisions to conduct larger field trials to evaluate efficacy. The immunological outcomes will provide data on the human antibody response, to determine if there is scope to further improve the PfRH5 immunogen in future iterations of the vaccine.

This research will benefit academics in three main areas:

a) Vaccine Developers

The proposed research will benefit scientists working in the field of malaria vaccine research. Information about the safety and quantity and quality of the immune responses induced by PfRH5 in malaria exposed infants and young children will guide further optimisation of the antigen and inform decisions to conduct larger field trials to evaluate efficacy against clinical malaria.

Data from the proposed research will be shared with the scientific community as soon as possible through presentation in scientific conferences, publication in open-access peer reviewed journals and open public domain platforms held by both the Jenner Institute and Ifakara Health Institute.

The University of Oxford has a long-standing collaboration with GSK, and together they are developing next-generation malaria vaccines including those targeting the blood-stage parasite using the PfRH5 antigen. They have recently completed the VAC057 Phase Ia clinical trial in Oxford using the ChAd63 RH5 vector funded by the European Commission MultiMalVax programme. The result of this proposed research will provide more data on the potential utility of the PfRH5 antigen as a candidate blood-stage vaccine and guide further research and development.

b) African Research Institution

The proposed research will increase the skill and knowledge base at Ifakara Health Institute which will increase the capability of the Institute to conduct more malaria vaccine research. Technology transfer that will happen during the research period will not only benefit malaria research but other research fields such as tuberculosis and HIV vaccine development. IHI has a Clinical Trial Facility (CTF) which conducts all phases of vaccine trials. The research team at IHI CTF plan to use the Controlled Human Malaria Infection model to investigate new drugs and vaccines against malaria including characterising vaccine-induced immune responses following immunisation. The knowledge and skills gained by the ARL candidate will enrich the team's knowledge base and facilitate clinical and immunological assessment of candidate malaria vaccines.

The ARL candidate will establish collaboration with the UK PI and other partners and this will facilitate more transfer of skills and technology and sharing platforms to conduct malaria vaccine research.

c) Global Health

Recently experts (SAGE committee) have advised the World Health Organisation to conduct a large pilot implementation program for the RTS,S candidate malaria vaccine in children aged 5-17 months in areas of moderate and high malaria transmission. This follows results of a large Phase III trial indicating potential benefit of a 4-dose vaccination regimen. Although RTS,S represents an important milestone in malaria vaccine development, inclusion of an effective blood-stage component is essential to improve efficacy and prolong protective efficacy.

PfRH5 is a new generation blood-stage candidate malaria vaccine antigen which, unlike other merozoite antigens, is highly conserved across parasite lines resulting to strain-transcending neutralising antibodies following immunisation. Although the current proposed research may not lead directly to the vaccine which can be used by the population, it will generate important data to inform further development of the this candidate antigen and allow decisions on whether to progress to larger (Phase IIb and III) field trials. An effective blood-stage malaria vaccine will be an important component in a multi-stage malaria vaccine to prevent malaria infection, disease and transmission. Therefore the ultimate impact of this research is to contribute towards efforts to improve the health and quality of life worldwide and especially in sub-Saharan Africa where more than 90% of the malaria deaths occur.