MICA: Development and GMP manufacture of a PfRH5 protein vaccine to induce strain-transcending immunity against blood-stage Plasmodium falciparum.

Plasmodium falciparum is the parasite that causes the most deadly form of human malaria. Current estimates suggest P. falciparum malaria affects 200-300 million people annually, resulting in the death of about 0.8 million individuals. Thus, despite increasing implementation of control measures, the burden of this devastating disease remains far too high. It remains unlikely that vaccines based on the whole parasite organism will be deployable, and therefore most efforts focus on vaccines encoding malaria proteins - so called 'subunit vaccines'. The most advanced malaria subunit vaccine, called RTS,S/AS01 and encoding a protein from the parasite called CSP, is currently in Phase III clinical trials across Africa, with early indications suggesting only 35% efficacy against severe disease in young children. Calls have been made for a second generation vaccine to exert 80% efficacy over four years. If this ambitious rhetoric is to be realised, new approaches to malaria subunit vaccine design are required.

Vaccines that elicit functional antibodies formed the foundation of success for 20th century vaccinology - with almost all licensed human products to date protecting individuals through the induction of antibodies. The malaria parasite has a number of complex life-cycle stages, and it is known that numerous stages of this cycle are susceptible to antibodies. These include the infectious sporozoite-stage which infects the liver (targeted by RTS,S), as well as the subsequent blood-stage infection which causes disease as well as the sexual cells that are taken up by mosquitoes in the infected bloodmeal thus leading to further transmission. However, with the exception of RTS,S, antibody-inducing subunit vaccine development for malaria has faced over a decade of disappointment in the clinic. One central reason for this is likely to have been a narrow focus upon malaria proteins which are highly recognised by the immune system in natural infection. As a consequence they have evolved to cope with immune pressure and are highly variable. Similarly, extremely large amounts of antibody are required to neutralise the parasite, and these levels have been difficult to achieve following human vaccination.

We have recently identified a potential solution to this problem. A protein called PfRH5 appears to perform a function that is essential in order for a parasite to invade red blood cells. It binds a protein called Basigin on the red blood cell's surface and this interaction is critical. Importantly, this interaction can be blocked by low levels of antibody, and even more remarkably, the protein is highly conserved, showing limited variation across lots of different parasite strains. This means antibodies induced by a vaccine can function against all the different types of P. falciparum parasite found in endemic areas. The PfRH5-basigin interaction appears to be the first Achilles' heel identified in the blood-stage parasite.

This three year programme of work will aim to produce a clinical grade vaccine targeting the PfRH5 protein. We have shown this protein can be made in a system that uses insect cells to make the malaria protein. We will optimise this system, and then develop a production process that is suitable for clinical grade vaccine manufacture. This process will be developed in collaboration with an industrial partner called ExpreS2ion Biotechnologies from Denmark who are world experts in the use of insect cells as a vaccine production system. Once the process has been developed, we will transfer it to a vaccine manufacturing facility at the University of Oxford where the clinical grade material will be produced, put into vials and extensively tested according to stringent quality controls processes. The final output of this research will be a batch of clinical grade PfRH5 protein vaccine. We will subsequently aim to take this new vaccine into early phase clinical trials in healthy adult volunteers in Oxford.

The Need: Current estimates suggest Plasmodium falciparum malaria affects 200-300 million people annually, resulting in the death of about 1 million individuals. The most advanced malaria subunit vaccine, RTS,S/AS01, is currently in Phase III clinical trials, with early indications suggesting only 35-50% efficacy against severe disease in young children. Calls have been made for a second generation vaccine to achieve 80% efficacy over four years. New approaches are thus urgently needed.

Rationale: No vaccine has yet proven effective against the blood-stage of P. falciparum, which causes the severe manifestations of malaria. Critical road blocks have included the need for exceptionally high antibody titres against known targets to confer protection coupled with problematic levels of antigen polymorphism. However, recent data from the Jenner Institute have identified the full-length P. falciparum Reticulocyte Binding Protein Homologue 5 (PfRH5) antigen as the highest priority vaccine target identified in the field for over a decade. We have shown in preclinical animal studies that antibodies induced by PfRH5 vaccination can block erythrocyte invasion to high efficiency and, critically, cross-inhibit all P. falciparum lines tested to date. Importantly we have also now demonstrated, for the first time, high-level efficacy induced by PfRH5 vaccination against heterologous strain challenge in an in vivo Aotus monkey-P. falciparum challenge model.

Solution & Development Plan: We have now identified an S2 Drosophila insect cell expression system as a viable GMP-compatible platform for production of this recombinant malaria antigen. This proposal aims to optimise and process develop this system for full-length PfRH5 protein production, prior to progression to GMP manufacture. The product produced by this work will enable subsequent Phase I/IIa clinical trials to assess the impact of high-titre antibodies against PfRH5 on blood-stage malaria infection in humans.

Aside from immediate academic beneficiaries / collaborators, results will also be shared with existing malaria vaccine development consortia and funders, such as the Initiative for Vaccine Research at the World Health Organisation and the PATH MVI funded by the Gates Foundation.

We have also found that there is substantial public interest in the malaria vaccine work undertaken at the Jenner Institute, and as such key results will also be presented to the public whenever possible in an appropriate manner. In December 2011, reports relating to the potential of the PfRH5 antigen as a vaccine candidate were covered by the UK national press and international radio. Dr Draper also regularly supports public engagement - through open seminars to other members of the wider University and the public, through departmental podcasts, and through visiting schools to encourage GCSE and A-level students to consider studying science and future science-related careers.

Ultimately, Plasmodium falciparum malaria continues to exert an unacceptable level of morbidity and mortality in the developing world, which is coupled with a devastating burden on resource-poor healthcare systems. In light of the low-level efficacy afforded by the world's leading pre-erythrocytic malaria vaccine candidate (RTS,S) in the field, continued calls for a vaccine that is 80% effective over 4 years, especially in areas of moderate to high transmission intensity, mean that a blood-stage component is almost certainly required. The long-term output of this research, if successful, could contribute an effective component(s) to such a vaccine formulation. If the PfRH5 product developed from this programme showed significant efficacy we are well placed to develop it further. The Jenner Institute is fortunate in having strong links with excellent malaria research groups in Africa and Asia where further assessment of the vaccine could take place. The ultimate end users of such a product would be the target population - infants in endemic areas who would be vaccinated against malaria in the first year of life, and potentially adults, travellers and military.