MICA: Large-Scale Vaccine Fill and Phase I Clinical Trial of the RH5.1/Matrix-M Vaccine against Blood-Stage Plasmodium falciparum Malaria

Vaccines that elicit functional antibodies form the foundation of success for human vaccinology. Consequently, delivery approaches that can impart improved and durable antibody responses are essential to the success of vaccines against a wide variety of difficult human diseases. Examples include seasonal respiratory viruses (such as influenza, RSV), emerging/pandemic pathogens (such as SARS-CoV-2) as well as parasites (such as Plasmodium - the causative agent of malaria).
Plasmodium falciparum is a parasite that causes the most deadly form of human malaria. Current estimates suggest P. falciparum malaria affects ~200 million people annually, resulting in the death of ~430,000 individuals - primarily children under the age of 5 in sub-Saharan Africa. Thus, despite increasing implementation of control measures, the burden of this devastating disease remains far too high and a vaccine is urgently needed. 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 in pilot implementation trials in Africa but can only provide ~36% efficacy against clinical malaria over four years. Calls have been made by the WHO for a second generation vaccine to exert 75% efficacy. If this ambitious rhetoric is to be realised, new approaches to malaria subunit vaccines are required, especially those that can induce longer-lasting antibody responses.

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. Over the last decade, we have developed a vaccine against a malaria protein called RH5 that performs a function that is essential 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 antibodies, and even more remarkably, the protein is highly conserved, showing limited variation across 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 RH5-basigin interaction appears to be the first Achilles' heel identified in the blood-stage parasite.
We previously manufactured a vaccine targeting this aspect of malaria biology, called RH5.1, using novel production methods that have since been used to make other vaccines, e.g. those for Covid-19. We then undertook a clinical trial in healthy adults in the UK formulating the RH5.1 vaccine in an adjuvant (which stimulates the immune system) called AS01 from GSK. We observed highly promising results, in particular that a delayed and reduced dose third shot (or booster) could dramatically improve the maintenance of the antibody response over time. In this project we will now produce more vials of RH5.1 in the UK and will then undertake a Phase I clinical trial in healthy UK adults using a different adjuvant called Matrix-M (from our new partner Novavax, who have used the same adjuvant in their vaccine for Covid-19 tested in a Phase 3 trial in the UK). Our clinical trial will address whether the delayed and/or reduced dose of the third booster vaccination leads to dramatic improvements in the antibody response. The RH5.1/Matrix-M vaccine offers the possibility of an efficacious blood-stage malaria vaccine that can proceed to future field efficacy testing in Africa, as well as a route to identification of a delayed-booster immunisation regimen that affords long-lasting human immunity. Importantly, this work will also exemplify robust vaccine platform delivery technologies that have broad applicability to a range of human diseases.

The Need: Delivery approaches and platforms that can impart sustained and durable immunity are essential to the success of vaccines against a wide variety of difficult human diseases. Examples include seasonal respiratory viruses (such as influenza, RSV), emerging/pandemic pathogens (such as SARS-CoV-2) as well as parasites (such as Plasmodium - the causative agent of malaria).
Rationale: We previously developed the first vaccine to show in vivo impact in humans against the disease-causing blood-stage form of the P. falciparum human malaria parasite. The vaccine (called RH5.1) targets the conserved and essential RH5 antigen used by the parasite to invade erythrocytes. With previous MRC DPFS funding support we successfully produced this novel recombinant protein to high yield using new platform biomanufacturing technologies, and with USAID funding, we tested RH5.1 formulated in AS01 adjuvant from GSK in a large Phase I/IIa trial in healthy UK adults. We identified a "delayed-fractional booster" immunisation regimen that dramatically improved the maintenance of the human antibody response over 2.5 years' follow-up, as compared to routine vaccine boosting at monthly intervals.
Solution & Development Plan: We now propose to fill our remaining RH5.1 vaccine material (~250mg) to give a second vaccine batch. We will test this vaccine batch in a Phase Ia clinical trial in healthy UK adults in order to i) refine the vaccine delivery regimen, testing a delayed versus delayed-fractional booster regimen; and ii) to bridge to the new Matrix-M adjuvant, with our partner Novavax. RH5.1/Matrix-M offers the possibility of an efficacious blood-stage malaria vaccine that can proceed to future field efficacy testing, as well as a route to identification of a delayed-booster immunisation regimen that affords long-lasting human immunity. Importantly, this work will also exemplify robust vaccine platform delivery technologies that have broad applicability to a range of human diseases.