MICA: A novel P. vivax pre-erythrocytic malaria vaccine for broad coverage: Progression to GMP manufacture of a clinical vaccine lot

Plasmodium vivax is the world's most widely distributed human malaria parasite. Approximately 2.49 billion people live at risk of infection and an estimate of 132-391 million clinical episodes per year. Elimination of P. vivax from endemic regions is substantially more difficult than P. falciparum, due to the ability to relapse in the weeks and months following a primary parasitaemia, via a dormant liver structure known as hypnozoite. The highest endemicity estimates of P. vivax malaria globally are fast growing economies in Asia, with the largest population at risk (84% of the global population or over 2 billion people). The southern islands of Asia-Pacific are also highly endemic, followed by the Americas and Africa. The current best practice to tackle vivax malaria is a drug (primaquine) that cannot be mass administered due to the risk of haemolysis caused by the frequent G6PD genetic trait. There is no licensed vaccine yet. Elimination of Plasmodium vivax (Pv) will be key to achieve malaria eradication, but it is proving to be far more difficult than elimination of P. falciparum (Pf). Countries where both malaria parasites co-exist have found that elimination of Pf is feasible but Pv is more resilient and extremely difficult to eliminate. The major reason for such resilience is the liver hypnozoite. This is an extraordinary structure that P. vivax has evolved to survive in temperate and cold regions. A hypnozoite can have the ability to hide for a long period of time to reactivate in a following hot season, where mosquitoes will be next available to take a blood meal containing parasites coming from the liver rather than from a mosquito bite. Major vivax drug developments are aimed at targeting the hypnozoite, but only one drug, primaquine, is effective to treat these structures. Therefore, pre-erythrocytic vaccines such as the one proposed here, could make P. vivax elimination economically feasible or even possible, by preventing hypnozoite formation or by eliminating such structure. We have developed a highly protective P. vivax pre-erythrocytic vaccine using the major sporozoite surface antigen (CSP) fused to the Hepatitis B virus Surface Antigen. This forms a virus-like particle (VLP) similar to Glaxo's RTS,S vaccine currently in phase III clinical trials. Our Rv21 particle in Matrix M adjuvant is highly efficacious, inducing complete, sterile protection in a highly sensitive mouse malaria model, using a very high challenge doses of transgenic parasites expressing vivax CSP. A P. vivax malaria vaccine inducing protection against the two major circulating P. vivax parasites (based on the CSP allele) is an ideal solution. Our Rv21 is the first vaccine that demonstrates high efficacy against both Pv CSP alleles, VK210 and VK247. The Rv21 VLP can form particles without the need of an extra HepB S antigen copy, which is the technology used by GSK's RTS,S and CSV-S,S. This permits the presence of more CSP antigen per HepB S (ratio 1:1), thus focusing the immune response towards the malaria antigen, rather than the carrier. We propose here to manufacture the Rv21 candidate vaccine to GMP standards. Our pre-clinical results indicate that this could be the most effective P. vivax vaccine yet developed with additional potential to prevent hypnozoite and relapse, while offering the possibility of medium term licensure and deployment. This project will take 30 months to complete and will involve GMP production of a vaccine lot, as well as ethics and regulatory approvals for a first-in-human clinical trial.