Malaria killed about 640 thousand people in 2020, largely young children in Africa. Rapid recent progress has led to two anti-sporozoite vaccine developers planning WHO prequalification applications in 2022. These include the new high efficacy R21/Matrix-M vaccine, to be supplied at the required large scale, and led by partners in this consortium. In parallel, recent progress with transmission-blocking malaria vaccines has led to substantial efficacy in a first direct skin feeding field trial. This opens up the prospect of a two-stage vaccine targeting both sporozoites and sexual-stage parasites that should have a major impact on malaria transmission, thereby enabling regional elimination and ultimate eradication. We propose here to develop such a vaccine assessing both established virus-like particle (VLP) vaccines in potent saponin adjuvants and also exciting new thermostable mRNA vaccines expressing the parasite antigens now showing high efficacy. Importantly, we will adopt new VLP design technologies, e.g. SpyCatcher bonding, that allow bivalent antigen display, to enable a single vaccine to protect against both the Plasmodium falciparum parasite, which causes most deaths, and the more widespread Plasmodium vivax parasite. A lead vaccine candidate will be down-selected based on well-studied pre-clinical efficacy models and induction of functional transmission-blocking antibodies, prior to GMP manufacture and a clinical trial in year 4. The consortium brings together academics, non-profits and a wide range of companies with both leading technologies and access to small and very large scale GMP manufacturing capacity. This programme builds on the recent success of several partners in the R21/Matrix-M programme and aims to accelerate the malaria eradication agenda by providing the first vaccine to tackle both major malaria parasite species, and confer both individual and community protection on the way to eradication.

Plasmodium vivax is the most widespread human malaria with 2.5 billion people living at risk in South America, Oceania and Asia. The revised Malaria Vaccine Technology Roadmap to 2030 recognises the severity of P. vivax malaria, calling for a vaccine intervention to achieve 75% efficacy over two years, now equally weighted with P. falciparum. However, if this ambition is to be realised, new and innovative approaches are urgently required to accelerate next-generation vaccine research and development, whilst the few known candidate antigens need to undergo early-phase clinical assessment. Here, we build on exciting breakthroughs in P. vivax vaccine research, recently pioneered in Europe, including new transgenic parasite technologies for functional assay development and production of a parasite clone that is safe for use in controlled human malaria infection (CHMI) clinical models. The Objectives of OptiViVax will now integrate ambitious multi-disciplinary scientific and clinical approaches around the parasite’s lifecycle and will use our increased knowledge of P. vivax immuno-biology to further develop next-generation vaccines with improved efficacy. We will diversify the portfolio of new antigens ready for clinical testing by reverse vaccinology and diversify their delivery with new platforms and adjuvants developed using sustainable and improved GMP bio-manufacturing know-how. In parallel, the efficacy of known leading antigens will be benchmarked for the first time using innovative design of clinical studies and CHMI models making these lead candidate vaccines ready for future field trials. Improved preclinical functional assays, using state-of-the-art transgenic parasite lines, will also allow for mechanisms of antibody-mediated protection to be deciphered. The availability of new functional assays and human challenge models will underpin the future framework for informed decision making by the clinical vaccine community, policy makers, funders and regulators.

Plasmodium vivax is the most widespread malaria and constitutes a significant proportion of human malaria cases. P. vivax accounts for 100-400 million clinical cases each year among the 2.5 billion people living at risk in Latin America, Oceania and Asia. The recently revised Malaria Vaccine Technology Roadmap to 2030 recognises the severity of P. vivax malaria and calls for a vaccine intervention to achieve 75% efficacy over two years – equally weighted with P. falciparum. However, despite this global health need, efforts to develop interventions against this parasite have lagged far behind those for P. falciparum, in large part because of critical bottlenecks in the vaccine development process. These include i) lack of assays to prioritise and down-select new vaccines due to lack of an in vitro P. vivax long-term culture system, and ii) lack of easy access to a safe controlled human malaria infection (CHMI) model to provide an early indication of vaccine efficacy in humans. The Objectives of this MultiViVax proposal will address these critical bottlenecks and shift the “risk curve” in order to better select successful vaccine candidates against multiple lifecycle stages of P. vivax: 1. We will establish a P. vivax CHMI model in Europe for the first time to facilitate the better selection of effective vaccines and remove the current bottleneck for their early-phase clinical testing. 2. We will utilise this CHMI model to identify novel antigens associated with protective blood-stage immunity in humans by taking advantage of recent advances in immuno-screening and parasite RNASeq. 3. We will progress existing vaccines targeting the current leading antigens for both the blood- and transmission-stages along the clinical development pipeline. 4. We will develop novel transgenic parasites for use in assays in order to overcome the current bottleneck in vaccine down-selection caused by the inability to culture P. vivax parasites.