Developing a new anti-sporozoite malaria vaccine

Malaria is one of the leading infectious causes of morbidity and mortality. There was an estimated 241 million malaria cases and 627,000 deaths in 2020 across 85 malaria endemic countries. When compared with data from recent years, this suggests that global progress has stalled, and that malaria mortality is increasing. There is an urgent need to develop new tools to combat this. Significant progress has been made in malaria vaccine development, with the first malaria vaccine, RTS,S/AS01, achieving prequalification this year (2022). However, the current production capacity of RTS,S/AS01 may not, at least initially, meet the needs of the target population. At the same time, the WHO goal of developing a malaria vaccine with protective efficacy of ≥75% against clinical malaria, for at-risk groups in malaria-endemic areas, over at least 2 years, has not yet been met. R21 is produced by using recombinant HBsAg particles expressing the central repeat and the C-terminus of the Plasmodium falciparum circumsporozoite protein. R21 was initially developed at the University of Oxford and is now manufactured by the Serum Institute of India Pvt. Ltd (SIIPL). R21 is combined with an adjuvant, Matrix-M, manufactured by Novavax AB, to produce the vaccine candidate R21/Matrix-M which targets P. falciparum malaria. In this thesis, I describe the clinical development assessing safety, immunogenicity and efficacy of the R21/Matrix-M malaria vaccine candidate across a phase I/IIa clinical trial in UK adults (chapter 3); a phase Ib clinical trial in Kenya in adults, young children and infants (chapter 4); and a phase IIb clinical trial in infants in Burkina Faso (chapter 5). I evaluate the composition of the gut microbiome of infants living in malaria endemic areas (the target population for R21/Matrix-M) to assess if this is affected by any specific participant factors. I also assess if the baseline gut microbiome suggests any correlation with antibody responses generated by R21/Matrix-M, and if any association exists between the gut microbiome composition and the total number of malaria episodes experienced at 12 months following vaccinations (chapter 6). The clinical development phases of R21/Matrix-M have demonstrated that the vaccine is safe, immunogenic and protective against malaria. Importantly, efficacy of ≥75% against clinical malaria was noted over 2 years in the target population of African infants, in the phase IIb trial, where vaccinations were administered prior to or at the start of the malaria season. The composition of the gut microbiome varied significantly according to age of the infant but had no impact on the antibody responses to the R21/Matrix-M malaria vaccine or the number of malaria episodes experienced by an infant. In my conclusions in this thesis, I have reflected on some of the key issues beyond the science that affect deployment and implementation of a successful malaria vaccine. In order to make strides in eliminating malaria in sub-Saharan Africa, it is necessary for there to be cooperation amongst multiple stakeholders; developments in manufacturing and delivery of vaccines; and grassroots participation in vaccine programmes. The results from these trials have led to a phase III trial across five African sites, in East and West Africa, evaluating the safety and efficacy of R21/Matrix-M in areas of differing malaria transmission in a larger number of infants and children. The aim is licensure of a safe, inexpensive vaccine, with high efficacy, that will significantly reduce the malaria disease burden.