Abstract
The leading malaria vaccine in development is the circumsporozoite protein (CSP)-based particle vaccine, RTS,S, which targets the pre-erythrocytic stage of Plasmodium falciparum infection. It induces modest levels of protective efficacy, thought to be mediated primarily by CSP-specific antibodies. We aimed to enhance vaccine efficacy by generating a more immunogenic CSP-based particle vaccine and therefore developed a next-generation RTS,S-like vaccine, called R21. The major improvement is that in contrast to RTS,S, R21 particles are formed from a single CSP-hepatitis B surface antigen (HBsAg) fusion protein, and this leads to a vaccine composed of a much higher proportion of CSP than in RTS,S. We demonstrate that in BALB/c mice R21 is immunogenic at very low doses and when administered with the adjuvants Abisco-100 and Matrix-M it elicits sterile protection against transgenic sporozoite challenge. Concurrent induction of potent cellular and humoral immune responses was also achieved by combining R21 with TRAP-based viral vectors and protective efficacy was significantly enhanced. In addition, in contrast to RTS,S, only a minimal antibody response to the HBsAg carrier was induced. These studies identify an anti-sporozoite vaccine component that may improve upon the current leading malaria vaccine RTS,S. R21 is now under evaluation in Phase 1/2a clinical trials.
Highlights
IntroductionWith the efficacy in the infant age group being considered too low to justify deployment, the pilot implementation trials aim to assess the operational feasibility of administering four vaccine doses all after five months of age as well assessing the extent to which RTS,S affects all-cause mortality[19]
In a short term Phase 2b trial in Kenyan adults, vaccination reduced the risk of infection by 67% in an area with low transmission intensity[29]. These results are encouraging, the levels of efficacy achieved by both RTS,S and ChAd63-modified vaccinia Ankara virus (MVA) multiple epitope (ME)-TRAP remain below the goals set by the Malaria Vaccine Technology Roadmap[30] and development of a more effective vaccine is a major priority
Following expression of the R21 fusion protein in P. pastoris, the yeast cell membranes were disrupted in lysis buffer and the CSP-HBsAg fusion proteins self-assembled into lipid-protein particles
Summary
With the efficacy in the infant age group being considered too low to justify deployment, the pilot implementation trials aim to assess the operational feasibility of administering four vaccine doses all after five months of age as well assessing the extent to which RTS,S affects all-cause mortality[19] Another advance in malaria subunit vaccine development has been the viral vector heterologous prime-boost approach, which aims to induce antigen-specific T cells that target infected hepatocytes[20]. RTS,S and ChAd63-MVA ME-TRAP, each target a different pre-erythrocytic stage antigen and predominantly induce different arms of the immune response, one approach to improve vaccine efficacy would be to combine these vaccines This would enable induction of high titres of CSP-specific antibodies to reduce sporozoite invasion, and high frequencies of TRAP-specific T cells to target the remaining infected hepatocytes. When evaluating the potential for using R21 as part of a multi-component vaccination strategy, protective efficacy was enhanced by combining R21 in MF59 with PbTRAP-based viral vectors
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