RTS,S/AS01 vaccine (Mosquirix™): an overview

Abstract

Malaria is an illness caused by Plasmodium parasites transmitted to humans by infected mosquitoes. Of the five species that infect humans, P. falciparum exacts the highest toll in terms of human morbidity and mortality, and therefore represents a major public health threat in endemic areas. Recent advances in control efforts have reduced malaria incidence and prevalence, including rapid diagnostic testing, highly effective artemisinin combination therapy, use of insecticide-treated bednets, and indoor residual spraying. But, reductions in numbers of cases have stalled over the last few years, and incidence may have increased. As this concerning trend calls for new tools to combat the disease, the RTS,S vaccine has arrived just in time. The vaccine was created in 1987 and began pilot implementation in endemic countries in 2019. This first-generation malaria vaccine demonstrates modest efficacy against malaria illness and holds promise as a public health tool, especially for children in high-transmission areas where mortality is high.

Keywords: AS01; Plasmodium; RTS,S; adjuvant; malaria; vaccine.

Figure 1.

Life cycle of the malaria parasite (courtesy of PATH malaria vaccine initiative, found at http://www.malariavaccine.org/malaria-and-vaccines/vaccine-development/life-cycle-malaria-parasite). Malaria infection begins when an infected female Anopheles mosquito bites a person, injecting Plasmodium parasites, in the form of sporozoites, into the bloodstream. 2. The sporozoites pass quickly into the human liver. 3. The sporozoites multiply asexually in the liver cells over the next 7–10 days, causing no symptoms. 4. In an animal model, the parasites, in the form of merozoites, are released from the liver cells in vesicles, journey through the heart, and arrive in the lungs, where they settle within lung capillaries. The vesicles eventually disintegrate, freeing the merozoites to enter the blood phase of their development. 5. In the bloodstream, the merozoites invade red blood cells (erythrocytes) and multiply again until the cells burst. Then they invade more erythrocytes. This cycle is repeated, causing fever each time parasites break free and invade blood cells. 6. Some of the infected blood cells leave the cycle of asexual multiplication. Instead of replicating, the merozoites in these cells develop into sexual forms of the parasite, called gametocytes, that circulate in the bloodstream. 7. When a mosquito bites an infected human, it ingests the gametocytes, which develop further into mature sex cells called gametes. 8. The fertilized female gametes develop into actively moving ookinetes that burrow through the mosquito’s midgut wall and form oocysts on the exterior surface. 9. Inside the oocyst, thousands of active sporozoites develop. The oocyst eventually bursts, releasing sporozoites that travel to the mosquito’s salivary glands. 10. The cycle of human infection begins again when the mosquito bites another person.

Figure 2.

Graphical depiction of circumsporozoite (CSP) and RTS,S structures. CSP comprises an N-terminal region containing a signal peptide sequence and Region I that binds heparin sulfate proteoglycans and has embedded within it a conserved five amino acid (KLKQP) proteolytic cleavage site sequence; a central region containing four-amino acid (NANP/NVDP) repeats; and a C-terminal region containing Region II [a thrombospondin (TSP)-like domain] and a canonical glycosylphosphatidylinositol (GPI) anchor addition sequence. The region of the CSP included in the RTS,S vaccine includes the last 18 NANP repeats and C-terminus exclusive of the GPI anchor addition sequence. Hepatitis B virus surface antigen (HBsAg) monomers self-assemble into virus-like particles and approximately 25% of the HBsAg monomers in RTS,S are genetically fused to the truncated CSP and serve as protein carriers. The CSP fragment in RTS,S contains three known T-cell epitopes: a highly variable CD4 + T-cell epitope before the TSP-like domain (TH2R), a highly variable CD8 + T-cell epitope within the TSP-like domain (TH3R), and a conserved “universal” CD4 + T cell epitope (CS.T3) at the C-terminus. (Figure courtesy of a recent publication¹⁶ and open access, http://creativecommons.org/licenses/by/4.0/).