A malaria vaccine is a vaccine that prevents malaria, a mosquito-borne infectious disease which affected an estimated 249 million people globally in 85 malaria-endemic countries and areas and caused 608,000 deaths in 2022. The first approved vaccine for malaria is RTS,S, known by the brand name Mosquirix. , the vaccine has been given to 1.5million children living in areas with moderate-to-high malaria transmission. It requires at least three doses in infants by age 2, and a fourth dose extends the protection for another 1–2 years. The vaccine reduces hospital admissions from severe malaria by around 30%.
Research continues with other malaria vaccines. The most effective malaria vaccine is the R21/Matrix-M, with a 77% efficacy rate shown in initial trials and significantly higher antibody levels than with the RTS,S vaccine. It is the first vaccine that meets the World Health Organization's (WHO) goal of a malaria vaccine with at least 75% efficacy, and only the second malaria vaccine to be recommended by the WHO. In April 2023, Ghana's Food and Drugs Authority approved the use of the R21 vaccine for children aged between five months and three years old. Following Ghana's decision, Nigeria provisionally approved the R21 vaccine.
The malaria vaccine is on the World Health Organization's List of Essential Medicines.
Approved vaccines RTS,S
RTS,S/AS01 (brand name Mosquirix) is the first malaria vaccine approved for public use. It requires at least three doses in infants by age 2, with a fourth dose extending the protection for another 1–2 years. The vaccine reduces hospital admissions from severe malaria by around 30%.
RTS,S was developed by PATH Malaria Vaccine Initiative (MVI) and GlaxoSmithKline (GSK) with support from the Bill and Melinda Gates Foundation. It is a recombinant vaccine, consisting of the Plasmodium falciparum circumsporozoite protein (CSP) from the pre-erythrocytic stage. The CSP antigen causes the production of antibodies capable of preventing the invasion of hepatocytes and also elicits a cellular response enabling the destruction of infected hepatocytes. The CSP vaccine presented problems in the trial stage due to its poor immunogenicity. RTS,S attempted to avoid these by fusing the protein with a surface antigen from hepatitis B virus, creating a more potent and immunogenic vaccine. When tested in trials as an emulsion of oil in water and with the added adjuvants of monophosphoryl A and QS21 (SBAS2), the vaccine gave protective immunity to 7 out of 8 volunteers when challenged with P. falciparum.
RTS,S was engineered using genes from the outer protein of P. falciparum malaria parasite and a portion of a hepatitis B virus plus a chemical adjuvant to boost the immune response. Infection is prevented by inducing high antibody titers that block the parasite from infecting the liver. In November 2012, a Phase III trial of RTS,S found that it provided modest protection against both clinical and severe malaria in young infants.
In October 2013, preliminary results of a phase III clinical trial indicated that RTS,S/AS01 reduced the number of cases among young children by almost 50 percent and among infants by around 25 percent. The study ended in 2014. The effects of a booster dose were positive, even though overall efficacy seems to wane with time. After four years, reductions were 36 percent for children who received three shots and a booster dose. Missing the booster dose reduced the efficacy against severe malaria to a negligible effect. The vaccine was shown to be less effective for infants. Three doses of vaccine plus a booster reduced the risk of clinical episodes by 26 percent over three years but offered no significant protection against severe malaria.
In a bid to accommodate a larger group and guarantee sustained availability for the general public, GSK applied for a marketing license with the European Medicines Agency (EMA) in July 2014. GSK treated the project as a non-profit initiative, with most funding coming from the Gates Foundation, a major contributor to malaria eradication.
In July 2015, Mosquirix received a positive scientific opinion from the European Medicines Agency (EMA) on the proposal for the vaccine to be used to vaccinate children aged 6 weeks to 17 months outside the European Union. A pilot project for vaccination was launched on 23 April 2019 in Malawi, on 30 April 2019 in Ghana, and on 13 September 2019 in Kenya.
In October 2021, the vaccine was endorsed by the World Health Organization for "broad use" in children, making it the first malaria vaccine to receive this recommendation.
The vaccine was prequalified by WHO in July 2022. In August 2022, UNICEF awarded a contract to GSK to supply 18million doses of the RTS,S vaccine over three years. More than 30 countries have areas with moderate to high malaria transmission where the vaccine is expected to be useful.
, 1.5million children in Ghana, Kenya, and Malawi had received at least one injection of the vaccine, with more than 4.5 million doses of the vaccine administered through the countries' routine immunization programs. The next 9 countries to receive the vaccine over the next 2 years are Benin, Burkina Faso, Burundi, Cameroon, the Democratic Republic of the Congo, Liberia, Niger, Sierra Leone, and Uganda.
R21/Matrix-M
The most effective malaria vaccine is R21/Matrix-M, with 77% efficacy shown in initial trials. It is the first vaccine that meets the World Health Organization's goal of a malaria vaccine with at least 75% efficacy. It was developed through a collaboration involving the Jenner Institute at the University of Oxford, the Kenya Medical Research Institute, the London School of Hygiene and Tropical Medicine, Novavax, and the Serum Institute of India. The trials took place at the Institut de Recherche en Sciences de la Santé in Nanoro, Burkina Faso with Halidou Tinto as the principal investigator. The R21 vaccine uses a circumsporozoite protein (CSP) antigen, at a higher proportion than the RTS,S vaccine. It uses the same HBsAg-linked recombinant structure but contains no excess HBsAg. It includes the Matrix-M adjuvant that is also utilized in the Novavax COVID-19 vaccine.
A phase II trial was reported in April 2021, with a vaccine efficacy of 77% and antibody levels significantly higher than with the RTS,S vaccine. A booster shot of R21/Matrix-M that is given 12 months after the primary three-dose regimen maintains a high efficacy against malaria, providing high protection against symptomatic malaria for at least 2 years. A phase III trial with 4,800 children across four African countries was reported in November 2022, demonstrating vaccine efficacy of 74% against a severe malaria episode. Further data from multiple studies is being collected. data from the phase III study had not been formally published, but late-stage data from the study was shared with regulatory authorities. In a study published in February 2024, data from the phase III trial showed an efficacy of 78% in children aged 5–17 months and an efficacy of 70% in children aged 18–36 months.
Ghana's Food and Drugs Authority approved the use of the R21 vaccine in April 2023, for use in children aged between five months to three years old. The Serum Institute of India is preparing to produce between 100 and 200 million doses of the vaccine per year, and is constructing a vaccine factory in Accra, Ghana. Following Ghana's decision, Nigeria provisionally approved the R21 vaccine.
In October 2023 the WHO endorsed the R21 vaccine against malaria, end of December 2023 it was added to the list of Prequalified Vaccines.
Further developments for a vaccine that targets the erythrocytic stage of the Malaria parasite have been made, provisionally named RH5.1/Matrix-M, which it is hoped will combine with the R21/Matrix-M pre-erythrocytic vaccine to create an even more efficacious second-generation Malaria vaccine.
Agents under development
A completely effective vaccine is not available for malaria, although several vaccines are under development. Multiple vaccine candidates targeting the blood-stage of the parasite's lifecycle have been insufficient on their own. Several potential vaccines targeting the pre-erythrocytic stage are being developed, with RTS,S and R-21/Matrix-M the two approved options so far.
Nanoparticle enhancement of RTS,S In 2015, researchers used a repetitive antigen display technology to engineer a nanoparticle that displayed malaria-specific B cell and T cell epitopes. The particle exhibited icosahedral symmetry and carried on its surface up to 60 copies of the RTS,S protein. The researchers claimed that the density of the protein was much higher than the 14% of the GSK vaccine.
PfSPZ vaccine
The PfSPZ vaccine is a candidate malaria vaccine developed by Sanaria using radiation-attenuated sporozoites to elicit an immune response. Clinical trials have been promising, with trials in Africa, Europe, and the US protecting over 80% of volunteers. It has been subject to some criticism regarding the ultimate feasibility of large-scale production and delivery in Africa since it must be stored in liquid nitrogen.
The PfSPZ vaccine candidate was granted fast track designation by the U.S. Food and Drug Administration in September 2016.
In April 2019, a phase III trial in Bioko was announced, scheduled to start in early 2020.
Other developments SPf66 is a synthetic peptide-based vaccine developed by the Manuel Elkin Patarroyo team in Colombia and was tested extensively in endemic areas in the 1990s. Clinical trials showed it to be insufficiently effective, with 28% efficacy in South America and minimal or no efficacy in Africa. This vaccine had no protective effect in the largest placebo-controlled randomized trial in South East Asia and was abandoned. The CSP (Circum-Sporozoite Protein) was a vaccine developed that initially appeared promising enough to undergo trials. It is also based on the circumsporozoite protein but additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR) protein covalently bound to a purified Pseudomonas aeruginosa toxin (A9). However, at an early stage, a complete lack of protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82% incidence of parasitaemia while the control group only had an 89% incidence. The vaccine intended to cause an increased T-lymphocyte response in those exposed; this was also not observed. The NYVAC-Pf7 multi-stage vaccine attempted to use different technology, incorporating seven P. falciparum antigenic genes. These came from a variety of stages during the lifecycle. CSP and sporozoite surface protein 2 (called PfSSP2) were derived from the sporozoite phase. The liver stage antigen 1 (LSA1), three from the erythrocytic stage (merozoite surface protein 1, serine repeat antigen, and AMA-1), and one sexual stage antigen (the 25-kDa Pfs25) were included. This was first investigated using rhesus monkeys and produced encouraging results: 4 out of the 7 antigens produced specific antibody responses (CSP, PfSSP2, MSP1 and PFs25). Later trials in humans, despite demonstrating cellular immune responses in over 90% of the subjects, had very poor antibody responses. Despite this following administration of the vaccine, some candidates had complete protection when challenged with P. falciparum. This result has warranted ongoing trials. In 1995 a field trial involving [NANP]19-5.1 proved to be very successful. Out of 194 children vaccinated, none developed symptomatic malaria in the 12-week follow-up period, and only 8 failed to have higher levels of antibody present. The vaccine consists of the schizont export protein (5.1) and 19 repeats of the sporozoite surface protein [NANP]. Limitations of the technology exist as it contains only 20% peptide and has low levels of immunogenicity. It also does not contain any immunodominant T-cell epitopes.