malaria vaccine malaria vaccine malaria vaccines are vaccines that prevent malaria, a mosquito-borne infectious disease which annually affects an estimated 247 million people worldwide and causes 619,000 deaths. the first approved vaccine for malaria is rts,s, known by the brand name mosquirix. as of april 2023, the vaccine has been given to 1.5 million 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%. malaria vaccinevaccine descriptiontargetmalariavaccine typeprotein subunitclinical datatrade namesmosquirixroutes ofadministrationintramuscularatc codej07xa01 (who) legal statuslegal status eu: rx-only approved in ghana, nigeria identifierscas number149121-47-1chemspidernone 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. in april 2023, ghana's food and drugs authority approved the use of the r21 vaccine for use in children aged between five months and three years old. following ghana's decision, nigeria provisionally approved the r21 vaccine. approved vaccines rts,s rts,s recombinant protein viruslike particle main article: 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 a 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 18 million 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. as of april 2023, 1.5 million children in ghana, kenya and malawi have received at least one shot of the vaccine, with more than 4.5 million doses of the vaccine administered through the countries' routine immunization programs. 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. as of april 2023 data from the phase iii study had not been formally published, but late-stage data from the study was shared with regulatory authorities. 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 100–200 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. agents under development screened cup of malaria-infected mosquitoes which will infect a volunteer in a clinical trial 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 main article: 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 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 . 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. a chemical compound undergoing trials for the treatment of tuberculosis and cancer—the jmjc inhibitor ml324 and the antitubercular clinical candidate sq109—is potentially a new line of drugs to treat malaria and kill the parasite in its infectious stage. more tests still need to be carried out before the compounds would be approved as a viable treatment. considerations the task of developing a preventive vaccine for malaria is a complex process. there are a number of considerations to be made concerning what strategy a potential vaccine should adopt. parasite diversity p. falciparum has demonstrated the capability, through the development of multiple drug-resistant parasites, for evolutionary change. the plasmodium species has a very high rate of replication, much higher than that actually needed to ensure transmission in the parasite's lifecycle. this enables pharmaceutical treatments that are effective at reducing the reproduction rate, but not halting it, to exert a high selection pressure, thus favoring the development of resistance. the process of evolutionary change is one of the key considerations necessary when considering potential vaccine candidates. the development of resistance could cause a significant reduction in efficacy of any potential vaccine thus rendering useless a carefully developed and effective treatment. choosing to address the symptom or the source the parasite induces two main response types from the human immune system. these are anti-parasitic immunity and anti-toxic immunity. "anti-parasitic immunity" addresses the source; it consists of an antibody response (humoral immunity) and a cell-mediated immune response. ideally, a vaccine would enable the development of anti-plasmodial antibodies in addition to generating an elevated cell-mediated response. potential antigens against which a vaccine could be targeted will be discussed in greater depth later. antibodies are part of