Breakthrough malaria vaccine RTS,S,R21 poised to save thousands of lives

Recent research published in the journal Nature Reviews Microbiology Malaria vaccines and their successes and failures are reviewed. Nearly half of the world's population is at risk of malaria, with pregnant women and young children being the most vulnerable. Women and children develop partial immunity over time, suggesting the potential for a vaccine. Malaria often presents as non-specific flu-like symptoms, leading to misdiagnosis and delayed treatment. Clinical features range from mild symptoms to severe complications, and mortality remains high unless prompt treatment is administered.

review: Malaria Vaccine: A New Era in Prevention and ControlImage credit: Kateryna Kon / Shutterstock

Malaria will kill more than 600,000 people in 2022, a death toll that has not improved since 2015. Malaria parasites Species that cause malaria in humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and P. Noureshiamong them, Plasmodium falciparum Malaria accounts for the highest number of cases and deaths. Malaria can persist despite treatment and existing immunity. Drug resistance in the parasite and insecticide resistance in mosquitoes hinder malaria control. Furthermore, parasites and mosquitoes resistant to existing interventions are spreading in Africa and beyond. The report highlighted that climate-induced factors such as food and economic insecurity may drive migration of non-immune groups into endemic areas, increasing their risk of malaria transmission.

Diagram of the malaria parasite life cycle.

The World Malaria Report 2023 highlights that rising temperatures, humidity and rainfall favor parasite and vector proliferation, increasing the intensity of infection and expanding risk areas. R21 and RTS,S are the first licensed vaccines against malaria and target the circumsporozoite protein (CSP) of the sporozoite. If deployed on a large scale, these vaccines could prevent child deaths every year. This will strengthen the first generation products and provide impetus to pursue goals such as protecting pregnant women and eradicating malaria. Therefore, this study reviewed the status of malaria vaccines to inform future developments and highlight their successes and failures.

RTS,S is recommended for children in areas with moderate to high transmission to reduce clinical malaria. In Phase III trials, RTS,S reduced clinical malaria by approximately 36% 48 months after the first vaccine dose. R21, approved in Ghana and Nigeria in 2023, reduced clinical malaria by approximately 75% (seasonal dosing) or 68% (standard dosing) over the next 12 months.

Malaria vaccines approach parasite life cycle stages

Pre-erythrocytic stage vaccines target liver stages and clinically asymptomatic sporozoites to prevent infection. Intrahepatic parasites are targeted by T cells and antibodies target sporozoites. Blood-stage vaccines target merozoite invasion proteins. Of the 37 blood-stage vaccine trials conducted between 2001 and 2015, 32 focused on three merozoite proteins, namely apical membrane antigen 1, merozoite surface protein 1 (MSP1), and MSP3, which had little or no effect in field or challenge studies. Infected erythrocytes are an alternative target for blood stages, but surface-dominant mutations have been shown to be effective in preventing infection. Plasmodium falciparum The erythrocyte membrane protein 1 (PfEMP1) family has hindered widespread vaccines. However, one PfEMP1, VAR2CSA, may be an exception. It is expressed on the surface of infected erythrocytes sequestered in the placenta and leads to adverse pregnancy outcomes. It is a leading vaccine candidate against gestational malaria. Furthermore, a transmission-blocking vaccine would induce antibodies against mosquitoes. antigen Or a parasite that lives in the spore-forming or sexual reproductive stage inside the mosquito.

Vaccine limitations, improvements and optimization

The R21 and RTS,S vaccines have been very successful, but their protection wanes after one year and therefore requires annual vaccination. Their effectiveness may vary depending on the intensity of infection and the timing of vaccination relative to the infection season. Quillaja saponaria It is incorporated into vaccine adjuvants, the supply of which is not unlimited, and furthermore, these vaccines are only indicated for young children.

Quillaja saponaria (soap bark tree or soap bark) is an evergreen tree in the Quillaceae family. Image credit: Akif CUBUK / Shutterstock

Efficacy The R21 in Phase 3 trials is higher than that of RTS,S. Both vaccines have similar Plasmodium falciparum R21, a fragment of CSP (PfCSP), displays PfCSP on all of the Hepatitis B surface antigen (HBsAg) capsid subunits, whereas RTS,S displays it on approximately 20% of these subunits. Thus, 5 μg of R21 results in a similar PfCSP content as 25 μg of RTS,S. Efforts to increase the potency and activity of blood-stage vaccines have relied on several adjuvants, such as AS02, Alhydrogel, and GLA-SE. In addition, coronavirus disease 2019 (COVID-19) vaccines use chemically modified nucleotides to reduce the innate immune stimulatory response. This approach has been implemented in Plasmodium falciparum-infected erythrocyte surface glutamic acid-rich protein (PfGARP). Plasmodium vivax Therapies targeting ookinete surface protein 25 (Pvs25) and PfCSP have shown promising results in preclinical studies. In addition, split dosing improved the efficacy of RTS,S against sporozoite challenge. Split dosing and other regimens have been R21 Vaccines. Timing of vaccination can be advantageous. For example, administering RTS,S before the transmission season increases efficacy. Furthermore, combining seasonal malaria chemoprophylaxis (SMC) with seasonal RTS,S vaccination reduced clinical malaria by 62.8% compared to SMC alone.

Addressing the needs of endemic communities

Malaria during pregnancy is associated with substantial fetal, neonatal, maternal and infant mortality. Treatment of infection during pregnancy is associated with fetal/neonatal mortality. Therefore, there is a need to develop a vaccine to reduce placental infection. Preconception administration of attenuated vaccines Plasmodium falciparum The pan-sporozoite (PfSPZ) vaccine was subsequently shown to be effective against infection during pregnancy for up to 2 years, laying the foundation for studies in pregnant women. Plasmodium vivax In 2020, it caused 18% to 72% of malaria cases in endemic areas outside Africa. It produces hypnozoites (dormant parasites) in the liver and relapses over months to years, hindering eradication efforts. Furthermore, drugs that remove hypnozoites cause hemolysis in people with glucose-6-phosphate dehydrogenase deficiency, hindering treatment. Plasmodium vivax They were few in number but effective.

Conclusion

together, R21 The RTS,S vaccine will reduce childhood mortality after large-scale deployment in Africa. Combining seasonal vaccination with chemoprophylaxis has reduced malaria incidence in Mali and Burkina Faso to approximately one-twentieth of historical incidence, suggesting that further improvements in childhood health can be achieved. Furthermore, new vaccine candidates and concepts may increase vaccination efficacy and expand indications in the future.