In January 2024 Cameroon launched the world’s first routine malaria vaccine programme. By incorporating the RTS,S vaccine into its standard immunisation schedule, Cameroon aims to protect thousands of children across Africa and significantly reduce malaria-related fatalities.
Closely following suit, the Côte d’Ivoire has recently become the first country to roll-out the new R21/Matrix-M™ vaccine, in another key advancement in the battle against malaria.
The launch of the vaccines, and the implementation of the mass vaccination programmes, marks a historic step in the global fight against malaria, one of the world’s most deadly diseases, and is a move predicated to save hundreds of thousands of children’s lives across Africa.
Causes, symptoms, and burden
“Malaria is a disease that is both preventable and curable, and yet a child dies of malaria every 30 seconds” (World Health Organisation, WHO).
Malaria is a life-threatening disease caused by Plasmodium parasites that are spread to humans through bites of infected mosquitoes. According to the 2023 World Malaria Report there were 249 million cases of malaria in 2022 (up from 244 million cases in 2021). The World Health Organisation (WHO) estimate that 600,000 people die of malaria each year, with children under five making up at least 80% of those deaths. Africa carries a disproportionately high share of the global malaria burden. According to the WHO, approximately 94% of global malaria cases and 95% of related deaths occurred in Africa.
Of the five Plasmodium parasite species that infect humans, P. falciparum is the deadliest. It is the cause of almost all malarial deaths and is the most prevalent species in Sub-Saharan Africa. P. vivax is the dominant malaria parasite in most countries outside of Africa. Although less virulent than P. falciparum, P. vivax, like all species, can still lead to severe infection and death if left untreated. Early treatment for mild malaria can stop the infection from becoming severe.
Current control strategies include rapid diagnostic testing, treatment using well-established antimalarial drugs, including highly effective artemisinin combination therapy, and vector control measures (insecticide-treated bed nets, etc.). However, incidence and mortality rates remain high. Issues such as ineffectiveness in the control of disease vectors and parasitic resistance to antimalarial drugs demonstrate the ongoing, urgent requirement for additional preventative methods.
Vaccine development
Anti-malaria vaccines have been in development since the 1960s. However, developing an effective vaccine has seen challenges. Many of the challenges are linked to the complex biology of the Plasmodium parasite. Not only does it have a complex life cycle, spanning both human and mosquito hosts, but is also has a complex and genetically diverse genome and an ability to evade the human immune system (which contributes to parasitic resistance to antimalarial drugs).
Vaccines are categorised by the stage of the parasite’s lifecycle targeted. “Pre-erythrocytic” vaccines target the parasite in the liver before it enters the bloodstream, “erythrocytic” vaccines target the parasite in the bloodstream, and “transmission-blocking” vaccines (TBVs) aim to induce antibodies against the parasite in the mosquito. It is predicted that pre-erythrocytic vaccines, which target the critical early stages of the life cycle in human hosts, will be most effective in preventing infection and transmission. In this stage, the parasite – in the form of sporozoites – undergoes development in the liver. After about 10 days to 4 weeks, the parasite leaves the liver and infects the host’s red blood cells. This is when malaria symptoms typically develop. Thus, targeting the early liver stages, during which a patient is asymptomatic, may prevent disease progression and severe infection.
The main target for pre-erythrocytic vaccines is the circumsporozoite protein (CSP), a major antigen on the surface of the sporozoite. The CSP is a protein of 412 amino acids that is expressed during the early phases of infection in the liver. It was the first malaria gene to be cloned and remains a focus in vaccine development.
RTS,S vaccine
RTS,S (trade name MosquirixTM) is the world’s first malaria vaccine and is the result of over 30 years of development by GlaxoSmithKline (GSK), in partnership with PATH’s Malaria Vaccine Initiative (with support from the Bill and Melinda Gates Foundation).
RTS,S is a recombinant protein-based vaccine that targets CSP and prevents infection by inducing high levels of antibodies that block the parasite from infecting the liver. It contains a truncated CSP – amino acids 207-395 of the CSP from the NF53 strain of P. falciparum – fused to the hepatitis B surface antigen, HBsAg, which acts as a protein carrier. Additional HBsAg is added to improve purification. The fused CSP-HBsAg and additional HBsAg components are expressed recombinantly in yeast and spontaneously self-assemble into virus-like particles displaying CSP and HBsAg at their surface. The vaccine also contains a chemical adjuvant to improve the immune response. The components are all assembled in lipoprotein particles.
In October 2021 the WHO approved RTS,S for widespread use. It is now recommended for use in children in regions with moderate-to-high transmission of P. falciparum malaria. Following successful pilot schemes in Kenya, Ghana, and Malawi – where a 13% drop in deaths in eligible children was seen – Cameroon began offering the RTS,S vaccine free of charge to children up to 6 months old.
The RTS,S vaccine has been shown to reduce symptomatic malaria cases by 39% and severe malaria by 30%, meaning that it could save the lives of over 1 in 3 children to which it is administered.
R21/Matrix-M™ vaccine
More recently, the R21/Matrix-M (R21) vaccine became the second anti-malaria vaccine to be recommended by the WHO. It is the most effective malaria vaccine with up to 77% efficacy shown in trials and is the first vaccine to meet the WHO’s goal of at least 75% efficacy.
R21 was co-developed by the University of Oxford, and the Serum Institute of India, utilising Novavax’s Matrix-M™ adjuvant technology (which is also used in the Novavax COVID-19 vaccine). It is closely related to the RTS,S vaccine, with the creators describing R21 as “a next-generation RTS,S-like vaccine”. Like RTS,S, the R21 vaccine targets CSP and is based on a truncated CPS fused to HBsAg. The CPS-HBsAg construct is also recombinantly expressed in yeast and self-assembles into virus-like particles. However, unlike RTS,S, R21 does not contain any additional HBsAg. This means that the particles of the R21 vaccine are covered with a higher proportion of CSP compared to those of the RTS,S vaccine. Not only does this result in greater potency, but it may also go some way to explain why R21 requires a lower dosage (5 µg compared to 25 µg for RTS,S), and why R21 is generally easier to manufacture (less CSP needs to be made to generate the same number of doses compared to RTS,S).
The vaccines also use different adjuvants to boost the immune response. Where RTS,S uses a mixture of lipids and saponin-based adjuvants, R21 uses only a saponin-based adjuvant. The lower complexity of the adjuvant used in R21 may also contribute to its relative ease of manufacture.
Côte d’Ivoire made history by becoming the first country to roll-out the R21 vaccine, with the first child receiving the vaccine on 15 July 2024. Like RTS,S, R21 will be administered in 4 doses (3 primary doses, one month apart, plus a 4th booster dose roughly a year thereafter).
The vaccine has also been authorised by Ghana, Nigeria, Burkina Faso, and the Central African Republic. In anticipation of mass roll-out of R21 in Cameroon and other countries, the Serum Institute of India has already manufactured 25 million doses of the vaccine. It has also committed to producing 100 million doses per year. The manufacturing capability of the Serum Institute of India – and its ethos that it is every person’s right to have access to affordable and essential disease prevention – means that the R21 vaccine can be delivered at scale, at speed, and at low cost ($4 per dose).
What does the future look like?
The launch of the two anti-malaria vaccines is a hugely significant, and critical, step in the fight against the disease, and is a major success in the decades long attempt to develop an effective vaccine.
According to the WHO:
“…the roll-out of the two malaria vaccines, RTS,S and R21, will result in sufficient vaccine supply to meet demand and benefit children living in areas where malaria is a major public health risk. Tens of thousands of young lives could be saved every year with the wide implementation of these malaria vaccines. Modelling estimates both vaccines prevent up to half a million child deaths over 12 years if the vaccine is scaled up to all Gavi-eligible countries”.
It is anticipated that the deployment of these vaccines, particularly when integrated with other, already established, control measures, will significantly advance the fight against malaria. Looking ahead, malaria could potentially be reduced to near-eradication levels, like the trajectory of other historically managed diseases.