Most vaccines get injected into muscle, swallowed by mouth, or squirted into the nose. But in a clinical study reported in January 2025 in Nature Medicine [1], researchers in the Netherlands used a less conventional method to deliver an investigational vaccine: mosquito bites. The mosquitoes carried malaria-causing Plasmod- ium falciparum parasites that had been genetically engineered to trigger a productive immune response without making people sick. Nine of ten study participants who each, in a single session, with- stood 50 bites from this laboratory strain of mosquitoes, success- fully fended off infection when challenged with infective malaria parasites six weeks later. This small proof-of-concept study sug- gests the possibility of achieving a high level of protection with a single immunization, a further step toward a long-sought highly effective vaccine to fight malaria, an ancient scourge that remains a leading cause of death in developing countries.
Malaria claimed 597 000 lives globally in 2023 [
2], nearly eight times more than coronavirus disease 2019 (COVID-19) [
3]. Ninety- five percent of malaria deaths occur in sub-Saharan Africa, mostly in children under five years of age [
2]. The disease is deeply con- nected with poverty. Since agricultural activity creates breeding grounds for malaria-transmitting
Anopheles mosquitoes (
Fig. 1), farming families face a higher risk of disease and sacrifice vital income in their struggle to access health services. It is a vicious cycle. Battling malaria makes people poor, “and if you are poor, you get more malaria,” said Umberto D’Alessandro, a clinician and professor of epidemiology who directs the Medical Research Council Unit, the Gambia at the London School of Hygiene & Trop- ical Medicine (London, UK).
The sad reality is that while a child dies of malaria every 1 to 2 min, the disease is quite preventable and treatable [
4]. To prevent disease spread in endemic areas, the World Health Organization (WHO) rec- ommends seasonal malaria chemoprevention (SMC)—monthly oral doses of sulfadoxine-pyrimethamine and amodiaquine (SPAQ)—for children during rainy months when transmission peaks. This interven- tion reduced clinical malaria cases by up to 88% in the first 28 days and about 61% during days 29-42 after administration in seven case con- trol studies of children in Burkina Faso, Chad, Mali, and Nigeria [
5].
For people with suspected infections, rapid tests that detect malaria-specific proteins from a pin prick of blood can give a diagnosis in 15 min. A three-day course of artemisinin-based combination (ACT) pills—the first-line malaria treatment recom- mended by WHO since 2001—can clear more than 95% of uncomplicated cases [
6].
These measures are inexpensive—0.20 to 0.30 USD for a rapid test, 0.20 to 0.30 USD to treat a child in a public health facility—said Justin Cohen, an infectious disease epidemiologist who leads the malaria and neglected tropical disease program at the Clinton Health Access Initiative(Boston, MA, USA). "For under a dollar, there is basically no reason anyone should die of malaria," Cohen said.
Yet after staying steady between 2000 and 2019, malaria infec- tions in endemic countries have risen in recent years, with an esti- mated 263 million new cases in 2023, up from 252 million in 2022 and 236 million in 2019 [
7]. The rising incidence comes, ironically, at the same time as the first two malaria vaccines (
Fig. 2), RTS,S and R21, have become commercially available, both having earned WHO recommendations as of October 2023 and capping more than 60 years of research [
8]. The vaccines target
P. falciparum, the most prevalent type of malaria in Africa; they are only weakly effective against
P. vivax, which causes most malaria in countries outside of Africa [
9]. While
P. vivax is less deadly than
P. falciparum, it still causes substantial morbidity, and on-going research is seeking to develop a vaccine for
P. vivax malaria.
The journey to the first approved vaccines was challenging for several reasons. First, the malaria parasite, a whole cell protozoan, has 5000 genes, a much larger genome than that of pathogenic bac- teria that cause, for instance, strep throat (1990 genes), as well as viruses that cause, for instance, smallpox (200 genes) or measles (eight genes). Furthermore, Plasmodium parasites display an ever- shifting set of proteins, which keeps its human hosts from develop- ing lasting immunity. Unlike measles, where one infection prompts lifelong immunity, for people chronically exposed to malaria “it takes a long time to get some kind of protection and the protection is partial,” said D’Alessandro.
Another complicating factor is the parasite’s multi-stage life cycle. Human infection begins when sporozoites get released from the bite of an infected female Anopheles mosquito. In humans, the sporozoites go through several rounds of expansion; first, within liver cells, then in successive cycles in red blood cells, where they make people sick. Infected blood cells clump and stick to vessel walls, which restricts blood flow and leads to more serious prob- lems, said D’Alessandro. “Someone can go into a coma. And you can have kidney failure and respiratory failure.”
Efforts to develop a malaria vaccine date back to the 1960s when researchers at New York University (NYU) School of Medicine showed that mice could resist malaria if immunized with radiation-weakened sporozoites, the infectious form of the malaria-causing parasite [
10]. Other researchers tested the concept in a human trial, immunizing three brave volunteers with bites from 379 irradiated infected mosquitoes over the course of 84 days. One individual resisted disease when challenged with unirradiated infected mosquitoes 15 days after the last immuniza- tion, then withstood an additional five immunization sessions and stayed protected after another challenge [
11].
Another critical discovery came in 1980, when the NYU team reported they could protect mice from malaria using antibodies against the circumsporozoite protein (CSP) on the surface of sporo- zoites [
12]. Since it is generally simpler to generate vaccines to a single, defined antigen than to try to target the more complex and dynamic sporozoite, the cloning and sequencing of CSP laid the groundwork for developing RTS,S—the first regulatory- approved vaccine for malaria, and the first-ever vaccine against a parasite.
The WHO pre-qualified RTS,S (brand name Mosquirix) in October 2021 for children in sub-Saharan Africa and other areas with moderate-to-high malaria transmission. Researchers at GlaxoSmithKline (Genval, Belgium) and the Walter Reed Army Institute of Research (Maryland, USA) created the vaccine by fusing fragments of CSP with a hepatitis B surface antigen (HBsAg) that self-assembles into virus-like particles.
In a phase 3 clinical trial across seven African countries that enrolled more than 15 000 children aged 5-17 months, RTS,S reduced malaria by 50% during the 12 months after three vaccine doses given at one-month intervals [
13]. Efficacy dropped to 46% by 18 months [
14], and to 28% after four years of follow-up. Receiving a booster vac- cine 18 months after the initial three-shot series increased the vac- cine’s efficacy to 36% at the four-year mark [
15]. Benefits were weaker in infants (6-12 weeks of age), where efficacy was 30% at 12 months, 27% at 18 months, and 18% after four years [
16].
In a subsequent study of pilot programs introducing RTS,S as part of national immunization programs in Ghana, Kenya, and Malawi [
17], more than 500 000 children received the vaccine from 2019 to 2023, with an intended schedule of three doses between ages 5-9 months and a fourth around 2 years or age. Overall, the study’s results confirmed the vaccine’s safety and associated its availability with a 32% reduction in hospitalizations for severe malaria and a 13% reduction in all-cause mortality [
17,
18].
Meanwhile, researchers at the University of Oxford and the Serum Institute of India developed a second vaccine, R21 (brand name R21/Matrix-M), using the same CSP-HBsAg fusion construct as in RTS,S, but with a different fragment containing a higher pro- portion of surface CSP and a different adjuvant. R21 has not been compared head-to-head with RTS,S, but a randomized phase 3 trial enrolling almost 5 000 children aged 5-36 months tested R21 at five sites in four African countries. The five sites included three standard sites with malaria transmission occurring throughout the year and two seasonal sites where most malaria illness and deaths occur dur- ing the rainy season and children under 5 receive chemoprevention during peak transmission periods. In this licensure trial, 3103 chil- dren received three doses of R21, four weeks apart, with a booster 12 months after the third dose. For the first 12 months after the third dose, vaccine efficacy was 67% at standard sites and 75% at sea- sonal sites [
19]. Based on these results, the R21 vaccine gained its WHO recommendation in October 2023 [
8]. As of early April 2025, 19 countries had introduced one or both malaria vaccines as part of their malaria control efforts [
20].
Getting vaccines to high-need but low-resource areas has pri- marily relied on funding from Gavi, the Vaccine Alliance (Geneva, Switzerland), a global health organization founded in 2000 that claims having helped immunize more than a billion children for potentially serious diseases including measles, polio, and now, malaria [
21]. As negotiated for Gavi by the United Nations Chil- dren’s Fund (UNICEF) in April 2023, per-dose prices for RTS,S and
R21 were ∼10 and 3.90 USD, respectively; Gavi subsidies further lowered the price of both vaccines to 0.20 USD for the poorest
countries, making delivery most of the cost of malaria vaccine pro- grams, not the vaccine itself [
22]. In March 2025, however, the Trump administration announced that the US government—Gavi’s third largest donor, behind the United Kingdom and the Gates Foundation (Seattle, WA, USA)—would end its financial support of Gavi. According to one news report, the United States has provided 13% of Gavi’s funding, including a grant worth 2.53 billion USD through the year 2030 [
23].
The Gates Foundation malaria vaccine approach remains unchanged, said Christian Ockenhouse, senior program officer for the foundation’s malaria efforts. “Our vaccine strategy is robust and will continue to pursue multiple avenues,” he said. According to Ockenhouse, these efforts include developing second-generation vaccines that ① use improved versions of CSP to boost the magni- tude and function of elicited antibodies, ② combine CSP with blood-stage antigens such as Rh5 (a merozoite-stage protein needed for the parasite’s invasion into the host red blood cell), and ③ include other antigens from multiple stages of the malaria parasite life cycle.
The biotech company Sanaria (Rockland, MD, USA) has built on the Netherlands team’s mosquito-bite approach and taken it a step further—purifying and cryopreserving the whole sporozoites for delivery into human volunteers by syringe. The company said it plans to test this new whole sporozoite vaccine in clinical trials in the United States, Germany, and Burkina Faso in 2025, with results expected within the next three years [
24].
Despite the availability of the new vaccines and now faced with malaria’s rising incidence and decreased funding, malaria experts stress the need to wisely deploy existing measures. “We need to keep investing in those tools of the future,” said Cohen, “but we also have to figure out how to save the most lives we can with what we have on the table today.”
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