Plasmodium parasites are as stealthy as pathogens come. The malaria-causing single-celled organisms have been adapting to the human lineage for longer than our species has existed, giving them millions of years of training in evading our immune systems and—until recently—an unshakable advantage over vaccine developers.
While SARS-CoV-2, the virus that causes COVID-19, only has 29 proteins, Plasmodium species have thousands. SARS-CoV-2’s spike protein, which it uses to invade human cells, is an obvious bullseye for vaccines, but Plasmodium is a moving target. After mosquitoes inject Plasmodium sporozoites into the bloodstream, the parasites hide away and multiply in liver cells, from which they emerge as bloodborne merozoites, which commence fever-inducing invasions of red blood cells. Some of the parasites shapeshift yet again and are picked up through mosquito bites. For each life stage, Plasmodium transforms its cloak of proteins—a challenge to vaccinologists. Many vaccine efforts have failed in the past.
All of this makes the official endorsement by the World Health Organization (WHO) of a vaccine against the deadliest human parasite, Plasmodium falciparum, the more impressive. On October 8, the WHO formally recommended broader use of the RTS,S, or Mosquirix, vaccine among children in sub-Saharan Africa and other areas of intense P. falciparum transmission. The decision paves the way for official approval as well as implementation and funding decisions around a wider vaccine rollout, which many hope could make a dent in the more than 400,000 annual deaths from malaria, most of which occur in kids under five. “The long-awaited malaria vaccine for children is a breakthrough for science, child health, and malaria control,” WHO director-general Tedros Adhanom Ghebreyesus says in a statement.
Yet the RTS,S vaccine has several flaws, chief among them its underwhelming efficacy—it prevents only around 30 percent of severe malaria cases in children under five. In addition, the studies underlying the WHO’s decision have drawn criticism in the past over ethical and possible safety issues, which some experts still say warrant further research. Nevertheless, many scientists express support for the WHO’s decision, not least because it opens the door for potentially more-effective vaccines.
“I think the WHO made the right call,” says epidemiologist James Tibenderana, the global technical director of the London-based Malaria Consortium. “All of us hope that the recommendation will help to reignite the research and development in malaria vaccines.”
The trials and tribulations of RTS,S
Development of the RTS,S vaccine began more than three decades ago at pharmaceutical company GlaxoSmithKline and the Walter Reed Army Institute of Research. Scientists aimed to induce antibodies against a piece of P. falciparum’s circumsporozoite protein, which coats the parasite’s initial sporozoite form. In addition to that peptide, the RTS,S vaccine uses components of a hepatitis B vaccine to provoke a strong antibody response. Very high antibody levels are needed to stall P. falciparum before it rushes to the liver, notes vaccinologist Adrian Hill of the University of Oxford’s Jenner Institute, who wasn’t involved in developing RTS,S. “We’re talking about something probably ten times higher . . . [than] levels that would protect you against COVID.”
In the early 2000s, RTS,S became the first malaria vaccine to be tested in large clinical studies, led by GlaxoSmithKline and the Gates Foundation–funded PATH Malaria Vaccine Initiative. Following a promising Phase 2 trial, a Phase 3 study in 2009 enrolled nearly 15,500 children aged between 6 and 12 weeks or between 5 and 17 months in seven sub-Saharan African countries. Participants were selected at random to receive three doses of the RTS,S vaccine or a control vaccine, each a month apart—with some receiving a fourth dose 20 months after the first. Within three to four years after the first dose, it was apparent that the vaccine’s efficacy was higher in the older group, and that four doses were better than three: with four doses, clinical malaria cases in children and infants were reduced by 36 and 26 percent, respectively, relative to controls.
“It doesn’t really prevent infection very effectively,” says malaria epidemiologist Philip Bejon, who directs the Wellcome-KEMRI-Oxford Collaborative Research Program in Kenya and is part of a team helping to evaluate later studies of RTS,S. But “if you have, say, three episodes where you’re unwell and seek treatment, that is preferable to having six episodes.”
Importantly, vaccine efficacy waned over time (the 36 percent efficacy over several years in children was a decrease from more than 50 percent efficacy at one-year post-vaccination). And in an extended analysis of the Phase 2 study, which tracked three-dose recipients for seven years, Bejon and his colleagues observed that in certain areas, RTS,S-vaccinated children actually had a slightly higher risk of clinical malaria episodes than unvaccinated kids. That’s likely because they were shielded from dangerous infections at young ages and are thus left with less natural immunity—a so-called rebound effect that has also been observed in some children who became more prone to developing malaria episodes after they stopped taking antimalarial drugs. In Bejon’s observations, this effect partially offset the vaccine’s benefit, but “the extent to which it’s an offset depends a lot on how much transmission there is,” Bejon says: at seven years following vaccination, efficacy against clinical malaria was 16.6 percent in low-transmission areas and -2.5 percent in high-transmission areas.
“To be a five-year-old who’s immune to severe malaria—to be blunt about it—involves an exposure to malaria [at] age one to four that might have killed you,” Bejon says. “You might say, ‘well, the vaccine means that you’ve got a less immune five-year-old.’ Yes, but you’ve also got an alive five-year-old.” The trial was too small to assess whether vaccinated children who contract malaria later on will ultimately be better or worse off than if they contracted it sooner, but “we expect younger children to be more vulnerable to death from severe malaria,” Bejon notes.
In a positive sign, a longer follow-up of the Phase 3 study—in which some participants received a fourth dose—found no evidence for a rebound effect, except for at one high-transmission site in Burkina Faso. Even with a fourth dose, Bejon says, “immunity will eventually fall, and there will be a consequence to that. But overall, there clearly is a reduction in terms of numbers of malaria episodes.”
“I think one of the improvements that could be made to RTS,S is to give a dose every 12 months throughout childhood,” Hill says, but adds that supply constraints in vaccine manufacture could make that difficult.
Addressing safety and ethics concerns
In addition to the modest and waning efficacy offered by RTS,S, data from the Phase 3 study hinted at possible safety risks of the vaccine: a tenfold increase in meningitis cases and a doubling in rare but severe cerebral malaria in RTS,S recipients compared to controls. In an independent analysis of trial data, epidemiologist Christine Stabell Benn of the University of Southern Denmark calculated a 24 percent increase in overall mortality among vaccine recipients—though not statistically significant, a worrying observation, she says. “A vaccine that protects against a deadly disease should also be associated with a decrease in overall mortality.”
Benn and her colleagues speculated that the mortality increase could be driven by a phenomenon suggested by some previous research, namely, that vaccines that aren’t composed of live pathogens can somehow make females more susceptible to other illnesses. Indeed, a 2016 analysis by Benn and her colleagues, and a later follow-up by study investigators, found a statistically significant increased mortality in girls—but not boys—who had received the RTS,S vaccine compared with those who hadn’t. The evidence “suggests that if you are a girl, the vaccine may reduce your risk of malaria, but this benefit is offset by a negative non-specific effect . . . that leads to increased overall mortality,” Benn tweeted last year.
By the time of Benn’s analysis, the European Medicines Agency had already issued a positive scientific opinion for the RTS,S vaccine based on the Phase 3 efficacy data, and it later concluded that the increase in female mortality was likely due to chance—a conclusion the WHO supported. Still, the WHO determined that questions around safety as well as practical aspects of the vaccine rollout required more study, and the agency coordinated a closely monitored pilot rollout of the vaccine. Funded by several global health initiatives, the pilot study has delivered the RTS,S vaccine to some 800,000 children in Ghana, Kenya, and Malawi since it began in 2019.
The WHO’s October endorsement of RTS,S was based on the first two years of this four-year pilot study, during which children received the first three doses. With more statistical power than previous studies, the study found that the vaccine reduced hospitalizations due to severe malaria by 30 percent, with no uptick in meningitis or cerebral malaria. And the “increased mortality in girls of the [size] that was suggested based on the results of the Phase three, is now ruled out, by the two years of data that are available,” says Bejon. Overall, the data suggest fewer malaria-related deaths in vaccinated versus unvaccinated areas, and the pilot study will continue in order to better understand the precise mortality benefits as well as the value of a fourth dose.
You might say, ‘well, the vaccine means that you’ve got a less immune five-year-old.’ Yes, but you’ve also got an alive five-year-old.—Philip Bejon, Wellcome-KEMRI-Oxford Collaborative Research Program
Benn, however, isn’t reassured. She considers it premature to draw conclusions, especially given that her calculations from trial data suggesting that the effects on cerebral malaria and female mortality was more pronounced after the booster dose at 20 months. By shortening the follow-up to two years, we “have zoomed in on this period with maximum benefits against malaria and minimum harms in terms of female mortality,” she says.
She and her colleagues expressed this and other concerns in a 2020 article in the British Medical Journal (BMJ). In addition, she notes that the study only broadly compared areas in which RTS,S had been rolled out versus areas in which it hadn’t, without following individual children. Particularly frustratingly to her is that it’s now difficult to test the vaccine more rigorously, she notes, as it’s considered unethical to deprive study participants of recommended vaccines. “I feel uncomfortable with giving that green signal as long as we still have a danger signal, which in my view has not been contradicted by the pilot implementation studies, simply because the study quality is so much lower than the Phase three trial,” she adds. “I think there is a moral obligation to investigate this properly.” (The WHO didn’t immediately respond to The Scientist’s questions regarding these concerns.)
Bioethicist Charles Weijer of Western University in Canada has also raised concerns about the implementation program. In what he sees as “a serious breach of international ethical standards,” the pilot rollout didn’t follow accepted ethical guidelines for these kinds of trials, which he helped write, he told the BMJ last year. The article states that it is unclear to what extent parents were informed about the safety concerns raised in the Phase 3 trial, and study participants weren’t informed that they were partaking in research. A WHO spokesperson remarked to the BMJ that because the study is merely a “pilot introduction,” rather than a “research activity,” it was sufficient to obtain “implied consent,” by providing information about the vaccine to parents through community outreach, health talks, and letters, and giving parents the option to vaccinate their children or not.
Several national and international health and ethics authorities reviewed and approved the protocols for the study and its evaluation, which were used to train healthcare workers involved in vaccinations, notes Samuel Harrison, a clinical epidemiologist and fellow at the Kintampo Health Research Center in Ghana, which is involved in the evaluation of the pilot study. As part of surveillance for adverse events during the implementation study, he and his colleagues haven’t observed any life-threatening side effects: “it’s very similar to other routine vaccines, basically some fever, some local reaction in terms of swelling.”
A new era of malaria control
With the WHO’s recommendation of widespread use of RTS,S, it’s up to African countries to formally adopt it into policy and license it with relevant authorities, and decide whether or not to conduct their own additional research before doing so, Tibenderana says. “To me, the earlier the better,” Harrison says of rolling out the vaccine. “I’ve seen malaria firsthand; I’ve seen children die of malaria. For me, even if the efficacy is 10 percent, it is significant .” One study estimated RTS,S could prevent around 23,000 child deaths annually if four doses are administered to all children in areas with a high malaria incidence, Nature reports. The vaccine could be a gamechanger, especially in light of the stagnation in numbers of malaria cases in Africa over the past five years despite interventions such as insecticides and antimalarials, Harrison says. “It’s a powerful additional tool that can complement existing interventions.”
And there are ways of improving the effectiveness of RTS,S, Tibenderana notes. A randomized controlled trial in Burkina Faso and Mali found that over three years, the vaccine could reduce children’s risk of clinical malaria by 60 percent, severe malaria by 71 percent, and death from the disease by 75 percent if administered in combination with antimalarial drugs and if the initial set of three doses and two subsequent doses are each timed such that they’re given just before the rainy season when malaria intensifies, according to results published in September.
—Samuel Harrison, Kintampo Health Research Center
Even if efficacy can be boosted, there are still challenges to ensuring RTS,S’s success, including vaccine hesitancy and misinformation, Harrison notes. Another key factor is money, Tibenderana adds; new funds are necessary for purchasing and distributing the vaccine, such that countries aren’t dipping into already constrained funds for other malaria control and elimination methods. Hill also points to challenges in the vaccine’s supply. While GlaxoSmithKline recently pledged to make 15 million annual doses at low cost, a modeling study estimated that around 100 million doses a year will be required to reach all children in high-transmission areas. “That’s kind of disappointing after 30 years of vaccine development—that you hopefully get the first licensed vaccine in 2022, 2023, and there isn’t enough of it by a factor of ten,” Hill says. In addition, there’s a limited supply of the key adjuvant required for its efficacy—called AS01—which is made from the bark of a South American tree and is also in demand for other vaccines.
Fortunately, there are other vaccine candidates on the horizon. In a recent Phase 2b, randomized trial, children aged 5 to 17 months in Burkina Faso who received four doses of the new R21 vaccine just before the rainy season had a record-setting 77 percent reduction in clinical malaria cases in the year following the vaccinations compared with controls. R21 uses an adjuvant called Matrix-M, which is easier to synthesize than AS01, says Hill, who helped develop R21. Oxford University, the vaccine company Novavax, and India’s Serum Institute have pledged to produce 200 million annual doses of R21 if and when regulators approve it, according to Nature. Other vaccines are under development to target different Plasmodium life stages, which Hill and others ultimately hope to combine into a multistage vaccine. “I think a reasonable target for 2040 is near-complete eradication” of malaria, he says.
The success of future vaccines ultimately boils down to financing, Tibenderana says; malaria vaccine research is woefully underfunded. To be successful, this new era of malaria control will require malaria-endemic countries to come up with new mechanisms of financing vaccine research, testing, and administration, he says. “As a global community, if malaria elimination is a good thing for the world—like we’re doing with polio—then the collective efforts to eliminate malaria from all these countries should be [considered] a global good.”