'Historic moment': Why the WHO endorsed the first malaria vaccine

For millions of people, malaria creates a grim drumbeat of death, heartbreak, and loss: Every seven seconds, someone gets a case of malaria, and every two minutes, the disease claims another victim under the age of five. That’s why public health experts rejoiced yesterday when the World Health Organization made a landmark decision to endorse the first vaccine against malaria.

Years of clinical trials have shown that this vaccine—known as RTS,S/AS01, or Mosquirix—is safe and helps protect against the disease, especially in concert with other malaria-fighting tools. With a 12-month efficacy of 56 percent, RTS,S lacks the eye-popping effectiveness of other modern vaccines. However, the vaccine’s target—the parasite Plasmodium falciparum—is orders of magnitude more complex than a virus.

“We have a number of things in our toolkit to fight malaria, and they’re all used together: bed nets, spraying, chemoprevention,” says Sean Murphy, a malaria vaccine developer at the University of Washington in Seattle. “This vaccine cannot replace all those tools.”

Also, the WHO recommendation doesn’t immediately usher in widespread use of RTS,S. Rather, it marks the beginning of the vaccine’s broader rollout and paves the way for individual African countries to issue their own approvals of the vaccine, with WHO assistance. Scaling up to the necessary tens of millions of annual doses will require billions of dollars of government and philanthropic donations to the international nonprofit GAVI, the Vaccine Alliance, which coordinates the financing of vaccination programs in developing countries.

But assuming the rollout begins soon, the benefits of this vaccine could be transformative at scale. In a study published last November in PLoS Medicine, researchers found that if 30 million doses of RTS,S were efficiently administered each year across subregions of 21 African countries, the vaccine could avert between 2.8 million and 6.8 million malaria cases each year—and save the lives of between 11,000 and 35,000 children under the age of five.

“I longed for the day that we would have an effective vaccine against this ancient and terrible disease,” Tedros Adhanom Ghebreyesus, the WHO’s director-general, said in a Wednesday press briefing. “Today is that day, a historic day.”

Designing the vaccine

In the past two decades, the world has made enormous progress toward curbing malaria thanks to widespread use of bed nets, rapid diagnosis, and the seasonal use of preventive antimalarial drugs. Between 2000 and 2015, with all of these interventions, the incidence of malaria cases among at-risk populations fell by 27 percent. But recently, progress has stalled. Between 2015 and 2020, cases declined by less than 2 percent.

In 2019, the world saw an estimated 229 million cases of malaria, 94 percent of which occurred in Africa. Millions of cases of malaria also occurred across Asia, the Middle East, and the Americas. In sum, these cases resulted in the deaths of some 409,000 people, two-thirds of whom were young children.

To drive meaningful progress against malaria once again, the WHO has been eager to introduce a malaria vaccine into the mix. More than 140 different malaria vaccine candidates are in development. Until RTS,S, none had won the WHO’s formal endorsement.

Making a malaria vaccine is extremely tricky because of the disease’s complexity. Most cases of malaria are caused by the parasite Plasmodium falciparum, whose genome contains more than 5,000 genes, far more than the mere 12 genes rattling around inside SARS-CoV-2, the coronavirus behind COVID-19. Further complicating matters, Plasmodium goes through multiple life stages as infections spread from the bloodstream into the liver and then back into the bloodstream, when the parasite infects red blood cells themselves.

“Viruses, certainly are very complex … [but] when you’re doing vaccine development, it’s very straightforward,” says Jason Kindrachuk, a virologist at the University of Manitoba in Winnipeg. With parasites, however, “we’re talking about organisms that are responsive to their surroundings and can change and adapt.”

“Why didn’t we have a vaccine sooner? It’s certainly not for a lack of trying,” he adds.

For decades, researchers have focused on the spore-like stage of Plasmodium—called a sporozoite—that first enters the human bloodstream and eventually wends its way to the liver. In 1983, researchers found that sporozoites are covered in a protein, called CSP, that provokes a strong immune response. In 1987, researchers at the U.S. pharmaceutical company GlaxoSmithKline and the U.S.’s Walter Reed Army Institute of Research decided to make a vaccine based on this protein.

The researchers’ idea was to engineer carrier proteins—in this case, a surface protein from the hepatitis B virus—that were studded with bits of CSP. These proteins would then self-assemble into microscopic blobs called “virus-like particles” that would trigger the immune system to make antibodies against CSP. That way, any Plasmodium sporozoites slathered in CSP would provoke an immediate immune response. (If you’ve been vaccinated for human papillomavirus (HPV) or hepatitis B, you’ve already received a vaccine based on a virus-like particle that’s customized to that particular pathogen.)

After a promising human “challenge” trial in 1996, researchers spent two decades building out clinical trials in African countries, publishing the key phase three trial results in 2015. The main reason for the lengthy process: safety. The target population for RTS,S is young children ages five to 18 months, but to prove the vaccine’s safety and efficacy, researchers had to start with adult clinical trials and work their way down to younger age groups.

“Some criticized the pace with which we did that, but we felt that, really, the safety of those kids and their vulnerability was such that we needed to proceed very, very carefully,” says Joe Cohen, who co-invented RTS,S while a researcher at GlaxoSmithKline.

Since 2019 more than 800,000 children in Ghana, Kenya, and Malawi have received at least one dose of the vaccine through a WHO pilot program. So far, the program has reported a 30-percent decrease in severe malaria cases among vaccinated children, on top of declines realized from other interventions such as bed nets.

Now Cohen is overjoyed to hear the WHO’s endorsement of the vaccine he helped guide through those decades of studies and trials. “I don’t know how to find the right words,” he says. “What a relief, and what an extraordinary thrill to know that the vaccine soon can be deployed widely and have a tremendous impact on public health in Africa.”

Layers of protection

Relative to the astoundingly effective COVID-19 vaccines and other routine vaccines, RTS,S may look like a modest performer. Phase three trials found that the shot had 56 percent efficacy among children between five and 17 months old in the first year after vaccination. When evaluated over four years, the vaccine’s efficacy dropped to roughly 36 percent.

WHO epidemiologist Mary Hamel, who manages the organization’s Malaria Vaccine Implementation Program, emphasized in a May interview that RTS,S does enough to make a difference in the fight against malaria. “To put this in perspective, [RTS,S has] about the same efficacy as the efficacy of a bed net, and we’ve seen the dramatic decline in malaria morbidity and mortality with bed nets,” she said. “This is something you could add on top.”

That additive benefit could be substantial. In a study published last month in the New England Journal of Medicine, researchers led by Daniel Chandramohan of the London School of Hygiene and Tropical Medicine found that combining RTS,S and preventive antimalarial drugs could reduce children’s risk of severe malaria by 70 percent.

The WHO pilot program has also found that more than two-thirds of children in Ghana, Kenya, and Malawi who are not sleeping under a bednet are benefiting from the RTS,S vaccine. If given alongside other childhood vaccinations, large numbers of children who currently can’t access other malaria interventions would at least have the protection of RTS,S.

When considering malaria’s lifelong effects on children’s physical and cognitive development, the vaccine’s benefits accrue all the more, adds Alejandro Cravioto, the chair of the WHO’s Strategic Advisory Group of Experts on Immunization. “A child that is repetitively sick is maimed for life,” Cravioto said in the Wednesday briefing. “In that sense, having anything that protects them, or helps them to be less sick during this growth phase, is essential.”

Rolling out the vaccine

Kate O’Brien, director of the WHO’s department of immunization, vaccines, and biologicals, said in the Wednesday briefing that GAVI will deliberate in early December over how much to invest in RTS,S. So far, GAVI and partner organizations have committed nearly $70 million to the WHO pilot program of RTS,S, which has administered 2.3 million doses so far.

In a statement, GlaxoSmithKline committed to supplying up to 15 million doses of RTS,S each year if funding and recommendations for the vaccine’s wider use fell into place. The company is also working to transfer production of the vaccine to the Indian company Bharat Biotech, which the Wall Street Journal reports would happen by 2028. GlaxoSmithKline also committed to selling the vaccines at no more than 5 percent higher than the cost of production.

Also on the table for discussion are dosing regimens. While the WHO pilot project has gone fairly smoothly so far, especially considering the added challenges of COVID-19, the vaccine is currently given in a four-dose regimen: three shots in three months, beginning at five months of age, and then a fourth booster shot at roughly 18 months old. In the WHO briefing, O’Brien added that the fourth booster’s necessity is still being evaluated.

In the long term RTS,S almost certainly won’t be the last malaria vaccine to win the WHO’s formal recommendation. The WHO has recognized that vaccines with even higher efficacies than RTS,S would save additional lives, so it set an audacious goal in 2013. By 2030, the health agency proclaimed, it wanted to see a 75-percent effective malaria vaccine.

A next-generation update to RTS,S, called R21, may be the first to claim that title. Lab studies of R21 began at Oxford from 2010 to 2012, and in 2019, researchers had worked up to a 450-person phase two trial in Burkina Faso’s Nanoro health district—which found that R21 had a remarkable 77-percent efficacy. Other vaccines are in development, including some based on harmless “attenuated” Plasmodium parasites that are administered via IV.

Though many steps remain in rolling out RTS,S and other malaria vaccines, world health officials are keeping their gazes on one thing above all else: a bright glimmer of hope.

“We still have a very long road to travel, but this is a long stride down that road,” Ghebreyesus said. “This vaccine is a gift to the world.”