At last, a malaria vaccine has passed important clinical trials

Every second, seven people somewhere on Earth encounter one of humankind’s most prolific killers: a shape-shifting parasite carried in the saliva of female mosquitoes that can evade our immune systems and live in our livers and blood cells. Every two minutes, the parasite claims another victim under the age of five years old—and brings another round of heartbreak and loss. This grim cycle plays out very hour, every day, every week, every year.

For more than a decade, Halidou Tinto has squared off against this killer. Tinto, an epidemiologist, expert on malaria, and a regional director of Burkina Faso’s Institute of Research in Health Sciences, serves the district of Nanoro, some 50 miles northwest of the capital Ouagadougou. With the arrival of the African monsoon each summer, malaria cases spike in Nanoro and communities across the country. Burkina Faso, a country of 20 million, records about 11 million malaria cases a year—as well as 4,000 deaths.

But after months of speaking with local families about participating in a new malaria vaccine trial, years of experience with running medical trials in the area, and decades of global research behind him, Tinto’s site in Nanoro is home to something else: hope.

In a study published in The Lancet on Wednesday, an international team has shared promising new data on a potential vaccine. The phase two trial, based on 450 children in Nanoro, evaluated the R21 malaria vaccine candidate, which has been under development in the United Kingdom for more than a decade. Researchers found that after children received three shots in an eight-week period and a booster 12 months later, the R21 vaccine was 77 percent effective at stopping malaria, when compared against a control rabies vaccine, rather than a standard placebo.

R21 is the first vaccine candidate for malaria to cross the 75 percent threshold, a goal the World Health Organization (WHO) first set in 2013. If borne out in bigger trials, R21 could add another powerful tool to the world’s malaria-fighting toolkit.

“We are enthusiastic, but we still need phase three trials to confirm the efficacy and the safety of the vaccine before we move on,” says Tinto, one of the study’s senior authors.

A complex parasite

The stakes are high. In 2019, the world saw an estimated 229 million cases of malaria, which killed some 409,000 people—two thirds of whom were young children.

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 in recent years, progress has stalled. But between 2015 and 2020 cases declined by less than two percent.

To make meaningful progress once again, the WHO is eager to introduce a malaria vaccine into the mix. More than 140 different malaria vaccine candidates are in development. For now, none are formally approved.

Making a malaria vaccine is extremely difficult, in part because this disease is complex. 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 rattling around inside the coronavirus that causes COVID-19. “There’s a lot of interest and a lot of excitement around vaccines at the moment, because of COVID-19 … but obviously, we’re targeting something quite different,” says lead study author Mehreen Datoo, a physician and doctoral candidate at Oxford’s Jenner Institute who is helping lead R21’s clinical development.

Unlike bacteria and viruses, parasites such as Plasmodium go through several life stages in the human body, which makes designing vaccines for them even harder. As a female mosquito sticks its proboscis into a person’s skin for a blood meal, Plasmodium parasites in the mosquito’s saliva can be transferred into the person’s bloodstream. Within half an hour, these parasites leave the bloodstream and set up shop in the liver, where they multiply by the thousands.

Next, the parasites return to the bloodstream, where they multiply rapidly in a vicious cycle: entering a red blood cell, replicating inside it, and then bursting the infected cell. Some of these parasites mature further, and once inside a mosquito that happens to drink the infected person’s blood, these Plasmodium work their way through the wall of the bug’s gut and enter its salivary glands—beginning the cycle anew.

At each point in the human body, Plasmodium multiplies, which means that the best way to cut off an infection is to stop it early, preferably before it starts infecting red blood cells. But how?

Engineering the new vaccine

For decades, researchers have focused on the Plasmodium life stage that first enters the human bloodstream, which is called a sporozoite. In 1983, researchers found that sporozoites are covered in a protein that provokes a strong response from the immune system. In 1987, researchers at the U.S. pharmaceutical company GlaxoSmithKline developed a test malaria vaccine based on this protein, which is called circumsporozoite protein, or CSP.

GlaxoSmithKline’s idea was to engineer carrier proteins that would contain bits of CSP and self-assemble into microscopic spherical blobs—technically called “virus-like particles”—that could then be injected into the human body, where they would trigger an immune response. If pathogens coated in the same protein later appeared, the immune system would show up ready to rumble. This technique is already used to make vaccines today. If you’ve been vaccinated for human papillomavirus (HPV) or hepatitis B, you’ve received a vaccine based on a virus-like particle.

In malaria’s case, researchers attached a snippet of CSP onto a protein plucked from the surface of the hepatitis B virus, which researchers already knew clumped together into spherical particles. When these proteins are made en masse in engineered yeast, they glom together into particles studded with bits of Plasmodium protein that encourage the body to make antibodies against CSP.

This vaccine, called RTS,S, is the single most tested vaccine candidate for malaria. (It’s produced commercially by GlaxoSmithKline under the name Mosquirix.) For the better part of three decades, researchers, philanthropies including the Gates Foundation, and GlaxoSmithKline have tried to get RTS,S off the ground. Trials have shown it to be safe, and in 2015, the European Medicines Agency gave it a positive recommendation, but not approval (primarily because it’s not being marketed in the EU). Since 2019, RTS,S has been given to more than 650,000 children in Ghana, Kenya, and Malawi, through pilot programs supported by the WHO.

Trials of RTS,S showed that in high-transmission areas where children can come down with malaria upwards of six times a year, the vaccine prevented some 4,500 cases of malaria for every 1,000 children vaccinated. Models suggest that for every 200 children given RTS,S, one child’s life will be saved.

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,” says WHO epidemiologist Mary Hamel, who manages the organization’s Malaria Vaccine Implementation Program. “This is something you could add on top.”

But relative to other vaccines—such as the astoundingly effective COVID-19 vaccines—RTS,S is a modest performer. Trials found that in the first year after vaccination, for every nine unvaccinated people who got malaria, four vaccinated people did, translating to an efficacy of roughly 55 percent. Four years post-vaccination, efficacy dropped to roughly 36 percent.

The WHO recognized that a more effective vaccine could save more 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.

Enter R21, the vaccine candidate in the Burkina Faso trial. R21 works similarly to RTS,S: attach a bit of Plasmodium protein to a hepatitis B protein, and make a spherical particle that stimulates the immune system.

But thanks to improvements in vaccine manufacturing techniques, R21’s particle is more efficient. As it turns out, there’s less Plasmodium protein on the outside of the RTS,S particle than there theoretically could be. For every hepatitis B protein that has a snippet of Plasmodium CSP, four do not. In R21, however, every protein has a Plasmodium snippet—giving the surface of its virus-like particle many more sites for antibodies to recognize and bind.

Lab studies of R21 began at Oxford from 2010 to 2012, and early “challenge” trials of the vaccine began several years later, with healthy volunteers in Oxford, London, and Southampton, U.K., who agreed to be infected with malaria to test the vaccine’s safety. These early results were promising enough to get the Serum Institute of India, one of the world’s biggest vaccine manufacturers, involved. In 2018, the institute licensed the vaccine from Oxford, agreeing to produce 200 to 300 million doses of R21 per year if it was formally registered.

Two years later, in May 2019, the bigger 450-person phase two trial in Burkina Faso began, in a health district centered on Nanoro. Tinto and his colleagues were extremely well-prepared: They had administered one of the trial sites for the RTS,S vaccine.

Fighting a neglected disease

Hamel, the WHO epidemiologist, lauded the R21 results. But like the study’s coauthors, she urged caution until after the 4,800-person phase three trials, which are starting in five sites in Burkina Faso, Kenya, Mali, and Tanzania. According to Tinto, results are likely in late 2023 or early 2024. Datoo adds that the R21 team could start the approvals process as soon as late 2022, if African legislators consider giving the vaccine emergency authorizations like those issued for COVID-19 vaccines.

One key question is how well the R21 vaccine protects against malaria under different transmission settings. In Burkina Faso, malaria cases spike in the country’s wet season, which lasts from June to November. In other parts of Africa, transmission persists year-round. In the R21 trial, researchers intentionally timed the three doses—which are each administered four weeks apart—to come right before the upswing of Burkina Faso’s wet season, to synchronize the high antibody levels triggered by the vaccine with the peak of malaria season.

For Hamel, the past two years—even with all the challenges of COVID-19—have shown just how effective vaccines might be against malaria. The WHO-backed pilot programs for the RTS,S vaccine are still on track, despite the pandemic’s disruptions to local health care systems. What’s more, broader studies of childhood vaccination programs in Africa have shown that among households where children don’t regularly sleep under bed nets, some 70 percent of children are vaccinated. If a malaria vaccine were deployed at scale and given alongside other childhood vaccinations, large numbers of children who currently can’t access other malaria interventions would at least have a malaria vaccine’s protection.

COVID-19 has also underscored just how much progress can be made when the global community acts with urgency to address a medical crisis. Hamel wishes that sense of urgency—and the resulting funds and logistical support—were there for malaria, too. “I think the biggest roadblock is complacency,” she says. “If this year was the first year that there were 265,000 deaths of children under five from malaria, we’d say it’s an emergency, and we’d get on top of it. But we’ve become accustomed to it.”

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