A new, powerful malaria vaccine may be on the horizon

In Burkina Faso, the months of May through September bring buckets of rain and, with it, the mosquitoes that spread malaria. Burkina Faso is one of the sub-Saharan countries in Africa where the disease is so entrenched that malaria is part of the vernacular.

“Everywhere, even in the villages, they talk about palu,” says Halidou Tinto, who leads clinical trials of malaria vaccines in the former French colony. “Malaria” in French is paludisme. “In my mother tongue (Moré), they call malaria ‘the bush disease,’ ” he says.

Globally, about 200 million people per year, in recent years, have contracted malaria. In 2019, about 400,000 people, 94% of whom were in Africa, died from the disease. In Burkina Faso, Tinto says, half its population of 20 million was infected in 2020. Babies and toddlers account for most of the malaria deaths in Africa. Their immune systems have little to no experience against Plasmodium falciparum, the parasite that mosquitoes inject when they bite.

While many sub-Saharan countries make malaria treatments free or low cost, distribute mosquito nets, and are even considering using genetically modified mosquitoes to reduce the insect’s population, people also want powerful vaccines that can prevent infection in the first place.

But developing a potent malaria vaccine has been a decades-long struggle. The only vaccine in use, a multidose shot called RTS,S, is up to 50% effective in the first year or so. That immunity wanes to about 28% over time. The vaccine, developed by GlaxoSmithKline and sold as Mosquirix, also comes with a troubling side effect: about 5% of the children in clinical trials had febrile seizures. Still, in 2015, the European Medicines Agency gave the vaccine a positive scientific opinion, which is an approval for something that won’t be used in the European Union. The World Health Organization began using it in Ghana, Malawi, and Kenya. Akpaka Kalu, the team leader of the WHO’s tropical and vector-borne diseases program in Africa, says in countries like Kenya, the disease is a year-round threat.

Fifty percent efficacy may seem low, but Tinto and Kalu say it’s good for now. It still saves thousands of children every year. But to truly create the malaria-free Africa that Kalu wants, he and other experts say that more than one vaccine is needed. More effective vaccines are also needed.

A more effective vaccine could come in the form of the University of Oxford’s R21, now in Phase 3 trials. In May, a multinational team led by Tinto and Oxford vaccine expert Adrian Hill reported promising Phase 2 results: 77% of the approximately 400 babies and young toddlers in Burkina Faso who received the three-dose regimen were protected against disease after 1 year, The control group received a rabies vaccine instead. This makes R21 the first malaria vaccine to meet the WHO’s goal, set in 2015, of 75% efficacy.

More than 100 malaria vaccines have been tested over the years, Hill says. None have had such high efficacy. At the end of July, Tinto’s team gave the final dose of a three-dose regimen to a group of 1,200 children in Nanoro, Burkina Faso. An additional 3,600 children are participating in Mali, Kenya, Tanzania, and another part of Burkina Faso. The 4,800 children will all get a booster shot next year. The question is now, in a larger trial with a wider age range, will the vaccine’s efficacy hold up?

While waiting for the answer, Hill is working on how to get the vaccine to those who need it. He has already secured an agreement with the global vaccine manufacturer Serum Institute of India to make 200 million doses of the vaccine per year. He hopes those doses can be sold for less than $5 apiece.

“That’s affordable when you remember that $2.5 billion is being spent this year on malaria control,” he says.

Whatever the efficacy, Kalu emphasizes how eagerly R21 is anticipated. His childhood was marred by malaria. He had it. He suspects his sister and brother died of the disease. When it was time to go to boarding school, Kalu’s father handed him spending money. He also gave his son malaria medications.

“If we have 10 efficacious vaccines, we will implement 10 of them,” Kalu says. “Any vaccine, just give me the vaccine. It’s my job to get children vaccinated provided it is efficacious and safe. That includes R21.”

The long road to a malaria vaccine

Tinto says that in his efforts to recruit families for malaria vaccine trials, he often hears, “Why is a vaccine taking so long?”

It’s a hard question, says Jill Weatherhead, a parasitologist at Baylor College of Medicine who has not been involved in trials of R21 or RTS,S. Some of the time lag boils down to biology. Some of it is technology. Some of it is human motivation.

Multiple Plasmodium species cause malaria, including P. falciparum, which is most prevalent in Africa, and P. vivax, prevalent in parts of Asia and Latin America. P. vivax is one of the two known Plasmodium species that can hide in the liver, popping up periodically to cause illness long after that first infectious mosquito bite.

Plasmodium species are complex, multicellular creatures with thousands of genes that are active or silent as the parasites morph from one life stage to another. By contrast, SARS-CoV-2, the virus that causes COVID-19, is made up of roughly 30 genes.

“Up until RTS,S, we’d never had a parasite vaccine. Ever,” Weatherhead says. “The reason is because of the complexity of these life cycles.”

Developing a good malaria vaccine requires several things, Weatherhead says. The vaccine must prompt the immune system to recognize the right bit of protein at the right time in the parasite’s life cycle. And for a pathogen that can evade the human immune response through genetic chicanery and basic hide-and-seek, you have to prove that your vaccine is protective: When a vaccinated person is confronted with the parasite year after year, can they fight the parasite off? Researchers have tried to develop vaccines that prompt the immune system to attack nearly every phase of the parasite’s life cycle. Hill says that in the process, they’ve learned that vaccines work best when focused on the sporozoite life stage, the form Plasmodium species are in when they enter humans from a mosquito bite. Once inside the human body, the parasite travels within minutes to an hour to the liver, creating a dauntingly short window for an infection-preventing immune response, Hill says.

RTS,S, which took about 10 years to develop, was funded in part by the Bill and Melinda Gates Foundation and the global health nonprofit Path (formerly known as the Program for Appropriate Technology in Health). RTS,S is an engineered protein that features two parts of the circumsporozoite protein from P. falciparum fused to the Hepatitis B surface antigen (HBsAg). GlaxoSmithKline uses this same antigen to formulate its hepatitis B vaccine. The genetic instructions to make the engineered protein are inserted into yeast that grows with untethered HBsAg protein. When the yeast cells are popped, the engineered protein that was made inside them gloms on to lipids and the free HBsAg, forming what are called viruslike particles.

Those particles are delivered with an adjuvant called Adjuvant System 01 (AS01), which boosts the immune response and is made by GSK. As part of the company’s plan to continue to supply the vaccine, Bharat Biotech will soon be making the adjuvant, according to a GSK spokesperson.

R21, which took Hill’s team about 10 years to develop and get to late-stage studies, is similar to its cousin but has some key differences. The newer vaccine involves prompting yeast to generate the same sections of the circumsporozoite gene fused to HBsAg. It’s also grown in yeast, but without the free-floating HBsAg. That protein is packaged in a nanoparticle called Matrix-M—the same adjuvant used in Novavax’s COVID-19 vaccine. Matrix-M is part saponin, part cholesterol, and part phospholipid.

Hill says these differences are likely what’s boosting the efficacy compared with RTS,S.

“It looks like R21 is more protective,” Hill says. “It looks like it’s safer.”

Testing malaria vaccines is as challenging as developing them. Depending on the part of Africa, trial coordinators have to wait for the rainy season to test their vaccines. The R21 trials also include a booster after 1 year. And Tinto says recruiting for a vaccine that people tell him they want still requires extensive groundwork.

To recruit his 1,200 families to participate in the R21 Phase 3 trial, Tinto and his team used their experience from participating in the RTS,S trials. They held information sessions for parents, spent time busting myths, and worked with both community and religious leaders to explain the role of this vaccine. Kalu and others say the long-term goal is to integrate malaria vaccines into the basic pediatric vaccine schedule.

Extra hurdles

But with all this effort, eradicating malaria doesn’t invoke the same political urgency as other public health crises, Weatherhead says.

She uses COVID-19 vaccines as an example. Billions of dollars were quickly allocated to developing these vaccines, and academic and industry scientists worked together to make them. The COVID-19 virus is far simpler than the malaria parasite, and once the products were made, trials went quickly, and regulatory agencies pushed to bring the vaccines to market.

Hill, who also co-led the team that made Oxford and AstraZeneca’s COVID-19 vaccine, says that in contrast, developing malaria vaccines has often been a start-and-stop process of hitting a milestone, asking for more funding, and waiting. R21 was funded by the Medical Research Council, Wellcome , the European Commission, the government-and-industry-based European and Developing Countries Clinical Trials Partnership, and most recently, the Serum Institute of India.

Malaria isn’t often found in wealthier nations, Hill says, so basic funding trickles in, and industry isn’t quick to get involved. Although COVID-19 vaccine maker BioNTech recently announced plans to put its messenger RNA platform to work on a malaria vaccine, in Hill’s long career, the only company that has entered the malaria vaccine race, let alone stayed the course, is GSK.

“No other drug company has made a substantial effort or even an effort, really, to be honest. You want to bring in big companies to deal with low-income disease vaccines,” Hill says, referring to malaria’s prevalence in developing nations, “and boy,” Hill says, “is it hard.”

But Hill acknowledges that no vaccine is going to rid the world of malaria. Plasmodium species thwart the human immune system by changing their proteins so that natural antibodies don’t recognize them anymore. It’s one of the reasons why people get infected over and over and why P. falciparum in one country or region might be slightly different, genetically, than the P. falciparum in another. That craftiness makes Tinto worried that the level of efficacy demonstrated in the Phase 2 trials in Burkina Faso might drop in a larger trial.

But the need for more and better malaria vaccines underscores the public health crisis that malaria is, says Kalu, the WHO leader. So many children die each year that it robs Africa of economic potential.

“This is what malaria can do,” he says. “It targets Africa’s future.”

All the pieces are in place to make and distribute R21, Hill says. He asks why, with the regulatory speed applied to COVID-19 vaccines, malaria vaccines can’t be treated with the same urgency.

“This is a [disease] killing more people in Africa than COVID,” Hill says. “All the COVID vaccines are getting an emergency use approval. Why wouldn’t a malaria vaccine with good efficacy get an emergency use approval? Nobody’s answering that question at the moment. But we’re certainly posing it.”