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Vaccination has worked wonders to drive down deaths from infectious disease. A few hundred years ago, less than 60 percent of children saw their fifth birthday. Now, 95 percent do. Vaccines — against smallpox, measles, polio, diphtheria, and more — have driven that progress.
But one of childhood’s biggest killers — malaria — has eluded effective vaccination. That, at long last, looks to be changing.
In a recently concluded clinical trial conducted by researchers from Oxford and the Clinical Research Unit of Nanoro, Burkina Faso, a new malaria vaccine called R21/MM demonstrated 77 percent efficacy in children in Burkina Faso. That’s a dramatic increase over the efficacy of the only currently available malaria vaccine, RTS,S, and might represent a huge breakthrough in the fight against the disease.
Malaria infects hundreds of millions of people every year and kills hundreds of thousands, mostly young children and pregnant women. It has been one of the top killers of children for thousands of years, and still is today. For most of history, it ravaged warm regions the world over. But in the 20th century, it was successfully eradicated from much of the world through insecticide spraying. In sub-Saharan Africa, though, it has remained a major threat — and climate change means that the geographic range the malaria-carrying mosquito can survive in has expanded.
Unsurprisingly, a malaria vaccine has been a major priority for researchers. But malaria has proven absurdly difficult to vaccinate against. It’s caused by a parasite, not a bacterium or virus, and the parasite’s functioning in the body includes suppressing the immune response. For many diseases, infection leaves you immune for life, but it’s possible to catch malaria over and over again. And for many diseases, a vaccine just involves exposing the body to a dead or attenuated version of the disease agent. But that doesn’t really get results with malaria.
Fortunately, vaccine science has been rapidly advancing, and these days we can do far more than simple exposure vaccines. While the R21/MM vaccine doesn’t use the specific technologies that led to an unprecedented vaccine against Covid-19, it’s part of the same overarching story: Scientists are getting better at designing highly effective vaccinations, and their triumphs will be a huge part of the fight against death and illness in the 21st century.
Why it’s hard to vaccinate against malaria
The Plasmodium parasite that causes malaria in humans needs both blood-sucking insects and humans for its life cycle. It grows inside a mosquito and is transferred to a human host when the mosquito bites them. Then the parasite migrates to the liver, replicates itself, and infects the blood — where it can be taken up by the bite of another mosquito.
When the parasite is in the blood, it causes fever, chills, and flu-like illness. Healthy adults usually recover, but those with a weaker immune system — especially young children and pregnant women — can easily die. (Older people who live in regions where malaria is endemic are, surprisingly, not especially vulnerable. The theory is that after sufficient exposure to malaria over a lifetime, the immune system develops a general anti-parasite response that might be more durable than malaria-specific immunity.)
Vaccinating against malaria is tricky. Parasites have much more going on than viruses, making targeting a vaccine harder. Multiple life stages have been explored as vaccine targets, mostly without success. “Malaria vaccine [development] has been a graveyard for really great ideas,” Derek Lowe, a researcher who writes about drug discovery, told me. “We’ve learned about a lot of stuff that doesn’t work.” Targeting the parasite once it’s in the blood, for example, has been tried repeatedly but never succeeded. Exposing the body to dead or neutralized Plasmodium? A dead end. Researchers have been working on this for decades, and progress has been rare.
The earliest success stories of vaccination involved vaccines against diseases that produce lifelong immunity, like smallpox and polio. Those are viruses, so they’re much simpler to target. And since you can’t be reinfected with those diseases, the vaccine only needs to provoke the same immune response as the disease did originally, and the patient is safe for life.
But in the case of malaria, naturally acquired immunity against malaria typically is only partial and fades out in a few years. Researchers have been working for decades to figure out how a vaccine can induce durable immunity, and most of that work has ended in frustrating failures. The only vaccine approved for malaria today, RTS,S, has been around since 2016. While it’s much better than nothing, it’s not great — it has an initial efficacy of around 55 percent, and annual booster shots are needed.
R21/MM, the new vaccine, represents a significant improvement. At 77 percent efficacy — meaning that a vaccinated person is 77 percent less likely to get malaria than an unvaccinated person — it could cut malaria deaths dramatically.
That said, the new vaccine still doesn’t quite stack up to the efficacy of vaccines for other childhood diseases. The measles vaccine is 97 percent effective, for instance, and one dose of the chickenpox vaccine prevents 85 percent of cases and nearly 100 percent of severe cases (a booster shot brings efficacy up to 98 percent).
But there’s no question that the new vaccine is a huge step forward. If the efficacy statistics from the phase 2 clinical trial (the first test of safety and efficacy in the target population) hold up in phase 3 (when the vaccine is distributed on a much larger scale, so that its efficacy and safety can be evaluated with more information, and compared against the existing best treatment), the vaccine will have the potential to save hundreds of thousands of lives every year once it’s distributed widely throughout malaria-affected areas, primarily sub-Saharan Africa.
How the new vaccine works
The R21/MM vaccine is what’s called a pre-erythrocytic vaccine, which means it targets the malaria-causing Plasmodium parasite during the earliest stages of its life cycle in the body, before it multiplies in the liver and enters the bloodstream. During this stage, malaria doesn’t yet have any symptoms; the plasmodium sporozoites grow silently until they release their next life stage, merozoites, into the bloodstream.
Many candidate malaria vaccines try to help the body target and destroy the parasite at the pre-erythrocytic stage, including RTS,S, the existing malaria vaccine. If the body can learn to recognize and have an immune response to the parasite at this stage, it can prevent it from multiplying in the liver, entering the blood, and causing symptomatic malaria.
Exposing the body to the malarial parasite isn’t itself enough to create durable immunity. Fortunately, modern vaccine researchers have a lot more tricks up their sleeves. The R21/MM vaccine targets a specific protein present on the surface of the Plasmodium parasite in its sporozoite form. (RTS,S targets the same protein — earlier research has established that it’s a particularly good target — but exposes the body to less of the protein, due to differences in the structure of the vaccine.)
Targeting a single protein can produce better-targeted and more consistent immunity than exposing the body to the whole disease agent. When the body is exposed to the whole disease agent, it’s hard to predict exactly what it will “learn” to fight. Showing it a single target protein ensures it’ll develop the antibodies scientists have determined that it needs the most. And the protein that R21/MM and RTS,S target is one that researchers have determined is very unlikely to mutate or vary among strains of malaria.
The next step of a successful vaccination is what’s called an adjuvant, an additive to the vaccine that kicks the immune system into higher gear. Protein-based vaccines are generally understood to need an adjuvant, because the body will not necessarily react to unfamiliar proteins by mounting a full immune response.
“What those do,” Lowe told me, “is they’re a totally separate ingredient that has nothing to do with the pathogen. But they basically set off your innate immune system that’s always there, surveilling for foreign-looking crap.” What makes a great adjuvant? Something people have strong reactions to. As long as the body finds it irritating and mounts an immune response, it can function as an adjuvant.
The research team behind R21/MM tested many different adjuvants to figure out which one provoked the strongest immune response, and the winner was a formulation called Matrix-M (that’s the MM in the vaccine’s name), an extract from the bark of a Chilean soap tree. Matrix-M is a proprietary invention of Novavax, also used in its highly effective Covid-19 vaccine.
This research has been in the works for years. In 2016, a trial was conducted in healthy adults in the UK, looking at the R21 vaccine alone and with the Matrix-M adjuvant. After success in the UK, another trial in healthy adults followed — this time in Burkina Faso, where malaria is endemic.
Once that early research was established to be safe, the research team began conducting studies in steadily younger cohorts. The group at the most risk from malaria is infants, but it’s generally easier to see if vaccines have health risks or side effects by looking at older cohorts. Once the vaccine was determined safe, research began in 5- to 17-month-old babies in Nanoro, Burkina Faso.
The R21/MM vaccine is administered with three shots, plus a booster shot one year later. That means distribution of the vaccine will be a real challenge, especially in poor areas with limited health care infrastructure, but it’s an improvement over RTS,S, which requires four shots for a full course of vaccination and, again, is significantly less effective.
In the phase 2 study published this week, researchers found that the R21/MM’s single booster shot a year later returns immunity to the full level achieved after the initial course of three shots. The results are “very exciting,” Halidou Tinto, the principal investigator for the trial in Nanoro, said.
Phase 3 trials begin right away at five sites across Africa, in order to test how the vaccine works in areas with different malaria prevalence. “We look forward to the upcoming phase 3 trial to demonstrate large-scale safety and efficacy data for a vaccine that is greatly needed in this region,” Tinto told the BBC.
The phase 3 trials might also help clarify whether all three shots and the booster are necessary, or whether there’s a way to induce good protection with a less demanding dosing regimen. With any luck, within a few years we’ll have the efficacy, safety, and dosing data needed for a rollout across malaria-afflicted areas.
The big picture
Malaria isn’t just one of the world’s biggest killers of children. It’s also one of the biggest barriers to good childhood health and development in affected areas. Malaria infection causes long-term problems including cognitive impairment, and likely has long-term developmental impacts on children even when they survive it.
The world has done a lot over the past few decades to fight malaria. Interventions like insecticide-treated bed nets and seasonal preventive treatment in the form of medications have driven death rates down from around 1 million every year as recently as the 1990s to around 400,000 today. But without an effective vaccine that can be distributed everywhere, it’s going to be incredibly difficult to eradicate the disease.
Researchers know that, and malaria vaccine research is one of the most active areas of vaccine research, with human challenge trials in the UK (meaning clinical trials where volunteers are deliberately infected with the disease), phase 1 and phase 2 clinical trials throughout areas with high malaria prevalence, and other promising ideas being pursued based on encouraging results in mice.
Now, all that effort is starting to pay off. In general, writing about malaria vaccines means emphasizing that everything is still early-stage, that there’s lots of reason to expect a new innovation or development to fall through, and that while every avenue is worth pursuing, the public should know that most of them won’t pay off.
That’s not true this time. This is a late-stage result, and there’s every reason to expect it to hold up. “This is excellent work,” Lowe told me. “This is the best news in the malaria vaccine world ever.”
This is the first vaccine to meet the World Health Organization’s threshold of 75 percent effectiveness for a malaria vaccine. With many other vaccine candidates making their way through trials, it almost definitely won’t be the last. The more we know about malaria — and about vaccination — the better we can design vaccines that are cheap, simple to store and administer, that don’t require too many booster doses, and that provoke a strong and enduring immune response.
For more than 100 years, vaccination has been one of humanity’s most powerful tools against disease. It’s a tool that gets more potent every day, as we learn more about what makes vaccines work and how best to point our immune system at the perfect target.
This latest development is worth celebrating. It’s an innovation that could mean saving the lives of hundreds of thousands of children. And if it fills you with optimism about the prospects of a world where vaccines inch us closer to eradicating diseases that have long plagued humanity, it should.
