It could save hundreds of thousands of lives.
/cdn.vox-cdn.com/uploads/chorus_image/image/69200784/1232556225.0.jpg)
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.
ALSO:
Malaria is notoriously hard to vaccinate against. A new vaccine technology might change that.
Malaria vaccine shows promise — now come tougher trials
A previous version of an experimental malaria vaccine was trialled at Ewin Polyclinic in Cape Coast, Ghana.Credit: Cristina Aldehuela/AFP/Getty
A vaccine against malaria has shown promise in early clinical trials, raising hopes that it might one day prove to be an effective weapon against one of the world’s biggest killers of children.
In a trial in 450 children aged 5–17 months, the vaccine, called R21, was up to 77% effective at preventing malaria over the course of one year — which, if confirmed, would clear a 75% effectiveness target set by the World Health Organization. The results are presented in a preprint posted on the server SSRN on 20 April1.
R21 is a modified form of a vaccine that has already been deployed in an ongoing study in hundreds of thousands of children in Malawi, Kenya and Ghana. That vaccine, called RTS,S or Mosquirix, is about 56% effective over one year, and 36% effective over four years.
R21 is designed to be both more potent and cheaper to produce than Mosquirix, says Kwadwo Koram, an epidemiologist at the University of Ghana in Accra. But it remains to be seen if the promising results from this trial, which was done in Nanoro, Burkina Faso, will hold up when the vaccine is tested in a larger study. “Now we all wait patiently to see what will come out,” says Koram. “If that shows 75% efficacy, then we would be very happy and jumping around.”
Researchers plan to test R21 in a larger trial of 4,800 children, which is slated to start next week, says Halidou Tinto, a lead author of the study and a parasitologist at the Health Sciences Research Institute in Nanoro. The team has also been working with the Serum Institute of India, a vaccine-manufacturing powerhouse in Pune that has pledged to produce at least 200 million doses of the vaccine each year if it is eventually authorized for use.
Slow progress
It took researchers less than a year to develop a roster of effective vaccines against COVID-19, but half a century of toil has still not yielded a vaccine against malaria that meets the World Health Organization’s efficacy goal. Part of the problem is low investment in preventing a disease that predominately affects low- and middle-income countries. Another issue is the malaria parasite (Plasmodium spp.) itself, which has a complex life cycle and the ability to mutate key proteins, generating fresh strains.
Initial hubris gave way to frustration as researchers realized that vaccines against malaria would be difficult to produce, says Nicholas White, who studies tropical medicine at Mahidol University in Bangkok. “People thought that it would be easy,” he says, “but it became increasingly clear that these parasites are clever.”
But the urgency has remained: malaria still kills about 400,000 people a year, most of them infants and children under the age of 5.
R21 and Mosquirix both target the malaria parasite in the sporozoite phase of its life cycle — the phase in which it enters the human body from its mosquito hosts. The vaccines include a protein secreted by the parasite at that stage, in the hope of stimulating an antibody response against it. R21 includes a higher concentration of these proteins.
Each of the vaccines is administered with a chemical called an adjuvant, which boosts immune responses to the inoculation. But the adjuvant used with R21 is easier to make than that used with Mosquirix, raising hopes that it could be cheaper, as well.
Still, White urges caution until larger trials have been conducted, noting that efficacy sometimes drops when studies are scaled up. “Definitely it’s exciting because of the possibility of large-scale production at relatively low cost,” he says. “But because it’s a small study, I don’t think you can say, ‘Wow, slam dunk, we’ve got a much better vaccine.’”
Lasting effects
Researchers will also be looking to see how durable the effects of the vaccine are. The R21 trial lasted for one year, but Burkina Faso is plagued by malaria for only about six months of each year, notes Stephen Hoffman, chief executive of Sanaria, a company in Rockville, Maryland, that is also developing malaria vaccines. During the second half of the study, there was only one case of malaria in the control group that did not receive the vaccine, Hoffman notes, making it impossible to judge whether the benefits of the vaccine lasted for the full year.
Researchers will continue to administer booster shots and follow the 450 participants for at least another year, says Tinto, and are hoping to extend the study for one to two years after that. The next, larger trial will also include countries in which malaria is a year-round threat, he says.
After Mosquirix, R21 is the candidate vaccine closest to widespread deployment, but researchers around the world are looking for ways to improve on these two vaccines, including targeting proteins expressed at different stages of the parasite’s life cycle. “I think R21 has now hit a ceiling for where we can go for this single-component vaccine,” says Stefan Kappe, who studies malaria-parasite biology and immunology at the Seattle Children’s Research Institute in Washington. “From here on out, we need to build on additional components.”
Kappe is collaborating with researchers at Sanaria who are looking for ways to inoculate people using a disabled version of the whole parasite, rather than individual proteins. The hope is that the approach will yield a broader and more durable immune response by exposing the immune system to the parasite’s full complement of proteins. But doing so will involve a series of technical challenges — including finding ways to grow the principal component of a vaccine, which must be aseptic, in mosquitoes.
For now, the R21 results are encouraging, says Koram. When coupled with other preventive measures, such as effective mosquito control, even a vaccine with less than 75% efficacy could help to reduce deaths, he says: “Every little piece is good.”
References
- 1.
Datoo, M. S. et al. Preprint at SSRN https://doi.org/10.2139/ssrn.3830681 (2021).
https://www.nature.com/articles/d41586-021-01096-7
Promising malaria vaccine to be tested in first large field trial
The island of Bioko, part of Equitorial Guinea, will be the site of a major malaria-vaccine trial.Robert Harding/Getty
A malaria vaccine that can provide up to 100% protection against the disease will be tested in a large clinical trial for the first time, to study its efficacy under real-world conditions.
The trial will begin in early 2020 on Bioko, an island off the coast of Equatorial Guinea, and will involve 2,100 people aged 2–50 years. The trial is intended to provide the efficacy and safety data needed for regulatory approval, says malaria researcher Steve Hoffman, who is leading the study and is chief executive of Sanaria, the company in Rockville, Maryland, that developed the vaccine. Equatorial Guinea’s government and private energy companies are sponsoring the trial.
In laboratory studies, the vaccine, called PfSPZ, has proven the most effective malaria vaccine developed so far, giving healthy volunteers complete protection.
PfSPZ works by eliciting an immune response against the malaria parasite Plasmodium falciparum. It is made of sporozoites (SPZ), the stage in the malaria parasite’s life cycle that infected mosquitoes inject into people during a bite. Sanaria isolates and purifies billions of sporozoites from farmed mosquitoes.
The vaccine is unique in using whole parasites as its ingredient; most candidate malaria vaccines include only a small number of genetically engineered parasite proteins. The abundance of proteins in the whole parasite vaccine explains why it provokes such a strong immune response.
But to be effective, PfSPZ must be injected intravenously. That poses challenges for mass vaccination campaigns because it is a more complex procedure than those typically used for other vaccines, where jabs penetrate the skin or muscles, or oral vaccines. However, Hoffman thinks the difficulties are surmountable.
Field efficacy
The trial on Bioko island, which has a population of about 280,000 people, is the first large test of the vaccine’s effectiveness in a region where malaria occurs.
PfSPZ’s efficacy in the field will inevitably be lower than in lab studies because people who have already had malaria are likely to have a weaker immune response, says Stefan Kappe, an immunologist who studies malaria at the Seattle Children’s Hospital in Washington. Local strains of the malaria parasite will also differ from the one used in the vaccine, he adds.
But even a reasonably effective vaccine could have a big impact, says Kappe. The prevalence of malaria on Bioko has dropped from 45% to 12.5% in 15 years through the use of conventional measures such as indoor insecticide spraying and bed nets laced with the chemicals. But experience in other parts of the world suggest that getting to zero is the most difficult part, he says. That might be possible only with the help of a vaccine. “This trial will be answering several questions for the first time, including whether a vaccine can completely eliminate malaria from this island environment,” he says.
If the trial is successful, Sanaria intends to carry out another one involving around 10,000 people on the island, says Hoffman. This study would compare disease levels between communities that receive the vaccine in addition to using standard malaria-prevention measures with levels in control communities that use only the standard measures, he says.
Hoffman expects the efficacy of the vaccine will be higher in this subsequent, larger trial than it will be in the upcoming trial, because of ‘herd immunity’ — when a sufficiently high percentage of a population is protected against a disease, making it difficult for the disease to spread to the few susceptible people left.
If the large trial is successful, Sanaria and its partners then plan to roll out the vaccine in the island’s entire population and assess its effectiveness.
Malaria
https://www.nature.com/articles/d41586-019-01232-4
