Dec. 2, 2021 -- The parasite that causes malaria can kill a person within 24 hours of symptoms appearing. Patients’ symptoms are flu-like, including a fever, headache, and chills. It all starts with a microscopic poke.
When a malaria-infected mosquito plunges her needle-like mouth through human skin, she releases immature forms of the parasites, called sporozoites, into the person's bloodstream. From there, they travel to the liver, then to red blood cells. The infected cells burst, releasing millions of daughter parasites called merozoites, which infect other red blood cells. The cycle persists until the parasites are killed -- and that’s becoming harder to do.
During the first 15 years of this century, worldwide efforts to curb malaria cut cases by 40%, and deaths fell by more than 60%. But in 2015, that progress plateaued. Since then, malaria has been quietly rising after cases had been falling steadily for over a decade.
Scientists know the parasites that cause malaria have evolved to resist drugs for as long as we’ve had them. These mutations have historically popped up first in Southeast Asia’s Greater Mekong Delta, and then spread to Africa, elsewhere in Asia, and South America from there -- but this time it’s different.
In late 2019, scientists in Rwanda announced they had reason to believe F. plasmodium -- by far the most common of the five malaria parasites, and the most deadly -- along the country’s northern border with Uganda was mutating to resist artemisinin, one of two partner drugs used in combination to treat malaria. Such evasion puts pressure on the other drug to eradicate the parasites by itself.
“Once you lose the partner drug, then you get treatment failure,” says David A. Fidock, PhD, a professor of microbiology and immunology at Columbia University in New York City.
In October of this year, the World Health Organization endorsed the first-ever malaria vaccine, the protein-based RTS,S/AS01. The four-dose vaccine, advanced by landmark COVID-19 prevention efforts, is a major milestone that scientists have painstakingly worked toward for decades.
But experts say the vaccine alone is not yet enough to stop malaria infections.
“The vaccine can regain the momentum in reducing disease, but it cannot replace drugs, it’s not effective enough,” Fidock says.
The fact that malaria is caused by parasites, rather than bacteria or a virus, is at the crux of why it’s been so difficult to develop a vaccine against it.
The P. falciparum parasite has roughly 5,300 genes “that it can use to evade anything the host can throw at it,” says Dyann Wirth, PhD, a professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health.
The new malaria vaccine will be most effective when it’s used along with existing prevention methods, including bed nets, chemical insecticides, and the frontline artemisinin-combination treatment, or ACT. The threat of resistance remains.
“Just as the virus that causes COVID has mutated, the parasites do the same. They are living elements that also want to survive, and the only way to survive is to mutate,” says Pascal Ringwald, MD, who leads the World Health Organization Global Malaria Program’s Drug Resistance and Containment Unit.
Parasites also need to be targeted during multiple stages of their life cycle, which involves two hosts: the mosquito and the infected human. Attacking at different stages in their life cycle appears key for effective vaccine treatments.
“You cannot depend on one vaccine, but you can use multiple vaccines to target different life stages of the parasite. So if you have a parasite that is resistant to a vaccine in one stage, you can target it at another stage,” says Solomon Conteh, a molecular virologist with the National Institute of Allergy and Infectious Diseases. “The RTS,S vaccine targets parasites before they can infect the liver, but this is just one stage of the parasite’s complex life cycle.”
A Damaging Legacy
Then there’s the fact that humans and mosquitoes, and therefore malaria parasites, have co-evolved for as long as our species has existed -- so closely that the parasites have left an imprint on the human genome. Genetic variations that affect red blood cells, most notably sickle cell anemia, are likely the result of malaria.
“These traits were likely selected by the malaria parasite by killing off humans that did not carry these mutations. This is a powerful evolutionary force, both the parasite on humans and humans on the parasite, and we are trying now to step in the middle of that evolutionary process,” Wirth says.
Disrupting the evolutionary relationship between humans and malaria is further complicated by unprecedented drug resistance. Although some variants have emerged naturally, most of the parasites' evolution has been the result of humans getting better at evading it.
This intervention “creates extreme pressure in which only the parasites that have evolved to evade the treatment can survive,” Wirth says. “The parasite has a lot of inherent variation, which is mostly driven from escaping the human immune response. As we design a vaccine, we need to overcome that propensity to evade treatment.”
A study published in August confirmed what researchers believed to be true in 2019. There is evidence of delayed malaria parasite clearance in Rwanda, meaning a drug is not effective right away at reducing the number of parasites that have infected the body -- a sign of partial resistance to the two-drug ACT. It's the first documented evidence of artemisinin resistance in Africa, where roughly 94% of malaria cases occur.
“The warning lights are definitely coming on in Africa because we have a precedent in Asia. We know that drug resistance in the Greater Mekong Delta region has rendered multiple drugs used in ACT useless,” Fidock says. “The first drug failed, and because it wasn’t working as quickly, there were more parasites for the partner drug to fight and more opportunities for the parasites to mutate. Once you get partner drug failure, you get treatment failure. Then we get a substantial spike in deaths.”
Until now, anti-malarial drug resistance has reliably emerged first in the Greater Mekong region, which covers parts of Cambodia, Laos, Myanmar, Thailand, Vietnam, and the southern province of Yunnan in China. Scientists have understood this, and they carefully monitored the region for any hint of drug resistance. When it did emerge, the strategy was to build a firewall of insecticide, bed nets, and aggressive treatment that kept the parasite from escaping the region. Sometimes it would, and a human would carry the parasite to other continents, including Africa.
But for the first time, that isn’t the case. This mutation cannot be traced back to Asia, the only other place in the world where ACT resistance exists. This means that for the first time, parasites independently mutated to resist treatment.
“The fact that artemisinin resistance emerged independently is something completely new; it makes it more complicated to contain,” Ringwald says. “Imagine a fire. If you have one forest burning, it's easier to contain, but if you have five different forests burning at the same time, it makes things far more complicated.”
According to Fidock, malaria deaths in Senegal increased by 10 times, once the dominant malaria drug chloroquine began to fail in West Africa, and he expects ACT resistance to eventually spread across the continent, making new treatments more important than ever.
Emerging vaccines, albeit tricky to pin down, are offering another tool that could take pressure off of combined-treatment drugs if one partner fails.
A resurgence of interest in developing a vaccine against malaria is an incredibly important piece of the puzzle that is malaria treatment and prevention, Fidock says. In the coming years, he says we can expect more groundbreaking developments, but the challenge remains complicated and will likely still require a multi-pronged approach.
Most people in areas where malaria prevalence is high develop a certain amount of immunity to the disease by the time they reach adolescence. That’s why the RTS,S vaccine, which is becoming available in parts of Africa, was created for kids ages 5 and younger. But a full dose of the vaccine is still only 30% effective against death. Experts are calling it a tool against malaria, one that’s best used along with other defenses.
“The vaccine is not 100% effective, so you still have people that fall sick, and you treat them with a drug, and that drug is artemisinin-based combination therapy,” says Conteh, who is part of a team that’s working on a vaccine that would target a different phase in the parasite’s life cycle than the RTS,S vaccine. The two could potentially be used in tandem, but trials are still underway.
Future vaccines will also have to address the sieve effect, in which parasites that look different enough to the immune system are able to slip through the protection.
“It’s not unlike what we’ve seen with the coronavirus. It's very effective against the original version, and less effective against the Delta variant,” Wirth says. “We expect this could happen with malaria vaccines.”
Multiple alleles -- or versions of a gene -- could be the answer.
“The pneumococcal vaccine contains as many as 24 different antigen types to protect against all the different strains. It's not uncommon to take a multi-approach to vaccines, and that could be used to create a malaria vaccine that’s protective against many different mutations,” Wirth says.
Despite its shortcomings, the RTS,S vaccine is the first huge step in figuring out what types of vaccines may work best in the future. Wirth says the mRNA technology mastered during the push for a COVID-19 vaccine will open new doors for vaccines against other diseases, which may include malaria.
“Mosquitoes have evolved with humans for thousands of years; they are very adapted to human metabolism. I think it's naive to think we will come up with a magic bullet, but we can create better vaccines,” she says.