December 2, 2021 – The parasite that causes malaria can kill a person within 24 hours of symptoms appearing. Patients’ symptoms are similar to those of the flu, including fever, headache, and chills. It all starts with a microscopic poke.
When a mosquito infected with malaria sinks its needle-like mouth through human skin, it releases immature forms of the parasites, called sporozoites, into the person’s bloodstream. From there they travel to the liver and then to the red blood cells. The infected cells burst, releasing millions of daughter parasites called merozoites, which infect other red blood cells. The cycle continues until the parasites are killed – and doing so becomes more and more difficult.
During the first fifteen years of this century, global efforts to reduce malaria reduced cases by 40%, and deaths decreased by more than 60%. But in 2015, that progress stalled. Since then, malaria rates have quietly risen after cases have been steadily declining for more than a decade.
Scientists know that the parasites that cause malaria have evolved to be resistant to drugs for as long as we have had them. Historically, these mutations first appeared in the Greater Mekong Delta in Southeast Asia, then spread to Africa, elsewhere in Asia, and from there to South America – 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 and deadly of the five malaria parasites along the country’s northern border with Uganda has been mutating to resist artemisinin, one of the partner drugs used together to treat malaria. This evasion pressures the other drug to eliminate the parasites on its own.
“Once you lose the partner drug, you lose the treatment,” says David A. Fidock, Ph.D., professor of microbiology and immunology at Columbia University in New York City.
In October of this year, the World Health Organization approved a first-of-its-kind malaria vaccine, RTS, S/AS01 protein-based. The four-dose vaccine, which was developed through COVID-19 prevention efforts, is a milestone that scientists have worked hard for for decades.
But experts say a vaccine alone is not yet enough to stop malaria infection.
“A vaccine can regain momentum in reducing disease, but it cannot replace drugs, and it is not effective enough,” Vidock says.
The fact that malaria is caused by parasites, not bacteria or viruses, is the crux of why it is so difficult to develop a vaccine against it.
The Plasmodium falciparum Diane Wirth, PhD, professor of immunology and infectious diseases at Harvard T.H. Chan School of Public Health, says the parasite has approximately 5,300 genes that “can be used to avoid anything the host might throw at it.”
For comparison, the largest viruses have about 200. SARS-CoV-2, the virus that causes COVID-19, has only 11.
The new malaria vaccine will be most effective when used in conjunction with existing prevention methods, including bed nets, chemical insecticides and artemisinin or ACT combination therapy. The threat of resistance remains.
“Just as the virus that causes COVID has mutated, so the parasites do the same. They are living things that also want to survive, and the only way to survive is to survive,” says Pascal Ringwald, who leads the drug resistance and containment unit at the World Health Organization’s Global Malaria Program mutation.
Parasites must also be targeted during multiple stages of their life cycle, which includes two hosts: the mosquito and the infected human. Attacking at different stages of their life cycle appears to be the key to effective vaccine therapies.
You cannot rely on a single 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 the vaccine at one point, you can target it at another,” says Solomon Conteh, a molecular virologist at the National Institute of Allergy and Infectious Diseases. “The RTS,S vaccine targets the parasites before they infect the liver, but that’s just a stage One of the complex life cycle of the parasite.”
Then there’s the fact that humans and mosquitoes, and thus malaria parasites, have co-evolved throughout our species’ existence—so much so that parasites have left an imprint on the human genome. Genetic variations affecting red blood cells, most notably sickle cell anemia, are likely the result of malaria.
It is possible that these traits were selected by the malaria parasite by killing humans who did not carry these mutations. That’s a strong evolutionary force, the parasite on humans and humans on the parasite, and we’re now trying to step in the middle of this evolutionary process,” says Wirth.
Disruption of the evolutionary relationship between humans and malaria is further complicated by unprecedented drug resistance. Although some variants appear naturally, most of the development of parasites has been the result of humans getting better at avoiding them.
This intervention “creates so much pressure that only parasites that have evolved to avoid treatment can survive,” says Wirth. The parasite has a lot of inherent versatility, which is mostly driven by escape from the human immune response. As we design a vaccine, we need to overcome this tendency to evade treatment.”
A study published in August confirmed what researchers believed to be true in 2019. There is evidence of delayed clearance of malaria parasites in Rwanda, which means the drug is not immediately effective in reducing the number of parasites infested in the body — a sign of partial resistance to the ingredient ACT. of two properties. It is the first documented evidence of artemisinin resistance in Africa, where approximately 94% of malaria cases occur.
“Warning lights are definitely coming in in Africa because we have a precedent in Asia. We know that drug resistance in the Greater Mekong Delta has rendered many of the drugs used in ACT useless,” says Vidoc. “The first drug failed, and because it wasn’t working as quickly, there were more parasites that the partner drug had to fight and more opportunities for the parasites to mutate. Once you catch your partner failing to take drugs, you get treatment failure. Then we see a huge rise in deaths. “.
So far, antimalarial drug resistance has reliably emerged first in the Greater Mekong region, which covers parts of Cambodia, Laos, Myanmar, Thailand, Vietnam, and the southern Yunnan province of China. The scientists understood this, and they carefully monitored the area for any sign of drug resistance. When it emerged, the strategy was to build a firewall of insecticides, bed nets, and aggressive treatment that prevented the parasite from escaping from the area. Sometimes, humans may transfer the parasite to other continents, including Africa.
But for the first time, this is not 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, the parasites have mutated independently to resist treatment.
“The fact that artemisinin resistance has emerged independently is something entirely new; it makes containment more complex,” Ringwald says. “Imagine a fire. If you have one forest burning, it’s easy to contain, but if you have five different forests burning at the same time, it makes things more complicated. “
According to Vidoc, malaria deaths in Senegal increased 10-fold, once the dominant drug chloroquine began failing to treat malaria in West Africa, and artemisinin resistance is expected to spread across the continent, making new treatments more important than ever.
Emerging vaccines, though difficult to identify, offer another tool that could take the pressure off combination therapy drugs if one partner fails.
Vidoc says the renewed interest in developing a malaria vaccine is a very important piece of the puzzle: malaria treatment and prevention. He says we can expect more ground-breaking developments in the coming years, but the challenge remains complex and will likely still require a multi-pronged approach.
Most people in areas with high malaria prevalence develop some level of immunity to the disease by the time they reach their teens. That’s why the RTS,S vaccine, which is now available in parts of Africa, was created for children 5 years old and younger. But a full dose of the vaccine is still only 30% effective against death. Experts call it a tool against malaria, and the best way to use it is with other defenses.
Conte, who is one of the team working on a vaccine that targets a different stage in the parasite’s life cycle than the RTS, S vaccine, says. The two can be used in tandem, but trials are still ongoing.
Future vaccines will also have to address the sieve effect, in which parasites that appear different enough to the immune system are able to slip through protection.
“It’s not the same as what we saw with the coronavirus. It’s very effective against the original version, and less effective against the delta variant,” says Wirth. “We expect this to happen with malaria vaccines.”
Multiple alleles – or copies of a gene – could be the answer.
The pneumococcal vaccine contains up to 24 different types of antigens to protect against all the different strains. It’s not uncommon to take a multi-vaccine approach, and this can be used to create a malaria vaccine that protects against many different mutations, says Wirth.
Despite its flaws, the RTS,S vaccine is a big first step in figuring out what types of vaccines might work best in the future. Wirth says the mRNA technology perfected while pressing for a COVID-19 vaccine will open new doors for vaccines against other diseases, which may include malaria.
“Mosquitoes have co-evolved with humans for thousands of years. They are highly adapted to human metabolism. I think it would be naive to think we would come up with a magic bullet, but we could make better vaccines,” she says.