December 2, 2021 – The parasite that causes malaria can kill a person within 24 hours of onset of symptoms. The patients’ symptoms resemble those of the flu, including fever, headache, and chills. It all starts with a microscopic shot.
When a mosquito infected with malaria plunges its needle-like mouth through human skin, it releases immature forms of parasites, called sporozoites, into a person’s bloodstream. From there, they go 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 persists until the parasites are killed – and it gets harder and harder to do.
In the first 15 years of this century, global efforts to fight malaria reduced cases by 40% and deaths by more than 60%. But in 2015, that progress leveled off. Since then, malaria has steadily increased after steadily declining cases for more than a decade.
Scientists know that the parasites that cause malaria have evolved to resist drugs for as long as we have them. These mutations historically first appeared in the Greater Mekong Delta in Southeast Asia and then spread to Africa, elsewhere in Asia and South America from there, but this time it’s different.
At the end of 2019, Rwandan scientists announced they had reason to believe F. plasmodium – by far the most common of the five malaria parasites, and the deadliest – along the country’s northern border with Uganda was mutating to resist artemisinin, one of the two partner drugs used in combination to treat malaria. Such an escape puts pressure on the other drug to eradicate the parasites on its own.
“Once you lose the partner drug, you get treatment failure,” says David A. Fidock, PhD, professor of microbiology and immunology at Columbia University in New York City.
In October of this year, the World Health Organization approved the first-ever protein-based malaria vaccine, RTS, S / AS01. The four-dose vaccine, advanced by COVID-19 prevention efforts, is a major milestone scientists have worked hard towards for decades.
But experts say the vaccine alone is not yet enough to stop malaria infections.
“The vaccine can regain the momentum needed to reduce disease, but it cannot replace drugs, it is not effective enough,” Fidock said.
The fact that malaria is caused by parasites, rather than bacteria or a virus, is central to why it has been so difficult to develop a vaccine against it.
The P. falciparum The parasite has around 5,300 genes “which it can use to evade anything the host can throw at it,” says Dyann Wirth, PhD, professor of immunology and infectious diseases at Harvard TH Chan School of Public Health .
For comparison, the largest viruses have around 200 of them. SARS-CoV-2, the virus that causes COVID-19, has only 11.
The new malaria vaccine will be more effective if used with existing prevention methods, including bed nets, chemical insecticides, and first-line artemisinin combination therapy, or ACT. The threat of resistance remains.
“Just as the virus that causes COVID has mutated, so do the parasites. These are living things that also want to survive, and the only way to survive is to mutate, ”says Pascal Ringwald, MD, who heads the Containment and Drug Resistance Unit of the Global Malaria Program. World Health Organization.
Parasites must also be targeted during several stages of their life cycle, which involves two hosts: the mosquito and the infected human. Attacking at different stages of their life cycle seems essential for effective vaccine treatments.
“You can’t depend on just one vaccine, but you can use multiple vaccines to target different stages of the parasite’s life. So if you have a vaccine resistant parasite at one stage, you can target it at another stage, ”says Solomon Conteh, molecular virologist at the National Institute of Allergy and Infectious Diseases. “The RTS, S vaccine targets the parasites before they can infect the liver, but this is only one stage in 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, including sickle cell anemia, are likely the result of malaria.
“These traits were probably picked by the malaria parasite by killing humans who did not carry these mutations. It’s a powerful evolutionary force, both parasite on humans and humans on parasite, and we’re now trying to get into the middle of that evolutionary process, ”Wirth said.
The disruption of the evolutionary relationship between humans and malaria is further complicated by unprecedented drug resistance. Although some variants emerged naturally, most of the evolution of parasites has been the result of improving humans’ ability to avoid them.
This intervention “creates extreme pressure in which only parasites that have evolved to escape treatment can survive,” says Wirth. “The parasite has a lot of inherent variation, which is mainly due to the evasion of the human immune response. When we design a vaccine, we have to overcome this propensity to evade treatment. “
A study published in August confirmed what researchers believed to be true in 2019. There is evidence of delayed elimination of the malaria parasite in Rwanda, meaning a drug is not immediately effective in reducing the number. of parasites that have infected the body – a sign of partial resistance to the ACT bi-drug. This is the first documented evidence of artemisinin resistance in Africa, where approximately 94% of malaria cases occur.
“The lights are definitely on in Africa because we have a precedent in Asia. We know that drug resistance in the Greater Mekong Delta region has rendered several drugs used in ACT useless, ”Fidock said. “The first drug failed, and because it didn’t work 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 therapy failure. Then we get a substantial increase in the number of deaths. “
So far, resistance to antimalarial drugs has first reliably emerged in the Greater Mekong region, which covers parts of Cambodia, Laos, Myanmar, Thailand, Vietnam and the southern province of Yunnan in China. Scientists understood this and carefully monitored the area for any suspicion of drug resistance. When it emerged, the strategy was to build a firewall consisting of insecticides, mosquito nets and aggressive treatment that kept the pest from escaping the area. Sometimes that would be the case, and a human would carry 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 resistance to ACTs exists. This means that for the first time, the parasites mutated independently to resist the treatment.
“The fact that resistance to artemisinin emerged independently is something completely new; it makes it harder to contain, ”Ringwald says. “Imagine a fire. If you have a forest that is burning it’s easier to contain, but if you have five different forests that are burning at the same time it makes things a lot more complicated.
According to Fidock, malaria deaths in Senegal increased tenfold, once the dominant antimalarial drug, chloroquine, began to fail in West Africa, and he expects resistance to ACTs. eventually spread across the continent, making new treatments more important than ever.
Emerging vaccines, while difficult to pin down, offer another tool that could reduce the pressure on combination therapy drugs in the event of a partner failure.
A renewed interest in developing a malaria vaccine is an incredibly important piece of the puzzle of malaria treatment and prevention, says Fidock. In the years to come, 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 with high malaria prevalence develop some immunity to the disease by the time they reach adolescence. This is why the RTS, S vaccine, which is becoming available in parts of Africa, was created for children 5 years of age and under. But a full dose of the vaccine is still only 30% effective against death. Experts call it a tool against malaria, one that is best used with other defenses.
“The vaccine isn’t 100% effective, so you always have people getting sick and you treat them with a drug, and this drug is artemisinin-based combination therapy,” says Conteh, who is part of the team. ‘a team working on a vaccine that would target a different phase of the parasite’s life cycle than the RTS vaccine, S. The two could potentially be used in tandem, but trials are still ongoing.
Future vaccines will also have to fight the sieve effect, in which parasites that appear different enough to the immune system are able to pass through protection.
“It’s no different from what we’ve seen 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 the malaria vaccines. “
Multiple alleles – or versions of a gene – might be the answer.
“The pneumococcal vaccine contains up to 24 different types of antigens to protect against all of the different strains. It’s not uncommon to take a multiple approach to vaccines, and this could be used to create a malaria vaccine that protects against many different mutations, ”says Wirth.
Despite its shortcomings, the RTS, S vaccine is the important first step in determining what types of vaccines might 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 suitable for human metabolism. I think it’s naive to think that we’ll find a silver bullet, but we can create better vaccines, ”she said.