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December 2, 2021 – The parasite that causes malaria can kill a person within 24 hours of the onset of symptoms. Patients’ symptoms are flu-like, including fever, headache, and chills. It all starts with a microscopic blow.
When a malaria-infected mosquito pierces its needle-like mouth through human skin, it releases immature forms of parasites called sporozoites into the human bloodstream. From there they travel to the liver, then to the red blood cells. 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 this is becoming increasingly difficult to do.
In the first 15 years of this century, global efforts to reduce malaria reduced cases by 40% and deaths by more than 60%. But in 2015, that progress reached a plateau. Since then, malaria has been rising steadily, with cases steadily declining for more than a decade.
Scientists know that the parasites that cause malaria have evolved to resist drugs while 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 – but this time differently.
At the end of 2019, Rwandan scientists announced that they had reason to believe F. plasmodium – by far the most common of the five malaria parasites and the deadliest – on the country’s northern border with Uganda, it mutated to resist artemisinin, one of two partner drugs used in combination to treat malaria. Such avoidance puts pressure on the other drug to kill the parasites on its own.
“Once you lose your partner drug, you fail to treat,” said David A. Fidok, Ph.D., a professor of microbiology and immunology at Columbia University in New York.
In October this year, the World Health Organization approved the first malaria vaccine of its kind, based on the RTS protein, S / AS01. The four-dose vaccine, developed through a remarkable effort to prevent COVID-19, is an important milestone that scientists have worked hard for decades.
But experts say the vaccine alone is still not enough to stop malaria infections.
“The vaccine can regain the momentum to reduce the disease, but it can’t replace the drugs, it’s not effective enough,” Fidok said.
First vaccine
The fact that malaria is caused by parasites and not by bacteria or a virus is at the root of why it has been so difficult to develop a vaccine against it.
IN P. falciparum the parasite has approximately 5,300 genes “that it can use to avoid anything the host can throw at it,” said Diane Wirth, Ph.D., professor of immunology and infectious disease at Harvard’s TH Chan School of Public Health.
By 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 combination therapy with artemisinin or ACT. The threat of resistance remains.
“Just as the virus that causes COVID has mutated, so do parasites. They are living elements that also want to survive, and the only way to survive is to mutate, “said Pascal Ringwald, MD, who heads the World Health Organization’s Global Sustainability and Drug Restriction Unit.
Parasites must also be targeted during many stages of their life cycle, which includes two hosts: a mosquito and an infected person. Attacks at different stages of their life cycle appear to be key to effective vaccine treatment.
“You can’t count on one vaccine, but you can use multiple vaccines to target different stages of the parasite’s life. So if you have a parasite that is resistant to a vaccine at one stage, you can direct it to another stage, ”said Solomon Contech, a molecular virologist at the National Institute of Allergy and Infectious Diseases. “The RTS, S vaccine targets parasites before they can infect the liver, but this is only one stage in the complex life cycle of the parasite.
Damaging heritage
Then there is the fact that humans and mosquitoes, and therefore malaria parasites, have evolved together as long as our species exists – so closely that the parasites have left their mark on the human genome. Genetic variations that affect red blood cells, especially sickle cell anemia, are likely to be the result of malaria.
“These traits are probably chosen by the malaria parasite by killing people who do not carry these mutations. It’s a powerful evolutionary force, both the parasite on humans and humans on the parasite, and now we’re trying to get in the middle of this evolutionary process, “says Wirth.
Disruption of the evolutionary link between humans and malaria is further complicated by unprecedented drug resistance. Although some variants have emerged naturally, most of the evolution of parasites is the result of humans becoming better at avoiding them.
This intervention “creates extreme pressure, under which only parasites that have evolved to escape treatment can survive,” says Wirth. “The parasite has many inherent variations, mostly due to the avoidance of the human immune response. When designing a vaccine, we need to overcome this tendency to avoid treatment. “
A study published in August confirmed what scientists believe is true in 2019. There is evidence of delayed clearance of malaria parasites in Rwanda, which means the drug is not effective immediately in reducing the number of parasites that have infected the body – a sign of partial resistance to ACT with two drugs. This is the first documented evidence of artemisinin resistance in Africa, where approximately 94% of malaria cases occur.
“The warning lights are definitely on 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,” Fidok said. “The first drug failed, and because it didn’t work so fast, there were more parasites for the partner drug to fight and more opportunities for the parasites to mutate. Once you get a failure from your partner’s drugs, you get a treatment failure. Then we get a significant jump in deaths. “
Moving target
So far, resistance to malaria drugs has appeared reliably first in the Greater Mekong region, which includes parts of Cambodia, Laos, Myanmar, Thailand, Vietnam and the southern province of Yunnan in China. Scientists understood this and closely monitored the region for any hint of drug resistance. When it appeared, the strategy was to build a protective wall of insecticides, bed nets and aggressive treatments that prevent the parasite from fleeing the region. Sometimes it happened and a person transmitted the parasite to other continents, including Africa.
But for the first time this is not the case. This mutation cannot be traced to Asia, the only other place in the world where ACT resistance exists. This means that for the first time, the parasites mutated independently to resist treatment.
“The fact that resistance to artemisinin has emerged independently is something completely new; that makes it harder to keep, ”says Ringwald. “Imagine a fire. If you have one burning forest, it is easier to limit, but if you have five different forests burning at the same time, it makes things much more complicated.
According to Fidok, malaria deaths in Senegal have increased 10 times after 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, although difficult to identify, offer another tool that could alleviate the pressure of combination therapies if one of the partners fails.
The resurgence of interest in developing a malaria vaccine is an incredibly important part of the puzzle that is treating and preventing malaria, Fidok said. In the coming years, he says, we can expect more revolutionary developments, but the challenge remains complex and will probably still require a multilateral approach.
Promising future
Most people in areas where the prevalence of malaria is high develop a certain immunity to the disease by the time they reach adolescence. That is why the RTS, S vaccine, which is becoming available in parts of Africa, is designed for children aged 5 and younger. But the full dose of the vaccine is still only 30% effective against death. Experts call it an anti-malarial agent that is best used in conjunction with other protections.
“The vaccine is not 100% effective, so you still have people who get sick and you treat them with a drug, and that drug is a combination therapy based on artemisinin,” said Contech, who is part of a team working on a vaccine. which would target a different phase of the parasite’s life cycle from the RTS, S vaccine. The two could potentially be used in tandem, but trials are still ongoing.
Future vaccines will also have to deal with the effect of the sieve, in which parasites that look different enough for the immune system can escape through the defenses.
“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 version, “says Wirth. “We expect this to happen with malaria vaccines.”
Multiple alleles – or gene variants – could be the answer.
“The pneumococcal vaccine contains up to 24 different types of antigens to protect against all different strains. It’s not uncommon to use a multifaceted approach to vaccines, and this can be used to create a malaria vaccine that protects against many different mutations, ”says Wirth.
Despite its shortcomings, the RTS, S vaccine is the first major step in figuring out which types of vaccines may work best in the future. Wirth says mRNA technology mastered during the pressure of the COVID-19 vaccine will open new doors for vaccines against other diseases that 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’re going to invent a magic bullet, but we can make better vaccines,” she said.
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