First malaria vaccine, despite all the hurdles, an important milestone

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WebMD Health

December 2, 2021 – The parasite that causes malaria can kill a person within 24 hours of symptoms appearing. Patients’ symptoms are flu-like, including fever, headache, and chills. It all starts with a microscopic puncture.

When a malaria-infected mosquito sticks 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 that becomes more and more difficult.

In the first 15 years of this century, global efforts to contain malaria have reduced the number of cases by 40% and the number of deaths by more than 60%. But in 2015 that progress slowed. Malaria has been on the rise since then, having steadily declined in the number of cases for over a decade.

Scientists know that the parasites that cause malaria are resistant to drugs as long as we have them. These mutations first appeared in the Great Mekong Delta of Southeast Asia in the past and then spread to Africa, elsewhere in Asia and South America – but this time it’s different.

In late 2019, scientists in Rwanda announced that they had reason to believe that F. plasmodium – by far the most common of the five malaria parasites and the deadliest – mutated along the country’s northern border with Uganda to produce artemisinin, one of the two partner drugs to treat malaria. Such bypassing puts pressure on the other drug to eradicate the parasite itself.

“The moment you lose your partner drug, treatment fails,” said David A. Fidock, PhD, professor of microbiology and immunology at Columbia University in New York City.

In October this year, the World Health Organization approved the first malaria vaccine, the protein-based RTS, S / AS01. The four-dose vaccine, fueled by groundbreaking efforts to prevent COVID-19, is a major milestone that scientists have worked meticulously towards for decades.

However, experts say the vaccine alone is not enough to stop malaria infections.

“The vaccine can get the disease going again, but it can’t replace medication, it’s not effective enough,” says Fidock.

First vaccine

The fact that malaria is caused by parasites rather than bacteria or viruses is why it was so difficult to develop a vaccine against it.

The P. falciparum parasite has approximately 5,300 genes “that it can use to evade anything the host throws 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.SARS-CoV-2, the virus that causes COVID-19, only has 11.

The new malaria vaccine will be most effective when used in conjunction with existing prevention methods, including mosquito nets, chemical insecticides, and frontline artemisinin combination treatment (ACT). The threat of resistance remains.

“Just as the virus that causes COVID mutates, so do the parasites. They are living elements that want to survive, and the only way to survive is to mutate, ”says Pascal Ringwald, MD, who heads the Drug Resistance and Containment Unit of the World Health Organization’s Global Malaria Program.

Parasites also need to be combated at several stages in their life cycle, which involves two hosts: the mosquito and the infected human. Attacks at various stages in their life cycle appear to be key to effective vaccine treatments.

“You can’t rely 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 attack it at another stage, ”says Solomon Conteh, 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 parasite’s complex life cycle.”

A harmful legacy

In addition, humans and mosquitoes and thus malaria parasites have developed together since the existence of our species – so closely that the parasites have left traces in the human genome. Genetic variations that affect red blood cells, particularly sickle cell anemia, are likely the result of malaria.

“These traits were likely selected by the malaria parasite by killing people who did not carry these mutations. This is a strong evolutionary force, both the parasite on humans and the humans on the parasite, and we are now trying to get right into this evolutionary process, ”says Wirth.

Disrupting the evolutionary relationship between humans and malaria is compounded by unprecedented drug resistance. Although some variants developed naturally, most parasites develop as a result of being better avoided by humans.

This intervention “creates extreme pressure under which only those parasites can survive that have developed in order to evade the treatment,” says Wirth. “The parasite has many inherent variations, mainly due to evading the human immune response. When developing a vaccine, we have 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 a delayed eradication of malaria parasites in Rwanda, which means that one drug does not work immediately to reduce the number of parasites that have infected the body – a sign that partial resistance to the two drugs is evident. ACT. It is the first documented evidence of artemisinin resistance in Africa, where around 94% of malaria cases occur.

“In Africa the warning lights are definitely going on because we have a precedent in Asia. We know drug resistance in the greater Mekong Delta has rendered several drugs used in ACT useless, ”says Fidock. “The first drug failed, and because it didn’t work as quickly, there were more parasites for the partner drug and more opportunities for the parasites to mutate. Once you have partner drug failure, you will get treatment failure. Then we get a significant increase in deaths. “

Moving target

So far, resistance to anti-malarial drugs first appeared reliably in the Greater Mekong region, which includes parts of Cambodia, Laos, Myanmar, Thailand, Vietnam and the southern Yunnan Province in China. Scientists have understood this and have been carefully monitoring the area for signs of drug resistance. When it surfaced, the strategy was to build a firewall using insecticide, mosquito nets, and aggressive treatment that kept the parasite from escaping the area. Sometimes it did, and a human carried the parasite to other continents, including Africa.

But that’s not the case for the first time. 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 mutated independently to resist treatment.

“The fact that the artemisinin resistance developed independently is something completely new; this makes containment more complicated, ”says Ringwald. “Imagine a fire. When a forest is on fire it is easier to contain it, but when five different forests are burning at the same time it becomes much more complicated. “

Fidock said malaria deaths in Senegal increased ten-fold when the dominant anti-malarial 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.

New vaccines, though difficult to diagnose, offer another tool that combined drugs could provide relief when one partner fails.

A resurgent interest in developing a vaccine against malaria is an incredibly important piece of the puzzle in malaria treatment and prevention, says Fidock. More groundbreaking developments can be expected in the coming years, but the challenge remains complex and will likely require a multi-pronged approach.

Promising future

Most people in areas with high malaria prevalence develop some immunity to the disease by the time they reach puberty. It is for this reason that the RTS, S vaccine, which is becoming available in parts of Africa, was developed for children ages 5 and younger. But a 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 defensive measures.

“The vaccine isn’t 100% effective, so there are still people who get sick and you treat them with a drug, and that drug is an artemisinin-based combination therapy,” says Conteh, who is part of a team that is on a vaccine that targets a different stage in the parasite’s life cycle than the RTS, S vaccine. The two could potentially be used together, but trials are still ongoing.

Future vaccines also need to address the sieve effect, where parasites that look different to the immune system can slip through the protection.

“It’s not dissimilar to what we saw with the coronavirus. It’s very effective against the original version and less effective against the Delta version, ”says Wirth. “We think this could happen with malaria vaccines.”

Multiple alleles – or versions 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-approach to vaccines, and that could be used to develop a malaria vaccine that protects against many different mutations, ”says Wirth.

Despite its shortcomings, the RTS, S vaccine is the first big step in figuring out what types of vaccines might work best in the future. Wirth says mRNA technology mastered in the search 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 well adapted to the human metabolism. I think it’s naive to think we’re going to develop a silver bullet, but we can make better vaccines, ”she says.

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