The development of the COVID-19 vaccines was a triumph of biotechnology. But that triumph has partly obscured the amount of luck involved in the process of vaccine development. We've been trying for decades to produce vaccines against HIV, but no amount of high-tech biology has gotten us there.

 

Malaria is another killer that has so far resisted vaccine efforts, but this spring brought hope that we are making progress. Back in May, a small clinical trial of a relatively traditional vaccine showed an efficacy of over 70 percent. And this week, a new paper describes a very different way of generating highly effective immunity to the malarial parasite.

Why is malaria so hard?

Malaria has resisted vaccination for several reasons. One is that the disease is not caused by just a single infectious agent. Instead, Malaria comes from several related species in the Plasmodium genus. Plasmodium falciparum typically causes more severe illnesses and has thus been the target of most vaccine efforts. But even if we're able to prevent infections by this strain, we won't see the end of malaria.

 

Targeting Plasmodium falciparum hasn't been a simple matter, either, as there are various regional strains that differ in ways that can be significant for immune system recognition. Even a single strain doesn't present an easy target for an immune response, though. The parasites undergo several distinct stages within the human body, with different proteins associated with each. And the parasite can alter other proteins on its surface to act as decoys that distract the immune system.

 

That said, researchers have gradually identified a handful of proteins that are consistently present on the surface of malarial parasites and are essential for their infectivity. That information has led to the development of vaccines that attempt to generate an immune response to these proteins.

Progress report

In a paper published in May, a large international team of researchers gave a progress report on one of those efforts. The work involved a vaccine developed in collaboration with Novavax and uses the same technology that went into the company's successful COVID vaccine. In short, the vaccine starts by taking a Plasmodium falciparum protein and modifying it so that it clusters into virus-sized particles. These particles are then injected alongside a chemical that boosts immune responses.

 

The team enrolled 450 infants in a malaria-prone region of Africa, with two groups given different doses of the vaccine and the third given an unrelated vaccine to serve as a control. The children were given three doses over three months, then a booster a year later. Testing showed that the two vaccine groups generated both antibodies and a T-cell response to the malarial parasite, with the levels being generally higher in the high-dose group. Antibody levels dropped slowly over time but quickly returned after the one-year booster shot.

 

Side effects were mild and typical of those seen with coronavirus vaccines.

 

The vaccine was very effective. Seventy percent of the participants in the placebo group ended up with a malaria infection by six months after the last of the three initial doses. In the two vaccine groups, only 29 and 26 percent of the participants did. That works out to an efficacy of 77 percent, a protection that stayed constant even as the children were followed out to a year after the third dose.

Is that really a vaccine?

While this news is welcome, some researchers still worry about basing a vaccine on a single protein, which could allow the malarial parasites to evolve a way of evading the immune response. Boosters using additional proteins could help manage that risk, but much of the vaccine effort has focused on using parasites that are inactivated either by radiation or genetic mutations. These would necessarily carry most of the proteins that the immune system is likely to see following an infection.

 

Results have been mixed so far, but a paper released today describes a variant on this approach that falls somewhere between a vaccine and a controlled infection.

 

The work relied on several overlapping factors. While resistance against most malarial drugs is widespread in wild populations, we can grow many lab strains that are still vulnerable to the drugs. Some of these drugs—called pyrimethamine—kill the parasites while they're multiplying in liver cells. This is an early, asymptomatic stage of the infection. Stopping the parasite here would mean that none of the complications of malaria will occur.

 

The immunization was a simple extension of this idea—expose people to parasites that are vulnerable to pyrimethamine while treating the patients with the drug. This process allowed the exposed people to develop a robust immune response to the earliest stage of the infection while keeping them from reaching any of the later, more dangerous stages. The researchers tested the same approach using the now-infamous chloroquine, which kills the parasites when they start multiplying in the blood.

 

The trial was a small safety test, with fewer than 10 people in each group (the groups used different doses of malarial parasites and one of the two drugs). And the testing involved people who were willingly infected with malarial parasites multiple times to either boost the vaccination or test its effectiveness.

A more promising future?

The results look promising. While low initial doses of parasites weren't very effective, seven of the eight people who received the high dose were protected from reinfection, indicating that the treatment provides sterilizing immunity. Perhaps more critically, in a group that was later infected by a different parasite strain than the one the participants were vaccinated against, protection remained strong. Seven out of nine participants avoided infection.

 

(Since chloroquine stops the parasites later than pyrimethamine, it's not surprising that people in those groups experienced more malarial symptoms during the vaccination protocol. One person also chose to withdraw from the study due to emotional problems that have been associated with chloroquine use.)

More to do

There's still a lot of work to do, both in terms of optimizing the protocol and understanding how it generates sterilizing immunity without allowing the parasite to get to the most immunogenic stages of infection, when the parasite spreads in blood cells. But if the results hold up in larger tests, the prospect of cross-strain protection is incredibly important. And the drug used for this purpose, pyrimethamine, is already widely employed as a prophylactic against malarial infections in pregnant women.

 

We're still a long way from having straightforward protection against a disease that kills nearly a half-million people every year. Both evolution and medical research regularly generate surprises; these two treatments are very early in the research phase, and evolution will kick in if either is widely adopted.

 

But it's hard not to be excited that lasting immunity against the most dangerous form of malaria might be possible. We may need to combine and modify techniques and find ways to boost immunity and counter new strains that appear. But we'll do so knowing that failure isn't inevitable.

 

The Lancet, 2021. DOI: 10.1016/S0140-6736(21)00943-0

 

Nature, 2021. DOI: 10.1038/s41586-021-03684-z  (About DOIs).