Could Vaccines Breed Super-Virulent Malaria?

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The rise of superbugs like MRSA provides sobering evidence that pathogens can evolve resistance to even the most powerful drugs. But pathogens can evolve resistance to vaccines, too.

One of the biggest worries for vaccine developers, aside from choosing the right strains to target, is that pathogens will evolve mutations in proteins targeted by the vaccine that will allow them to escape immune surveillance, rendering the vaccine ineffective. But as new research published in PLOS Biology from evolutionary biologist Andrew Read suggests, that’s not all vaccine developers should worry about. Working in a rodent model of malaria, Read’s group shows that vaccines can also drive the evolution of more virulent pathogens.

I should stress at the outset that these results do not suggest anything about vaccine safety. In fact, the thought that people could misinterpret the results as a reason to doubt vaccine safety keeps Read up at night. What they do suggest is that vaccines, like drugs, place selective pressures on pathogens–and that pathogens may respond to these selective pressures in unpredictable ways.

mosquito

A feeding malaria-infected female Anopheles sp. mosquito releases parasites, which infect human liver cells and mature before rupturing in a form that can invade red blood cells and cause disease. (Illustration: CDC, 1976)

Read, who directs the Center for Infectious Disease Dynamics at Penn State University, specializes in the ecology and evolution of infectious diseases. For more than a decade, he’s studied how malaria parasites respond to drugs and vaccines.

Malaria parasites, which kill close to a million African children every year, “do evolution on steroids,” Read told a TEDMED audience in April. They’ve evolved resistance to every drug deployed against them. That’s why public health officials hailed early results of the first large-scale trial of a malaria vaccine (called RTS,S), announced last October, as a remarkable achievement, even though the vaccine reduced disease by just about half.

But it’s this type of “leaky” vaccine—which may ameliorate symptoms and lessen the incidence of disease but doesn’t stop transmission—that opens the door for natural selection. Some parasites survive. And that means they can evolve.

When people think of vaccine-driven evolution, Read says, they usually think of mutations in proteins targeted by the vaccine that allow the pathogen to escape detection. “But there are many different ways evolution could run.”

If parasites under pressure of vaccination acquire mutations in genes that aren’t targeted by the vaccine but trigger aggressive growth or more efficient invasion of tissues, vaccination could promote the evolution of “superhot,” highly virulent strains.

Researchers have already seen evidence for the evolution of more virulent pathogens in chickens vaccinated against Marek’s disease and in cats vaccinated against feline calicivirus.

Theoretically, malaria parasites that infect vaccinated individuals but survive could become hotter and hotter as they pass through vaccinated populations, placing unvaccinated individuals at greater risk of severe disease.

And that’s just what the research from Read’s lab shows: when malaria parasites evolve in immunized mice, they cause more severe symptoms in unvaccinated mice.

To test the possibility that vaccination might allow more virulent pathogens to evolve, Victoria Barclay, a postdoctoral researcher in Read’s lab, first immunized mice with AMA-1, a component of a malarial protein used in several vaccines now in human clinical trials. Then, in what’s known as “serial passage” experiments, she sequentially transferred rodent malaria parasites (P. chabaudi) from one vaccinated mouse to another, simulating the natural process of disease transmission. She then repeated the process in unvaccinated mice. (Learn more about the experiments in the related synopsis.)

“The parasites get nastier when we evolve them through vaccinated mice,” says Read. “They do more damage in unvaccinated mice after evolving through the vaccinated ones.”

Read insists that there’s no telling how malaria parasites will evolve in response to vaccination in the human trials. In the paper, Read and his coauthors call for “extreme caution” in extrapolating their results to humans, noting that generalizing from animal models is notoriously difficult in malaria. “We don’t know what might happen,” says Read. “My point is we need to figure it out.”

And that’s no trivial task. For Read, the first step in evaluating the “evolutionary risk” of vaccines is to collect data on the parasites to look for genetic differences between those found in vaccinated and unvaccinated individuals. If people are still transmitting parasites after vaccination, it would be important to monitor those parasites to figure out why they survived. It could be because of changes in proteins targeted by the vaccine. Or it could be because the parasites reproduce more aggressively, which means they could become more virulent.

One thing that would help vaccine developers figure out how to apply results like these from preclinical models to human malaria is insight into any genetic changes associated with increased virulence. “Understanding the changes at the molecular level would be valuable for us to better understand how to most effectively use data like this,” says Ashley Birkett, director of research and development at PATH Malaria Vaccine Initiative, a partner in the RTS,S phase III clinical trial.

Birkett says they’re collecting samples from both control and vaccinated groups in the RTS,S trial right now and looking for potential changes associated with vaccination in malaria parasites. He acknowledges that their primary focus is the vaccine-targeted protein. “The key observation from this paper is that researchers tend to focus on the selection pressure on the antigen in which they’re immunizing, and that’s a very fair point.”

“With the AMA-1 vaccines, we’re quite focused on how immune selection pressure is impacting the sequence of the AMA-1 allele. This paper is saying that we need to look more broadly at that, and I think that point is well taken,” Birkett adds.

But Birkett would like to know more about the mechanism of virulence in the rodent malaria model to help him search for evidence of it in the human parasites. He’d also like to see experiments where animals are infected with mosquitoes rather than through blood transfer to get a better sense of how the findings translate to clinical disease and vaccination in the field. He acknowledges that such work is both technically and logistically challenging.

The new findings add to evidence from veterinary studies that vaccines can elicit multiple evolutionary outcomes in pathogens. And for Read, that means it’s time to change the way vaccine studies monitor pathogens.

“We’re very well set up as a society to evaluate the safety of vaccines for individuals who receive them but what we aren’t good at is evaluating evolutionary safety when we start changing the environments of these pathogens.”

“When we attack our germs with vaccines, the germs fight back,” Read warned the TEDMED audience. “We’re picking a fight with natural selection. And natural selection is one of the most powerful life forces in the universe.”

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Andrew Read spoke at TEDMED in April (see video below). Here’s the “science kit” he provided for his talk:

I made four points (three more than the TEDMED folk advise), but here’s my bottom line. Much of medicine attacks living things that harm us, like germs, worms, cancers, and malaria-bearing insects. Life evolves back – and that evolution harms and kills. We have to manage medically-driven evolution, but the necessary science is rudimentary. Let’s get serious about what Darwin began.

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