Curing disease is really a matter of outfoxing evolution. When we assault bacteria or viruses or cancer cells with drugs, they evolve ways of resisting those drugs. We attack, they counter-attack. Take malaria: the Plasmodium parasites that cause the disease have repeatedly evolved to resist our best anti-malarial drugs. The mosquitoes that carry the parasites have evolved to resist the insecticides we poison them with. And now, Victoria Barclay from Pennsylvania State University has found that some malaria vaccines could drive Plasmodium to become even deadlier than it is now.
Several malaria vaccines are in development, but none have been licensed yet. Barclay vaccinated mice with a protein that’s found in several of these vaccines, and then exposed them to Plasmodium. After a few generations, the parasite became more ‘virulent’ – that is, it caused more severe disease. And it did so via an evolutionary escape route that is rarely considered.
Vaccine creators aren’t naive to the possibility of resistance. They’re trying to train the immune system to recognise and destroy Plasmodium by presenting them with proteins on the parasite’s surface, and they know that the parasites could evolve their way around this defence by changing the structure of those proteins. To prevent that from happening, we could use proteins from a diverse range of Plasmodium parasites, so that vaccines would work against several strains.
But vaccines could drive the evolution of Plasmodium in other ways that are arguably more dangerous. For example, the parasites might adapt by reproducing more aggressively, so that they overwhelm the immune response that’s primed by the vaccine.
Until recently, this was a hypothetical concern. Then in 2004, Andrew Read – the head of Barclay’s group and a proponent of the idea of “evolutionary medicine” – showed that Plasmodium becomes more virulent after spending time in mice that had been previously immunised. In that experiment, the immunity came from exposure to the entire parasite. Now, Barclay has shown that exposure to a single protein will do the same thing.
She vaccinated mice with AMA-1 – a malarial protein that’s found in at least ten of the vaccines currently being trialled. These mice were good at suppressing normal Plasmodium parasites (of a species that causes malaria in rodents), but almost totally ineffective at containing more virulent strains. If virulent strains have such a big advantage in vaccinated mice, they ought to evolve naturally.
That’s exactly what Barclay saw. She allowed normal Plasmodium strains to incubate for a week in vaccinated mice, before taking blood samples and injected them into more vaccinated mice. These “serial passages” went on for 20 rounds. By the end, the parasites grew much faster and wrecked 20 percent more red blood cells. They had become more virulent, something that didn’t happen when Barclay did the same experiment with unvaccinated mice.
In one way, these results are surprising. AMA-1 is very variable, and some scientists have suggested that this is a problem. If the protein is already diverse, it should be easier for the parasites to evolve a version that skirts around the vaccine-induced protection. But that’s not what Barclay found. The virulent parasites hadn’t changed their ama-1 gene in any way. They must have altered other genes that allowed them to reproduce more quickly. They were sneaking past the vaccine-induced immune response; they were simply overwhelming it by numbers.
“It’s a nice paper, by a strong group, with rigorous methods,” says Mahamadou Thera from Mali’s Malaria Research and Training Center. If the same thing happened in humans, the worry is that unvaccinated people would face deadlier versions of the disease. But Barclay writes that that “we are a long way from being able to assess the likelihood of this occurring in human malaria populations, were a malaria vaccine to go into widespread use.”
For a start, she used a different species of Plasmodium to the one that infects humans. She also artificially transferred the parasite from mouse to mouse with a syringe, which may not truly reflect the spread of the parasite via mosquitoes. (However in the team’s earlier study, they did use mosquitoes and although that reduced the heightened virulence of the evolved parasites, it didn’t bring that virulence back down to original levels.)
And Barclay only studied vaccines that target malaria at the red blood cell stage. Others attack Plasmodium at an earlier part of its life cycle, when it’s in the liver. These include RTS,S, a potential vaccine that apparently halves the risk of developing malaria. It’s not clear if such vaccines would also drive the evolution of more virulent parasites, but since RTS,S is closest to being licensed, that’s certainly an important question.
“It is certainly a worry that we have in terms of the [proteins] that we have in the vaccine pipeline,” says Kirsten Lyke, who works on malaria vaccines. “The bottom line is that no one really knows [what will happen] because we have not successfully produced a licensed malaria vaccine to date.”
Thera adds that there are “reasonable hopes” that some malaria vaccines could be sterilising – that is, they would provide total, leak-free protection against the disease, either by training the immune system with whole weakened parasites or by recruiting T-cells to attack them.
Caveats aside, Barclay’s study is a much-needed wake-up call. Even when we know that parasites can evolve to evade our weapons, we risk making things worse if we don’t consider all the evolutionary options that are open to them.
Malaria vaccines still have the potential to save millions of lives, and this study should not undercut their significance or potential. But Barclay thinks that scientists who are running vaccine trials should now analyse the full suite of active genes in the parasites from vaccinated people, and those from the control group. That should help us spot the genetic signs of greater virulence before such enhanced parasites have a chance to spread. Fortunately, Thera says that we have both the tools and the samples we need to carry out this type of work. It’s just a case of doing it.
Barclay says that her study probably applies to many other vaccines that don’t offer fool-proof protection against their respective diseases. For example, Bordetella pertussis – the bacterium behind whooping cough – is on the rebound, and Barclay says, “The strains of pertussis that are appearing are reported not only to have the potential to evade the protective effects of vaccination, but also to increase disease severity.” Future vaccines against flu and HIV may face similar problems, since our natural immunity against these diseases is so poor.
“As vaccines are continuously developed against those difficult diseases, we hope our study will make vaccine developers mindful of the different types of evolution that might occur, and to inaugurate any necessary precautions,” says Barclay. “The last thing we need is a situation, analogous to the drug-resistance treadmill, whereby the subsequent vaccines just add to the resistance problem.”
Reference: Barclay, Sim, Chan, Nell, Rabaa, Bell, Anders & Read. 2012. The Evolutionary Consequences of Blood-Stage Vaccination on the Rodent Malaria Plasmodium chabaudi. PLoS Biology http://dx.doi.org/10.1371/journal.pbio.1001368
Image by James Gathany via CDC
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