Malaria vaccines could make malaria nastier. In mice given an experimental vaccine now in trials, the malaria parasite evolved to get round the immunity – and in the process caused more severe disease.
Malaria kills 2000 children every day, sickens millions repeatedly, and helps keep tropical nations in poverty. Yet there is still no vaccine, partly because the parasite takes different forms as it moves from mosquitoes to human blood, to liver cells, red blood cells and back to mosquitoes.
One malaria vaccine – RTS,S – is in large-scale trials. It targets the liver stage of the parasite. Other vaccines in trials target the blood-cell stage, and contain a parasite protein called AMA-1, meant to prime the body’s immune system to attack it.
These vaccines all seem likely to be “leaky”, allowing vaccinated people to still acquire and transmit some parasites. Parasites that pass through vaccinated people this way could start resisting the vaccine in two ways, saysAndrew Read at Pennsylvania State University in University Park. The parasites’ AMA-1 could change so that vaccine-induced immunity won’t recognise it, a process called immune escape. Or parasites may emerge that dodge immunity in other ways, which could make the disease more virulent.
Rise in virulence
In 2004 Read tested this by passing mouse malaria repeatedly between mice made immune by natural infection. Those parasites indeed became more virulent, but it wasn’t clear how.
Read has now repeated the experiment using an AMA-1 vaccine. His team passed blood-cell-stage malaria parasites 10 times between mice that had been given the AMA-1 vaccine. By the end, the parasites reached higher densities, and caused more anaemia, than those passed between unvaccinated mice. Parasites from vaccinated mice were more virulent in unvaccinated mice as well.
“The real eye-opener was that there was no immune escape,” says Read. “Parasite AMA-1 was unchanged.”
Instead, the parasites had other changes in gene activity that allowed them to escape vaccine-induced immunity, and these changes also made them more virulent. A vaccine that did this in people would lose its effectiveness very quickly, says Read, while boosting the deadliness of local malaria, particularly for unvaccinated people.
Clinical trials test whether vaccines protect people from disease, but don’t look for impacts on the actual pathogens, apart from some that have tracked immune escape. Read says that in future such trials should also track which genes are active in malaria parasites in vaccinated people.
Journal reference: PLoS Biology, DOI: 10.1371/journal.pbio.1001368