Malaria parasites in vaccinated laboratory mice evolve and become more virulent, according to research at Penn State. The mice were injected with a critical component of several candidate human malaria vaccines that now are being evaluated in clinical trials. "Our research shows immunization with this particular type of malaria vaccine can create ecological conditions that favor the evolution of parasites that cause more severe disease in unvaccinated mice," said Andrew Read, Alumni Professor of Biological Sciences at Penn State.
"We are a long way from being able to assess the likelihood of this process occurring in humans, but our research suggests the need for vigilance. It is possible that more-virulent strains of malaria might evolve if a malaria vaccine goes into widespread use," Read said. The research, which will be published in the July 31 issue of the scientific journal PLoS Biology, showed that more-virulent malaria parasites evolved in response to vaccination, but the exact mechanism is still a mystery. It was not due to changes in the part of the parasite targeted by the vaccine.
No malaria vaccine ever has been approved for widespread use. "Effective malaria vaccines are notoriously difficult to develop because the malaria parasite is very complex. Hundreds of different malaria strains exist simultaneously within any local region where the disease is prevalent," Read said. Most vaccine developers use only small sections of the malaria parasite to produce an antigen molecule that then becomes a key ingredient in a highly purified malaria vaccine. Read’s lab tested the antigen AMA-1, a component of several such vaccines now in various stages of clinical trials.
"Our laboratory experiments followed clues from theoretical studies and earlier experiments that suggested that some malaria vaccines could favor the evolution of more-virulent malaria parasites," Read said. If candidate vaccines do not completely eliminate all the malaria parasites, the parasites that remain have opportunities to evolve. A mosquito then could transfer the evolved parasite from the vaccinated person into a new host -- a process called leaking. "Leaky vaccines create a situation that further fosters parasite evolution," Read said.
The study found that parasites causing worse malaria symptoms in unvaccinated mice evolved after "leaking" consecutively through as few as 10 vaccinated mice. "The parasites that are able to survive in the immunized hosts must be stronger after having survived exposure to the vaccine," Read said. "The vaccine-induced immunity apparently removed the less virulent malaria parasites, but left the more virulent ones."
The AMA-1 antigen used in the study triggers the body to make anti-malaria antibodies. These antibodies recognize the AMA-1 antigen on the parasites and disable the malaria infection. The shape of the antigen ensures that the antibodies can bind securely with the malaria parasite -- like pieces in a jigsaw puzzle -- an important step in producing immunity. Scientists already knew that vaccines become obsolete when evolutionary mutations change the parasite’s antigen structure in such a way that the antibody is not able to lock onto the targeted part of the parasite. But the study showed the malaria parasite evolved within the vaccinated mice even without any detectable changes in the antibody target on the parasite.