August 1, 2012
Dangerous Malaria Gives Researchers Concern
(Ivanhoe Newswire) — According to research from Penn State University, malaria parasites evolving in vaccinated laboratory mice become more lethal. The mice were injected with a critical component of several candidate human malaria vaccines that are currently 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," Andrew Read, Alumni Professor of Biological Sciences at Penn State, was quoted as saying. "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."
The research showed that more-virulent malaria parasites evolved in response to vaccination, but the mechanism remains a mystery. It was not due to changes in the part of the parasite targeted by the vaccine.
There has never been a malaria vaccine 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 was quoted as saying. Most vaccine developers only use small sections from the malaria parasite to create an antigen molecule that becomes an important ingredient in a highly purified malaria vaccine. For this study, researchers tested the antigen AMA-1, a component of several such vaccines that are now in differing 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 was quoted as saying. If candidate vaccines do not completely destroy all of the malaria parasites, the parasites that remain have opportunities to evolve. A mosquito could potentially transfer the evolved parasite from the vaccinated person into a new host in a process called "leaking."
"Leaky vaccines create a situation that further fosters parasite evolution," Read was quoted as saying.
The study found that the parasites that were causing worse malaria symptoms in unvaccinated mice evolved after consecutively "leaking" 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 was quoted as saying. "The vaccine-induced immunity apparently removed the less virulent malaria parasites, but left the more virulent ones."
The AMA-1 antigen activates the body to make anti-malaria antibodies. These antibodies recognize the AMA-1 antigen on the parasites and restrict the malaria infection. The shape of the antigen ensures that the antibodies can securely bind with the malaria parasite -- like pieces in a puzzle -- an important step in producing immunity. Scientists already knew that vaccines become obsolete when evolutionary mutations change the parasite's antigen structure so that the antibody is not able to lock onto the targeted part of the parasite. However, this new study showed that the malaria parasite evolved within the vaccinated mice even without any noticeable changes in the antibody target on the parasite.
"We were surprised to find that more-virulent strains of malaria evolved even while the gene encoding the key antigen remained unchanged," Victoria Barclay, the postdoctoral scholar in Read's lab who conducted the laboratory experiments and who is the corresponding author of the PLoS Biology paper, was quoted as saying. "We did not detect any changes in the gene sequence." The researchers determined that evolution must have taken place somewhere in the parasite's genome. Read's lab now is searching for the exact locations on the parasite's DNA where the mutations occurred.
"Generalizing from animal models is notoriously difficult in malaria," Read was quoted as saying, so the researchers do not yet know if this newly recognized type of evolution could happen in human malaria or with other rapidly evolving diseases, like viruses that cause AIDS or cervical cancer. "What we do know is that in Victoria Barclay's experiments in our lab at Penn State; with our parasites, our mice, and with this particular antigen; the malaria parasites that evolved through vaccinated hosts become more virulent."
"Vaccines are one of the most fantastically cost-effective health gains we've ever had, so there is no question that we should proceed on all fronts to develop a safe and effective vaccine against malaria," Read was quoted as saying. "At the same time, our research is revealing new reasons to proceed with vigilant caution."
Read believes that vaccine researchers leading clinical trials should carefully monitor for parasite evolution at the vaccine target, as well as watch for mutations throughout the parasite's entire genome.
"This sort of monitoring also should go on once a new vaccine goes into widespread use," he was quoted as saying. "It appears that in a world with leaky vaccines, virulent pathogen strains can evolve. Different vaccines or other transmission-blocking measures might be needed to stop the spread of any evolved parasites."
Source: PLoS Biology, July 2012