Preventing malaria using genetically modified malaria parasites

Two vaccines against malaria have been rolled out in some countries in Africa. Besides vaccines, scientists have been using genetically altered mosquitoes to stop the spread of malaria. One is the release of radiation-sterilised male mosquitoes to prevent eggs from hatching. Another is engineering mosquitoes that slow the growth of malaria-causing parasites in the gut thereby preventing transmission of malaria to humans. The other method is using genetically modified mosquitoes that can spread resistance to malaria-causing parasites by thriving and mating with wild mosquitoes.

Now, in a radical approach, scientists have shifted their focus from genetic modification of malaria-causing mosquitoes to malaria-causing parasites. They have genetically modified malaria-causing parasites so that the parasites do not cause disease. Instead, they prime the immune system during the initial stage of their life cycle in the liver and before they enter the bloodstream. Malaria-causing parasites cause infection and symptoms begin to show only when they move into the bloodstream from the liver stage.

The priming of the immune system, like in the case of vaccines, by the genetically modified malaria parasites shield the individuals when malaria-causing mosquitoes bite them later. While the genetic modification kills the parasites by completely arresting its growth on day six during the liver stage (late-arresting parasite), the parasites have sufficient time to prime the immune system far more effectively than when the parasites are killed on day one (early-arresting parasite) of entering the liver.

In a small trial, researchers exposed nine healthy adults who had not had malaria to 50 bites by mosquitoes that carried the genetically modified late-arresting parasites that were designed to die on day six of the liver stage, eight healthy adults with the early-arresting parasites, and three adults in the placebo group who were bitten by uninfected mosquitoes. The 50 mosquito bites were considered as one immunisation session, and the participants were exposed to three such sessions in all. Each successive immunisation session was set at 28-day interval.

Three weeks after the third immunisation session, all participants were exposed to controlled human malaria infection by means of five bites from mosquitoes infected with genetically unaltered P. falciparum parasite. This was to test the efficacy of genetically modified malaria parasites in priming the immune system.

As per the results published in the New England Journal of Medicine, the efficacy results were striking. While eight of nine (89%) participants primed by late-arresting parasites were protected from malaria when exposed to mosquitoes carrying unaltered P. falciparum parasite, only one of eight (13%) participants who were primed by early-arresting parasites was protected from malaria. No participants in the placebo arm were protected from malaria.

The titres of antibodies targeting key P. falciparum antigens in both the early-arresting and last-arresting parasite groups were far higher than those observed in the placebo group and did not differ between participants in the two intervention arms. This suggests that the vastly different timings of killing the parasites in the liver did not affect the amount of antibody produced. But there were differences in the cellular immunity in the two intervention groups. Though the overall cellular frequency T-cell lineages remained similar, certain P. falciparum-specific T cells were seen only in participants who were primed by mosquitoes carrying the last-arresting parasites. “This suggests an important independent role of late-liver-stage antigens in inducing gamma delta T-cell responses,” they write.

Sporozoites, which are the infective stage of the malaria parasite, when attenuated by radiation also offers protection against malaria. And in contrast to the genetically modified parasites used in this study, the protection offered by radiation-attenuated sporozoites against malaria ranged between 50% and 90%. However, administration of radiation-attenuated sporozoites by means of mosquito bites requires higher doses (approximately 1,000 mosquito bites) to reach levels of protection similar to the level offered by last-arresting parasites used in this study.

“Our findings suggest that parasites arresting late during the liver stage offer improved protection, as compared with early-arresting sporozoites, and provide a step toward a next-generation malaria vaccine,” they write. However, they also caution that the conclusions from the trial are limited by the small sample size, and urge that studies with greater numbers of participants be done for better understanding of both the efficacy and the safety profile of genetically modified last-arresting parasites. They also note that the “immunologic assessments were exploratory, and the relevance of the variables associated with last-arresting-induced protection needs confirmation”. Also, the durability of immune protection offered by last-arresting parasites needs to be assessed especially against heterologous P. falciparum strains where malaria is endemic.