Generating vaccines toward eukaryotic pathogens has always presented challenges for researchers. While single-celled eukaryotic parasites, such as those that cause malaria may not seem close to humans evolutionarily, at the cellular level vaccine targets become limited due to homology with host molecules. However, now a team of investigators at Yale University has identified a novel target within the malaria parasite that protects against infection against the pathogen in mouse models—paving the way for the development of a human vaccine that works by targeting the specific protein that parasites use to evade the immune system.
Findings from the new study were published today in Nature Communications through an article titled “Neutralization of the Plasmodium-encoded MIF ortholog confers protective immunity against malaria infection.” Malaria is the second leading cause of infectious disease worldwide and took close to a half-million lives in 2016. To date, no completely effective vaccine exists, and infected individuals only develop partial immunity against disease symptoms.
In previous studies, the Yale team described a unique protein produced by malaria parasites, Plasmodium macrophage migration inhibitory factor (PMIF), which suppresses memory T cells, the infection-fighting cells that respond to threats and protect the body against reinfection.
In the current study, the researchers collaborated with Novartis Vaccines to test an RNA-based vaccine designed to target PMIF. First, using a strain of the malaria parasite with PMIF genetically deleted, they observed that mice infected with that strain developed memory T cells and showed stronger anti-parasite immunity.
“We showed the impact of PMIF immunoneutralization on the host response and observed improved control of liver and blood-stage Plasmodium infection, and complete protection from re-infection,” the authors wrote. “Vaccination against PMIF delayed blood-stage patency after sporozoite infection, reduced the expression of the Th1-associated inflammatory markers TNF-α, IL-12, and IFN-γ during blood-stage infection augmented Tfh cell and germinal center responses, increased anti-Plasmodium antibody titers, and enhanced the differentiation of antigen-experienced memory CD4 T cells and liver-resident CD8 T cells. Protection from re-infection was recapitulated by the adoptive transfer of CD8 or CD4 T cells from PMIF RNA immunized hosts.”
The Yale team subsequently used two mouse models of malaria to test the effectiveness of a vaccine using PMIF. One model had an early-stage liver infection from parasites carried by mosquitos, and the other, a severe, late-stage blood infection. In both models, the vaccine protected against reinfection. As a final test, the researchers transferred memory T cells from the immunized mice to “naïve” mice never exposed to malaria. Those mice were also protected.
“If you vaccinate with this specific protein used by the malaria parasite to evade an immune response, you can elicit protection against re-infection,” explained senior study investigator Richard Bucala, M.D., Ph.D., professor at Yale School of Medicine. “To our knowledge, this has never been shown using a single antigen in fulminant blood-stage infection.”
The research shows, first, that PMIF is critical to the completion of the parasite life cycle because it ensures transmission to new hosts, said the scientists, noting it also demonstrates the effectiveness of the anti-PMIF vaccine.
The next step for the research team is to develop a vaccine for individuals who have never had malaria, primarily young children. “The vaccine would be used in children so that they would already have an immune response to this particular malaria product, and when they became infected with malaria, they would have a normal T cell response, clear the parasite, and be protected from future infection,” Dr. Bucala noted.
The researchers also noted that because the PMIF protein has been conserved by evolution in different malaria strains and targets a host pathway, it would be virtually impossible for the parasite to develop resistance to this vaccine. Numerous other parasitic pathogens also produce MIF-like proteins, said the scientists, suggesting that this approach may be generalizable to other parasitic diseases—such as Leishmaniasis, Hookworm, and Filariasis—for which no vaccines exist.