Investigators from Yale School of Medicine, in collaboration with Novartis Vaccines, Inc, have developed a novel vaccine that successfully protects against malaria infection in a mouse model.
Even though global deaths from malaria have declined by 60% since 2000, there are still a startling number of cases of the disease around the world. In fact, in 2016, there were an estimated 216 million cases of malaria worldwide and 445,000 deaths, according to the US Centers for Disease Control and Prevention (CDC).
In an opening address of the First Malaria World Congress, hosted by Melbourne, Australia, in July, Tedros Adhanom Ghebreyesus, PhD, Director-General of the World Health Organization, reflected on the need to continue research related to malaria. “Countries must take a comprehensive approach, including vector control, early detection and treatment with effective medicines,” he said, “To combat insecticide and drug resistance, research and development of new tools is essential.”
Although progress is being made by large scale interventions to reduce the number of cases of malaria, which is the second leading cause of infectious diseases in the world, there is currently no effective vaccine that prevents infection. This is partly due to the fact that exposure to malaria parasites does not lead to long-term immunity; exposure only partially protects against disease manifestations, and infections continue to recur, often asymptomatically.
In a new study, investigators from Yale School of Medicine, in collaboration with Novartis Vaccines, Inc, report the effects of a novel vaccine that successfully protected against malaria infection in a mouse model. The results have been published in Nature Communications.
According to the investigators, “the novel vaccine delayed blood-stage patency after sporozoite infection and 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 vaccine, which is an RNA-based vaccine, is designed to target the Plasmodium macrophage migration inhibitory factor (PMIF), the protein responsible for suppressing memory T cells.
“We think PMIF as a vaccine target is highly trackable because it elicits remarkable levels of protection and targets the precise protein that the malaria parasite uses to escape host immunity,” Richard Bucala, MD, PhD, professor of medicine, epidemiology, and pathology, at Yale School of Medicine and an author of the study told Contagion®.
“We used a novel vaccine platform—a self-amplifying RNA replicon—which is essentially a defective RNA virus that produces a vaccine antigen and has a track record for eliciting both antibody and T cell responses, which are considered essential for memory and for protection from malaria,” he continued.
In the early stages of the study, investigators genetically modified a strain of the malaria parasite to delete the PMIF protein and infected mice with the strain. They observed that the mice infected with the strain developed memory T cells and exhibited stronger immunity against the parasite.
To test the effectiveness of the vaccine, the investigators used 2 mouse models. One group of mice had early-stage liver infections from mosquito-borne parasites, and the other group had severe late-stage blood infections. The investigators found that in both groups, the vaccine protected against future reinfection with the malaria parasite.
According to the researchers, the vaccine would be increasingly difficult for the parasite to become resistant to because the PMIF protein targets a host pathway and has been conserved by evolution. This could lead to promising futures for vaccinations for other parasitic diseases that produce similar proteins, such as leishmaniasis, hookworm, and filariasis.
“If you vaccinate with this specific protein used by the malaria parasite to evade an immune response, you can elicit protection against re-infection,” said Dr. Bucala a statement, “To our knowledge, this has never been shown using a single antigen in fulminant blood-stage infection.”
Dr. Bucala and his team shared that their future steps will focus on developing a vaccine for individuals who have never been infected with malaria that can produce an immune response to regulate T-cell responses and clear the parasite if the person becomes infected. This would be a critical development for young children, especially in Sub-Saharan Africa where malaria is endemic.