Malaria remains one of the world’s major public health challenges. Despite recent advances, including the introduction of malaria vaccines, the protection they provide is still partial, and the complexity of the Plasmodium parasite’s life cycle makes it difficult to develop broad and long-lasting immunity.
A new study from GIMM researchers, published in the Journal of Infectious Diseases, with the support of Merck KGaA, explores an approach that seeks to combine two functions in a single intervention: eliminating the parasite while allowing the immune system to develop memory against future infections. The study, led by Claudia Demarta-Gatsi, Diana Moita, Diana Fontinha, Raquel Ventura, Helena Nunes-Cabaço, Thomas Spangenberg and Miguel Prudêncio, evaluated the potential of cabamiquine (CBQ) in mouse models of malaria.
A controlled risk: treating the infection without completely preventing exposure to the parasite
Conventional treatment strategies aim to eliminate the parasite as quickly as possible. The approach investigated in this study is different: it uses a drug capable of blocking Plasmodium growth at a controlled point during infection, allowing the immune system to be exposed to a broader range of parasite components without allowing the infection to progress to severe disease. A strategy known as infection-and-treatment.
Cabamiquine is a novel oral antimalarial that inhibits the Plasmodium eukaryotic elongation factor 2 (eEF2), interfering with parasite protein synthesis, that is currently in Phase 2 clinical development in combination with pyronaridine. One of the drug’s relevant characteristics is its activity across different stages of the parasite’s life cycle, including the liver and blood stages. The study aimed to address a central question: could CBQ, by controlling the infection, also contribute to the development of protective immune memory?
In an initial series of experiments, mice were exposed to sporozoites, the form of the parasite transmitted by mosquitoes, and subsequently treated with a single dose of CBQ.
The treatment prevented the liver infection from progressing to detectable blood-stage infection.
The study also explored a second possibility: using CBQ when the parasite is already in the blood stage of infection, when malaria symptoms occur. At this stage, the researchers treated the animals after parasitaemia had reached a defined level and subsequently exposed them to the parasite again. A single administration of CBQ in combination with pyronaridine, which corresponds to the therapeutic strategy currently under clinical development, was able to clear the initial infection and induce protection against severe disease caused by the second exposure to the parasite.
A bridge between treatment and vaccination
The findings presented in this study point to a particularly interesting concept: the possibility of using an antimalarial drug not only to treat or prevent an infection, but also to transform a controlled infection into an opportunity for the immune system to learn. This approach could be relevant in settings where exposure to Plasmodium is repeated. Rather than immediately eliminating all exposure to parasite antigens, treatment could allow sufficient exposure to stimulate immune memory while keeping the parasite under control.
“Next steps should include studies aimed at better understanding the relationship between cabamiquine’s pharmacological activity, the duration of exposure to parasite antigens, and the development of immune memory”, Miguel Prudêncio notes. The ultimate goal, therefore, would be to transform the process of treating an infection itself into an opportunity to prepare the immune system for the next one.