Understanding Malaria, Immunity, and Hope for the Future

April 25, 2025

In honor of World Malaria Day (April 25th) and the publication of a landmark new study in Science Immunology,  we caught up with Prasanna Jagannathan, MD, Associate Professor of Infectious Diseases at Stanford Medicine. 

Jagannathan and his collaborators, including PhD student Jason Nideffer and Maria Grazia Roncarolo, MD, have uncovered new insights into how the immune system remembers and responds to malaria infections — findings that could help shape future vaccines and treatments.

Here, Jagannathan reflects on what first inspired his work, the ongoing challenges in the global fight against malaria, and why he remains hopeful for the road ahead.

1. What first inspired you to work on malaria, and what has kept you dedicated to this area of research?

During my clinical training, I had the opportunity to do a research rotation in Uganda, where I saw firsthand the enormous toll malaria takes on communities.

In highly endemic areas, the main way to prevent malaria is through insecticide-treated bednets. Yet despite their use, children still experience a staggering number of infections. In a study we conducted in Eastern Uganda, children had, on average, nearly three episodes of malaria by their first birthday — and some had as many as 10.

What fascinates me, and what inspired my work, is that over time, children living in these areas can tolerate malaria parasites without showing symptoms. Despite decades of research, we still don’t fully understand how this immune tolerance develops. Our lab is working to uncover the mechanisms behind it, with the goal of designing better vaccines and preventive strategies.

2. From your perspective, what are the biggest challenges we still face today in the fight against malaria?

Malaria cases and deaths remain unacceptably high, especially among young children, and are rising again in several regions. In 2023 alone, the World Health Organization estimated over 260 million cases and nearly 600,000 deaths worldwide.

Many countries face ongoing challenges, including funding shortfalls, gaps in surveillance, and the growing threat of drug resistance in both parasites and mosquitoes. Regional conflicts, displacement, food insecurity, and the limited durability of current preventive tools — including vaccines — make the situation even more difficult.

The burden is especially heavy in 11 African countries, which account for about two-thirds of the world’s malaria cases. This includes Uganda, where malaria remains a major health challenge. At Stanford, we are partnering with the Infectious Diseases Research Collaboration in Uganda to better understand how the immune system protects against malaria, with the goal of improving prevention efforts.

3. Your team's newest research just published in Science Immunolgy sheds new light on how the immune system remembers malaria infections. For someone without a science background, how would you describe what your team discovered?

As part of his PhD research, Jason Nideffer, working with Drs. Maria Grazia Roncarolo and myself, studied CD4 T cells — key players in the immune response.

By following Ugandan children over time, he was able to track individual T-cell clones during and after malaria infections. We found that the same T-cell clones could persist in the body for hundreds of days and re-expand when a child got malaria again — a powerful example of how the immune system remembers past infections. Although we’ve long known immune memory exists, this was one of the first times it’s been shown so clearly in humans.

We also found that the malaria response was dominated by a group of cells called type 1 regulatory T (Tr1) cells. These cells expanded with each malaria infection and kept their unique identity over time. Our findings not only shed light on malaria immunity, but also deepen our understanding of how immune memory works more broadly.

4. What brings you the most hope right now, as a researcher working toward better prevention and treatment?

Two malaria vaccines were recently approved by the World Health Organization, and one of them, R21/Matrix-M, is being rolled out to young children across many African countries this year.

Other promising tools are also in development, including monoclonal antibodies, new chemoprevention strategies, and next-generation mosquito control efforts. On the horizon, long-acting injectable treatments — similar to what’s being developed for HIV — could offer lasting protection against malaria.

Our lab is continuing to study Tr1 cells and the immune mechanisms that support natural tolerance to the malaria parasite. We hope that understanding these pathways will help inspire new strategies to prevent malaria and overcome current challenges in elimination efforts.