Results of partnership between the Ragon Institute, GSK Vaccines, Janssen Vaccines, WRAIR, and PATH is key step in understanding human protection against Plasmodium falciparum infection; could help accelerate clinical trials of future malaria vaccines
Researchers at the Ragon Institute of MGH, MIT and Harvard, in collaboration with the global health non-profit PATH, the Walter Reed Army Institute of Research, and pharmaceutical companies GSK and Janssen Vaccines & Prevention B.V., have discovered two markers of immunity in response to the RTS,S/AS01 malaria vaccine that correlated strongly with protection from infection. The ability to identify a successful immune response to the RTS,S/AS01 vaccine could greatly reduce the amount of time and funding needed to develop more effective malaria vaccines. The results of this study were recently published in the journal Science Translational Medicine.
“It is clear from our results that the key to making a vaccine successful is to understand the quality of the response – what parts of the immune system respond and how – rather than just measuring the quantity of the response,” said Dr. Galit Alter, Professor of Medicine at Harvard Medical School and a Group Leader at the Ragon Institute of MGH, MIT and Harvard. “We’re incredibly excited about the potential broader implications of these results for the malaria field.”
In this study, the Alter lab, collaborating with Dr. Ulrike Wille-Reece of PATH’s Malaria Vaccine Initiative, and Dr. Erik Jongert of GSK Vaccines, studied the immune response to the RTS,S/AS01 malaria vaccine to identify what features of the vaccine-induced immune response correlated with protection from infection. Several previous studies examined humoral, cellular, and transcriptional predictors of protection and described the contribution of select immune features to protection from the parasite. Here, the group used systems serology, a platform technology developed by the Alter lab, to define key features of the antibody response that could reliably identify vaccinated individuals that were protected from malaria infection from those who weren’t. They found a vaccine immune response that included antibody-mediated phagocytosis and engagement of the Fc gamma receptor 3A was more likely to indicate protection from malaria.
Malaria, a disease caused by the mosquito-borne parasite Plasmodium falciparum, affects more than 200 million people each year. The most advanced malaria vaccine (RTS,S/AS01) is only partially effective; in a large Phase 3 trial it was shown to reduce clinical malaria cases by 40% and severe malaria cases by 30% in young African children.
“A key problem for malaria vaccine development is that there are no identified correlates of immunity, and we don’t really know how most candidates tested in clinical trials actually work,” said Dr. Ulrike Wille-Reece, Scientific Advisor for PATH’s Malaria Vaccine Initiative. “Having a surrogate for vaccine-induced protection would allow future trials to proceed more readily, saving money and time and accelerating the development of next generation vaccines to protect individuals most at risk of malaria.”
Using systems serology, Drs. Jon Fallon, Jishnu Das, Todd Suscovich, and colleagues, including a collaboration with Dr. Doug Lauffenburger of MIT, began a detailed study of the immune system’s response to the vaccine. Dr. Alter’s team was able to find two responses unique to healthy US adults who were protected by the RTS,S vaccine, irrespective of the vaccine formulation. The first response was antibody-mediated phagocytosis, which involves antibodies attaching to the pathogen and driving pathogen-uptake by immune cells known as phagocytes - immune cells that can engulf and digest harmful invaders. The second response was antibody mediated Fc gamma receptor 3A (FCGR3A) engagement, known to trigger killing of antibody-bound targets. Among the cells that express FCGR3A, natural killer cells, which are able to kill invading pathogens, have been implicated in anti-pathogen responses. Together, these antibody functions were highly predictive of protection from infection across vaccine regimens and even across additional vaccine trials.
This major step in understanding protection against P. falciparum infection has been long awaited. These data can now be incorporated into larger field studies, including to determine if they predict protection from malaria in young African children, who are the most-at risk from malaria, and to guide the optimal use of the RTS,S vaccine, as well as selection and design of more effective vaccines. This will help researchers develop a detailed understanding of the precise response they aim to elicit and what vaccine design and components can drive that response, a process known as rationale vaccine design.
About the Ragon Institute of MGH, MIT and Harvard
The Ragon Institute of MGH, MIT and Harvard was established in 2009 with a gift from the Phillip T. and Susan M. Ragon Foundation, creating a collaborative scientific mission among these institutions to harness the immune system to combat and cure human diseases. With a focus on HIV and infectious diseases, the Ragon Institute draws scientists, clinicians and engineers from diverse backgrounds and areas of expertise to study and understand the immune system with the goal of benefiting patients.
PATH is a global organization that works to accelerate health equity by bringing together public institutions, businesses, social enterprises, and investors to solve the world’s most pressing health challenges. Our team of innovators comprises more than 1,500 employees in offices in 20 countries. With expertise in science, health, economics, technology, advocacy, and dozens of other specialties, PATH develops and scales solutions—including vaccines, drugs, devices, diagnostics, and innovative approaches to strengthening health systems worldwide. We work in more than 70 countries to transform bold ideas into sustainable solutions that improve health and wellbeing for all, reaching over 150 million people, on average, each year.