Scientists have not identified many antigens — proteins that spur a protective immune response — for use in malaria vaccines. Now there appears to be one more with significant, if preliminary, promise. A team of researchers led by Dr. Jonathan Kurtis and Dipak Raj of Brown University and Rhode Island Hospital has identified PfSEA-1.
They found it by looking for proteins recognized by antibodies in kids who are malaria resistant but not by antibodies in kids who are susceptible. They learned that the protein blocks the malaria parasite from leaving the blood cells it manages to infect. Kurtis described the research in an interview below with David Orenstein.
Why has it been so difficult to develop vaccines for malaria?
Several factors have conspired to stymie efforts to develop a broadly effective malaria vaccine. First, the parasite is incredibly complex, with multiple lifecycle stages and the ability to change its dominant surface proteins rapidly. Second, vaccine development for the past four decades had focused on basic science paradigms. This has resulted in the majority of vaccine candidates identified either in rodent models or as the targets of commonly developed antibodies in highly exposed humans. It is now quite clear that rodent models of infectious diseases, particularly their immunologic mechanisms, are poor simulacrums of human disease. Furthermore, parasite antigens that are highly immunogenic (i.e., they are recognized by the majority of individuals in an endemic area) are unlikely to be protective; rather they represent decoys specifically deployed by the parasite to distract our immune system.
Our departure from this paradigm was to emphasize the intersection of population biology and basic science in our discovery efforts. We specifically designed our studies to identify the rare parasite antigens recognized by only resistant individuals.
What are the main results that suggest PfSEA-1’s potential for a vaccine?
PfSEA-1 was discovered by starting with naturally occurring protective human immune responses. A principal obstacle in the decades-long search for a malaria vaccine has been generalizing discoveries made in mice to human malaria. By beginning with humans, we hoped to identify vaccine targets that will be relevant in humans. Using molecular gymnastics, we identified parasite proteins that are only recognized by antibodies in children who were resistant to malaria but not by antibodies in susceptible children. We subsequently demonstrated that vaccination with one of these proteins, SEA-1 could protect mice from a lethal malaria infection. We chose a mouse model that no blood stage vaccine had ever succeeded in, specifically to set a high bar for success.
More importantly, in our cohort of over 750 children, kids who made antibodies to PfSEA-1 did not develop severe malaria, while children without these antibodies were susceptible to this severe complication. Lastly, we have generalized these results to an entirely independent cohort of Kenyan adolescents and adults and demonstrated that antibodies to PfSEA-1 predicted resistance to malaria infection. Together, these results augur well for ultimately inducing resistance by vaccinating humans with PfSEA-1 based vaccines.
What does PfSEA-1 do?
PfSEA-1 is essential to allow the parasite to escape from one infected red blood cell and infect additional blood cells. This cycle of expansion in red blood cells is critical for parasite survival and is the key process that leads to morbidity and mortality in humans. Using molecular techniques, we decreased the amount of PfSEA-1 that parasites could produce and demonstrated that these altered parasites had a significant growth defect. More importantly, antibodies to PfSEAs prevent the parasites from escaping from red blood cells, presumably by interfering with the function of PfSEA-1.
What happens next? For example, is PfSEA something you can test directly in human clinical trials of safety and efficacy?
There are three major areas for further study. First, we need to understand the role that PfSEA-1 plays in the process of parasite egress from red blood cells. By understanding what PfSEA-1 interacts with to affect egress, we will identify additional targets in this critical pathway. Second, we need to understand the role of cellular immunity in PfSEA-1-mediated protection. Cellular immunity is critical for long-lived antibody responses, but detailed analysis of cellular responses requires fresh blood samples, thus we are currently planning to enroll new cohorts in east Africa to address this question. Lastly, we need to move PfSEA-1-based vaccines into nonhuman primate challenge trials using human-use approved vaccine adjuvants. Following successful nonhuman primate studies, Phase I safety trials in humans can begin.
Some of the original research you describe in the paper goes back to 1997. Please describe the scale of the effort.
This work describes a very broad arc of inquiry, beginning with field work, followed by laboratory investigations, culminating in more field work. Our project represents an excellent example of intra and extra-mural NIH collaboration. The senior investigators primarily responsible for the field-based components of the work (Patrick Duffy and Michal Fried) are intramural scientists at NIAID. Patrick was my postdoctoral advisor in 1996 in Kisumu, Kenya, and we have had a productive relationship ever since. When we wanted to generalize our protective anti-PfSEA-1 results to an independent cohort of humans, we naturally chose the Kenyan cohort we had recruited during my postdoctoral fellowship.
Perhaps more critically, our project demonstrates the power of discovery poised at the intersection of epidemiology, biostatistics, molecular biology, and immunology. We firmly believe that such interdisciplinary and inter-institutional co-operation is necessary to make progress toward a vaccine for the greatest single agent killer of children on the planet.