September 04, 2013
By C.J. Janovy
|Barney S. Graham, M.D., Ph.D.|
When the journal Science reported last month that an early stage clinical trial of a malaria vaccine had been found to be safe protection against malaria in healthy adults, it was big news.
CNN reported that it was "first time any vaccine trial has shown 100% success in protecting subjects from the mosquito-borne tropical disease, which sickens more than 200 million a year and killed about 660,000 in 2010." Of course, CNN noted, more research is needed. But according to the Washington Post, "If the vaccine works as promised, it would be an extraordinary scientific milestone: the first highly effective vaccine against a parasite. And this particular parasite has been living in human hosts — and killing them — since humans evolved."
Though his name didn't make headlines, one of the key figures in the discovery and co-senior author on the manuscript is a graduate of the University of Kansas School of Medicine. Barney S. Graham, M.D., Ph.D., is chief of the Viral Pathogenesis Laboratory and Clinical Trials Core at the National Institute of Allergy and Infection Diseases, and supervised the conduct of the trial at the NIH Clinical Center in collaboration with investigators at the Walter Reed Army Institute of Research and the Naval Medical Research Center. Graham earned his medical degree from the KU School of Medicine-Wichita in 1979, and went on to earn a Ph.D. from Vanderbilt University in 1991. He grew up in Olathe and Paola, and he still comes home to visit family.
The new vaccine involved a feat of microscopic bioengineering on the part of one of Graham's colleagues, Stephen L. Hoffman, M.D., head of the biotechnology company Sanaria Inc., in Rockville, Md. Hoffman is a former director of the malaria program at the Naval Medical Research Center, and has devoted his career to different approaches in search of a malaria vaccine.
Working with mosquitoes raised in insectaries, Hoffman developed a method using a dissecting microscope to gather sporozoites (SPZ) of the malaria-causing parasite Plasmodium falciparum (Pf) from the insects' salivary glands, then freeze the sporozoites and recover them for use in an intravenous vaccine, now known as PfSPZ Vaccine.
Graham says Hoffman turned to this method after a decade of "trying more elegant approaches with more modern techniques," such as attempting to create a vaccine using single antigens and gene-based delivery using DNA or vaccine vectors. "Dr. Hoffman decided he would go back to the roots of malaria vaccinology," Graham explains. In the 1960s and '70s, Graham notes, Ruth and Victor Nussenzweig (she is a professor of medical and molecular parasitology, and he is a professor of preventive medicine) of NYU Langone Medical Center discovered they could immunize humans against malaria by irradiating infected mosquitoes — thus weakening the parasitic sporozoites — and allowing them to bite people, which would trigger an immune response. "Over 40 years ago, they showed that if you got around 1,000 mosquito bites from irradiated mosquitoes, that would protect you from an infectious challenge from a live parasite," Graham says. "The problem is that irradiated mosquitoes can't be scaled-up as a practical vaccine."
Despite the challenges of dissecting mosquitoes' salivary glands, Graham says, Hoffman's method is practical. "One person can harvest around 500 doses per day," he says. "The trick is not to just isolate the sporozoites but to cryospreserve them in a way that allows recovery without significant loss of antigenicity or immunogenicity."
The Phase I trial took place at the NIH Clinical Center in Bethesda, with 57 healthy adult volunteers who never had malaria; 40 participants received the vaccine and 17 did not. All of the participants were exposed to bites by five mosquitoes carrying the P. falciparum strain and monitored as outpatients for seven days. They were then admitted to the NIH Clinical Center, where they stayed until they were diagnosed with malaria, treated with anti-malarial drugs and cured of infection — or shown to be free of infection.
The approach had detractors, but Graham stepped in at a crucial moment to ensure that the trial could take place.
"Most of our work is on viral vaccines — HIV, influenza, respiratory syncytial virus, Ebola, Marburg (which is similar to Ebola), West Nile, SARS, and other emerging infections," Graham says. "But I also consult for different groups involved in malaria and Tb vaccine development. Dr. Hoffman got to a place in his program where he found that injecting the parasites just below the skin didn't provide protection from infection, and increasing skepticism led some of Hoffman's backers to withdraw funding." But Graham saw the potential in Hoffman's work.
"Using the clinical trial resources we have available to our program, we had a small window of opportunity and time. Despite the fact that we're mostly a virology vaccine group, we decided to do this very complicated, challenging study. My role was in recognizing that it was a pivotal study that would either provide proof-of-concept or bring the program to an end."
The Vaccine Research Center also had an expert on malaria immunity in Robert A. Seder, M.D., chief of the Cellular Immunology Section of the NIAID. "Because of Bob's expertise and interest in the trial and the impact it could have on the field," he says, "we decided to go ahead and do it." Seder was principal investigator of the trial.
They enrolled the first study participant in October 2011; the exciting results came a year later. "In October 2012, we had all those people in the hospital and very few people were getting infected. We woke up every morning and examined people and did their smears, and day after day they remained uninfected."
Graham credits A.L. Chapman, Ph.D., who was an anatomy professor during Graham's years as a medical student, for providing his first research experience. Chapman became KU Medical Center's first dean of graduate studies and served as Executive Vice Chancellor in 1995; he retired in 1999. "I owe a lot to him for providing my first exposure to biomedical research," Graham says. "I was co-author on one of the papers that came out of his lab. That was a big influence for me."
As one of the first graduates of the KU School of Medicine–Wichita program, Dr. Graham has some advice for today's medical students.
"I wish I could talk to them about some of the extraordinary technologies that are becoming available that provide an atomic level understanding of disease pathogenesis," he says, noting that the field of vaccinology has changed radically in the last five years. "For example, the convergence of new techniques to rapidly isolate human monoclonal antibodies, perform deep sequencing of antibody repertoires, and define precise structures recognized by neutralizing antibodies, has opened up a new era of structure-based vaccine design that will have a dramatic impact on future vaccine development and our understanding of infectious diseases in general. I'm stunned there aren't more people wanting to go into science — students at all levels, not just medical students — when there's so much opportunity now. We have so many amazing technologies to understand things at such a deep level. I encourage students to think about that, learn more about it and look for opportunities in science they can pursue."