It was at the University of Michigan’s School of Public Health that Thomas Francis Jr., one of America’s most accomplished virologists and epidemiologists, wrote his groundbreaking paper on “original antigenic sin,” arguing that a person’s first flu exposure affects subsequent influenza exposures.
Aubree Gordon, assistant professor of epidemiology, hopes to continue Francis’ work.
Gordon and an international team of researchers, co-led by Paul Thomas of St. Jude Children’s Research Hospital, secured a $35 million, seven-year National Institutes of Allergy and Infectious Diseases grant to look into that first infection or exposure through influenza vaccination and its effects.
“The grant will allow us to look at ‘imprinting,’ which is this idea of how your first flu exposure affects future exposures,” she said. “And it’s fitting that this work, originally observed and written about at the University of Michigan, will continue to be studied, at least in part, here.
“We’ve actually realized that flu exposure history probably affects your susceptibility to additional influenza infections, although we don’t really understand why. It probably explains why sometimes the vaccine works really well in certain age populations and not others.”
The grant will allow Gordon and colleagues in Nicaragua to continue the cohort she’s been leading there since 2011, and will add similar cohorts in Los Angeles and New Zealand. Collaborators also include researchers from multiple other U.S. institutions and Australia.
“These cohorts provide a unique opportunity to define the basic immunological mechanisms in B and T cells that mediate the imprinting effect,” said Thomas, a member of the St. Jude Department of Immunology. “The fantastic team we’ve assembled will be able to provide an in-depth characterization of the developing immune system.”
On the frontier of flu research
The School of Public Health has long been on the cutting edge of influenza research. In addition to Francis — who would also work with his former protegé, Jonas Salk, in the development of the polio vaccine — the school also was home to Hunein “John” Maassab, who developed the technology of what would become the nasal-spray influenza vaccine FluMist.
Another of the school’s well-known professors is Arnold Monto, who worked under Francis on the Tecumseh Study, a large-scale, long-range epidemiological study that followed an entire village in an effort to understand the chronic and acute disease dynamics.
When the Hong Kong flu pandemic broke out in 1968, Monto and his team vaccinated a large percentage of the village’s school-age population, proving that “herd immunity” worked. This method is still key to addressing an influenza outbreak. Monto continues to counsel international health organizations such as the World Health Organization, and is the author of many groundbreaking papers including his 2005 paper warning of the dangers of an avian influenza pandemic.
“University of Michigan researchers have been at the forefront of research on influenza, which continues to be a major threat to global public health,” said F. DuBois Bowman, dean of SPH. “We’re excited this grant will allow us to continue on this tradition and make a contribution towards one day developing a universal flu vaccine.”
From dengue to influenza
Gordon initially became involved with the cohort in Nicaragua as a graduate student while at the University of California, Berkeley. There, she met professor Eva Harris, who had been working with a cohort focusing on dengue research in the Central American country.
As a part of dissertation work, Gordon added influenza onto that existing cohort study to form an influenza cohort. Later, in 2010, Harris and Gordon received funding to establish the ongoing influenza cohort and Gordon brought it to U-M when she came to the university in 2014.
Getting a cohort group going is an intensive process. To recruit newborns, researchers talk to mothers during their pregnancy and explain in detail what participating in the study entails. Depending on the family’s preferences, they’ll meet at a medical center or the family’s home, collect samples, have ID batches for participants, and do a number of surveys such as breastfeeding and vaccination history, exposure to smoke, size of the house, how many people live there, access to water—all factors that are updated regularly. As part of the arrangement in the community, they also provide medical care for the study participants.
In addition to the pediatric cohort, the U-M/Nicaraguan team conducts a number of other influenza studies, and Gordon collaborates with UC-Berkeley and Nicaragua’s Ministry of Health and other organizations on a number of studies on mosquito-borne viral illnesses. They follow households for influenza, which has allowed researchers to also look into rates of infection within families.
In addition, the cohorts have provided opportunities to do research on how flu virus spreads and what factors might make it more likely for someone to get the infection, as well as vector-borne diseases like dengue, Zika and chikungunya.
While the original cohort was funded to look at some more basic questions around the burden and seasonality of the flu, expanding it will help look at the question of imprinting and repeat infections.
“I absolutely felt like I had to capture those first infections. It’s really that design that helped us to get this grant and, of course, we have an amazing team,” Gordon said.