2/27/2025
PITTSBURGH – Pre-existing immunity against seasonal H1N1 flu might help explain why most reported human cases of H5N1 bird flu in the U.S. have not resulted in lethal outcomes, suggests a new study by University of Pittsburgh School of Medicine and Emory University researchers. The report was published last week in Emerging Infectious Diseases.
In a ferret model of virus transmission used to study the potential of viruses to spread between people, pre-existing immunity appeared to influence infection severity in ferrets. Compared to immunologically naïve animals, ferrets that were immune to H1N1 because of an earlier infection were protected against severe disease and death caused by a strain of H5N1 bird flu currently circulating in wild birds, poultry and cows. Ferrets without prior immunity had more severe illness and fatal outcomes.
The study underscores the contributions of pre-existing immunity to flu viruses in shaping disease severity against future infections and highlights the need for a concerted effort to consider pre-existing immunity in the context of pandemic risk assessment. As of this article’s writing, the World Health Organization rates the bird flu risk to the general population as low, despite the first death reported in the U.S.
“All human flu pandemics emerge in the context of pre-existing immunity,” said lead author Valerie Le Sage, Ph.D., research assistant professor of microbiology and molecular genetics at the University of Pittsburgh. “Our model isn’t perfect because the human immune response is complicated. But if we are using ferrets as surrogates for humans, it is very important to do so in the context of prior immunity.”
An ongoing outbreak of H5N1 bird flu virus has been spreading in dairy cow herds across state lines since March 2024. Yet, despite its deadliness for poultry, foxes, mink, cats and even whales, dolphins and seals, the virus has not appeared to be devastating cow populations and has not caused severe disease in the majority of cases.
To understand why, researchers at the Pitt Center for Vaccine Research and at Emory University looked at ferrets. Unlike other mammals that are used to study flu transmission in the lab, ferrets develop clinical symptoms of flu infection that closely resemble humans. They develop a fever, sneeze and have a runny nose. Ferrets are also used to model the way that the virus transmits through a tightly knit population or in small, contained spaces, that can emulate conditions in places such as schools or daycare centers.
Among the small number of ferrets that were intranasally infected with H5N1, only those that had been previously exposed to H1N1 survived the infection. Despite a similar degree of lung tissue damage, ferrets without prior immunity exhibited higher fever and greater weight loss and decrease in playfulness compared to those with H1N1 prior immunity, which also seemingly helped the animals to clear out virus from their nasal passages faster and limited the infection to the respiratory tract. In contrast, immunologically naïve ferrets displayed signs of systemic infection with virus particles spreading throughout the body, including the heart, liver and spleen.
The mechanism behind how prior infection with seasonal H1N1 might protect the animals against H5N1 is not fully known, because antibodies made to the H1N1 virus do not inactivate the H5N1 virus. Therefore, it is unlikely that seasonal vaccination against H1N1 will protect against severe disease from H5N1. The U.S. Centers for Disease Control and Prevention recommends annual flu vaccination to protect against seasonal flu viruses. There is no recommendation for vaccination against H5N1 at this time.
“The study findings suggest that pre-existing immunity against H1N1 from prior infections will not protect someone from getting infected with H5N1, but it can make the infection less severe. However, young kids whose immune system has not yet been exposed to a lot of viruses, people who are immunocompromised or those with other underlying health conditions can still get seriously ill,” said senior author Seema Lakdawala, Ph.D., professor of microbiology and immunology at Emory University’s School of Medicine.
“Further study into whether vaccination can provide the same level of protection is still needed. Immune responses generated by infection are different from those generated by vaccination,” Lakdawala added.
Other authors of this research are Bailee Werner, B.S., Grace Merrbach, B.S., Sarah Petnuch, B.S., Douglas Reed, Ph.D., Anita McElroy, M.D., Ph.D., and Paul Duprex, Ph.D., all of Pitt; Louise Moncla, Ph.D., of the University of Pennsylvania; and Aoife O’Connell, B.S., and Nicholas Crossland, D.V.M., both of Boston University.
This research was supported in part by the National Institutes of Health (S10OD030269, S10OD026983 and UC7AI180311), Department of Health and Human Services (contract 75N93021C00015), and the Burroughs Wellcome Fund (CAMS 1013362.02).