New research from the Perelman School of Medicine at the University of Pennsylvania suggests that prior exposure to seasonal flu viruses may provide some Natural Immunity to H5N1 avian influenza virus.
The study, published in Nature Medicine, found that older adults exposed to flu viruses before 1968 are likelier to have antibodies that recognize H5N1. In contrast, younger adults and children have little to no pre-existing immunity.
These findings suggest that in an H5N1 outbreak, children and younger adults may face the highest disease burden—and could benefit the most from vaccination, even with vaccines that don’t perfectly match the current circulating strain.
Decades-old flu Exposure Provides Partial Protection
Scientists have long known that early childhood exposure to influenza viruses can shape the immune system for life. This study, led by Dr. Scott Hensley, a professor of microbiology at Penn Medicine, examined blood samples from over 150 people born between 1927 and 2016 to analyze their immune responses to different flu strains.
The results showed that:
- Older adults born before 1968, who were likely first exposed to H1N1 or H2N2 viruses, had higher levels of antibodies that could bind to the stalk of the H5N1 virus.
- Younger individuals and children not exposed to older flu strains had significantly lower levels of cross-reactive antibodies.
“We found that antibody responses primed by H1N1 and H3N2 viruses decades ago can cross-react with H5N1 viruses circulating today,” Hensley explained. “Most of these cross-reactive antibodies cannot prevent infection, but they may help limit disease severity in the case of an H5N1 pandemic.”
How the Immune System Responds to H5N1 Vaccines: Natural Immunity to H5N1
To determine how different age groups respond to H5N1 vaccines, researchers studied another group of individuals born between 1918 and 2003 before and after they received an H5N1 vaccine in 2004. The vaccine did not fully match the current H5N1 strain circulating in birds and cattle, but it still provided valuable insights into immune response.
- Older adults already had higher H5N1-fighting antibodies before vaccination, and their antibody levels increased slightly after receiving the vaccine.
- After vaccination, children and younger adults who started with low antibody levels saw a significant increase in H5 stalk-targeting antibodies.
- The newly generated antibodies in younger individuals could bind to the older H5N1 strain and the current clade 2.3.4.4b strain, which has been spreading among cattle and birds.
Implications for Future H5N1 Outbreaks
Although H5N1 does not yet spread efficiently between humans, researchers warn that continued circulation in mammals could lead to mutations that allow the virus to infect human airway cells more efficiently. If that happens, H5N1 could spread from human to human, increasing the pandemic risk.
“In the event of an H5N1 pandemic, all age groups will likely be highly susceptible, but children could be at the highest risk of severe disease,” Hensley said. “If this is the case, children should be prioritized for H5N1 vaccinations.”
While more research is needed, these findings highlight the potential value of existing H5N1 vaccines—even those not explicitly tailored to the current circulating strain—particularly for younger populations who lack prior immunity. Natural Immunity to H5N1
Reference: Tyler A. Garretson, Jiaojiao Liu, Shuk Hang Li, Gabrielle Scher, Jefferson J. S. Santos, Glenn Hogan, Marcos Costa Vieira, Colleen Furey, Reilly K. Atkinson, Naiqing Ye, Jordan T. Ort, Kangchon Kim, Kevin A. Hernandez, Theresa Eilola, David C. Schultz, Sara Cherry, Sarah Cobey, Scott E. Hensley. Immune history shapes human antibody responses to H5N1 influenza viruses. Nature Medicine, 2025.
