A revolutionary study from the Perelman School of Medicine at the University of Pennsylvania discovered that earlier exposure to particular seasonal influenza viruses can generate cross-reactive immunity against the H5N1 avian influenza virus. The findings, published in Nature Medicine, show that older persons who were exposed to flu viruses before 1968 are more likely to have antibodies that bind to H5N1. This finding implies that younger adults and children might benefit the most from H5N1 vaccinations, even if the vaccines are not specially developed for the present circulating strain.

"We know that early childhood influenza exposures can elicit immune responses that last a lifetime," said Dr. Scott Hensley, a microbiology professor and senior author of the study. "We discovered that antibody responses that were primed by H1N1 and H3N2 viruses decades ago can cross-react with H5N1 avian viruses that circulate now. The majority of these cross-reactive antibodies cannot prevent infections, but they will likely decrease disease if there is an H5N1 pandemic."

H5N1 has been present in birds for many years, but a novel strain, clade 2.3.4.4b H5N1, has recently migrated to cattle. While this strain does not now attach well to human upper airway receptors, continued mutation through mammalian circulation may increase its transmissibility to humans, raising pandemic risks.

Influenza viruses have two important proteins, hemagglutinin and neuraminidase, which allow them to infect cells. The hemagglutinin protein has a quickly developing head and a relatively stable stalk. Current influenza vaccines largely target the hemagglutinin head, limiting infection but not providing broad immunity.

Researchers examined blood samples from more than 150 people born between 1927 and 2016. They found that older people, especially those born before 1968 who were probably exposed to H1N1 or H2N2 strains, had more antibodies that could bind to the stalk of H5N1 hemagglutinin proteins. The study concluded that a person's birth year has a considerable influence on their level of cross-reactive immunity against H5N1. Conversely, young toddlers without prior exposure to seasonal flu viruses exhibited low levels of these antibodies.

To further investigate immunological responses, the researchers examined how people born in different years reacted to an H5N1 vaccine from 2004. They obtained blood samples from people born between 1918 and 2003 before and after vaccination. The 2004 vaccine did not exactly match the current clade 2.3.4.4b H5N1 strain, but it nevertheless supplied useful information.

Prior to vaccination, older persons showed elevated levels of H5 stalk-binding antibodies. After receiving the vaccine, their antibody levels climbed slightly. Young babies, on the other hand, had a much stronger response, with a big rise in H5 stalk-binding antibodies after being vaccinated. These antibodies were able to fight both the 2004 H5N1 virus and the clade 2.3.4.4b strain that is currently going around.

"In the event of an H5N1 pandemic, all age groups will likely be highly susceptible, but it is possible that the highest disease burden will be in children," Hensley told me. "If this is the case, children should be prioritised for H5N1 vaccinations."

These findings have significant implications for pandemic preparation. H5N1 is still an emerging concern because it has not spread widely from person to person yet. However, the study implies that current flu vaccinations, particularly those that target hemagglutinin stalks, may provide some protection against future epidemics.

Vaccination plans may need to prioritise younger people who lack pre-existing immunity to provide better protection against catastrophic disease outcomes in the event of an H5N1 pandemic.