#18,372
Four months ago, in Preprint: Immune History Shapes Human Antibody Responses to H5N1 Influenza viruses, we looked at a report that suggested that younger people may be more heavily impacted by an H5 virus, and that they may benefit more from a pandemic vaccine than adults.
This is not exactly a new idea, as 18 years ago, in a blog called A Predilection For The Young, I wrote about H5N1's affinity for infecting, and often killing, younger adults, adolescents, and children.
More recently, in Cambodia - of the 18 H5N1 cases reported over the past 24 months - 4 have been in adults and 3 of them survived. Among the 14 children infected - while several had mild symptoms - most were severe and half (n=7) have died.
In 2016's Science: Protection Against Novel Flu Subtypes Via Childhood HA Imprinting, we looked at research which suggested the influenza HA Group type (I or II) you are first exposed to makes a significant, and lasting, impression on your immune system.
- Those born prior to the mid-1960s were almost certainly first exposed to Group 1 flu viruses (H1N1 or H2N2)
- Those born after 1968 and before 1977 would have been exposed to Group 2 (H3N2)
- After 1977, both Group 1 and 2 viruses co-circulated, meaning the first exposure could have been to either one.
Yesterday the preprint mentioned at the top of this blog was published in Nature Comms (see link below).
Immune history shapes human antibody responses to H5N1 influenza viruses
While the full study is behind a paywall, the preprint remains freely available, and we have the following press release from Penn State. I'll have a postscript after the break.
Previous exposures to older flu strains prime the immune system to produce antibodies against H5N1, and children would likely benefit the most from H5N1 vaccinations
March 13, 2025
PHILADELPHIA— Prior exposures to specific types of seasonal influenza viruses promote cross-reactive immunity against the H5N1 avian influenza virus, according to new research from the Perelman School of Medicine at the University of Pennsylvania. Older adults who were exposed to seasonal flu viruses that circulated prior to 1968 were found to be more likely to have antibodies that bound to the H5N1 avian flu virus. The findings, published today in Nature Medicine¸ suggest that younger adults and children would benefit more from H5N1 vaccines, even those not tailored specifically to the current strain circulating in birds and cattle.
“We know that early childhood influenza exposures can elicit immune responses that last a lifetime,” said senior author Scott Hensley, PhD, a professor of Microbiology. “We found that antibody responses that were primed by H1N1 and H3N2 viruses decades ago can cross-react to H5N1 avian viruses circulating today. Most of these cross-reactive antibodies cannot prevent infections, but they will likely limit disease if we have an H5N1 pandemic.”
Potential protection from a rapidly changing virus
H5N1 viruses have circulated in birds for many years, but a new version, called clade 2.3.4.4b H5N1 virus emerged more recently, and has since spread among cattle. This current H5N1 strain does not bind well to receptors in the human upper airway, but widespread circulation in mammals could lead to mutations that help the virus infect human airway cells and increase transmission. If this occurs, H5N1 could potentially start spreading from human to human.
Influenza viruses are covered with two lollipop-shaped proteins called hemagglutinin and neuraminidase, for which the viruses are named (H5N1, for example). These proteins are what allows a virus to attach to “healthy” cells and start the process of infection. Current influenza vaccines primarily elicit antibodies that recognize hemagglutinin proteins, and prevent them from infecting a person’s cells. The lollipop “heads” of hemagglutinin proteins evolve more frequently while the “sticks” of the hemagglutinin lollipops, called stalks, don’t evolve as quickly.
Researchers tested blood samples from over 150 people born between 1927 and 2016 for antibodies targeting the stalk proteins of different influenza viruses, including H5N1. They found that blood samples from older adults born prior to 1968 who were likely first exposed to H1N1 or H2N2 in childhood had higher levels of antibodies that could bind to the stalk of the H5N1 virus. They found that an individual’s birth year was closely linked to the amount of H5N1-fighting antibodies in their blood. Young children who were not exposed to seasonal flu viruses possessed low levels of antibodies that could fight H5N1.
Existing vaccines are effective
To determine how individuals with different birth years respond to H5N1 vaccinations, researchers obtained blood samples from a separate group of individuals born between 1918 and 2003 before and after they were vaccinated with a 2004 H5N1 vaccine that did not perfectly match the clade 2.3.4.4b H5N1 virus that is currently circulating.
Consistent with the researchers’ initial findings, older adults had higher amounts of antibodies that could bind to H5 stalks before vaccination. Following vaccination, H5 stalk antibodies increased slightly in older adults, but increased substantially in children. These antibodies bound to both the 2004 H5N1 virus and to the clade 2.3.4.4b H5N1 virus that is circulating today.
“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,” said Hensley. “If this is the case, children should be prioritized for H5N1 vaccinations.”
This research was supported by the National Institute of Allergy and Infectious Diseases (75N93021C00015, R01AI08686).
Although any `protection' provided by past exposure to HA Group 1 viruses is likely to be limited, and any advantage to those born before 1968 may be offset by other age-related comorbidities, the prospect of a pandemic virus that targets children and adolescents is particularly harrowing.
While not as severe, in 1977 we saw this principle in action. An H1N1 flu virus - which had not been seen in 20 years (and likely escaped from a laboratory in China or Russia) - reappeared and began a global pseudo pandemic.One that primarily affected those born after the 1957 H2N2 pandemic. As a young (24 y.o.) paramedic I transported scores of sick kids to the hospital, but was never infected.
Although not as pronounced, the 2009 H1N1 pandemic also skewed towards infecting a younger cohort. The CDC’s estimate of average and median age of death due to the 2009 Pandemic virus reads:
Based on two CDC investigations of confirmed 2009 H1N1-related deaths that occurred during the spring and fall of 2009, the average age of people in the U.S. who died from 2009 H1N1 from April to July of 2009 was 40. The median age of death for this time period was 43. From September to October of 2009, the average age of people in the U.S. who died from 2009 H1N1 was 41, and the median age was 45.
While prioritizing the H5 vaccine for younger patients may make sense, it remains to be seen whether an increasingly vaccine-adverse society will embrace that option.
All of which makes anything we can do to avoid an H5 pandemic very much worth the effort.
