Preprint: Immune History Shapes Human Antibody Responses to H5N1 Influenza viruses - Nature Comms (updated Mar 13th)

[Michael Coston]

Preprint: Immune History Shapes Human Antibody Responses to H5N1 Influenza viruses

Note: Those familiar with OAS (original antigenic sin) and immune imprinting may wish to skim, or skip, my rather lengthy intro.

#18,390


Nearly 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. The WHO chart (above) illustrates that pattern with disturbing clarity.

Six years later we saw the opposite trend with avian H7N9 in China, which skewed heavily toward older adults (see H7N9: The Riddle Of The Ages).

The concern here is that an H5N1 pandemic might be far more impactful for young adults and children than for those, say . . . over 50. While we think of flu taking its biggest toll on the elderly, we've seen 3 flu pandemics in relatively recent history where the burden shifted to a younger cohort.

• The 1918 pandemic showed a unique W-Shaped Curve (see below), where young adults (25-30) were particularly hard hit, while mortality rate actually dropped in those over the age of 60.

• In 1978, H1N1 returned after an absence of 20 years (potentially from a lab leak in Russia or China) sparking a pseudo-pandemic (aka `the Russian Flu') that primarily affected those under the age of 20 (see mBio: The Reemergence Of H1N1 in 1977 and The GOF Debate).

• While the average (mean) age of a flu-related fatality in a `normal’ flu season here in the United States is about 76 years, the average during the (relatively mild) 2009 H1N1 pandemic was half that; at 37.4 years (see Study: Years Of Life Lost Due To 2009 Pandemic).

Over the past decade we've seen a lot work on the idea that the first flu HA type (Group 1 or 2) you are exposed to can shape your immune response to influenza for the rest of your life through a process called Original Antigenic Sin (OAS) (see PLoS Path.: Childhood Immune Imprinting to Influenza A).

• 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.

Over the past few months we've looked a a flurry of studies on the immune response to H5N1 (an HA Group 1 virus), and the effects of previous H1N1 vaccination and/or infection. A few of many include:

Two More Preprints Suggesting Prior H1N1 Infection May Provide Some Cross-Protection Against `Bovine' HPAI H5N1

Preprint: Targets of influenza Human T cell Response are Mostly Conserved in H5N1

Preprint: Pre-existing H1N1 Immunity Reduces Severe Disease with Cattle H5N1 Influenza Virus

Frontiers Vet. Sci: Influenza Virus Immune Imprinting - Clinical Outcome In Ferrets Challenged with HPAI H5N1

All of which brings us to a new preprint, which suggests that younger people may be more heavily impacted by an H5 virus, and that they may benefit more from a pandemic vaccine than adults. I've only posted the abstract, and some brief excerpts, so follow the link to read it in its entirety.

I'll have a bit more after the break.

Immune history shapes human antibody responses to H5N1 influenza viruses

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 Ort, Kangchon Kim, Kevin A. Hernandez, Theresa Eilola, David C. Schultz, Sara Cherry,arah Cobey, Scott E. Hensley

doi: https://doi.org/10.1101/2024.10.31.24316514

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Abstract

Avian H5N1 influenza viruses are circulating widely in cattle and other mammals and pose a risk for a human pandemic. Previous studies suggest that older humans are more resistant to H5N1 infections due to childhood imprinting with other group 1 viruses (H1N1 and H2N2); however, the immunological basis for this is incompletely understood.

Here we show that antibody titers to historical and recent H5N1 strains are highest in older individuals and correlate more strongly with year of birth than with age, consistent with immune imprinting.

After vaccination with an A/Vietnam/1203/2004 H5N1 vaccine, both younger and older humans produced H5-reactive antibodies to the vaccine strain and to a clade 2.3.4.4b isolate currently circulating in cattle, with higher seroconversion rates in young children who had lower levels of antibodies before vaccination. These studies suggest that younger individuals might benefit more from vaccination than older individuals in the event of an H5N1 pandemic.

(SNIP)

Based on our studies and the observation that H5N1 viruses have typically caused more disease in younger individuals 15,16, it is possible that older individuals would be partially protected in the event of an H5N1 pandemic.

Younger individuals who have fewer group 1 influenza virus exposures would likely benefit more from an H5N1 vaccine, even a mismatch stockpiled vaccine 28 174 . It will be important to continue to test new updated vaccine antigens in individuals with diverse birth years, including children.

It will also be important to closely monitor clade 2.3.4.4b H5N1 virus circulating in wild and domestic animals, as well as spillover infections of humans, so that we can continue to evaluate the pandemic risk of these viruses.

(Continue . . . )


Although recent reports of `mild' H5N1 infections in American farm workers are somewhat reassuring, there are no guarantees how long that will persist.

The virus continues to evolve, and in Cambodia H5N1 has killed roughly 1/3rd of those that it has hospitalized over the past 2 years, and in China, H5N6 has a reported fatality rate of 50%.

While it is widely assumed that a some (perhaps large) number of milder cases go unreported, and the `real world' CFR (Case Fatality Rate) is likely far lower, even a 1%-2% fatality rate would have a devastating impact.

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. Which makes the rapid development of a safe and effective H5 vaccine a high priority.

But, as we saw last week in SCI AM - A Bird Flu Vaccine Might Come Too Late to Save Us from H5N1 - there are many obstacles to overcome - including the growing public distrust of vaccines.

Given the stakes, it is still worth doing everything we can to keep the H5N1 virus from becoming a pandemic.

https://afludiary.blogspot.com/2024/11/preprint-immune-history-shapes-human.html

[sharon sanders]

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[Michael Coston]

Nature Comms: Immune history shapes human antibody responses to H5N1 influenza viruses




Credit ACIP/CDC

#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.

H5 viruses belong to HA Group 1, while H7 viruses belong to HA Group 2, which may explain why China's H7N9 epidemic was so heavily skewed towards older individuals (see comparison chart below).




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


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

Nature Medicine (2025)Cite this article

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.

Older adults might be more resistant to bird flu infections than children, Penn research finds

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.


https://afludiary.blogspot.com/2025/03/nature-comms-immune-history-shapes.html