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

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

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Not quite 17 years ago I wrote the first of a series of blogs on H5N1's apparent preference for infecting, and often killing, young people (see A Predilection For The Young). The WHO chart above,- from 2007 - shows the trend clearly, with 80% of all H5N1 fatalities reported in those under the age of 40. 

We would revisit this unsettling phenomenon often (see 2008's Because They're Young), and while many potential causes were discussed (including children potentially having more contact with poultry), answers remained elusive.  

In 2013 this trend was unexpectedly reversed when avian H7N9 emerged in China, a subtype which demonstrated a clear affinity for infecting those over 40 (see H7N9: The Riddle Of The Ages).  Here, we only rarely saw infections in those under the age of 20, and nearly all were mild. 

There was precedence, of course. During the 1918 Spanish flu, the death rates among those in their teens, 20s, and 30s was reportedly much higher those in their 50's and 60's.  

In 1977-78, the H1N1 seasonal flu virus - which had been absent for 20 years, suddenly appeared in the Far East, and caused a pseudo-pandemic, primarily affecting those born after 1957. 

And during the  2009 H1N1 pandemic, we saw a similar age shift, where people in their 40's were hardest hit.  Here is what the CDC had to say about the impact of the virus in 2012's First Global Estimates of 2009 H1N1 Pandemic Mortality Released by CDC-Led Collaboration.

2009 H1N1 Pandemic Hits the Young Especially Hard

This study estimated that 80% of 2009 H1N1 deaths were in people younger than 65 years of age which differs from typical seasonal influenza epidemics during which 80-90% of deaths are estimated to occur in people 65 years of age and older.

By early in the last decade many researchers were convinced that the first flu you are exposed to early in life `primes' your immune system to preferentially fight similar influenza infections.  

That process, coined `Original Antigenic Sin' or OAS in 1960 by Thomas Francis, Jr. in his article On the Doctrine of Original Antigenic Sin that postulates that when the body’s immune system is exposed to and develops an immunological memory to one virus, it may be less able to mount a defense against a subsequent exposure to a second slightly different version of the virus.

We looked at some early research on this in 2010's EID Journal: Original Antigenic Sin And Pandemic H1N1.  Older people in 1918 had presumably been exposed to a similar virus in the mid-to-late 1800s, while those born before 1957 (when H1N1 was circulating) had an immune advantage in the 2009 pandemic. 

Over time, this theory was refined to say that the HA Group type (I or II) you are exposed to first could substantially affect your immune response to influenza A (see Science: Protection Against Novel Flu Subtypes Via Childhood HA Imprinting).

The idea is that if your first influenza exposure was to H1N1 or H2N2 (Group 1), you may carry some limited degree of immunity to H5 viruses (H5N1, H5N6, etc.), while if your first exposure was to H3N2 (Group 2), you may carry some degree of protection against H7 viruses instead (see Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression).

• 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. 

All of which brings us to a preprint, published today in Nature Portfolio, which suggests the reasons behind the recent spate of mild H5N1 presentations in the United States may be due to prior exposure to the H1N1 virus. 

Pre-existing H1N1 immunity reduces severe disease with cattle H5N1 influenza virus

Seema Lakdawala, Valerie Le Sage, Bailee Werner, Grace Merrbach, and 7 more

This is a preprint; it has not been peer reviewed by a journal.

https://doi.org/10.21203/rs.3.rs-4935162/v1

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This work is licensed under a CC BY 4.0 License

Abstract

The emergence of highly pathogenic H5N1 avian influenza in dairy cattle herds across the United States has caused multiple mild human infections. There is an urgent need to understand the risk of spillover into humans. Here we show that pre-existing immunity from the 2009 H1N1 pandemic influenza virus provided protection from mortality and severe disease to ferrets intranasally infected with bovine H5N1.

Additionally, a differential tissue tropism was observed with little dissemination to organs outside the respiratory tract in H1N1 immune ferrets and significantly less bovine H5N1 virus was found in nasal secretions and the respiratory tract. Taken together, these results suggest that mild disease in humans may be linked to prior immunity to human seasonal influenza viruses.

(SNIP)

Neutralization assays conducted with human sera against the H5N1 clade 2.3.4.4b strain A/dairy cattle/Texas/24008749001/2024 (cow/Tx/24 H5N1) and the 2009 H1N1 pandemic virus (H1N1pdm09) revealed high levels of circulating antibodies against H1N1pdm09 in individuals of all ages (Supplemental Data Fig 1).

Surprisingly, 20% of individuals had levels of cross-neutralizing antibodies against cow/Tx/24 H5N1 that were above the limit of detection; thSuffice to say, any pandemic that disproportionately affects the young is ese individuals were born in the 1940s, 1950s and 1960s, with only 4% of individuals born after 1970 having detectable cross-neutralizing antibodies (Supplemental Data Fig 1). This data indicates that younger individuals would be more susceptible to cattle H5N1 infection. 

 

Supplemental Data Figure 1. Neutralizing antibody titers of H1N1 and cattle H5N1 in human sera by age cohort. Sera collected from the indicated number of healthy individuals in 2020-2021 with birth years ranging from 1940-2009 were tested for neutralizing antibodies against 2009 H1N1 pandemic virus and cow/Tx/24 H5N1. Each dot represents the neutralizing antibody titer of a single individual to neutralize 100 TCID50 of H1N1pdm09 (black) or cow/Tx/24 H5N1 (red) on MDCK cells. The line indicates the geometric mean value for a given birth decade and the dotted line represents the limit of detection for the assay.

          (SNIP)

All adults have pre-existing immunity from repeated influenza virus infections over their lifetime. Statistical modeling analysis of known human cases of H5N1 and H7N9 indicate that childhood HA imprinting provides lifelong protection against severe infection and death from these viruses15 .

Most of the H5N1 human case reports have not included the age of the dairy and poultry farm workers infected. However, it is likely they are younger than 50 or 60 years of age, and thus would be highly susceptible to H5N1 infection, yet have circulating H1N1 influenza antibodies. Prior H1N1 influenza virus immunity may explain the mild H5N1 2.3.4.4b infections in humans during the cattle current outbreak.

          (Continue . . . )

 

While it is tempting to say that our exposure to the ubiquitous 2009 H1N1 pandemic virus has saved us all from the wrath of the H5N1 virus, the reality is H5N1 continues to produce severe illness and deaths in other parts of the world.  

Since 2010 the WHO has been notified of 428 H5N1 cases around the world, with 181 fatal outcomes (42%).  All of these occurred after the bulk of the 2009 H1N1 pandemic.  Granted, this is a significant improvement over the case fatality rate prior to the 2009 Pandemic, which sat at over 60% (282 deaths out of 468 cases).  

Even more telling, of the 16 H5N1 cases reported by Cambodia over the past 18 months, only 3 have been in adults and all of them survived. Among the 13 children infected - while several had mild symptoms - most were severe and nearly half (n=6) have died.

While it seems likely that there are other factors at play - including differences in the innate virulence of various H5Nx strains - this study suggests previous exposure to the pdmH1N109 virus may help blunt the impact of H5N1 infection.   At least in ferrets. 

How this translates to humans, is more difficult to say. 

While ferrets are considered the `gold standard' for influenza research, they are not humans, and so these results may not translate 100% to a human immune system which may have had decades of complex, and repeated, encounters with influenza viruses (and vaccines).

A lot may still depend upon one's first influenza A exposure.  Or on other factors still undiscovered.  

The evidence suggests an H5Nx pandemic is most likely to impact younger generations the hardest, particularly those under the age of 50.  Making it all the more important that we do all that we can now to prevent it.