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

Credit CDC Antigenic Characterization

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One of the big mysteries surrounding recent human infections with HPAI H5N1 clade 2.3.4.4b viruses in the United States has been their relatively mild presentation.  In the past, H5N1 has had a fearsome reputation and a high CFR (case fatality rate) among hospitalized patients. 

Twelve years ago, in Differences In Virulence Between Closely Related H5N1 Strains, we compared the fatality rates of H5N1 infection in Indonesia ( > 80%) to that of Egypt (35%) and Bangladesh (0%).  While Bangladesh has since reported a single fatality, their CFR remains relatively low at 12.5%.

The oft-cited 50% CFR of HPAI H5N1 was only true in a handful of - mostly Asian - nations, and since the emergence and spread of clade 2.3.4.4b, has fallen dramatically.  

In contrast, in Cambodia, where an older clade 2.3.2.1c continues to circulate, nearly 40% of the 16 cases reported in the past 2 years have died. 

Another change we are seeing is that clade 2.3.4.4b - at least in the United States - suddenly appears to be transmitting more readily from poultry and cattle to humans.  Between April 2022 and April 2024 only 1 human infection was reported in the U.S., but in the 7 months since more than 30 cases have been reported. 

The HPAI H5 virus - in all of its incarnations - continues to mutate and evolve, sometimes gaining pathogenicity or transmissibility, and sometimes losing it. Each variant (subtype, clade, genotype, etc.) is on its own evolutionary path, meaning what we see today may not hold true tomorrow.  

Four months ago the CDC released a report (CDC A(H5N1) Bird Flu Response Update: Population Immunity to A(H5N1) clade 2.3.3.4b Viruses) which - based on an analysis of sera (blood) collected from people of all ages in all 10 HHS regions - found:

Data from this study suggest that there is extremely low to no population immunity to clade 2.3.4.4b A(H5N1) viruses in the United States.  Antibody levels remained low regardless of whether or not the participants had gotten a seasonal flu vaccination, meaning that seasonal flu vaccination did not produce antibodies to A(H5N1) viruses.

This means that there is little to no pre-existing immunity to this virus and most of the population would be susceptible to infection from this virus if it were to start infecting people easily and spreading from person-to-person. This finding is not unexpected because A(H5N1) viruses have not spread widely in people and are very different from current and recently circulating human seasonal influenza A viruses.

But the mystery remains as to why human illness appears to be attenuated with recent H5N1 infections, particularly since the virus remains quite deadly to other mammalian species (cats, mice, foxes, etc.).   

One intriguing possibility we've seen explored in recent months has been that some (perhaps many) humans have some cross immunity to this H5 virus from past infection (or vaccination against) seasonal H1N1. 

A few past blogs include:

• Last December an EID Journal article speculated that the seasonal flu shot might provide some limited protection, since the the NA (neuraminidase) gene segment in our seasonal H1N1 virus is antigenically similar to the NA gene segment in the clade 2.3.4.4b H5N1 virus.

• In last May's Nature Dispatch: Risk Assessment On HPAI H5N1 From Mink, the authors also offered that: While different influenza A virus subtypes are antigenically distinct, some degree of cross-protection against H5N1 may be conferred by prior exposure to these seasonal strains, especially against the N1 neuraminidase.

• Last August, a Preprint: Pre-existing H1N1 Immunity Reduces Severe Disease with Cattle H5N1 Influenza Virus, suggested the reason behind the recent spate of mild H5N1 presentations in the United States may be due to prior exposure to the H1N1 virus.

• And just last month, researchers in Preprint: Targets of influenza Human T cell Response are Mostly Conserved in H5N1, suggested preexisting T cell immune memory from seasonal influenza may be cross-reactive with the H5N1 virus.

While some degree of cross-protection would obviously be a good thing, there are no guarantees that future variants of H5 will retain those qualities, or that this potential protection is well distributed in the population. 

As we've discussed previously, younger people may be more susceptible to H5N1 than older adults (see here, here, and here). And even a CFR of 1% or 2% - assuming the virus had a high attack rate - would produce a major pandemic. 

All of which brings us to two new preprints, each presenting evidence that prior exposure to seasonal H1N1 may help attenuate the severity of infection with our current `bovine' H5N1 strain.  While not yet peer reviewed, both have excellent pedigrees. 

Due to their length and copyright restrictions, I've only posted the links and (1) abstract. Those wanting a deeper dive will need to download and read the full reports.  I'll return with a postscript after the break.

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

Valerie Le Sage, Bailee D. Werner, Grace A. Merrbach, Sarah E. Petnuch, Aoife K. O'Connell, Holly C. Simmons,  Kevin Raymond McCarthy, Douglas Scott Reed, Louise H. Moncla, Disha Hillier Bhavsar, Florian Krammer, Nicholas Crossland, Anita McElroy, W. Paul Duprex, Seema Lakdawala

doi: https://doi.org/10.1101/2024.10.23.619881

Posted October 23, 2024

CC-BY-NC 4.0 International 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 clinical disease to ferrets intranasally infected with bovine H5N1.

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

This second preprint has a more restrictive copyright, so you'll need to follow the link to read the abstract/full report.   

Immune History Modifies Disease Severity to HPAI H5N1 Clade 2.3.4.4b Viral Challenge

Pamela H Brigleb, Bridgett Sharp, Ericka Kirkpatrick Roubidoux, Victoria A. Meliopoulos, Shaoyuan Tan, Brandi Livingston, Dorothea R. Morris, Tyler Ripperger, Lauren Lazure, Velmurugan Balaraman, Alexis Thompson, Katie Kleinhenz, Kiril M Dimitrov, Paul Thomas, Stacey Schultz-Cherry

doi: https://doi.org/10.1101/2024.10.23.619695

While there is some evidence that the `bovine' genotype of H5N1 may be partially attenuated by past exposure to the seasonal H1N1 virus, there are no guarantees that that genotype - or even that subtype/subclade - will spark the next pandemic.  

Still, if I weren't already well vaccinated against seasonal H1N1, I'd seriously consider getting the vaccine this fall. 

Not only would that reduce the chances of experiencing a co-infection which might produce a reassortant virus, it might provide a small edge against more serious illness from H5, should it ever begin its world tour. 

No guarantees, of course. But during a pandemic, you need every advantage you can get.