mBio: Low levels of influenza H5N1 HA and NA antibodies in the human population are boosted by seasonal H1N1 infection but not by H3N2 infection or influenza vaccination

 
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#18,932

Over the past 18 months we've seen numerous (mostly) mild - sometimes even subclinical - human infections with the bovine B3.13 genotype of H5N1. Unlike other subclades (e.g. 2.3.2.1e) and genotypes, this `bovine' variant (so far) appears to be less virulent in humans.

This, despite the initial CDC assessment (see July 14th, 2024 H5N1 Update):

CDC analyzed sera (blood) collected from people of all ages in all 10 HHS regions. Blood samples were collected during the 2022-2023 and 2021-2022 flu seasons. These samples were challenged with H5N1 virus to see whether there was an antibody reaction. 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.

These studies were focused on the HA component of the H5N1 virus, but we've previously seen studies suggesting NA antibodies may play a role as well (see EID Journal: A(H5N1) NA Inhibition Antibodies in Healthy Adults after Exposure to Influenza A(H1N1)pdm09).

Since then, we've seen a number of studies suggesting that prior infection (or possibly vaccination) with the H1N1pdm virus may - due to H5N1 having a similar NA gene - covey some (unknown) degree of protection in humans.

 A few examples include:

Preprint: Cross-Reactive Human Antibody Responses to H5N1 Influenza Virus Neuraminidase are Shaped by Immune History

Preprint: Neuraminidase Imprinting and the Age-related Risk of Zoonotic Influenza

Two EID Journal Articles On Prior Immunity From A(H1N1)pdm09 Infection Against H5N1 (in Ferrets)

How much real-world protection past H1N1 exposure might offer is - or how long it lasts - is unknown, but it has been suggested it might provide an `edge' against severe disease; at least against some H5N1 variants.

While the notion that some degree of immunity to H5N1 might exist gets a lot of attention by the mainstream media, the reality is, it is likely to be quite small. But knowing what drives this immunity might help researchers create more effective vaccines against H5N1 in the future. 

All of which brings us to a new study, published on Friday in mBio, which uses blood samples from a relatively small cohort of JHH & JHMI employees (n=73) (vaccinated, unvaccinated, and some with recent H1N1 or H3N2 infection) to test for (binding & reactive) HA & NA antibodies against H5N1 (including Bovine B3.13). 

While you'll want to follow the link to read the report in its entirety, briefly they found:

• at baseline, they confirmed humans have low levels of antibodies targeting the H5N1 hemagglutinin (HA) and neuraminidase (NA) proteins

• NA antibodies, however, were more common and more reactive than HA antibodies

• Seasonal influenza vaccination did not appear to significantly boost those antibodies

• But recent H1N1 (but not H3N2) infection resulted in increased NA cross-reactive neutralizing antibodies against the Bovine B3.13 genotype of H5N1

• They don't appear to have directly tested other genotypes (like D1.1, D1.3) for comparison

While promising, the authors cautioned:

Since there are no established correlates of protection for A/H5N1 infection in the human population, we cannot make any conclusions about how these cross-reactive antibodies against bovine A/H5N1 might modulate infection or disease severity.

First the abstract, and a couple of brief excerpts, after which I'll return with brief postscript.

Low levels of influenza H5N1 HA and NA antibodies in the human population are boosted by seasonal H1N1 infection but not by H3N2 infection or influenza vaccination
Authors: Anne P. Werner , Cosette G. Schneider, Elgin H. Akin, Juliahna Hayes, Katherine Z. J. Fenstermacher , Richard E. Rothman, Lynda Coughlan , Andrew Pekosz  apekosz1@jhu.eduAuthors Info & Affiliations
https://doi.org/10.1128/mbio.02145-25

ABSTRACT

An increase in the number of human cases of influenza A/H5N1 infection in the USA has raised concerns about the pandemic potential of the virus. Pre-existing population immunity is a key determinant for risk assessment and pandemic potential for any virus.

Antibody responses against the bovine A/H5N1 hemagglutinin (HA) and neuraminidase (NA) proteins were measured among a population of influenza-vaccinated or influenza-infected individuals. Modest titers of bovine A/H5N1 HA-binding antibodies and low to undetectable neutralizing antibody titers were detected in a cohort of 73 individuals.

Conversely, bovine A/H5N1 NA-binding and neuraminidase-inhibiting antibody titers were comparable to those against a human A/H1N1 NA at baseline. Seasonal influenza vaccination failed to significantly increase antibody titers against both HA and NA glycoproteins of bovine A/H5N1.

Recent infection with human A/H1N1 but not A/H3N2 viruses induced significant increases in bovine A/H5N1-neutralizing antibody, as well as increases in NA-binding and NA-inhibiting antibodies to bovine A/H5N1 NA.

While the degree of protection afforded by these A/H5N1 cross-reactive antibodies is not known, incorporating NA or enhancing current seasonal vaccine formulations to increase NA-specific antibody titers may increase antibody breadth and protection against both seasonal and pandemic influenza viruses.

IMPORTANCE

A/H5N1 influenza A viruses continue to pose a pandemic threat to humans. Recent infection of dairy cattle and poultry with A/H5N1 in the USA has magnified that concern. We determined the level of antibodies that recognize A/H5N1 hemagglutinin (HA) and neuraminidase (NA) proteins in a population in Baltimore, MD. We show that while low levels of H5 HA-binding and A/H5N1-neutralizing antibodies are present, there is a significantly stronger recognition of bovine N1 NA. Vaccines that target the N1 NA protein may induce protective antibody responses in humans due to the presence of cross-reactive human N1 NA antibodies.

(SNIP)

We show evidence that supports changing current seasonal vaccine formulations to either include greater NA content or to manipulate immunogen design to increase immunofocusing toward immunosubdominant domains of IAV HA and NA (25, 66, 77, 78).

The work presented here reiterates the importance of NA as a conserved antigen between human seasonal viruses and A/H5N1 HPAIs and underscores the need for investigation of NA-mediated antibody responses and their role in protective immunity. NA-centered vaccine design would enable robust boosting of cross-reactive N1 antibodies and may serve as a more feasible approach to increasing population-level pre-existing antibodies to A/H5N1 compared to HA-focused vaccines. 

       (Continue . . . )

While all of this could lead to more NA-centered vaccine designs, which might instill better population immunity against a potential H5N1 pandemic, none of this is likely to happen overnight. 

• In 2010 Dr. Klaus Stohr, former head of the World Health Organization's global influenza program, floated the idea (see The Prime Of Our Lives) of including potential future pandemic strains in yearly seasonal flu shots to create some degree of pre-existing immunity.

• In a similar vein, in 2011 (see Nature: A Preemptive H2N2 Vaccine Strike?), researchers concerned over the possible return of H2N2 (last seen in the 1960s), suggested including an H2N2 strain in the yearly jab.

Those ideas never gained traction, and in all likelihood would have faced massive resistance from a vaccine-wary public. Tweaking the NA content of the seasonal flu shot would likely garner far less backlash, but its effectiveness remains unknown. 

This study, however, does provide new avenues for exploration.  And that may eventually lead to more effective vaccines in the down the road. 

But in the short term, if H5N1 (or any other respiratory virus) decides to embark on a world tour, your best friend will likely be your stash of N95/KN95 masks in your first aid supplies.