Tuesday, September 16, 2025

EID Journal: Effect of Seasonal Influenza Vaccines on Avian Influenza A(H5N1) Clade 2.3.4.4b Virus Infection in Ferrets


Credit ACIP

#18,874

While it's not a new idea (see 2008's Seasonal Flu Vaccine May Offer Some Protection To H5N1), given the recent proliferation of HPAI H5 around the globe - and the expected (> 6 month) lag time in deploying a strain-specific vaccine -  hopes of deriving some degree of protection from the seasonal jab are once again being investigated.

The recent spate of relatively mild human infections with the (bovine) genotype B3.13 H5N1 virus has raised hopes that preexisting immunity - either from previous influenza A infection or the flu vaccine - may be a mitigating factor.

Research is limited, however, to in vitro and lab animal studies (mostly ferrets and mice), as it would be unethical to intentionally challenge a human with the H5N1 virus. 

And results have been mixed. 

Two months ago, in Study: Preexisting Immunity to the 2009 Pandemic H1N1 Virus Reduces Susceptibility to H5N1 Infection and Disease in Ferrets, we looked at an encouraging report from Penn State University.

Seasonal flu immunity protects against severe illness from bird flu in ferrets

A study in ferrets — which have remarkably similar respiratory systems to humans — suggests that widespread immunity to H1N1 seasonal influenza virus may explain why exposure to H5N1 bird flu causes only mild symptoms in humans

While previously exposed ferrets encouragingly fared better than flu-naive test subjects, there are a number of caveats to consider, including:

  • First, that ferrets are a good - but hardly perfect - analog for the pathogenicity of influenza A in humans. 
  • Third, the bovine B3.13 genotype is but one of hundreds of HPAI H5N1 variants already in the wild, and there are no guarantees that it will emerge as the next pandemic contender. 
  • Fourth, we continue to watch other HPAI H5 subtypes - including H5N5 and H5N6 - which may someday supplant H5N1 as the dominant subtype. These are particularly worrisome because of their novel NA genes.

Last May, in EID Journal: Investigation of Influenza A(H5N1) Virus Neutralization by Quadrivalent Seasonal Vaccines, United Kingdom, 2021–2024 we looked at an in vitro study of H1N1 specific neutralizing antibodies  against two H5N1 strains (Bovine B3.13 H5N1 & Cambodian clade 2.3.2.1c), which found:

  • While QIVs significantly boosted neutralizing antibodies against seasonal A(H1N1), they detected little to no neutralizing antibody response against the two H5N1 strains
  • Most participants (all age < 59) had no detectable neutralizing titers against the Texas H5N1 strain, and only a few had low-level titers for the Cambodia strain.
  • No evidence that QIV vaccination provided a boost in cross-reactive immunity to H5N1
While disappointing, this study is far from conclusive, as cross-neutralization might also occur in the absence of detectable nAbs.   

Yesterday the EID Journal revisited the topic, with a study from the CDC and other partners, which once again examines the potential impact of seasonal flu vaccination against H5N1 infection (in ferrets). 

This study tested 3 different types of seasonal flu vaccines. 
  • IIV3 (inactivated trivalent vaccine, Fluarix)
  • LAIV (live attenuated nasal vaccine, FluMist)
  • RIV (recombinant HA vaccine, Flublok)
While no cross-reactive response against H5 was detected after vaccination, some cross-reactive NA and HA stalk antibodies were observed, especially in LAIV and IIV3 groups.

In the end, LAIV provided the most protection - while RIV and IIV3 provided less -  but all vaccinated groups cleared the H5N1 virus faster than controls (note: LAIV vaccines are limited for use in healthy people aged 2 through 49 years who are not pregnant).
 
Whether these benefits would extend to humans, or be as pronounced against other genotypes/clades is unknown.  It is conceivable, however, that seasonal vaccines might reduce mortality rates in the opening months of a pandemic. 

Due to its length, I've only posted the abstract and some excerpts.  Follow the link to read it in its entirety. I'll have a postscript after the break.

 
Xiangjie Sun1, Jeeva Subbiah1, Jessica A. Belser, Nicole Brock, Shane Gansebom, Zhu-Nan Li, Yu-Jin Jung, Feng Liu, Terrence M. Tumpey, Taronna R. Maines, Min Z. Levine, and Ian A. York 

Abstract

Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b viruses have infected >1,000 herds of dairy cattle and hundreds of poultry flocks in the United States since the beginning of 2024. Seventy human cases have been reported during that period, mainly through occupational exposure.
Although prior influenza A(H1N1)pdm09 virus infection has been shown to confer protection against influenza A(H5N1) clade 2.3.4.4b virus infection in the ferret model, it remains unclear if influenza vaccines, known to elicit a less potent and narrower cross-reactive immune response, can achieve a similar effect.
In this article, we demonstrate that immunization with commercially available human seasonal influenza vaccines also confers partial protection against disease caused by H5N1 clade 2.3.4.4b virus in ferrets, which is partially associated with the presence of cross-reactive antibodies targeting H5N1 virus antigens.
 
(SNIP)

Although vaccination against human seasonal IAV remains the most effective way of protecting against seasonal influenza virus infection, it is unclear whether seasonal influenza vaccine immunity could confer cross-protection against H5N1 viruses. In this article, we report the results of testing the ability of several human seasonal vaccines to protect ferrets against disease induced by clade 2.3.4.4b B3.13 IAV infection.
(SNIP)
Despite the low cross-reactive response induced by the vaccines, vaccination still conferred some protection against H5N1 disease in ferrets.
LAIV, which induced both antistalk antibodies and cross-reactive anti-N1 antibodies, gave the strongest protection against disease and reduced virus shedding.
RIV, which induced antistalk HA antibodies but no anti-NA response, also provided some protection against weight loss and reduced the duration of virus shedding.
IIV3, which induced only low levels of antistalk HA antibodies but did induce cross-reactive N1 antibodies, provided limited protection against weight loss and reduced the duration of virus shedding.
(SNIP)
The findings that both prior human seasonal IAV infection and vaccination with commercially available human seasonal influenza vaccines confers some cross-protection against disease caused by the B3.13 genotype H5N1 in the ferret model is intriguing.
However, unlike most adult humans who receive seasonal influenza vaccination, the laboratory ferrets used in this study are completely naive to influenza, and their response to the vaccines might not fully reflect the adult human response.
The function and extent of cross-protection between immunity to human seasonal viruses and potentially zoonotic HPAI requires further investigation, particularly given the complex landscape of existing IAV immunity in the general population and its potential influence on the immune response elicited by seasonal influenza vaccination. This consideration is especially true for LAIV. Despite the cross-protection against the H5N1 virus observed in LAIV-vaccinated ferrets, the ability of LAIV to replicate in the upper respiratory tract of humans with existing immunity and to elicit antibody response is limited (45).

In conclusion, this study demonstrates that seasonal influenza vaccination can potentially provide cross-protection against the B3.13 genotype of H5N1 virus. Although the applicability to humans is currently unknown, revealing this benefit in the naive ferret model is a crucial step to further exploring the benefits of seasonal influenza vaccination in reducing the effects of HPAI H5N1 in human populations.
        (Continue . . . )

Regardless of whether the seasonal flu vaccine directly protects against H5N1 infection, there are still good reasons to get the jab, prior to - and even during - an H5Nx pandemic.

  1. It still may provide some small boost to your immune response.  Neutralizing antibodies aren't the only immune defense against infection. 
  2. It could help prevent a co-infection with H5N1 and seasonal flu, which has the potential for being more severe.
  3. Co-infections could also help generate a reassorted `hybrid' virus (see Preprint: Intelligent Prediction & Biological Validation of the High Reassortment Potential of Avian H5N1 and Human H3N2 Influenza Viruses).


There are plenty of other advantages to getting the seasonal flu vaccine, of course. A few past blogs include:

Nature: Severe Influenza in Pregnancy Linked to Neurodevelopmental Disorders in Offspring

Pediatrics: Maternal Flu Vaccination Extends Protection To Infants

PloS One: Early Risk of Acute Myocardial Infarction Following Hospitalization for Severe Influenza

CDC: Another Study Linking Severe Influenza To Heart Damage

Sometime the next few weeks I'll roll up my sleeve to get my 20th seasonal flu shot in as many years. In all of that time I've only caught the flu once (summer 2009), before the pandemic H1N1 vaccine was released. 

While I recognize it probably only provides my age group with 30%-40% protection, given the long list of things that can go wrong during or following flu infection, I'll take whatever advantage I can get.

And if, perchance, it prevents a pandemic-inducing reassortment with a novel virus - or takes the edge off a severe H5N1 infection - so much the better. 

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