EID Journal: Cross-Protection against Influenza A(H5) Clade 2.3.4.4b Viruses after A(H1N1)pdm09 Infection

[Michael Coston]

EID Journal: Cross-Protection against Influenza A(H5) Clade 2.3.4.4b Viruses after A(H1N1)pdm09 Infection​

#19,411

Over the past 32 months we've seen at least six dozen human infections from HPAI H5 (H5N1 & H5N5) in the United States, and while most have been described as mild or moderate, 3 people have died.

It seems likely, based on limited seroprevalence testing (see JAMA Open: Asymptomatic Human Infections With Avian Influenza A(H5N1) Virus Confirmed by Molecular and Serologic Testing), that the actual number of infections is higher.

Which suggests that H5N1 may not be quite as deadly as originally feared. Of course, even a 2%-3% fatality rate would put it in the same league as the 1918 pandemic.

An early assessment by the CDC (July 14th, 2024 H5N1 Update) reported that `. . . that there is extremely low to no population immunity to clade 2.3.4.4b A(H5N1) viruses in the United States'.

Since then, however, we've seen a number of studies which have reported serological evidence of limited immunity - particularly in older cohorts - against some strains of H5N1.

Probably not enough to prevent infection, but perhaps enough to reduce the severity of infection.

Initially, the focus was on HA immune imprinting (see Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression), where the HA group (1 or 2) you are first exposed to is thought to provide some degree of protection against other HAs in that group.

How much real-world protection early or past H1/H2 exposure might offer against H5Nx - or how long it might last - are unknown, but it has been suggested it might provide an `edge' against severe disease.

More recently, we've seen attempts to quantify the impact of the first NA (Neuraminidase) one is exposed to (see last December's Nature Comms: Pre-existing Cross-reactive Immunity to HPAI 2.3.4.4b A(H5N1) Virus in the United States).

This study found`very low levels of pre-existing binding antibodies to the HA head of the HPAI A(H5N1) 2.3.4.4b virus', but slightly more encouragingly, `. . . substantial cross-reactive binding antibodies to N1 neuraminidase (NA) of 2.3.4.4b A(H5N1).

Regarding the the value of cross-reactive antibodies to the N1 Neuraminidase, the authors wrote:

Neuraminidase antibodies have been considered as an independent correlate to protect against influenza 20. Although they cannot prevent infection, neuraminidase antibodies can prevent virus egress, reduce viral shedding, and thus could attenuate disease and lessen disease severity 21,22,23.

All of which brings us to a new research letter, published yesterday in the EID Journal, which reports that ferrets pre-exposed to H1N1 saw less severe illness when challenged with H5N1 or H5N5 than influenza-naive ferrets.

A few caveats:

• While an encouraging finding, this was a relatively small study, and ferrets aren't a perfect analog for humans.
• Also, pre-exposed ferrets only had one prior exposure - to H1N1pdm09 - whereas the human population typically has a much messier exposure history to a variety of flu viruses (many first imprinted with H3N2, or pre-2009 H1N1).
• The challenge experiments appear to have been conducted roughly 3 months after H1N1 infection, and it is unknown if - or how quickly - protection might wane.

Not unexpectedly, pre-exposed ferrets exposed to H5N5 did not fare quite as well as those challenged with H5N1, and there are no guarantees that any future H5 pandemic would carry a closely matching N1 Neuraminidase.

Still, this is a fascinating report, and it may partially explain why recent H5N1 infections have been less deadly than originally feared.

Follow the link to read the report in its entirety.

Volume 32, Number 12—December 2026
Research Letter

Cross-Protection against Influenza A(H5) Clade 2.3.4.4b Viruses after A(H1N1)pdm09 Infection

Xiangjie Sun, Jessica A. Belser, Zhu-Nan Li, Nicole Brock, Joanna A. Pulit-Penaloza, Troy J. Kieran, Claudia Pappas, Hui Zeng, Jessie C. Chang, Paul J. Carney, Brandon L. Bradley-Ferrell, James Stevens, Min Z. Levine, and Taronna R. Maines

Abstract

We challenged ferrets previously infected with influenza A(H1N1)pdm09 virus with H5N1 or H5N5 clade 2.3.4.4b viruses to assess cross-protection. Results show that previous A(H1N1)pdm09 virus immunity conferred partial protection against both viruses, with slightly reduced protection against H5N5 compared with H5N1, potentially reflecting the absence of cross-reactive N5 neuraminidase antibodies.

(SNIP)

Preimmune ferrets challenged with either H5N1 or H5N5 virus shed similar levels of virus in nasal wash samples during days 1–4 postinfection (range of mean peak titers 103.8–105.2 PFU/mL) as naive controls but exhibited reduced titers in throat swab samples on day 4 for H5N5 virus and days 2 and 3 for H5N1 virus (Figure 2, panels A, B).

Viral clearance from nasal washes occurred 2–4 days earlier in preimmune ferrets. We detected H5N1 virus less frequently in rectal swab samples from preimmune animals than from naive controls, whereas we did not observe that reduction for ferrets infected with H5N5 virus (Figure 2, panels A, B).

Influenza A(H1N1)pdm09 virus preimmunity did not substantially reduce viral titers in the upper respiratory tract (nasal turbinates) or soft palate after H5N1 or H5N5 virus challenge (Figure 2, panels C, D). However, A(H1N1)pdm09 preimmunity largely prevented viral dissemination to the lower respiratory tract (trachea and lungs) and extrapulmonary tissues for both viruses, with only sporadic low-level viral detection. However, intestinal viral titers were comparable between preimmune and naive ferrets challenged with H5N5 virus (Figure 2, panels C, D).

Detection of group 1 HA stalk antibodies after A(H1N1)pdm09 infection (Appendix Figure), together with previous evidence of HA stalk-mediated cross-protection against disease caused by the influenza A viruses within the same phylogenetic group (3,9), suggests that cross-reactive HA stalk antibodies might contribute to protection against A(H5) viruses. In addition, N1 cross-reactivity might further enhance protection against H5N1 virus. Consistent with our findings, limited N5 cross-reactivity has been reported in humans despite detectable N1 responses (10).


Further studies using H5-specific HA stalk antigens and functional assays are needed to determine the contribution of cross-reactive antibodies and cellular immunity to protection against zoonotic influenza A viruses. Our findings showed that previous A(H1N1)pdm09 viral infection conferred partial cross-protection against H5N1 and H5N5 viruses in ferrets, reducing disease severity, lethality, and viral dissemination.

Dr. Sun is a microbiologist in the Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. Her research primarily focuses on using the ferret model to understand influenza virus pathogenicity and transmissibility.

https://afludiary.blogspot.com/2026/11/eid-journal-cross-protection-against.html