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.

Oregon ODA Reports Its First Outbreak of HPAI H5 In Dairy Cattle

 

#19,410

A little over a month ago Washington State became the 20th U.S. state to report HPAI H5N1 in dairy cattle, and since has racked up 43 outbreaks. Just over a week ago (Nov 2nd), Indiana Reported their 1st Infected Herds (n=2) becoming the 21st affected state, and late yesterday Oregon became the 22nd.

Oregon had previously reported two pigs infected with H5N1 in the fall of 2024 on a mixed species farm which had experienced an outbreak in poultry. Oregon has also reported 62 poultry outbreaks, primarily among backyard producers (including 1 human infection).  

With the recent addition of Washington and Oregon, only Montana and North Dakota remain unscathed in the western half of the nation. 

 The full statement from the Oregon Department of Agriculture (ODA) follows:

First Detection of Highly Pathogenic Avian Influenza in Oregon Dairy Cattle Confirmed

AFFECTED DAIRY UNDER QUARANTINE; MILK AND FOOD SUPPLY REMAIN SAFE FOR CONSUMPTION

Affected dairy under quarantine; milk and food supply remain safe for consumption

Milk from a Morrow County dairy tested positive for highly pathogenic avian influenza (HPAI). This is the first detection of HPAI in Oregon dairy cattle.

Preliminary detection of HPAI was identified through Oregon's routine statewide milk surveillance program, with preliminary results reported by the Oregon Veterinary Diagnostic Laboratory (OVDL) at Oregon State University (OSU) on November 6, 2026. The Oregon Department of Agriculture (ODA) immediately initiated an on-farm investigation and submitted additional samples to the United States Department of Agriculture (USDA) National Veterinary Services Laboratory (NVSL) for confirmation. Positive results were confirmed on November 10, 2026.

Oregon’s routine statewide milk surveillance program identified the detection, demonstrating the effectiveness of the state's ongoing monitoring efforts. No additional affected dairies have been identified at this time.

Pasteurized milk and dairy products remain safe to consume, and there is no concern about the safety of the commercial milk supply. Pasteurization effectively inactivates the HPAI virus, and milk from sick animals is prohibited from entering the commercial milk supply. The U.S. Food and Drug Administration (FDA) continues to advise against consuming raw (unpasteurized) milk because it does not undergo the heating process that kills viruses and bacteria.

"While this detection is significant, it is not unexpected given the continued spread of HPAI among dairy cattle nationally," said Dr. Ryan Scholz, State Veterinarian for ODA. "Oregon's milk surveillance program worked exactly as intended, identifying this infection quickly and allowing us to respond rapidly with our state and federal partners. This detection demonstrates the value of the monitoring and preparedness efforts supported by Oregon's dairy industry and animal health partners since 2024."

ODA has placed the affected dairy under quarantine, and enhanced biosecurity measures are in place. The quarantine restricts animal movement and implements additional disease control measures while response activities are conducted. Response activities are focused on the impacted dairy and associated epidemiologic investigation. In most cases, infected dairy cows are expected to recover within a few weeks.

ODA is coordinating closely with USDA, Oregon Health Authority (OHA) and Morrow County Public Health officials, OVDL, and Oregon's dairy industry partners as the investigation continues. Oregon's statewide dairy surveillance program, launched in December 2024, was established to detect HPAI early and support rapid response efforts. The program allows state and federal officials to implement disease control measures quickly when detections occur.

Public health officials are providing education to farm workers exposed to infected animals and will monitor them for symptoms of avian influenza throughout the outbreak. "With the use of appropriate personal protective equipment, the risk to farm workers remains low. Our public health approach is focused on ensuring rapid testing and treatment for any individuals who develop symptoms to prevent severe disease," said Melissa Sutton, M.D., medical director, respiratory viral pathogens, OHA. No human cases associated with this incident have been identified in Oregon. According to OHA and the Centers for Disease Control and Prevention (CDC), the current public health risk to the general population remains low. No cases of person-to-person transmission associated with this virus have been identified.

HPAI was first detected in U.S. dairy cattle in March 2024 and has since been identified in multiple states. USDA provides current information on HPAI detections in livestock. Oregon began statewide dairy milk surveillance in December 2024 and continues to test milk from all licensed dairy operations routinely. ODA appreciates the cooperation of Oregon dairy producers and industry partners who participate in ongoing surveillance, disease reporting, and biosecurity efforts that help protect animal health and Oregon's dairy industry.

Symptoms of HPAI in Dairy Cattle

Symptoms can include:

• Decrease in feed consumption with a simultaneous decrease in rumination and rumen motility.
• Respiratory signs, including clear nasal discharge.
• Acute drop in milk production.
• Abnormal tacky or loose feces.
• Lethargy.
• Dehydration.
• Fever.
• Thicker, more concentrated, colostrum-like milk, or no milk production in severely affected animals.

Some infected cattle may show no clinical signs. Most infected cattle recover within two to three weeks.

Suspected cases of HPAI in any animal species should be reported immediately to ODA at 503-986-4711.

For more information regarding HPAI in livestock, please visit the ODA HPAI webpage (http://oda.direct/AvianInfluenza).

After a slow start in the spring of 2024, HPAI detections in cattle peaked that fall (see chart below), and then began a sharp decline during the spring of 2025.

Between June 2025 and April 2026 monthly detections were reduced to single digits. 

(Chart generated with Gemini AI using USDA data)

After nearly a year of greatly diminished activity, we began to see an increase in reports - first from Idaho, and then from other states - starting in June of 2026.   

While we are still well below the levels reported in Oct-Dec 2024, this recent uptick is noteworthy, as is the recent spread to 3 previously unaffected states. 

Stay tuned.  

HK CHP Reports 6 H9N2 Cases over the past 4 Reporting Periods

 

#19,409

As of today's report, Hong Kong's CHP has reported a total of 23 H9N2 cases over the past 6 months, with 6 of those reported by the CHP since October 19th.   As you can see by the dates in the above graphic, there continue to be substantial delays in reporting, with 5 of the 6 cases reported occuring in September. 

Four of the six cases are in children (who are more likely to be screened for the virus), while two are in elderly adults. 

While H9N2 infection is typically mild or moderate, some patients are hospitalized, and a few deaths have been reported.  The two most recent cases - announced today - were previously reported on in the WHO WPRO weekly avian flu report released on October 28th.

Human infection with avian influenza A(H9N2) virus

From 23 to 29 October 2026, two new cases of human infection with avian influenza A(H9N2) virus were reported to WHO in the Western Pacific Region, both from China. Both cases were paediatric patients, one from Liaoning Province, with symptom onset on 20 September 2026, and one from Guangxi Zhuang Autonomous Region, with symptom onset on 13 October 2026. Both cases had exposure to poultry. All close contacts of both cases tested negative for influenza A. Both cases had fully recovered at the time of reporting.

Since 2015, a total of 189 cases of human infection with avian influenza A(H9N2), including two deaths (both with underlying conditions), have been reported to WHO in the Western Pacific Region. Of these,186 were reported from China, two were from Cambodia, and one was from Viet Nam.

Most human infections with avian influenza A(H9N2) have been associated with exposure to infected poultry or contaminated poultry environments, and the majority of cases have been mild. Sporadic human infections continue to be expected in areas where H9N2 viruses circulate in poultry populations. Current evidence indicates that H9N2 viruses have not acquired the ability for sustained human-to-human transmission, and the risk of further community-level spread remains low.

Last August, in WHO Influenza at the human-animal interface (Aug 7th) - Uptick in H9N2 Cases in China, we looked at this recent increase in reported cases. Whether this is due to more frequent spillovers, or better surveillance, isn't known.

Despite being clearly zoonotic - LPAI H9N2 is considered a `non-reportable' disease in poultry or wild birds by WOAH (see Terrestrial Animal Code). Complicating matters, China's attempts to control LPAI H9N2 through vaccines have been less than successful.

Several recent Chinese studies have found signs that LPAI H9N2 is becoming better adapted to mammals, warning of its pandemic potential; including:

• In early August, in EM&I: Genetic evolution, phylodynamics, geographic spread of H9N2 avian influenza viruses in China from 2014 to 2025: an increasing potential zoonotic risk, we saw yet another Chinese study warning that H9N2 was accruing mammalian adaptations which increases its zoonotic risk.

• Five months ago, in Viruses: Epidemiological and Virological Characteristics of H9N2 Avian Influenza Virus in Jiangsu Province, China, 2024, researchers warned that that Jiangsu’s circulating H9N2 viruses have acquired human receptor preference and mammalian adaptation, posing silent infection and pandemic risks

• In October 2025, in China CDC Weekly: Epidemiological and Genetic Characterization of Three H9N2 Viruses Causing Human Infections, investigators reported a number of indicators of increased mammalian adaptation within the virus, including an enhanced ability to infect upper respiratory (α2,6-sialic acid) tract receptors, and a number of HA protein mutations, including; H191N, A198V, Q226L, and Q234L.

• The Asian Y280/G57 lineages have shown increasing signs of mammalian adaptation (see EM&I: Enhanced Replication of a Contemporary Avian Influenza A H9N2 Virus in Human Respiratory Organoids)), while the African and Middle Eastern Lineages (mostly European G1-like) are older and less evolved.

• In the summer of 2025, in Nature: Genetic diversity of H9N2 avian influenza viruses in poultry across China and implications for zoonotic transmission, researchers reported rising prevalence of key mutations associated with increased infectivity and pathogenicity in mammals.

While H9N2 doesn't garner the kind of headlines that H5N1 gets, our own CDC lists two lineages (A(H9N2) G1 and A(H9N2) Y280) as having at least some pandemic potential, and several candidate vaccines have been developed.

So we watch these developments with more than just academic interest. 

PNAS: Rare recovery of reassortants between contemporary clade 2.3.4.4b H5N1 viruses and human influenza A viruses in vitro

 

Coinfection leading to Antigenic `Shift' 

or Reassortment 

#19,408

Last week, in When Flu Viruses Collide, we looked at the concerns over rare - but documented - instances of seasonal flu reassorting with a novel flu virus, and producing a biologically `fit' hybrid.  

At least 2 pandemics in the last century (1957 and 1968) are believed the product of such an interaction. This is the reason why yearly flu vaccination has long been recommended for people who raise pigs or work with poultry and the CDC now urges vaccination in dairy workers.

In 2024, Chinese scientists looked at the reassortment potential of H5N1 and H3N2 (see Preprint: Intelligent Prediction & Biological Validation of the High Reassortment Potential of Avian H5N1 and Human H3N2 Influenza Viruses) and predicted the risks to be relatively high.

Another, older (2010) study (see PNAS: H3N2 And H5N1 Reassortment) found that Reassortment between avian H5N1 and human H3N2 influenza viruses creates hybrid viruses with substantial virulence.

While viewed as possible, it isn't clear how compatible contemporary seasonal viruses are for reassorting with currently circulating HPAI H5Nx viruses.

Complicating matters, since there is great diversity among all of these viruses - and they continually evolve - only partial answers are obtainable.

To that end, we have a brief report published yesterday in PNAS, which describes (partially successful) attempts to create reassortants using `weakened' (live attenuated NS1-truncated) clade 2.3.4.4b H5N1 HPAIVs of the B3.13 and D1.1 genotypes, and older (circa 2009 and 1968) human-adapted pdmH1N1 and H3N2 IAVs in MDCK II cells. 

Today's panoply of seasonal flu viruses have evolved considerably since those lineages emerged. But these are well characterized lab strains, with reverse genetic clones widely available, and their use likely makes comparisons with earlier studies easier. 

The authors acknowledge these (and other) limitations, but despite those constraints, they were able to generate 20 reassortants (0.74%). They report: 

Polymerase assays identified human IAV subunits, particularly H1N1 PA or H3N2 PB2, that increased H5N1 polymerase activity. Thus, contemporary clade 2.3.4.4b H5N1 viruses can reassort with human IAVs, but factors beyond polymerase compatibility may limit their recovery.

This study did not test these reassortants' fitness, transmissibility or disease severity, so it cannot predict real-world risk.  It does, however, suggest that contemporary clade 2.3.4.4b H5N1 viruses can reassort with human IAVs. 

Although it is not a particularly long report, I've only posted some excerpts. Follow the link to read it in its entirety. 

Rare recovery of reassortants between contemporary clade 2.3.4.4b H5N1 viruses and human influenza A viruses in vitro

Jakob Ankerhold, Susanne Kessler https://orcid.org/0000-0002-9720-8291, Philipp P. Petric, +4 , and Kevin Ciminski https://orcid.org/0000-0001-5397-7497 kevin.ciminski@uniklinik-freiburg.deAuthors Info & Affiliations

Edited by Peter M. Palese, Icahn School of Medicine at Mount Sinai, New York, NY; received September 8, 2026; accepted October 12, 2026 

November 9, 2026

123 (46) e2631654123

https://doi.org/10.1073/pnas.2631654123 

Abstract

Influenza A virus (IAV) pandemics can arise when animal-derived and human-adapted IAVs exchange genome segments; however, whether contemporary clade 2.3.4.4b H5N1 viruses can generate viable reassortants with human IAVs is unclear. Here, we tested the reassortment potential of two clade 2.3.4.4b H5N1 viruses with human-adapted H1N1 and H3N2 IAVs using a biosafe reassortment system. Across multiple coinfection conditions, we genotyped 2,698 plaque-purified viral clones and recovered 20 reassortants (0.74%). Polymerase assays identified human IAV subunits, particularly H1N1 PA or H3N2 PB2, that increased H5N1 polymerase activity. Thus, contemporary clade 2.3.4.4b H5N1 viruses can reassort with human IAVs, but factors beyond polymerase compatibility may limit their recovery.

 

Zoonotic influenza A viruses (IAVs) pose a constant pandemic threat, with previous pandemics often associated with reassortment between animal-derived and human-adapted IAVs (1). Reassortment requires coinfection of a cell and compatibility between viral genome segments from different host-adapted lineages (2). Highly pathogenic avian influenza viruses (HPAIVs) of the H5 clade 2.3.4.4b have created an unusually broad ecological interface for such events. Since 2020, these viruses have spread globally among wild birds and mammals and entered U.S. dairy cattle, resulting in human exposure and zoonotic infections (3–6). Although sustained human transmission has not been documented, cocirculation with seasonal human IAVs creates opportunities for coinfection and reassortment.

Previous studies showed that prepanzootic H5N1 HPAIVs can reassort with human IAVs (7–10). However, the reassortment potential of contemporary clade 2.3.4.4b H5N1 HPAIVs remains unknown. Here, we tested two clade 2.3.4.4b H5N1 HPAIVs, representing different viral genotypes associated with U.S. dairy cattle outbreaks (3, 5) in combination with human-adapted H1N1 and H3N2 IAVs. We show that contemporary clade 2.3.4.4b H5N1 viruses can form viable reassortants with human IAVs in vitro and identify distinct vRNP compatibility patterns.

(SNIP)

Discussion

In this study, we show that contemporary clade 2.3.4.4b H5N1 HPAIVs can reassort with human-adapted H1N1 and H3N2 IAVs, but reassortants represented only 0 to 2.3% of plaque-purified clones under the in vitro conditions tested. This finding is consistent with the absence of documented reassortment events involving human IAV segments in clade 2.3.4.4b H5N1 HPAIVs to date.

However, the low observed recovery frequency of reassortants does not indicate complete genetic incompatibility, as recovered reassortants carried human IAV polymerase segments and selected human IAV subunits increased H5N1 polymerase activity in human cells. Thus, our data separate reassortant recovery under the tested conditions from the functional properties of the resulting polymerase constellations.

As clade 2.3.4.4b H5 HPAIVs undergo frequent and complex reassortment with avian IAVs (4, 6), the factors potentially limiting reassortment with human-adapted IAVs remain unclear (2). Several limitations should be considered: MDCK II cells do not recapitulate natural infection dynamics or selective pressures, and the observed H5N1 replication advantage and viral progeny composition may differ in relevant hosts. Additionally, using NS1-truncated viruses and early pandemic representatives rather than contemporary seasonal isolates limits generalizability, while the absence of reassortant characterization limits conclusions about replication fitness, transmissibility, and pathogenicity.

Because no standardized benchmark for IAV reassortment exists, observed recovery frequencies cannot be directly compared across IAV combinations. Despite these limitations, our study provides a functional framework for interpreting reassortment risk during the ongoing clade 2.3.4.4b H5 panzootic.

       (Continue . . . )

 

Nature Sci Reports: The effect of the time of day of influenza vaccination on antibody and T-cell responses in older adults

Photo Credit - CDC PHIL

#19,407

Ten years and just over 8,000 blogs ago, in Vaccine: Taking Your Best Shot, we looked at a study published in the Journal Vaccine which suggested the time of day one is vaccinated may make a difference in the body's immune response.

The cluster-randomized trial followed 276 adults (over 65) across 24 GP practices in the West Midlands, UK who - between 2011 and 2013 - were assigned to receive their flu shots either in the morning or afternoon.

Follow up blood work showed higher antibodies against H1N1 and Influenza B (but not H3N2) in the morning vaccination cohort. (note: a follow-up Corrigendum - published several months later - weakened the evidence, finding that the influenza B result was no longer statistically significant).

Last week, a new study published in Nature Scientific Reports, revisits the idea and reports: 

Individuals vaccinated in the early morning (09:00) showed an approximately 32% stronger antibody response compared to individuals vaccinated in the afternoon (14:00)

That said, their results were mixed. Their main analysis found no statistically significant differences between vaccination periods, but a secondary analysis favored morning vaccination over early afternoon.

But curiously, not over late afternoon. 

Whether this effect actually results in improved vaccine protection hasn't been established, and the reasons behind the purported `afternoon trough' - assuming it is more than just a statistical variation - remains unclear. 

It is possible our internal body clocks may play a role. Some people (like myself) are early risers, so the same appointment time may fall at different points in our `biological day'.  

The researchers explored that possibility using patient's sleep schedules, but those results were inconclusive as well.  

Make of it what you will.  

I've posted the abstract and a snippet from the discussion. Follow the link to read the study in its entirety.

The effect of the time of day of influenza vaccination on antibody and T-cell responses in older adults 
 
Published: 05 November 2026
  
Download PDF 

Tamara M. J. Brouwers, Koen Vink, Martijn Vos, Harry van Dijken, Marijn E. Snik, Jan van de Kassteele, Lisa Beckers, Debbie Smit, Deborah Oomen, Teun Guichelaar, Tobias N. Bonten, Laura Kervezee, Jacco Wallinga & Debbie van Baarle

Abstract

Increasing evidence suggests that time of day of vaccine administration affects immune responses. We aimed to determine the optimal time of day for influenza vaccination by characterising temporal patterns in vaccine-induced immune responses. Additionally, we assessed the effect of vaccination time relative to an individual’s circadian phase on immune responses.

 A randomised controlled trial was conducted with 278 participants aged 60–85 years, who received influenza vaccination at a randomised time between 09:00 and 17:00. 

Antigen-specific antibody titers and T-cell responses to three vaccine strains (A/H1N1, A/H3N2 and B/Victoria) were measured pre- and one month post-vaccination. A permutation-based test was used to determine differences in strain-specific immune responses between the three randomisation time blocks (09:00–11:40, 11:40–14:20, 14:20–17:00). 

As a secondary analysis, strain-specific immune responses were jointly analysed in a single generalised additive mixed-effects model (GAMM) to assess the overall impact of influenza vaccination timing. The permutation-based test found no significant differences in immune responses between the three vaccination time blocks. A GAMM revealed that morning vaccination resulted in significantly higher antibody responses across strains than early afternoon vaccination(p = 0.045), but not late afternoon vaccination (p = 0.498). 

Antibody responses displayed a non-significant non-linear pattern from 09:00 to 17:00, with the model suggesting highest responses in participants vaccinated at 09:00. A similar trend was observed for T-cell responses.

Irrespective of chronotype, vaccinations administered at the start of an individual’s day tended to elicit the strongest vaccine-induced immune responses. Although statistical evidence for a time-of-day effect was limited, numerically higher antibody and T-cell responses were consistently observed in the morning group.

        (SNIP)

Discussion 

This study showed a consistent trend toward stronger strain-specific antibody and T-cell responses among older adults vaccinated in the morning compared to those vaccinated in the afternoon. However, the differences between vaccination time groups did not reach statistical significance in our primary analysis. After adjustment for variation in baseline antibody titers using GAMM analyses, overall antibody responses differed significantly between the morning and early afternoon vaccination groups, but not between the morning and late afternoon vaccination groups. An important strength of the study is its assessment of temporal patterns in vaccine-induced immune responses across a continuous vaccination window from 09:00 to 17:00. A trend was observed toward stronger vaccine-induced immune responses following vaccination in the early morning (at 09:00).

       (SNIP)

In conclusion, we consistently showed that morning influenza vaccination tended to result in stronger vaccine induced immune responses than (early) afternoon vaccination in adults aged 60–85 years. Our results contribute to the growing evidence on the effect of vaccination timing on vaccine-induced immune responses and suggest potential clinical relevance in older adults. Optimising the timing of vaccine administration may therefore offer a safe and cost-effective strategy to enhance immunogenicity of current influenza vaccines, although further investigation into clinical outcomes is warranted. 

       (Continue . . . )  

IJID Review Article: The H5N1 avian influenza threat: a European Perspective on Research Gaps and State of Preparedness

 

#19,406

While the next pandemic could arise from a wide variety of sources (see WHO 2024 Pathogens Prioritization Report), the most obvious contender today is HPAI H5Nx, which continues to expand its host range as it spreads around the globe. 

Despite the near-inevitability of another pandemic crisis, the world remains slow to embrace that stark reality, and prepare seriously. 

Three years after the start of the last pandemic, in 2023's Lancet Preprint: National Surveillance for Novel Diseases - A Systematic Analysis of 195 Countries, the authors found that the self-reported 66% readiness score for detecting and dealing with novel viruses was not supported by the available evidence.  They wrote:

`A minority of countries have public evidence of novel disease consideration, and significant geographical heterogeneity exists in where this is located.'

Today, most surveillance is passive, and much of what is detected, isn't readily shared. There are often long delays in submitting viral sequences (see Nature: Lengthy Delays in H5N1 Genome Submissions to GISAID) - averaging 7 months - but sometimes taking 1 to 2 years. 

We've also seen repeated warnings from public health agencies that our surveillance systems are not designed to detect novel viruses. 

In 2024 the ECDC issued guidance for member nations on Enhanced Influenza Surveillance to Detect Avian Influenza Virus Infections in the EU/EEA During the Inter-Seasonal Period., which cautioned:

Sentinel surveillance systems are important for the monitoring of respiratory viruses in the EU/EEA, but these systems are not designed and are not sufficiently sensitive to identify a newly emerging virus such as avian influenza in the general population early enough for the purpose of implementing control measures in a timely way.

Similarly, in 2023's analysis from the UKHSA (see TTD (Time to Detect): Revisited), they estimated there could be dozens or even hundreds of undetected human H5N1 infections before public health surveillance would likely detect them, potentially over a period of weeks or months. 

While we've seen a steady chorus of voices from the scientific community calling for more aggressive surveillance and testing (see here, here, here, here, and here) - the world seems content to don blinders and hope for the best.

Today we've a review article in the International Journal of Infectious Diseases (IJID) that examines the current H5N1 threat, and Europe's readiness to deal with it. 

While they cite progress, they urge that Europe strengthen preparedness now, because an emerging human outbreak would likely far outpace our ability to manufacture and deploy vaccines. 

I've only posted some brief excerpts, so follow the link to read the review in its entirety.  I'll have a brief excerpt after the break.

The H5N1 avian influenza threat: a European Perspective on Research Gaps and State of Preparedness

Lone Simonsen 1, Tyra Grove Krause 2 3, Anders Gorm Pedersen 4, Lars E Larsen 5, Marlies Jilles Francine Goedknegt 1, Ramona Trebbien 2, Olav Hungnes 6, Preben Aavitsland 6, Otto Helve 7, Richard J. Webby 8, Marc-Alain Widdowson 9, Bolette Søborg 2, Marion Koopmans 10 11 12, Eskild Petersen 1

10.1016/j.ijid.2026.109220 

Highlights

•  Surveillance must strengthen One Health with closer collaboration between human and veterinary public health.

• Functional assays measuring H5N1 binding to α2,3- or α2,6 sialic acid will help.

• Detect early receptor switching.

• Novel vaccine platforms like the mRNA and Adenovirus must be developed to seasonal influenza to be available for rapid manufacture in a pandemic situation.

Abstract

H5N1 influenza clade 2.3.4.4b has spread from South East Asia through migratory birds since 2020. The expansion seeded frequent spillovers into wild and domestic mammals including cattle in the United States. While the risk for humans not in direct contact with infected animals is low, the widespread presence and opportunities for evolution constitutes a pandemic threat.

If sustained human-to-human transmission (H2H) would emerge, there is limited time to mount a public health response. Initially, non-pharmaceutical interventions (NPIs) are needed until vaccines are available. Experience with H5N1 viruses since 1997 suggests that infections are seen mostly in people born after 1968, indicating that people under sixty may be at particular risk.

Closely monitoring viral diversity and evolution in wild life, and at the human animal interface, using integrated One Health surveillance and genome-based selection of viruses for further characterization for instance receptor affinity of H5N1 to human receptors is mandatory.

        (SNIP)

An influenza A pandemic in our lifetime is highly likely, given there were four in the last 100 years. However, the severity of a future influenza pandemic remains uncertain - it could be as devastating as 1918 or as mild as 2009.[73]

A robust European strategy must be developed during “peace time”, with sustained investment in diagnostics, surveillance, and flexible vaccine manufacturing. Additionally, it is crucial to anticipate, address and counter anti-science and anti-vaccine sentiments, which posed significant challenges during COVID-19. Effective mitigation and vaccination efforts depend on public trust in health authorities.

Although this review focused on the H5N1 threat, the next pandemic could be caused by another influenza A subtype, a coronavirus, or an entirely different pathogen. Given this uncertainty, preparedness efforts should prioritize surveillance anticipating a broad range of pathogens.

       (Continue . . . ) 


While it remains to be seen how the world responds to growing calls for pandemic preparedness (see UN High-Level Meeting on Pandemic Prevention, Preparedness and Response (PPPR)), there are things you can do as an individual to reduce your risk from a pandemic.

As we discussed in  #Natlprep 2025: Personal Pandemic Preparedness, buried in the CDC's archives are a number of useful documents for individuals, schools, and employers on dealing with a pandemic.:

• Get Your Household Ready For Pandemic Flu {PDF - 16 pages]
• Get Ready for Pandemic Flu: Educational Settings [PDF – 16 pages]
• Get Ready for Pandemic Flu: Workplace Settings [PDF – 16 pages]  

I also recommend getting (and being) a Flu Buddy, availing yourself of the vaccines that are available now (Flu/COVID/RSV, Pneumonia, etc.), stockpiling OTC meds and PPE, and being prepared to shelter in place. 

Even if a pandemic doesn't come in the near future, these are all things that would benefit you and your family during any prolonged emergency. 

And those, sadly, appear to be increasingly common.  For more on that, you may wish to revisit:

The UK's `Be Ready' Preparedness Campaign

September Is National Preparedness Month (#NPM26)

#Natlprep 2026: Pandemic Planning At Both Ends of the Spectrum

UK National Risk Register 2026 - Urges Citizen Preparedness