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

Credit NIAID

#18,867

During the 2009 H1N1 pandemic younger people were much harder hit than the elderly, with the average age of flu-related death temporarily plummeting from 76 (see Study: Years Of Life Lost Due To 2009 Pandemic) to just 41 (cite CDC).

In 2010's EID Journal: Original Antigenic Sin And Pandemic H1N1, we looked at a highly plausible explanation; that the first flu subtype one is exposed to early in life creates a lasting impression on your immune system.

Those born before 1957 appeared the least susceptible to severe infection in 2009.  Between 1918 and the end of 1956, H1N1 was the only influenza A virus in circulation, which neatly fit into that analysis. 

We saw a similar pattern during 1977 return of the `Russian (H1N1) flu' which, primarily affected those under the age of 20.

 Over the past 15 years it has become increasingly apparent that the first influenza subtype you are exposed to makes the biggest, and most lasting, impression on your immune system (see Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression).

At first, it was assumed that the HA subtype (H1, H2, or H3) was the main driver of immunity, but about a decade ago a new idea emerged; that the HA Group (1 or 2) could provide some degree of cross-protection as well.

There are 18 known HA (hemagglutinin) subtypes,which are divided into two major HA groups. Depending from which group your first exposure came, you may carry some degree of cross-protection against novel flu viruses of that same group.

In other words, if your first influenza exposure was to H1N1 or H2N2 (group 1), you may carry some degree of immunity to the H5 viruses (H5N1, H5N6, etc.). If, however, your first exposure was to H3N2 (group 2), you may carry some protection against H7N9 instead.

But there is still a lot left to unravel when it comes to the complex human immune response to novel flu subtypes.  

Over the past couple of years, we increasingly seen the idea that one's first exposure to the other influenza A surface protein - the NA (neuraminidase) - may also play an important role in long-term immunity. 

All of which brings us to a new preprint which seems to add weight to that argument.  While there are still a great many unknowns (including whether all N1 neuraminidases are created equal), this study suggests that an NA match may overshadow the HA group match when it comes to antibody responses. 

When it comes to influenza immunity, everything is relative. 

Whatever small advantage there may be against H5N1 to those born prior to 1957 may well be negated by other factors, including advancing age and declining immune systems.  

And while this study would suggest that those born between 1968 and 1977 (1st exposure likely to H3N2) might be the most susceptible to an H5N1 virus, how much more is difficult to say.  

I've reproduced the abstract and some excerpts from the preprint. Follow the link to read it in its entirety.   I'll have a postscript after the break.

Cross-reactive human antibody responses to H5N1 influenza virus neuraminidase are shaped by immune history

Jordan T. Ort, Ashley Sobel Leonard, Shuk Hang Li, Reilly K. Atkinson, Lydia M. Mendoza,  Marcos Costa Vieira, Sydney Gang,  Sarah Cobey,  Scott E. Hensley
doi: https://doi.org/10.1101/2025.09.02.25334929
This article is a preprint and has not been certified by peer review [what does this mean?].  

Preview PDF

Abstract

H5N1 highly pathogenic avian influenza viruses have spread globally and pose a risk for a human pandemic. Prior studies suggest that early life exposures to group 1 influenza viruses (H1N1 and H2N2) prime antibodies that cross-react to the hemagglutinin of H5N1, which is also a group 1 virus.

Less is known about how immune history affects antibody responses against the neuraminidase (NA) of H5N1 viruses. Here, we measured NA inhibition antibodies against multiple H5N1 viruses using sera from 155 individuals born between 1927 and 2016.

We found that individuals primed in childhood with H1N1 viruses were more likely to possess higher levels of antibodies that cross-react with the NA of H5N1 viruses compared to individuals primed in childhood with H2N2 or H3N2 viruses. While young children rarely possessed cross-reactive NA antibodies, we found that childhood infections with contemporary H1N1, but not H3N2, viruses can elicit them.

These data suggest that immune history greatly impacts the generation of cross-reactive NA antibodies that can inhibit H5N1 viruses.

       (SNIP)

These studies indicate that immune imprinting affects the priming of NA antibody responses  across the human population, which may impact differential H5N1 risks between age groups.  Our data are consistent with recent work that suggest that in addition to HA group-level imprinting, homosubtypic NA imprinting can further modulate the risk of zoonotic influenza infection, including between H5N1 and H5N6 viruses which differ only by NA subtype 34. This has far-reaching implications, as our studies predict that H5 viruses may cause differential levels of disease in the human population after reassortment with a novel NA.

While we found that initial exposure to an H1N1 virus confers high levels of cross-reactive N1 antibodies, and others have examined the role of NA imprinting in shaping age-specific seasonal influenza infection patterns35,36, further longitudinal studies are necessary to fully ascertain the importance and contribution of early-life infections. 

(SNIP)

Although we identified similar patterns of cross-reactivity to each of the tested H5N1 NAs— including the reassorted NA of the D1.1 genotype—determining the epitopes targeted by these antibodies will be key to understanding their potential breadth. Given the diversity of N1 genes in wild birds39, and the propensity of H5 viruses to undergo reassortment 1,40, it will be important to establish if certain N1 lineages could escape pre-existing immunity.

A better understanding of how immune imprinting affects cross-reactive antibody responses within diverse human populations will be useful for risk assessment of new viral strains with pandemic potential.

       (Continue . . . )

 

For more on this topic, you may wish to revisit:

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

Preprint: Population Immunity to HPAI 2.3.4.4b A(H5N1) Viruses in the United States and the Impact of Seasonal Influenza on A(H5N1) Immunity

Preprint: Pre-existing H1N1 Immunity Reduces Severe Disease with Cattle H5N1 Influenza Virus

JAMA Int. Med: Azelastine Nasal Spray for Prevention of SARS-CoV-2 Infections

 

#18,866

Unless and until the CDC's ACIP makes a ruling on the availability of the COVID vaccine, tens of millions of Americans (including seniors, like myself) are finding it difficult (or, in some states, impossible) to get a COVID shot without a doctor's prescription (see map above).

Even with a prescription, some pharmacies are unwilling to provide shots until a decision is rendered by the CDC. Which, as we go into the fall respiratory season, puts a lot of people at greater risk of infection. 

There are other options, of course.  I continue to wear an N95/KN95 mask in crowded indoor environments, since the COVID vaccine only provides partial protection.  I've now gone 4+ years without so much as a sniffle, and I'll continue to do so for the foreseeable future. 

But there have been some intriguing studies suggesting that some types of OTC medications may be an adjunct to help prevent COVID and other respiratory infections (see The Lancet Resp. Med.: Nasal sprays & Behavioural Interventions Reduced Infections & Improved Recovery Times).

Many of these studies have been in vitro, or have been observational in nature (see PNAS Intranasal neomycin evokes broad-spectrum antiviral immunity in the upper respiratory tract), but last week JAMA Int. Medicine published a fascinating (albeit, modest) randomized placebo-controlled clinical trial which showed encouraging results from an Azelastine nasal spray against COVID infection.

As always, none of what follows is medical advice, and is provided for educational purposes only. If you find merit in these findings, and wish to pursue them, consult your physician. 

In short, they divided a study cohort of 450 subjects into 2 (roughly equal) groups; a control arm which took a placebo and an arm which took a 0.1%, Azelastine nasal spray 3 times a day for 56 days.   

At the end of the study those taking the active ingredient saw a 67% reduction in PCR confirmed COVID infection. Note: there were some (mostly mild) AEs (adverse effects) reported in both groups.  

I've posted the abstract below.  Follow the link to read the research paper in full.  After which I'll have more for your consideration.

Azelastine Nasal Spray for Prevention of SARS-CoV-2 InfectionsA Phase 2 Randomized Clinical Trial

Thorsten Lehr, PhD1; Peter Meiser, PhD2; Dominik Selzer, PhD1 

JAMA Intern Med
Published Online: September 2, 2025
doi: 10.1001/jamainternmed.2025.4283

Key Points

Question Is regular application of azelastine nasal spray associated with reduced risk of SARS-CoV-2 infections?

Findings In this randomized placebo-controlled clinical trial that included 450 participants, the incidence of laboratory-confirmed SARS-CoV-2 infections was significantly lower with application of azelastine nasal spray compared with placebo treatment.

Meaning The use of azelastine nasal spray may help to reduce the risk of SARS-CoV-2 infections.

Abstract

Importance Limited pharmaceutical options exist for preexposure prophylaxis of COVID-19 beyond vaccination. Azelastine, an antihistamine nasal spray used for decades to treat allergic rhinitis, has in vitro antiviral activity against respiratory viruses, including SARS-CoV-2.

Objective To determine the efficacy and safety of azelastine nasal spray for prevention of SARS-CoV-2 infections in healthy adults.

Design, Setting, and Participants A phase 2, double-blind, placebo-controlled, single-center trial was conducted from March 2023 to July 2024. Healthy adults from the general population were enrolled at the Saarland University Hospital in Germany.

Interventions Participants were randomly assigned 1:1 to receive azelastine, 0.1%, nasal spray or placebo 3 times daily for 56 days. SARS-CoV-2 rapid antigen testing (RAT) was conducted twice weekly, with positive results confirmed by polymerase chain reaction (PCR). Symptomatic participants with negative RAT results underwent multiplex PCR testing for respiratory viruses.

Main Outcome The primary end point was the number of PCR-confirmed SARS-CoV-2 infections during the study.

Results A total of 450 participants were randomized, with 227 assigned to azelastine and 223 to placebo; 299 (66.4%) were female, 151 (33.6%) male, with a mean (SD) age of 33.0 (13.3) years. Most were White (417 [92.7%]), with 4 (0.9%) African, 22 (4.9%) Asian, and 7 (1.6%) of other ethnicity. In the intention-to-treat (ITT) population, the incidence of PCR-confirmed SARS-CoV-2 infection was significantly lower in the azelastine group (n = 5 [2.2%]) compared with the placebo group (n = 15 [6.7%]) (OR, 0.31; 95% CI, 0.11-0.87).

As secondary end points, azelastine demonstrated an increase in mean (SD) time to SARS-CoV-2 infection among infected participants (31.2 [9.3] vs 19.5 [14.8] days), a reduction of the overall number of PCR-confirmed symptomatic infections (21 of 227 participants vs 49 of 223 participants), and a lower incidence of PCR-confirmed rhinovirus infections (1.8% vs 6.3%). Adverse events were comparable between the groups.

Conclusions and Relevance In this single-center trial, azelastine nasal spray was associated with reduced risk of SARS-CoV-2 respiratory infections. These findings support the potential of azelastine as a safe prophylactic approach warranting confirmation in larger, multicentric trials.

Trial registration EudraCT number: 2022-003756-13

        (Continue . . . )

While this study used an Rx 0.1%, Azelastine nasal spray, in 2021 a more potent 0.15% formulation was approved for OTC sale in the United States.  

While a 67% reduction in infection is impressive, this study followed a relatively small cohort, was conducted in a single location, and against a (likely) limited number of variants. 

For more detailed analysis by a physician,  I'd highly recommend spending 20 minutes watching the following MedCram Youtube video by Dr. Roger Seheult, MD. 

As we go into the fall respiratory season, I'll be getting the flu shot - and with luck, a COVID shot - in the next few weeks. But I'll also continue to wear my facemask in crowded venue, and may add the Azelastine spray to my arsenal. 

While it's a hassle - because of my age (71) and accrued co-morbidities -  I find the risks of COVID reinfection (see partial list below), along with the dangers of flu, RSV, and other winter nasties to be enough to warrant these extra precautions on my part. 

As always, YMMV.

EHJ: Accelerated Vascular Ageing After COVID-19 Infection: The CARTESIAN Study

AHA: COVID-19 May Trigger New-Onset High Blood Pressure

JAMA: Additional Evidence Of A Post-COVID/Diabetes Link

Nature: Long-term Cardiovascular Outcomes of COVID-19

 

WHO DON: Ebola Virus Disease - Democratic Republic of the Congo (Sept 5th)

 

#18,865

Two days ago we looked at the WHO AFRO Announcement of A New Outbreak of Ebola In the DRC, which cited 28 suspected cases, and 15 deaths (4 HCWs), in the Bulape and Mweka health zones in Kasai Province, DRC.

This is reportedly the 16th Ebola outbreak in the DRC since 1976, and the first reported from the DRC since 2002.  Overall, roughly 3 dozen outbreaks have been reported over the past 4 decades, mostly from central and west Africa.

While most outbreaks are limited in size, twice in the past dozen years we've seen extended outbreaks with the number of deaths running into the thousands (2014-2016 & 2018-2020). 

Overnight the WHO published the first detailed DON (Disease Outbreak News) report on this latest outbreak.  For now, the WHO describes the National risk as high; regional risk is moderate; and the global risk remains low.

Due to its length, I've only posted the link and some excerpts (including the risk assessment).  Follow the link to read it in its entirety. 

Ebola virus disease - Democratic Republic of the Congo
5 September 2025

Situation at a glance

On 1 September 2025, WHO received an alert from the Ministry of Health of the Democratic Republic of the Congo (DRC) regarding suspected cases of Ebola virus disease (EVD) in the Bulape Health Zone, Kasai Province, DRC. The first known index case was a pregnant woman who presented at Bulape General Reference Hospital on 20 August 2025 with symptoms of high fever, bloody diarrhoea, haemorrhage and extreme weakness. She died on 25 August from multiple organ failure. 

On 4 September 2025, following confirmatory laboratory testing, the Ministry of Health declared an outbreak of EVD. Ebola virus disease is a serious, often fatal illness in humans. The virus is transmitted to humans through close contact with the blood or secretions of infected wildlife and then spreads through human-to-human transmission. As of 4 September 2025, 28 suspected cases, including 15 deaths (case fatality ratio (CFR): 54%), have been reported from three areas of the Bulape health zone (Bulape, Bulape Com and Dikolo) and Mweka health zone.

Among the deaths, four are health-care workers. About 80% of the suspected cases are aged 15 years and older. Six samples were collected from five suspected cases and one probable death from Bulape health zone and arrived on 3 September at the National Public Health Laboratory (INRB) in Kinshasa for confirmation testing.

All five samples tested positive for Ebola virus (EBOV) through GeneXpert and Polymerase Chain Reaction (PCR) assays on 3 September 2025. The Ministry of Health, with support from WHO and partners, is implementing public health response measures to contain the outbreak.

WHO assesses the overall public health risk posed by the current EVD outbreak as high at the national level, moderate at the regional level and low at the global level.

(SNIP)

 WHO risk assessment

This is the 16th EVD outbreak in the DRC since 1976. The current outbreak occurs after almost three years without a confirmed EVD outbreak in the country. The last EVD outbreak in the country was declared on 15 August 2022 in Beni city, North Kivu province, with one single case reported who later died, and the MoH declared the end of the outbreak on 27 September 2022. In the Bulape district, the epicentre of the current outbreak, the last EVD outbreak was recorded in 2007.

This outbreak is occurring in a complex epidemiological and humanitarian context. The country is facing several outbreaks, including mpox, cholera, and measles. In addition, the country is experiencing a long-term economic and political crisis. The country's resources and capacity to effectively respond to the current outbreak are therefore limited.

The epicentre of this outbreak is in the proximity of the Tshikapa city, the capital city of the Kasai province, and the Angolan border (approximately 100 to 200 kilometres, depending on the nearest border crossing point). Although the affected district is a hard-to-reach rural area relatively far from the two main urban centres of Mbuji Mayi and Kananga, population movements between different parts of the province are frequent, especially between Bulape and Tshikapa.

In addition, epidemiological investigations are ongoing with transmission chains, and the source of the outbreak has not yet been identified; therefore, additional infected people cannot be ruled out. The date of symptom onset for the first case is not yet known, as well as the therapeutic itinerary prior to health facility consultation, which further increases the likelihood of an ongoing community transmission with further risk of spread to other health districts.

WHO assesses the overall public health risk posed by the current EVD outbreak as high at the national level, moderate at the regional level and low at the global level.

       (Continue . . . )
 

MMWR: HPAI H5N1 Infection In A Child With No Known Exposure - San Francisco, CA (Dec 2024-Jan 2025)

 
70 Confirmed H5N1 Cases - 7 Probable

#18,864

While the sharp decline in human infections with HPAI H5N1 in the United States over the past 7 months is somewhat reassuring, the reality is it requires a combination of both diligence and luck to detect community cases of novel influenza infection. 

It has been estimated in the past that less than 1-in-100 novel swine flu infections are picked up by passive surveillance (see CID Journal: Estimates Of Human Infection From H3N2v (Jul 2011-Apr 2012). 

Many with mild or moderate symptoms will not seek a doctor's advice, and among those who do, most will not be tested for novel influenza.  And of course, asymptomatic cases are almost certain to be missed. 

A year ago 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.

While a little over two years ago, a study from the HKHSA (see UK Novel Flu Surveillance: Quantifying TTD) warned that it could take between 3 and 10 weeks - and anywhere between a few dozen to a few thousand community cases - before community spread would become apparent to authorities. 

So, while the recent lull in human cases may be reassuring, it may not fully reflect the situation on the ground.

Yesterday the CDC's MMWR published a long-awaited report on the investigation into a child's infection last December with HPAI H5N1 in California (see Presumptive Bird Flu Case Identified In San Francisco).

This is one of four cases (3 confirmed, 1 Probable) in the United States since mid-2024 where the source of infection remains unknown (i.e. no known exposure to dairy cows, poultry, wild birds, or other infected animals). 

While this investigation found `no laboratory evidence of human-to-human transmission among close contacts', the devil is always in the details.  

• Confirmation of the  child's H5N1 infection was delayed nearly 4 weeks (27 days) after the onset of illness, and contact tracing and testing occurred well past the time where valid PCR results would be expected. 

• Of 84 potential contacts,  67 met the CDC close-contact definition. But of those, only a small number were actually tested via PCR or serology (n=14).  In all, only 9 contacts were tested for post-exposure antibodies. 

 

FIGURE 2. Network analysis of human A(H5N1) influenza cases and possible contacts (N = 84)* — San Francisco, California, January 2025

In their analysis, the authors discuss these (and other) limitations - none of which are unique to this investigation - as we've seen previously:

WHO DON Update On Mexico's Fatal H5N1 Infection

NEJM: Critical Illness in an Adolescent with Influenza A(H5N1) Virus Infection

CDC: Serology Results On Missouri H5 Patient's Contacts (Updated)

In January of 2025, we looked at a CDC HAN: Accelerated Subtyping of Influenza A in Hospitalized Patients - and while some progress appears to have been made - it is unclear what the level of compliance is to these guidelines across the nation. 

And of course, these are only likely to capture hospitalized patients. Those attending clinics or private physicians are less apt to be tested for novel flu. 

While I've only posted some excerpts, the following MMWR report is well worth reading in its entirety, particularly for its detailed look at the challenges related to contact tracing and testing in the wake of a delayed diagnosis.

Highly Pathogenic Avian Influenza A(H5N1) Virus Infection in a Child with No Known Exposure — San Francisco, California, December 2024–January 2025

Weekly / September 4, 2025 / 74(33);522–527
 
Farrell A. Tobolowsky, DO1; Eric Morris, MPH1; Lina Castro, MPH1; Tina Schaff1; Monica Jacinto1; Joseph P. Clement, MS1; Min Z. Levine, PhD2; Julia C. Frederick, PhD2; Feng Liu, PhD2; Crystal Holiday, PhD2; Marie K. Kirby, PhD2; C. Todd Davis, PhD2; Krista Kniss, MPH2; Sonja J. Olsen, PhD2; Rahil Ryder, MS3; Debra A. Wadford, PhD3; Godfred Masinde, PhD1; George Han, MD1; A. Danielle Iuliano, PhD2; Seema Jain, MD1 

Summary

What is already known about this topic?

As of January 1, 2025, 37 human cases of highly pathogenic avian influenza (HPAI) A(H5N1) had been detected in California, none of which occurred in San Francisco.

What is added by this report?

On January 9, 2025, a case of HPAI A(H5N1) infection was identified in a school-aged child in San Francisco through enhanced surveillance (influenza A virus subtyping of a sample of specimens weekly). No source of exposure was identified, and investigations found no laboratory evidence of human-to-human transmission among close contacts.

What are the implications for public health practice?

Enhanced surveillance and timely subtyping of a subset of influenza A–positive specimens, including specimens from persons without known A(H5N1) exposure, are important to detect avian influenza A virus infections. Public health investigations are critical to monitoring for human-to-human transmission.

Article PDF


Abstract

In response to a highly pathogenic avian influenza (HPAI) A(H5N1) outbreak in U.S. dairy cows detected in March 2024, with subsequent identification of human cases, the San Francisco Department of Public Health instituted enhanced influenza surveillance (influenza A virus subtyping of a sample of specimens weekly) in June 2024. As of January 1, 2025, 37 human cases of influenza A(H5N1) had been detected in California, none of which occurred in San Francisco. 

On January 9, 2025, enhanced surveillance detected a human influenza A(H5N1) virus genotype B3.13 infection in a school-aged child in San Francisco with mild illness. Case investigation and contact tracing were conducted to ascertain exposures and detect possible human-to-human transmission. Activities comprised a household visit that included an environmental assessment, close contact interviews and surveys, and molecular and serologic testing. 

Sixty-seven close contacts (household, school, and health care) were identified. Upper respiratory tract specimens collected from seven asymptomatic household contacts and four symptomatic school contacts all tested negative for influenza virus by real-time reverse transcription–polymerase chain reaction (rRT-PCR). Although antibodies against influenza A(H5N1) were detected in the index patient, serologic testing of a convenience sample of nine close contacts identified no detectable A(H5)-specific antibodies.

Despite an extensive investigation, the infection source remains unknown; no human-to-human transmission was identified among close contacts by rRT-PCR and serologic testing. Continued enhanced surveillance and timely subtyping of a subset of influenza A–positive specimens are essential components of a comprehensive strategy to detect human novel influenza A virus infections, including among persons without known exposures to A(H5N1) viruses.

(SNIP)
 

Index Case Investigation

The index patient lived in an urban environment, did not travel, and had no reported exposure to dairy cows, cats, poultry, birds or other wild animals in the 10 days prior to the illness onset; the family had a pet dog. There were no animals at school, and the patient’s family did not work in occupations that increase risk for A(H5N1) virus infection (handling, slaughtering, defeathering, butchering, culling, caring for, or milking infected animals). A member of the patient’s family purchased raw poultry at a live bird market 2 weeks before the child’s illness onset; the poultry was cooked and consumed the same day it was purchased.
Investigation of Close Contacts

Among 84 persons identified as possible contacts of the index patient (seven household, 53 school, and 24 health care), 67 (80%) met the close contact definition (Figure 2). No household contacts reported illness. School absences were reported for 34 (64.2%) school contacts, 26 (76.5%) of whom were interviewed (one teacher and parents of 25 children). All interviewed parents reported respiratory illnesses in their children, including seven who were symptomatic at the time of interview. The teacher had had influenza-compatible symptoms but was asymptomatic at the time of interview. Four persons were tested for one or more respiratory viruses (COVID-19, RSV, or influenza) previously while ill; all test results for influenza were negative. Among the 24 health care worker contacts from three facility visits (two urgent care, one emergency department), 11 (45.8%) completed a survey, including seven who had close contact with the patient; none reported influenza-compatible symptoms. All 11 available respiratory (oropharyngeal and nasal) specimens from close contacts (seven household and four school) were A(H5)-negative by rRT-PCR.

Serum specimens were collected from the index patient (32 days from onset to convalescent serum collection), three adult household contacts, two school contacts, and four health care contacts. Among these nine contacts, the median interval between their first exposure to the index patient and serum collection was 45 days (range = 9–47 days), and the median interval between their last exposure and serum collection was 26 days (range = 0–46 days). The patient had antibodies to all three wild-type A(H5N1) viruses, with elevated antibody titers in all assays, consistent with recent H5N1 infection: A/Texas/37/2024 (B3.13) (MN titer = 160, HI titer = 320); A/Michigan/90/2024 (B3.13) (MN titer = 320, HI titer = 226); and A/Washington/240/2024 (D1.1) (MN titer = 113, HI titer = 320). All nine close contacts’ serology results were negative for all three wild-type A(H5N1) viruses.

Discussion

Although no exposure was identified, clinical presentation, molecular testing, and positive serology with elevated antibody titers confirmed HPAI A(H5N1) infection in this child. The absence of laboratory (molecular and serologic) evidence of current or recent A(H5N1) virus infection among close contacts suggests no human-to-human transmission. At least two other U.S. patients with confirmed A(H5N1) infection, including another unrelated pediatric patient in the San Francisco Bay Area, had no known exposure to A(H5N1) virus–infected domestic poultry, wild birds, dairy cows, or other infected animals (3,4).

Although no dairy processing facilities are located in San Francisco, the city is situated on a migratory bird route, and in 2024, A(H5) virus was detected in a live bird market, wild birds, and San Francisco wastewater (H5N1 bird flu detected in SF, first in California city wastewater). Although the family purchased poultry at a live bird market (the child did not accompany them to the market), the parents were confident that the child was not exposed to raw poultry, recent A(H5) testing in the market was negative, the cooked poultry consumption occurred more than 2 weeks before the child’s symptom onset, and neither parent had evidence of infection, arguing against infected poultry exposure as the source. Although no wild bird exposure was reported, the child did spend time outside at school; therefore, environmental exposure is theoretically possible. As there were no clear risk factors or exposure to A(H5N1) virus, the infectious source remains unknown.

The genetic differences between the patient’s two positive specimens collected at separate time points likely reflect replication in the child during the intervening 25 days. Persistently positive influenza PCR test results have been previously reported, yet the duration of A(H5N1) viral nucleic acid detection and infection in humans is unknown and likely varies with virus and host factors (9). Although the second (oropharyngeal) swab collected from the patient was positive for A(H5N1) 4 weeks after the first, sequencing did not reveal mutations indicating mammalian adaptation.

Limitations

The findings in this report are subject to at least three limitations. First, because this case was identified through enhanced surveillance, which at the time included batch testing, there was a delay between specimen collection and the influenza A virus subtyping that led to detection of the case: as a result, the investigation occurred after the patient’s illness had resolved and at the end of the 10-day monitoring period for close contacts, subjecting interviews to recall bias and limiting public health interventions such as real-time testing, isolation, antiviral treatment, and postexposure antiviral prophylaxis.

Second, it was not possible to interview or collect respiratory and serum specimens from all close contacts; therefore, assessment of signs and symptoms and immunologic response was not comprehensive. 

Lastly, although household and health care contacts were assessed for asymptomatic infection, only symptomatic school contacts received molecular or serologic testing; thus, asymptomatic infection might have been missed.

Implications for Public Health Practice

A(H5N1) virus infections in humans without a clear animal exposure have rarely occurred in the United States (CDC Confirms H5N1 Bird Flu Infection in a Child in California) but have been documented in other countries where A(H5N1) viruses have circulated in wild birds for years. Continued enhanced surveillance and real-time subtyping of a subset of influenza A positive specimens at public health laboratories, including among persons without known risk for exposure to A(H5N1) virus, is an important part of comprehensive novel influenza surveillance strategies (Summer 2025 Influenza Surveillance).

Although the child had no known dairy cow exposure, sequencing results indicated that this case was associated with the 2024–2025 California dairy cow outbreak. The B3.13 genotype associated with this outbreak has also been detected in birds and felines (10), highlighting the continued transmissibility of the virus across susceptible species. Given the wild and domestic animal reservoirs for A(H5N1), a continued One Health approach supports surveillance of wild and domestic animal reservoirs for identification of additional animal cases and risk factors for cross-species and animal-to-human transmission.

WHO AFRO Announces A New Outbreak of Ebola In the DRC

 

#18,863

While there have been scattered media reports, and some preliminary press releases from the local health authorities (see FluTracker's Thread) over the past 24 hours, today the WHO African Regional Office officially recognized an outbreak of Ebola in the DRC. 

At this point in time there are 28 suspected cases, and 15 deaths (4 HCWs), in the Bulape and Mweka health zones in Kasai Province. The virus has been identified as Ebola Zaire. 

The official announced from the WHO follows.

Democratic Republic of the Congo declares Ebola virus disease outbreak in Kasai Province
04 September 2025

Kinshasa – Health authorities in the Democratic Republic of the Congo have declared an outbreak of Ebola virus disease in Kasai Province where 28 suspected cases and 15 deaths, including four health workers, have been reported as of 4 September 2025.

The outbreak has affected Bulape and Mweka health zones in Kasai Province where health officials have been carrying out investigations after the cases and the deaths reported presented with symptoms including fever, vomiting, diarrhoea and haemorrhage. Samples tested on 3 September at the country’s National Institute of Biomedical Research in the capital Kinshasa confirmed the cause of the outbreak as Ebola Zaire caused by Ebola virus disease.

A national Rapid Response Team joined by World Health Organization (WHO) experts in epidemiology, infection prevention and control, laboratory and case management has been deployed to Kasai Province to rapidly strengthen disease surveillance, treatment and infection prevention and control in health facilities. Provincial risk communication experts have also been deployed to reach communities and help them understand how to protect themselves.

Additionally, WHO is delivering two tonnes of supplies including personal protective equipment, mobile laboratory equipment and medical supplies. The area is difficult to reach, taking at least one day of driving from Tshikapa (the provincial capital of Kasai), with few air links.

“We’re acting with determination to rapidly halt the spread of the virus and protect communities,” said Dr Mohamed Janabi, WHO Regional Director for Africa. “Banking on the country’s long-standing expertise in controlling viral disease outbreaks, we’re working closely with the health authorities to quickly scale up key response measures to end the outbreak as soon as possible.”

Case numbers are likely to increase as the transmission is ongoing. Response teams and local teams will work to find the people who may be infected and need to receive care, to ensure everyone is protected as quickly as possible.

The country has a stockpile of treatments, as well as 2000 doses of the Ervebo Ebola vaccine, effective to protect against this type of Ebola, already prepositioned in Kinshasa that will be quickly moved to Kasai to vaccinate contacts and frontline health workers.

The Democratic Republic of the Congo’s last outbreak of Ebola virus disease affected the north-western Equateur province in April 2022. It was brought under control in under three months thanks to the robust efforts of the health authorities. In Kasai province, previous outbreaks of Ebola virus disease were reported in 2007 and 2008. In the country overall, there have been 15 outbreaks since the disease was first identified in 1976.

Ebola virus disease is a rare but severe, often fatal illness in humans. It is transmitted to people through close contact with the blood, secretions, organs or other bodily fluids of infected animals such as fruit bats (thought to be the natural hosts). Human-to-human transmission is through direct contact with blood or body fluids of a person who is sick with or has died from Ebola, objects that have been contaminated with body fluids from a person sick with Ebola or the body of a person who died from Ebola.

FDA Issues New Warning On H5N1 Detected In Cat Food

#18,862

Yesterday the USDA added a domestic cat from San Francisco to their Mammals with H5N1 list, with a collection date in July and a confirmation date in late August, making the 3rd cat in a month added to the list (see screenshot below).

While we rarely get details on these cases (145 domestic cats reported to date), late yesterday the FDA issued a new warning on contaminated (raw, frozen) cat food, which is believed linked to this latest death. 

Since late last year we've seen a spate of similar reports, including:

NYC DOH Update: H5N1 In Cats Linked To Raw Food & Suspected Cat-to-Cat Transmission

Washington State (WSDA) Announces 2 Households with H5N1 Infected Cats Linked to Raw Food

Oregon Dept. of Agriculture Statement On H5N1 In Domestic Cats - WSDA Health Alert on Raw Pet Food

LA County Animal HAN: H5 Bird Flu Confirmed in Three Additional Domestic Cats in LA County & in One Commercially Available Raw Pet Food Product

Last January US FDA Issued New Requirements For Pet Food Manufacturers - APHIS Updates Turkey Surveillance Policies, although it left the corrective steps largely up to the manufacturers (see snippet below).

Under the PCAF requirements, animal food businesses must conduct a reanalysis of their food safety plan when the FDA determines it is necessary to respond to new hazards and developments in scientific understanding.

The FDA has determined that it is necessary for cat and dog food manufacturers covered by the PCAF rule, who are using uncooked or unpasteurized materials derived from poultry or cattle (e.g., uncooked meat, unpasteurized milk, unpasteurized eggs) in cat or dog food, to reanalyze their food safety plans to include H5N1 as a new known or reasonably foreseeable hazard.

Admittedly, there are limits to what a manufacturer can do to prevent H5N1 contamination of raw milk, dairy, and poultry products. The only safe assumption is that raw food products carry more inherent health risks than pasteurized, or cooked products.

According to Whole Genome Sequencing (WGS), this incident is linked to the Bovine B3.13 genotype of H5N1, which is primarily found in dairy cows, but has spilled over into poultry on occasion. 

The press release from the USDA (below) curiously states this B3.13 genotype ` . . .  involves a virus lineage that was detected from about November to December 2024 and is no longer circulating' - which based on the data provided, is hard to explain - as the B3.13 genotype has been reported in dairy cattle well into 2025. 

It also appears, based on the dates provided by the USDA, that this cat died sometime in July, and we are only now being informed about it. 

The full statement from the FDA follow. 

FDA Notifies Pet Owners That Tests Show H5N1 Contamination in Certain Lots of RAWR Raw Cat Food Chicken Eats

CVM Updates

Following up on a case of H5N1 Highly Pathogenic Avian Influenza in a cat, testing performed by the U.S. Food and Drug Administration, state and local public health and agriculture partners, and federal partners suggests a link between the strain of H5N1 virus detected in the cat and in certain lots of RAWR Raw Cat Food Chicken Eats, a product the cat consumed before falling ill. FDA is sharing information about the testing for public awareness. The agency continues to investigate and will update this notice should new information become available.

Summary

• FDA has found that certain lots of RAWR Raw Cat Food Chicken Eats sliders tested positive for H5N1. The affected lots are Lot CCS 25 077 (Sell By 09/18/26) and Lot CCS 25 093 (Sell By 10/03/26).

•  The San Francisco Department of Public Health (SFDPH) was notified a cat that ate product from Lot CCS 25 093 became ill with H5N1 and was euthanized. After initial polymerase chain reaction (PCR) testing of the open product sample from Lot CCS 25 093 collected from the pet owner by SFDPH detected H5N1, confirmatory PCR testing and subsequent whole genome sequencing (WGS) of a diagnostic sample from the cat and the open product sample from Lot CCS 25 093 were performed by USDA National Veterinary Services Laboratories (NVSL).

• FDA collected and tested two retail samples of the same RAWR Chicken Eats product with a different lot number (CCS 25 077) and Sell By date (09/18/26). Both samples were positive for Influenza A Virus, and WGS was performed on one sample, which was also positive for H5N1.

• FDA is concerned about the lots of RAWR Raw Cat Food Chicken Eats described above because whole genome sequencing suggests the H5N1 detected in the now-deceased cat and in Lots CCS 25 093 and CCS 25 077 of the Chicken Eats product originated from a common source of contamination.

• WGS results also indicated that H5N1 from all three samples were within the same WGS cluster, indicating relatedness. The cluster involves a virus lineage that was detected from about November to December 2024 and is no longer circulating, supporting that the cat became ill from eating Lot CCS 25 093 of the Chicken Eats product.

• NVSL testing of the cat, Lot CCS 25 093, and Lot CCS 25 077 identified the H5N1 as genotype B3.13. The B3.13 genotype virus has previously been found in other brands of raw poultry-based pet foods that were associated with the illness or death of cats.

• FDA is not aware of any human cases of HPAI contracted through exposure to contaminated pet food.

About H5N1 Highly Pathogenic Avian Influenza in Cats and Dogs

H5N1 is a virus that can cause illness and death in birds/poultry and mammals such as domestic cats and large felids, like panthers, bobcats and mountain lions. Dogs can also contract HPAI, although they usually exhibit mild clinical signs and low mortality compared to cats. At present, HPAI has not been detected in dogs in the United States, but there have been fatal cases in other countries. The United States Department of Agriculture’s Animal and Plant Health Inspection Service maintains a list of animals that have tested positive for the virus.

Animals who are very young, very old, or have weak immune systems are especially at risk of contracting HPAI.

According to the American Veterinary Medical Association, you should seek veterinary care if your cat or dog appears to have any of the following signs:

• Fever
• Lethargy
• Low appetite
• Reddened or inflamed eyes
• Discharge from the eyes and nose
• Difficulty breathing
• Neurologic signs, like tremors, seizures, incoordination, or blindness

While no human H5N1 infections have been identified among people from handling raw pet food products, humans can become infected if active virus gets into their eyes, nose, or mouth. It is important for people to wash their hands after handling any pet food products and sanitize contact surfaces.

Information about Products Tested

RAWR Raw Cat Food Chicken Eats, Sell By 09/18/26, is sold frozen in 2.5-pound resealable plastic bags containing 40 1-ounce sliders. The product is sold in retail stores nationwide and online. The bags are yellow and white with black lettering. This product is also marked with lot code CCS 25 077, printed in the center on the back of the bag.

RAWR Cat Food Chicken Eats, Sell By 10/03/26, is sold frozen in 2.5-pound resealable plastic bags containing 40 1-ounce sliders. The product is sold in retail stores nationwide and online. The bags are yellow and white with black lettering. This product may also be marked with lot code CCS 25 093.