Lack of H5 Reassortment in a Human Case? - That Headline was SO Yesterday...

Preprint released overnight documents H5 2.3.4.4b reassortment in earlier severe Mexican human H5N2 case

It seems like just yesterday (wait, it WAS just yesterday!) that I penned a short column with reassurances that the H5N5 isolated from the Washington state H5N5 fatality was an un-reassorted virus: A Reassuring Assessment of the H5N5 Virus Behind the Washington Fatality The conclusion was that while un-reassorted H5 viruses are certainly of concern in their own right and subject to further mutations, they are not wholesale new viral combinations with greater unknown risks for pathogenicity in mammals and humans.

Well, this morning Michael Coston once again flagged a medRxiv preprint in his early morning column that documents a re-assorted H5N2 isolate from a recent Mexico City human and canine case: Avian Flu Diary: Preprint: Emergence of a Novel Reassorted HPAI A(H5N2) Virus Associated with Severe Pneumonia in a Young Adult

Quoting the Avian Flu Diary post:

On October 18th, in the ECDC Summary: Human Infection with Avian Influenza A(H5) virus - Mexico - 2025, a few more details emerged, but it still wasn’t clear whether this was H5N1, H5N2, or some other subtype.

About a week ago, the WHO published their latest Influenza at the human-animal interface summary and assessment report, which identified the full subtype as H5N2, but further characterization of the virus was reportedly still underway.

Somewhat intriguingly, that report did disclose:

Respiratory samples collected from close contacts including hospital contacts, tested negative for influenza viruses. During the epidemiologic investigation, several animals (including birds) and bird droppings were found in the building where the case resides, in an area the case passes frequently. A dog was identified as a pet at the case’s residence. Samples collected from the animals tested positive for influenza A(H5). Information on whether this virus was a high or low pathogenicity avian influenza virus (HPAI or LPAI) is pending further testing

Overnight, a fascinating new preprint has appeared on the medRxiv server, which provides additional - and somewhat concerning - details on this latest case. It turns out this H5N2 virus was a new reassortment between the local, long-endemic, LPAI H5N2 virus in Mexico and the clade 2.3.4.4b H5N1 virus circulating globally.

While numerous H5N1 reassortments have occurred in the past, producing scores of new H5N1 genotypes (e.g. A3, B3.13, D1.1, D1.2, D1.3, etc.), this introduces a novel subtype - HPAI H5N2 - to an already crowded field.

Here is the link to the medRiv release: Emergence of a novel reassorted high pathogenicity avian influenza A(H5N2) virus associated with severe pneumonia in a young adult | medRxiv

Abstract

Background Infection of backyard and poultry with low pathogenicity avian influenza LPAI A(H5N2) viruses has occurred in Mexico since 1994, and the first human infection caused by this influenza virus was detected in 2024. Since its emergence in the Americas, frequent reassortments between high pathogenicity avian influenza HPAI A(H5N1) and LPAI viruses has occurred. In September 2025, the Instituto Nacional de Enfermedades Respiratorias of Mexico City identified an unsubtypeable influenza A virus infection in a young adult patient later determined to be a reassortant HPAI (H5N2) virus with a clade 2.3.4.4b HA. Methods We analyzed clinical and epidemiologic data from this patient. Respiratory samples were tested for influenza RT-qPCR assays. Genomic sequence and phylogenetics analyses were performed to provisionally assign a new genotype to the novel HPAI A(H5N2) reassortant virus. Results The patient presented with fever and tachypnea, later developed hemoptysis and thoracic pain, with oxygen saturation decreasing to 70%. CT scan showed bilateral ground-glass opacities consistent with diffuse alveolar hemorrhage and zones consistent with consolidation. Clinical improvement was observed and the patient was discharged. Through viral complete genome analysis, we identified an HPAI A(H5N2) virus with genes from both clade 2.3.4.4b A(H5N1) viruses similar to those detected in North America during 2022-2023 and genes from the LPAI A(H5N2) viruses detected in Mexico during 2024. Conclusions This is the first ever laboratory-confirmed human infection caused by an HPAI A(H5N2) virus infection, suggesting a new genotype provisionally classified as B3.14. The relationship of the virus with the severity of illness remains unknown.

The Discussion section of the preprint concludes with the following:

…Viral sequence evidence suggests that the human virus (A/Mexico City/INER_INF1427_2025) and the HPAI A(H5N2) avian viruses detected during 2025 represent reassortment between an enzootic LPAI A(H5N2) virus ancestor from 2024 detected in Central Mexico and the A(H5N1) clade 2.3.4.4b genotype B3.2 viruses detected during 2022-2023. Lack of more recently detected B3.2 genotype viruses containing genes with higher nucleotide similarity to the virus from the human case likely reflects under-sampling or less sequencing of viruses that may be present in wild birds or poultry in the region. The highest nucleotide similarity of the PB1, NP and NA genes (98%) of the human virus compared to LPAI A(H5N2) viruses from avian and human hosts in 2024, suggests co-circulation of HPAI A(H5N1) and LPAI A(H5N2) viruses in the region resulting in reassortment (Figure 5). We hypothesized that the high disease burden of HPAI viruses in chickens in this geographical area in September 2025 could be the reason of the human infection, although direct contact between the patient in this study and poultry or other domestic animals could not be confirmed. Human to-human transmission seems implausible and follow-up investigation of close contacts of the case did not identify other H5-positive individuals. Further studies are required to determine the predicted pathogenicity and the transmissibility of the virus and its potential threat to human health. Although obesity was the sole comorbidity, the patient exhibited unusually extensive pulmonary damage, underscoring the need for further characterization of their pathogenic potential of this or related viruses. Since no cases of this reassorted A(H5N2) influenza virus in humans have been previously reported, we are unaware of the clinical outcomes that this HPAI virus subtype may have in humans. Given the virus’s propensity for rapid genetic reassortment, genomic surveillance is essential, particularly for emerging strains. Such surveillance forms a critical component of global preparedness and rapid response strategies, enabling countries to strengthen viral diagnostics, vaccine development and therapeutic strategies to prevent widespread outbreaks. In summary, our findings support the emergence of a new clade 2.3.4.4b reassortant virus provisionally classified as genotype B3.14 and the first ever global human case of an HPAI A(H5N2) virus infection.

Tantalizing Stones Unturned (Yet)

I recall a Sherlock Holmes mystery regarding a dog who didn’t bark:

I’m thinking we may have virus isolated from a dog here that has yet to bark…at least I hope we have a viable sample for full analysis. Recall above that the WHO dispatch stated:

During the epidemiologic investigation, several animals (including birds) and bird droppings were found in the building where the case resides, in an area the case passes frequently. A dog was identified as a pet at the case’s residence. Samples collected from the animals tested positive for influenza A(H5).

Thus, investigators should possess positive viral samples from the family dog that resided in the home of the affected patient, plus other samples from resident birds. Is there an accompanying animal preprint underway, I hope? We’ll see what, if anything is released regarding animal isolates in the next weeks and months.

This is a classic “One Health” investigation that could provide the world influenza community with so much valuable information! Sequences, accompanied by good epidemiological information (if willingly provided), could provide good information on likely degree of relationship and directionality of spread, i.e. dog to person, versus person to dog, versus unrelated infections. Are the nearby avian infections related viruses? Other better-trained virologists/epidemiologists can dream up a whole host of additional information that any related sequence information from close animal and avian contacts would generate. And all this is before we even begin to address any opportunities for possible cooperation in follow-up serological studies, if at all feasible.

Finally, I note that this was predominantly an effort by our Mexican colleagues, with one CDC contributor. That is exactly what we need for world-wide risks - world-wide competence! We are all only as safe as the expertise we field across the globe - let’s get back to pulling our weight with WHO ASAP.

John