A(H5N1) Avian Influenza Virus: Issues of Concern in a One Health Perspective

The neurotropism and neuropathogenicity of the A(H5N1) influenza virus in birds and mammals like pinnipeds and cetaceans (1-5) are of concern, along with the rapidly growing number of virus-susceptible animals, including several species phylogenetically distant from each other (6). 
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H5N1: Has there been human-to-human transmission, and do we have a vaccine?

With H5N1 still a worldwide concern, Elisabeth Mahase looks at the latest developments, including preparations for a vaccine Much of the spotlight has been on Cambodia in the past week, where an 11 year old girl died after being infected with an H5N1 virus. The girl, from Prey Veng province in the south of the country, was admitted to the National Paediatric Hospital on 21 February with severe pneumonia and died a day later. The authorities notified the World Health Organization of the situation and shared the genetic sequencing data, which showed that the virus belonged to the influenza A virus subtype H5N1 but was the 2.3.2.1c clade, different from the clade causing concern in other parts of the world.1 Of the girl’s 12 close contacts who were identified (four with symptoms, eight without), only one, the girl’s father, tested positive for H5N1. The others tested negative for H5N1 and for SARS-CoV-2. Not necessarily. Although the investigation into what happened in Cambodia is ongoing, WHO has said there was currently no evidence of human-to-human transmission. In an update it said, “While further characterisation of the virus from these human cases is pending, available epidemiological and virological evidence suggest that current A(H5) viruses have not acquired the ability of sustained transmission among humans, thus the likelihood of sustained human-to-human spread is low.” Health officials in Cambodia have also said that the cases show no sign of human-to-human transmission.2 Although …

Further issues of interest are undoubtedly represented by the transmission of the virus to cattle from wild birds, with cows from 9 States in USA having hitherto tested positive to ad hoc laboratory investigations (7). Noteworthy, while most infected cows tend to develop mild clinical signs - with the subsequent risk of getting A(H5N1) avian influenza virus largely undetected in cattle -, consistent amounts of viral infectivity have been also found in raw, unpasteurized bovine milk (8). In this respect, an article recently posted on a "preprint server" (9) describes a strikingly high expression of both the avian - sialic acid (SA) alfa 2-3 gal - and the human - SA alfa 2-6 gal - influenza virus receptors in the bovine mammary gland tissue, thus "candidating" cattle as a new "mixing vessel" theoretically allowing the genetic reassortment/recombination between influenza viruses originating from different animal sources, as it "historically" happens in pigs with avian and human viruses. By contrast, a far lower expression of these receptor molecules was detected in the bovine upper airways, with an even more limited presence of both viral receptors occurring at brain level, which largely justifies the sporadic, if not rare, occurrence of respiratory and neurologic symptoms in infected cattle (9). Although there are few available studies aimed at defining how the A(H5N1) avian influenza virus spreads between cattle and people, one dairy worker in Texas (where the first case of this viral infection in cows was ascertained on March 25, 2024) developed a bilateral, virus-induced conjunctivitis (10). Furthermore, despite the almost 900 human cases of A(H5N1) viral disease which have been reported from 2003 until now by the World Health Organization (WHO) - 52% of which with a fatal outcome -, no evidence of sustained viral interhuman transmission has been obtained, thus far. Nevertheless, based upon the well-known propensity of influenza viruses to undergo mutations in their genomic make-up, coupled with the rapidly and consistently expanding viral host range, the possibility the A(H5N1) virus will become easily transmissible between people, thereby acquiring a "pandemic behaviour", appears to be largely justified. Still of concern and as previously reported with poliovirus as well as with SARS-CoV-2 betacoronavirus (11), the A(H5N1) virus has been recently identified in wastewater samples. More in detail, these were collected from nine cities in Texas, with variant analysis suggesting either an avian or bovine origin, although other potential sources, with special reference to humans, could not be ruled out (12).

As a concluding remark, an ad hoc multidisciplinary "preparedness and readiness effort", based upon the lessons learned from the COVID-19 pandemic and accompanied by a close intersectorial collaboration between human and veterinary medicine, is urgently needed in order to properly facing this alarming scenario, within a sound One Health perspective's framework.

References 
1) Ariyama, N., et al. (2023). Highly Pathogenic Avian Influenza A(H5N1) Clade 2.3.4.4b Virus in Wild Birds, Chile. Emerg. Infect. Dis. 29:1842-1845. doi: 10.3201/eid2909.230067.
 

2) Puryear, W., et al. (2023). Highly Pathogenic Avian Influenza A(H5N1) Virus Outbreak in New England Seals, United States. Emerg. Infect. Dis. 29:786-791. doi: 10.3201/eid2904.221538.

3) Gamarra-Toledo, V., et al. (2023). Mass Mortality of Sea Lions Caused by Highly Pathogenic Avian Influenza A(H5N1) Virus. Emerg. Infect. Dis. 29:2553-2556. doi: 10.3201/eid2912.230192.

4) Thorsson, E., et al. (2023). Highly Pathogenic Avian Influenza A(H5N1) Virus in a Harbor Porpoise, Sweden. Emerg. Infect. Dis. 29:852-855. doi: 10.3201/eid2904.221426.

5) Murawski, A., et al. (2024). Highly pathogenic avian influenza A(H5N1) virus in a common bottlenose dolphin (Tursiops truncatus) in Florida. Commun. Biol. 7:476. doi: 10.1038/s42003-024-06.

6) Di Guardo, G., Roperto S. (2024). AH5N1 avian influenza, a new pandemic behind the corner? (Rapid Response). BMJ https://www.bmj.com/content/380/bmj.p510/rr.
7) Reardon, S. (2024). Bird flu in US cows: Where will it end? Nature 
8) Gerhard, D. (2024). Deciphering the unusual pattern of bird flu symptoms in cows. The Scientist Magazine 
 
10) Uyeki, T.M., et al. (2024). Highly pathogenic avian influenza A(H5N1) virus infection in a dairy farm worker. N. Engl. J. Med. 
doi:10.1056/NEJMc2405371.
 
11) Clark, J.R., et al. (2023). Wastewater pandemic preparedness: Toward an end-to-end pathogen monitoring program. Front. Public Health 11:1137881. doi:10.3389/fpubh.2023.1137881.
 
12) Tisza, M.J., et al. (2024). Virome sequencing identifies H5N1 avian influenza in wastewater from nine cities. MedRxiv preprint 2024.05.10. doi:https://doi.org/10.1101/2024.05.10.24307179.

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