Other Potential Flash Points For Pandemic Influenza

#18,032

While the world is understandably focused on the discovery of HPAI H5N1 in U.S. cattle, it is worth remembering that this isn't the only potential flash point for avian flu.  A few (of many) examples include:

• In October of 2022, we learned of a mink farm in Spain where H5N1 had spread rapidly, generating rare mutations (see Eurosurveillance: HPAI A(H5N1) Virus Infection in Farmed Minks, Spain, October 2022), which resulted in a new risk analysis from the CDC.
• Last summer and fall we were focused on outbreaks in cats in Poland and South Korea, along with dozens of fur farms infected with H5N1 in Finland.
• Also last summer, in PNAS: Mink Farming Poses Risks for Future Viral Pandemics, we looked at an excellent opinion piece penned by two well known virologists from the UK (Professor Wendy Barclay & Tom Peacock) on why fur farms - and mink farms in particular - are high risk venues for flu.
• Over the past year we've seen reports of tens of thousands of marine mammals killed by H5N1 (see here, here, and here) in North America, South America, and Europe.

While only a small percentage are ever reported, there are spillovers into mammals occurring all over the world (see USDA map below).  Most are presumed to be dead-end infections, but we've seen the impact of California Condors feeding on infected carrion. 

Not only are there several clades of H5N1 in circulation around the world, there are literally dozens of genotypes within these clades. And within each genotype, there may be variants.  Meaning we aren't dealing with one threat, but rather an array of similar viruses all pursuing different evolutionary paths. 

If we get lucky, and HPAI H5N1 somehow fizzles in cattle, we aren't in the clear.  HPAI H5Nx is firmly entrenched in birds around the globe, expanding its mammalian host range, and it is continually running GOF (Gain of Function) experiments. 

Since the HPAI in cattle story has overshadowed nearly everything else, today a couple of recent studies showing the expanding diversity, and growing capabilities, of HPAI H5N1 outside of the United States.  

First stop, a report in  Virologica Sinica on the growing threat from H5 clade 2.3.4.4b viruses in China as they transitioned from H5N8 to H5N1 during 2021 and 2022.

Evolutionary dynamics and comparative pathogenicity of clade 2.3.4.4b H5 subtype avian influenza viruses, China, 2021–2022
Siru Lin a 1, Junhong Chen a 1, Ke Li d 1, Yang Liu a 1, Siyuan Fu a, Shumin Xie a, Aimin Zha a, Aiguo Xin a, Xinyu Han a, Yuting Shi a, Lingyu Xu a, Ming Liao a b c, Weixin Jia a b cShow more

https://doi.org/10.1016/j.virs.2024.04.004Get rights and content
Under a Creative Commons license
 

Highlights

• The evolutionary and biological properties of major pandemic H5 AIVs isolated from China in 2021–2022 were analyzed.
• H5Nx isolates originated from H5N8, with high evolutionary rate in H5N1 and H5N8 and a declining trend in H5N6 in 2015–2022.
• HI assay suggests that A(H5N1) viruses may be antigenically distinct from the circulating H5N6 and H5N8 strains.
• Representative viruses of three H5 AIVs isolates exhibit variable tissue tropism and pathogenicity in mice.
• A(H5N1) viruses have a higher risk of emergence in the future.

Abstract

The recent concurrent emergence of H5N1, H5N6, and H5N8 avian influenza viruses (AIVs) has caused significant avian mortality globally. Since 2020, frequent human-animal interactions have been documented. To gain insight into the novel H5 subtype AIVs (i.e., H5N1, H5N6 and H5N8), we conducted a comparative analysis on phylogenetic evolutionary and biological properties of H5 subtype AIVs strains isolated from China between January 2021 and September 2022. 

Phylogenetic analysis revealed that the 41 H5Nx strains belonged to clade 2.3.4.4b, with 13 related to H5N1, 19 to H5N6, and 9 to H5N8. The genetic relatedness analysis based on global 2.3.4.4b viruses showed that all the viruses described in this study was likely originated from H5N8, exhibiting a heterogeneous evolutionary history between H5N1 and H5N6 during 2015–2022 worldwide. 

In this context, we further estimated that H5N1, characterized by higher evolutionary rates in 2021–2022 and more sites under positive selection pressure in 2015–2022. The antigenic profiles of novel H5N1 and H5N6 exhibited notable variations. Further hemagglutination inhibition assay suggest that some A(H5N1) viruses may be antigenically distinct from the circulating H5N6 and H5N8 strains.

Mammalian challenge assays demonstrated that the H5N8 virus (21GD001_H5N8) displayed the highest pathogenicity in mice, followed by the H5N1 virus (B1557_H5N1) and then the H5N6 virus (220086_H5N6), suggesting a heterogeneous virulence profile of H5 AIVs in the mammalian hosts.

Based on the above results, we consider that A(H5N1) viruses have a higher risk of emergence in the future. Collectively, these findings unveil a new landscape of different evolutionary history and biological characteristics of novel H5 AIVs in clade 2.3.4.4b, contributing to a better understanding for designing more effective strategies for the prevention and control of novel H5 AIVs.

Half a world away, in South America, researchers tracking the spread of HPAI H5N1 through marine mammals continue to find mammalian adaptations, and have reasons to believe mammal-to-mammal transmission may be occurring. 

Highly pathogenic avian influenza H5N1 virus infections in pinnipeds and seabirds in Uruguay: implications for bird-mammal transmission in South America

Gonzalo Tomás, Ana Marandino, Yanina Panzera, Sirley Rodríguez, Gabriel Luz Wallau, Filipe Zimmer Dezordi, Ramiro Pérez, Lucía Bassetti, Raúl Negro, Joaquín Williman ... Show more

Virus Evolution, veae031, https://doi.org/10.1093/ve/veae031

Published:13 April 2024 Article history

PDF

ABSTRACT

The highly pathogenic avian influenza viruses of the clade 2.3.4.4b have caused unprecedented deaths in South American wild birds, poultry, and marine mammals. In September 2023, pinnipeds and seabirds appeared dead on the Uruguayan Atlantic coast.

Sixteen influenza virus strains were characterized by real-time reverse transcription PCR and genome sequencing in samples from sea lions (Otaria flavescens), fur seals (Arctocephalus australis), and terns (Sterna hirundinacea). Phylogenetic and ancestral reconstruction analysis showed that these strains have pinnipeds as the most likely ancestral host, representing a recent introduction of the clade 2.3.4.4b in Uruguay.

The Uruguayan and closely related strains from Peru (sea lions) and Chile (sea lions and a human case) carry mammalian adaptative residues 591K and 701N in the viral polymerase basic protein 2 (PB2). Our findings suggest that the clade 2.3.4.4b strains in South America may have spread from mammals to mammals and seabirds, revealing a new transmission route.

          (Continue . . . .)

A reminder that the rapid growth and evolution of HPAI H5 was a threat long before it was detected in American cattle, and will remain so, even if we dodge this bovine bullet.