Avian flu alert: Understanding the circulating influenza virus H5N1’s threat – Observer Research Foundation

For a little over three years now, scientists have been tracking a genetically distinctinfluenza virus, originally affecting birds (avian influenza) and mammals in the Americas (Figure 1), that is now causing a widespread outbreak in cattle across the United States (US). Reports of 13 human cases from close contact with dairy animals in the US have cast a spotlight on the evolving nature and zoonotic potential of avian influenza viruses. These reports have also raised an alert in organisations working on pandemic preparedness across the world, advocating close monitoring and assessment of current threat levels. While the current avian influenza outbreak in the US poses a low public health threat due to limited human-to-human transmission, we should be attentive to the potential of this zoonotic virus to cause significant disruptions.

A salient feature that puts this family of influenza viruses in the pandemic watchlist is their ability to cross-species boundaries and mix up their genomes, while continuing to accumulate mutations. These changes can result in viruses that are so different from the circulating/past influenza viruses that previous exposures or vaccinations may no longer work, or the virus may even be able to infect a completely new host with no existing immunity to this virusresulting in outbreaks and the threat of a pandemic.

Figure 1: Avian Influenza detected in mammalian species across the world

Source: WOAH

Since early 2022, numerous mammalian species around the world have succumbed to avian influenza, caused by the Highly Pathogenic Avian Influenza (HPAI) H5N1 sub-type of Influenza A viruses. While the primary targets/hosts of HPAI H5N1 (one of the types of the avian influenza virus) are birds, massive deaths of elephant seals and sea lions as a result of an H5N1 outbreak were reported from South America in 2023. As the virus continues to mutate and adapt, monitoring these cross-species transmissions becomes ever more critical.

Figure 2: Countries that reported human Avian Flu H5N1 cases to WHO between 2022-2024

Source: WHO andCDC

The transmission of the H5N1 virus to humans is rare (Figure 2), typically requiring close contact with infected birds or animals and their secretions. In the 2024 outbreak of bovine HPAI H5N1 affecting 171 cattle herds across 13 states in the USA only 13 cases have been confirmed, and there has been continuous monitoring of people who have interacted closely with animals. The detection of the virus in unpasteurised/raw milk has added another layer of complexity. Although this might sound alarmingheat inactivates the virus in milk, making pasteurisation an effective safeguard.

Another intriguing feature of the bovine HPAI H5N1 outbreak in the USA is its genetic distinctiveness. The virus strain causing the outbreak in the Americas belongs to clade 2.3.4.4b, setting it apart from its Southeast Asian counterparts. The expansion of this strain likely began with a single introduction from an infected bird in late 2023 or early 2024. This genetic insight has real-world implications for tracking and controlling outbreaks.

Genetic sequencing of viruses from the human cases of bovine HPAI H5N1 would help address these questions.

Since the range of animals that can be infected by a virus depends on whether or not they have the right binding partner for the virus, changes in what a virus binds to are important to monitor for understanding receptor affinity. A study published in July 2024 found that a HPAI H5N1 virus isolated from a cow from the US 2024 cattle outbreak, was able to bind to the sialic acids expressed in the human upper respiratory tract. If this change is seen frequently it could have implications for human infections. It is also important to monitor the genomes of bovine HPAI H5N1 viruses for emergence and expansion of other mutations that facilitate replication and transmission in mammals. Genetic sequencing of viruses from the human cases of bovine HPAI H5N1 would help address these questions.

From a preparedness standpoint, many countries do have stock-piles of the H5N1 vaccine. A study published in July 2024 confirmed that these vaccines, derived from earlier strains of HPAI H5N1, generated cross-neutralising antibodies against the circulating H5N1 clade 2.3.4.4b viruses, with seroconversion rates of 60-95 percent in vaccinated individuals after 2 or 3 doses of the vaccines. This suggests that these stockpiled vaccines could serve as bridging vaccines until updated H5N1 vaccines become available. Not all countries have a national stockpile nor is the global capacity currently sufficient for scaling emergency vaccine production and equitable distribution. As part of the Pandemic Influenza Preparedness Framework, the WHO has launched an initiative to advance mRNA vaccine development against human avian influenza. Additionally, Oseltamivir (brand name Tamiflu) which has been used in the treatment of human influenza viruses, is currently being recommended for both the treatment and post-exposure prophylaxis of HPAI H5N1 in the US.

The limited availability of genetic data from these outbreaks hampers our ability to understand the local circulation of the virus and monitor its evolution.

Globally, avian influenza outbreaks in birds are a regular occurrence. In India several states, including Andhra Pradesh, Maharashtra, Kerala, and Jharkhand, are grappling with ongoing outbreaks in birds. While there have been no human cases of H5N1 reported in India, a case, of H9N2 was recently confirmed in West Bengal. The limited availability of genetic data from these outbreaks hampers our ability to understand the local circulation of the virus and monitor its evolution. This gap in data means that we do not know if the avian influenza H5N1 clade 2.3.4.4b is present in India nor do we have adequate genomic surveillance in place to monitor introduction and spread.

On the other hand, India is a long-standing contributor to WHO's Global Influenza Surveillance and Response System (GISRS), with National Institute of Virology recognised as a WHO National Influenza Centre (NIC) since 1980. India also has at least three (as of 2019) manufacturers of influenza vaccines and multiple companies that produce generic versions of Tamiflu.

A key gap for a public health response is going to be the absence of timely surveillance data signalling a local outbreak. This is primarily due to two reasons, one being the non-availability of H5N1 diagnostic kit and the other being delays in genomic sequencing. India does have an Action Plan for Prevention, Control and Containment of Avian Influenza (2021) with a focus on animals. Towards the end of 2023, the WHO organised a regional workshop on Preparedness and Resilience for Emerging Threats (PRET) Initiative. Subsequently India initiated the development of a National Preparedness Plan for Respiratory Viruses in alignment with WHO-PRET. If the technical packages and proposed networks assist with simulations and drills for testing the system, it could prove to be an invaluable framework helping the country address gaps in preparedness.

India does have an Action Plan for Prevention, Control and Containment of Avian Influenza (2021) with a focus on animals.

Indias pandemic threat level from bovine HPAI H5N1 does seem low from the available data. However, India has one of the largest livestock populations in the world. Consequently, the situation across the world does warrant a call for an integrated effort with transparent data sharing among stakeholders both in animal health and public health. Multiple initiatives such as the One Health framework being formed in are key in developing tools and strategies for early detection of an outbreak, preventive measures and an outbreak response that spans/considers multiple species.

Chitra Pattabiraman is a virologist/molecular biologist who consults with multiple organizations on projects related to infectious disease, diagnostics, emerging infections, environmental surveillance, animal health and public health in India.

Siva Athreya is a Professor at the International Centre for Theoretical Sciences-TIFR.

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Avian flu alert: Understanding the circulating influenza virus H5N1's threat - Observer Research Foundation