The highly pathogenic avian influenza (HPAI) A(H5N1) virus of the 2.3.4.4b clade emerged during 2020, rapidly spreading across Africa, Asia, and Europe. By 2021-2022, the virus had reached North America and later expanded to South America, leading to severe mortality among seabirds. This particular clade caused a significant shift in its host range, infecting mammals and raising concerns about interspecies transmission.
- In 2022-2023, H5N1 spread along the coasts of Peru and Chile, infecting and killing 30,000 sea lions. Other marine mammals, including dolphins and otters, were also affected.
- The situation in Argentina highlighted the devastating potential of the virus, as it killed over 17,000 elephant seals, wiping out 97% of the pups in some areas.
- Traditionally, H5N1 infections in mammals were rare and typically not transmissible among them. This pattern shifted as the virus began infecting terrestrial mammals and humans.
Escalation of H5N1 in Terrestrial Mammals and Humans
By March 2024, H5N1 was detected in cattle in Texas, marking the first known case of the virus infecting livestock in the United States. A farm worker in the U.S. contracted the virus, with symptoms appearing on March 27, a few days after the detection in cattle. This event marked a troubling milestone in the virus’s zoonotic potential.
- As of November 22, 2024, 58 human cases of H5N1 were reported in the U.S., with the virus spreading to 616 dairy herds across 15 states.
- California alone accounted for 402 infected herds. This widespread outbreak signaled a critical need for enhanced biosecurity and monitoring.
Pathogenesis in Mammals
The 2.3.4.4b clade has shown a unique ability to infect the mammary glands of cows, with milk from infected cattle containing high levels of viral RNA and infectious particles. The presence of the virus in milk raised concerns about transmission to offspring through breastfeeding and potential human exposure. Controlled studies on cattle were challenging, prompting researchers to use ferrets as a model organism for studying the virus’s behavior.
Ferrets as a Model for H5N1 Research
Recent studies have revealed critical insights into how the H5N1 virus affects lactating mammals and their offspring. Researchers infected the mammary glands of lactating ferrets with the H5N1 virus (2.3.4.4b clade) to study its transmission and pathogenicity.
- Findings:
- 100% fatality was observed in lactating ferrets and their suckling kits due to the virus.
- Viral RNA levels in milk increased significantly over time, indicating active replication of the virus in the mammary glands.
- Suckling kits showed high viral RNA levels in their oral and nasal cavities, with low levels of the virus detected in the lungs of lactating ferrets but high levels in the lungs of the kits.
These findings demonstrated that H5N1 infection in the mammary gland causes mastitis-related diseases and facilitates transmission to suckling offspring through milk. The severity of the disease was highlighted by the 100% mortality rate among ferret kits within four days post-inoculation.
Mechanisms of Transmission and Viral Kinetics
Researchers observed significant differences in the viral kinetics between lactating ferrets and their kits.
- Infected kits showed a marked increase in viral RNA in the oral cavity, peaking four days post-inoculation, suggesting that milk was a primary transmission route.
- Prolonged contact between infected kits and their mothers resulted in increased viral RNA levels in lactating ferrets, particularly in the nasal cavities.
- Viral transmission occurred from infected milk to the respiratory system, causing severe infections in both the mother and the offspring.
The study highlighted that H5N1-positive milk directly contributed to respiratory infections in ferret kits, which subsequently infected their mothers through close contact.
H5N1 vs. H1N1
The severity of disease caused by the H5N1 2.3.4.4b clade was significantly greater than that caused by the H1N1 virus in the same experimental setup. Researchers noted that the intramammary H5N1 infection resulted in more severe disease outcomes for lactating ferrets and their kits, underscoring the unique pathogenic potential of the H5N1 clade.
H5N1 in Humans and Broader Zoonotic Risks
Avian influenza A(H5N1), a subtype of the influenza A virus, primarily affects birds but can infect mammals, including humans, through exposure to infected birds or their secretions.
- Between 2003 and November 2024, the World Health Organization (WHO) recorded 948 confirmed human cases of H5N1, resulting in 464 deaths, a fatality rate of about 50%. However, this rate might be lower as mild cases often go undiagnosed.
- The virus spreads rapidly among bird populations through saliva, mucus, and feces, with symptoms ranging from mild respiratory issues to sudden death.
In humans, H5N1 infections primarily affect the lower respiratory tract, causing severe pneumonia. The avian hemagglutinin preferentially binds to alpha-2,3 sialic acid receptors, which are more abundant in the lower respiratory tract of humans, limiting its transmissibility but increasing its severity.
Global Pandemic Potential
H5N1 was first identified in farmed birds in southern China in 1996. Over the years, it has become the dominant strain in bird populations worldwide. With its ability to adapt and infect a wide range of hosts, including mammals, the virus poses a significant pandemic threat.
- The virus has a high mutation rate typical of RNA viruses, and its segmented genome allows for genetic reassortment, enabling it to acquire new characteristics.
- Infected wild birds act as asymptomatic carriers, spreading the virus over vast distances through migration.
Prevention and Mitigation Strategies
Efforts to control H5N1 outbreaks focus on a combination of vaccination, biosecurity measures, and antiviral drugs.
- Vaccines:
- Several candidate vaccines, including Aflunov and Seqirus/Audenz, are prepared to tackle zoonotic H5N1 strains. However, vaccine production can take months during a pandemic due to the need for strain-specific formulations.
- Countries like China mandate vaccination for poultry, using bivalent or trivalent vaccines targeting multiple subtypes.
- Antiviral Treatments:
- Drugs such as oseltamivir (Tamiflu) and zanamivir (Relenza) are effective when administered early in infection.
- These drugs can reduce symptom severity and act as prophylactics in high-risk individuals.
- Public Health Measures:
- Avoiding contact with sick birds and using personal protective equipment (PPE) are crucial for individuals working with poultry or wild birds.
- Monitoring and controlling the movement of infected animals can help limit the virus’s spread.
The spread of H5N1 from ferrets to suckling kits underscores the virus’s evolving adaptability and its ability to exploit new transmission routes. The findings from ferret studies offer valuable insights into the potential risks posed by intramammary infections, particularly in mammals. With the virus demonstrating high mortality rates in both experimental and natural settings, its continued spread across multiple species highlights the urgent need for global cooperation in monitoring, research, and containment efforts. As H5N1 continues to mutate and expand its host range, it remains a formidable challenge to public health and veterinary systems worldwide.