Study reveals why H5N1 flu cases today are less severe than historic outbreaks

By Tarun Sai LomteReviewed by Susha Cheriyedath, M.Sc.Jan 13 2025

New findings reveal how contemporary H5N1 avian flu viruses adapt to suppress human immune responses, leading to milder illness but underscoring the importance of vigilant monitoring for future risks.

Dispatch: Comparison of Contemporary and Historic Highly Pathogenic Avian Influenza A(H5N1) Virus Replication in Human Lung Organoids. ​​​​​​​Image Credit: Credit: NIAID and CDC

In a recent study published in the journal Emerging Infectious Diseases, researchers compared viral replication and immune responses in human lung organoids (hLOs) infected with highly pathogenic avian influenza A (HPAI) viruses of the H5N1 subtype.

In North America, HPAI H5N1 clade 2.3.4.4b viruses have been circulating in avian species since 2021 and have also been detected in mammalian species, including unusual hosts like domestic dairy cattle.

In 2024, HPAI H5N1 clade 2.3.4.4b virus was detected in cattle, which spread to herds in 16 states across the United States (US). The broadened host range and transmission of clade 2.3.4.4b viruses have raised critical concerns about their spillover to humans.

As of January 6, 2025, 66 cases of infection with HPAI H5N1 virus have been confirmed in the US, many of which were linked to cattle exposure. Nevertheless, recent outbreaks have led to the detection of poultry-related human cases.

Further, a virus isolated from a dairy farm worker in Texas was closely related to cattle viruses, suggesting this was likely a consequence of direct cow-to-human transmission. Reported symptoms from these cases ranged from mild respiratory illness to conjunctivitis, and only one fatality has been recorded, a stark contrast to the 50% mortality rate associated with historic HPAI H5N1 infections.

The Study and Findings

In the present study, researchers assessed viral replication, immune responses, and cell survival in human alveolar epithelium infected with historical and contemporary HPAI H5N1 viruses.

First, alveolar type 2 (AT2) cells from adult stem cell-derived hLOs and induced pluripotent stem cell-derived human lung organoids (ihLOs) were infected with three HPAI H5N1 isolates.

These included contemporary isolates from cattle (A/bovine/Ohio/B24OSU-342/2024) and humans (A/Texas/37/2024), and a historic human isolate (A/Vietnam/1203/2004) from a fatal case in 2004.

The team found that the historic isolate replicated higher titers in hLOs and ihLOs compared to the cattle isolates. However, the Texas human isolate showed enhanced replication fitness compared to the cattle isolate, possibly due to the presence of the PB2 E627K mutation, which has been linked to increased replication in mammalian hosts.

Next, the team quantified cell death in lung organoids. Organoids infected with the historic isolate had earlier cell death; infection with the other isolates also caused cell death, but all three isolates showed similar levels of cell death at 96 hours post-inoculation, suggesting extrinsic factors may govern in vivo pathogenicity.

Further, they quantified the induction of interferon (IFN)-stimulated genes (ISGs), such as ISG15 and ISG20, and proinflammatory cytokines: IFN-β, tumor necrosis factor (TNF)-α, interleukin 6 (IL-6), and IL-1β.

The highest ISG induction was detected in organoids infected with the historic isolate, which was most pronounced in hLOs. By contrast, contemporary isolates appeared to suppress ISG responses, particularly in hLOs, despite detectable viral replication. This suppression of ISG responses in hLOs suggests an adaptation by contemporary isolates to counteract the human interferon system.

Proinflammatory cytokines exhibited distinct patterns: ihLOs infected with contemporary isolates and hLOs infected with the cattle or historic isolate showed the strongest induction. These differences in immune activation may partially explain the reduced disease severity observed in contemporary infections.

Conclusions

Taken together, the study investigated viral replication, immune responses, and cell survival in human alveolar epithelium infected with HPAI H5N1 virus isolates.

Contemporary viral isolates showed reduced replication in lung organoids compared to the historic isolate, plausibly explaining why recent human influenza cases with clade 2.3.4.4b viruses have resulted in mild illness.

Moreover, the ability of contemporary isolates to counteract the human IFN system may contribute to lower disease severity observed with clade 2.3.4.4b viruses. The historic isolate elicited substantially higher ISG induction, whereas contemporary isolates elicited reduced induction despite detectable viral replication.

Overall, HPAI H5N1 clade 2.3.4.4b viruses currently circulating in cattle and other mammals appear to cause less severe illness in humans than historic HPAI viruses; however, they should be continuously monitored for changes that impact their transmission and pathogenicity.

Chronological Overview of Significant Global HPAI Outbreaks 

1878: First description of avian influenza as "fowl plague" in northern Italy, identified as a contagious disease causing high mortality in poultry.

1959: First known H5N1 outbreak in Scotland, affecting chickens.

1997: H5N1 infects humans for the first time in Hong Kong, resulting in 18 infections and 6 deaths; approximately 1.3 million chickens are culled to control the outbreak.

2003: Re-emergence of H5N1 in humans, with cases reported in China and widespread outbreaks in poultry across several Asian countries.

2004: H5N1 spreads to additional Asian countries, leading to significant poultry outbreaks and human infections, with notable cases in Vietnam and Thailand.

2005: H5N1 was detected in migratory birds at Qinghai Lake, China; the virus spread to Europe, the Middle East, and Africa through bird migration.

2006: H5N1 reaches India, North Africa, and Europe, causing outbreaks in wild bird populations and domestic poultry.

2007: Significant H5N1 outbreaks occur in countries including Japan, the United Kingdom, and Saudi Arabia, affecting both poultry and wild birds.

2008–2019: Multiple HPAI outbreaks worldwide, with various subtypes (e.g., H5N8, H7N9) causing infections in birds and sporadic human cases, particularly in Asia.

2020–2024: H5N1 clade 2.3.4.4b becomes predominant, causing widespread outbreaks in wild birds and poultry across Asia, Europe, Africa, and the Americas; human cases remain rare but are closely monitored.