H2N2 is a subtype of influenza A virus. It gained global attention in 1957 when it caused a major worldwide health event. While it no longer circulates widely among humans, H2N2 remains a potential future threat due to its continued presence in animal populations.
The 1957 Pandemic
The H2N2 virus first emerged in late February 1957 in China’s Yunnan Province, rapidly reaching epidemic levels by mid-March. From there, it quickly spread to Hong Kong in early April, then to Singapore, Taiwan, Borneo, Japan, and other regions, ultimately circling the globe. The World Health Organization (WHO) issued a global flu pandemic alert as the virus continued its international spread.
The pandemic, often called the “Asian Flu,” caused an estimated 1 to 4 million deaths worldwide, with around 80,000 to 116,000 deaths in the United States. Unlike typical seasonal influenza that disproportionately affects the very young and elderly, this pandemic saw nearly 40% of U.S. deaths in individuals under 65 years of age. Many fatalities were due to bacterial pneumonia, a common complication following viral infection, even with antibiotics available at the time.
The pandemic occurred in two main waves, with a second, devastating wave hitting the Northern Hemisphere in November 1957. This global health crisis underscored the need for effective vaccine production and strong public health responses, highlighting the importance of global surveillance and rapid response systems in managing future influenza threats. The H2N2 pandemic was the second major influenza pandemic of the 20th century, following the 1918-1919 pandemic and preceding the 1968 pandemic.
Viral Biology and Zoonotic Origins
Influenza A viruses are characterized by two surface proteins: hemagglutinin (HA) and neuraminidase (NA). For H2N2, these are specifically the H2 and N2 subtypes, which allow the virus to attach to and enter host cells, and then release new viral particles. These proteins are important antigens, meaning they are recognized by the host’s immune system, which then produces antibodies against them.
Influenza viruses can undergo changes in their antigenic structure through two main mechanisms: antigenic drift and antigenic shift. Antigenic drift involves the accumulation of small, random mutations in the HA and NA genes, leading to gradual changes in the surface proteins. These minor modifications can cause periodic epidemics as existing immunity becomes less effective. This process allows the virus to evade detection by the immune system over time, necessitating yearly updates to influenza vaccines.
Antigenic shift, conversely, is a sudden, major change in the influenza A virus, typically occurring when two different influenza viruses infect the same host cell and exchange genetic material. This “reassortment” can create a new virus subtype with novel HA and/or NA proteins, to which most of the population has no pre-existing immunity. The H2N2 virus itself emerged from such an event, believed to be a reassortment between avian and human influenza strains in pigs. This sudden change can lead to pandemics, as seen with the 1957 H2N2 outbreak.
Influenza A viruses naturally circulate in various animal reservoirs, particularly wild birds and domestic poultry, as well as pigs. These animals can serve as “mixing vessels” where different influenza strains can reassort, producing new strains with the potential to infect humans.
Current Threat and Preparedness
While the H2N2 virus disappeared from widespread human circulation in 1968, replaced by the H3N2 subtype, it continues to circulate in avian and swine populations. This persistence in animal reservoirs poses a reintroduction risk, making H2N2 a virus with significant pandemic potential. The re-emergence of an H2N2 virus is considered one of the more likely scenarios for a new influenza pandemic.
A major concern regarding H2N2 is the concept of population immunity. Individuals born after 1968 have had no exposure to H2N2 in human circulation, meaning they possess little to no natural immunity against this specific subtype. As new birth cohorts are added to the global population, the overall level of immunity against H2N2 continues to decline, leaving a large portion of the population vulnerable should the virus re-emerge and acquire efficient human-to-human transmissibility.
Global surveillance efforts are in place to monitor influenza viruses circulating in both human and animal populations. Organizations like the World Health Organization (WHO) coordinate these efforts, tracking changes in genetic and antigenic characteristics of zoonotic influenza A viruses. This monitoring helps in the selection and development of candidate vaccine viruses (CVVs) for pandemic preparedness. Several H2N2 vaccine candidates have been generated and tested in preclinical and clinical studies, demonstrating safety and immunogenicity in healthy adult volunteers. These preparedness measures aim to mitigate the threat of re-emerging influenza strains, including H2N2, by enabling timely vaccine production and response.