Pandemic Paradox: Early Life H2N2 Pandemic Influenza Infection Enhanced Susceptibility to Death during the 2009 H1N1 Pandemic

Abstract

Recent outbreaks of H5, H7, and H9 influenza A viruses in humans have served as a vivid reminder of the potentially devastating effects that a novel pandemic could exert on the modern world. Those who have survived infections with influenza viruses in the past have been protected from subsequent antigenically similar pandemics through adaptive immunity. For example, during the 2009 H1N1 “swine flu” pandemic, those exposed to H1N1 viruses that circulated between 1918 and the 1940s were at a decreased risk for mortality as a result of their previous immunity. It is also generally thought that past exposures to antigenically dissimilar strains of influenza virus may also be beneficial due to cross-reactive cellular immunity. However, cohorts born during prior heterosubtypic pandemics have previously experienced elevated risk of death relative to surrounding cohorts of the same population. Indeed, individuals born during the 1890 H3Nx pandemic experienced the highest levels of excess mortality during the 1918 “Spanish flu.” Applying Serfling models to monthly mortality and influenza circulation data between October 1997 and July 2014 in the United States and Mexico, we show corresponding peaks in excess mortality during the 2009 H1N1 “swine flu” pandemic and during the resurgent 2013–2014 H1N1 outbreak for those born at the time of the 1957 H2N2 “Asian flu” pandemic. We suggest that the phenomenon observed in 1918 is not unique and points to exposure to pandemic influenza early in life as a risk factor for mortality during subsequent heterosubtypic pandemics.

Co‐degradation of interferon signaling factor DDX3 by PB1‐F2 as a basis for high virulence of 1918 pandemic influenza

“…The causes of excess mortality during the 1918 pandemic, especially among healthy young adults, are poorly understood. Unique features of the 1918 H1N1 pandemic have been ascribed to the dysfunction in host inflammatory and immunological responses shaped by past influenza infections in the H1N1‐naïve population (McAuley et al , ; Gagnon et al , ). The lack of an adaptive immune response in this age group (unlike in older adults), and consequent reliance on the innate antiviral response, could explain the detrimental effects of innate‐type I IFN suppression as reported here.…”

Survival of the Weakest? Culling Evidence from the 1918 Flu Pandemic

“…argue that these explanations are unlikely to explain the temporal pattern in their data.5 Recent evidence suggests that the 1918 flu pandemic decreased conception rates and increased miscarriages(Chandra and Yu, 2015;Chandra and Lu, 2015). We focus on stillbirth effects, because we can directly observe this outcome in our data.6 Influenza protection by childhood exposure to related influenza strains in childhood is also discussed in van Wijhe et al (2018),Gagnon et al (2018),Gagnon et al (2015), andGagnon et al (2013). SeeBaumgarth et al (2013) for a comprehensive summary of antibody-mediated immunity in the context of influenza infections.7Hayden et al (1998) experimentally infected human subjects with an influenza A virus of subtype H1N1 to investigate their cytokine response.…”

A Complex Dance: Measuring the Multidimensional Worlds of Influenza Virus Evolution and Anti-Influenza Immune Responses

“…These studies led to great enthusiasm for the feasibility of a universal influenza vaccine. However, using the same analysis methods, a Canadian group published a contradictory finding: early life exposure of 1957 H2N2 "Asian flu" virus enhanced the morality of flu during 2009 H1 pandemic flu and 2013-2014 H1N1 outbreak [72]. Overall, there are more questions about the role of OAS and imprinting on the cross-reactivity or cross-prevention of influenza infection, and the clinical immunology studies on the cross-reactive B cell response to influenza infection and vaccination are currently underway.…”