Abstract
ABSTRACTRecent 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.
Highlights
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
Similar protection has been reported during the 1968 H3N2 “Hong Kong flu” pandemic for those exposed to the 1890 “Russian flu” pandemic, which is thought to have been caused by an H3Nx-like virus [7, 10], and again during the 2009 H1N1 “swine flu” pandemic for those exposed to 1918 H1N1 or immunized against the 1976 “Fort Dix, New Jersey” H1N1 virus [11,12,13]
The elevation in mortality for those up to 60 years old suggests that early life exposure to the H2N2 pandemic strain was sufficient to elevate risk, even if it was not necessarily their first exposure to influenza virus
Summary
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. Reported situations in which previous influenza virus exposures have enhanced susceptibility are rare and poorly understood One such instance occurred in 1918 — when those born during the heterosubtypic 1890 H3Nx influenza virus pandemic experienced the highest levels of excess mortality. ® mbio.asm.org 1 instances, prior exposure to pandemic influenza virus strains can enhance susceptibility during subsequent pandemics These results have important implications for pandemic risk assessment and should inform laboratory studies aimed at uncovering the mechanism responsible for this effect. Exposure to heterosubtypic viruses (within the same HA group) has been shown in boost titers of broadly neutralizing antibodies (bnAbs) that bind to the HA stalk domain [14,15,16], which at least partly account for the levels of protection observed among the elderly in many instances
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