System Complexity in Influenza Infection and Vaccination: Effects Upon Excess Winter Mortality

Unexpected outcomes are usually associated with interventions in complex systems. Excess winter mortality (EWM) is a measure of the net effect of all competing forces operating each winter, including influenza(s) and non-influenza pathogens. In this study over 2400 data points from 97 countries are used to look at the net effect of influenza vaccination rates in the elderly aged 65+ against excess winter mortality (EWM) each year from the winter of 1980/81 through to 2019/20. The observed international net effect of influenza vaccination ranges from a 7.8% in EWM estimated at 100% elderly vaccination for the winter of 1989/90 down to a 9.3% in EWM for the winter of 2018/19. The average was only a 0.3% reduction in EWM for a 100% vaccinated elderly population. Such outcomes do not contradict the known protective effect of influenza vaccination against influenza mortality per se-they merely indicate that multiple complex interactions lie behind the observed net effect against all-causes (including all pathogen causes) of winter mortality. This range from net benefit to net disbenefit is proposed to arise from system complexity which includes environmental conditions (weather, solar cycles), the antigenic distance between constantly emerging circulating influenza clades and the influenza vaccine makeup, vaccination timing, pathogen interference, and human immune diversity (including individual history of host-virus, host-antigen interactions and immunosenescence) all interacting to give the observed outcomes each year. We propose that a narrow focus on influenza vaccine effectiveness misses the far wider complexity of winter mortality. Influenza vaccines may need to be formulated in different ways, and perhaps administered over a shorter timeframe to avoid the unanticipated adverse net outcomes seen in around 40% of years.