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

Abstract

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% reduction in EWM estimated at 100% elderly vaccination for the winter of 1989/90 down to a 9.3% increase 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.

Roles for Pathogen Interference in Influenza Vaccination, with Implications to Vaccine Effectiveness (VE) and Attribution of Influenza Deaths

“…Heterologous immunity provides a basis for some of the unanticipated outcomes of influenza vaccination previously observed [ 3 ]. However, this is a poorly studied area.…”

“…This review represents the fourth part in a series on the determinants of excess winter mortality [ 1 , 2 , 3 ]. In the first part, excess winter mortality (EWM) was shown to be directly measurable using monthly deaths (all-cause mortality).…”

“…Over-counting of estimated influenza deaths was demonstrated [ 2 ]. The next study demonstrated that influenza vaccination was associated with increased total mortality in around 40% of winters and that the long-term average benefit from influenza vaccination over a 40-year period was a mere 0.3% reduction in excess winter mortality at a theoretical 100% vaccination rate in the elderly [ 3 ]. In a single pathogen world such an outcome would be illogical, however, we live in a highly complex multi-pathogen world where system complexity theory shows that well intended interventions can lead to unexpected outcomes.…”

“…In a single pathogen world such an outcome would be illogical, however, we live in a highly complex multi-pathogen world where system complexity theory shows that well intended interventions can lead to unexpected outcomes. The mechanisms behind pathogen interference were suggested as a potential source of the unanticipated increased mortality observed in some winters [ 3 ].…”

“…Winter mortality, influenza infection and vaccination form a multidimensional complex problem [ 2 , 3 ]. Here, we detail the complex components within a structured framework regarding the role of pathogen interference and its potential impact upon the net effects of influenza vaccination, upon the measurement of vaccine effectiveness (VE) and upon the estimation of influenza deaths.…”