Trends in excess winter mortality (EWM) were investigated from the winter of 1900/01 to 2019/20. During the 1918–1919 Spanish flu epidemic a maximum EWM of 100% was observed in both Denmark and the USA, and 131% in Sweden. During the Spanish flu epidemic in the USA 70% of excess winter deaths were coded to influenza. EWM steadily declined from the Spanish flu peak to a minimum around the 1960s to 1980s. This decline was accompanied by a shift in deaths away from the winter and spring, and the EWM calculation shifted from a maximum around April to June in the early 1900s to around March since the late 1960s. EWM has a good correlation with the number of estimated influenza deaths, but in this context influenza pandemics after the Spanish flu only had an EWM equivalent to that for seasonal influenza. This was confirmed for a large sample of world countries for the three pandemics occurring after 1960. Using data from 1980 onward the effect of influenza vaccination on EWM were examined using a large international dataset. No effect of increasing influenza vaccination could be discerned; however, there are multiple competing forces influencing EWM which will obscure any underlying trend, e.g., increasing age at death, multimorbidity, dementia, polypharmacy, diabetes, and obesity—all of which either interfere with vaccine effectiveness or are risk factors for influenza death. After adjusting the trend in EWM in the USA influenza vaccination can be seen to be masking higher winter deaths among a high morbidity US population. Adjusting for the effect of increasing obesity counteracted some of the observed increase in EWM seen in the USA. Winter deaths are clearly the outcome of a complex system of competing long-term trends.

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.

Recent studies demonstrate distinct changes in gene expression in cells exposed to a weak magnetic field (MF). Mechanisms of this phenomenon are not understood yet. We propose that proteins of the Cryptochrome family (CRY) are “epigenetic sensors” of the MF fluctuations, i.e., magnetic field-sensitive part of the epigenetic controlling mechanism. It was shown that CRY represses activity of the major circadian transcriptional complex CLOCK/BMAL1. At the same time, function of CRY, is apparently highly responsive to weak MF because of radical pairs that periodically arise in the functionally active site of CRY and mediate the radical pair mechanism of magnetoreception. It is known that the circadian complex influences function of every organ and tissue, including modulation of both NF-κB- and glucocorticoids- dependent signaling pathways. Thus, MFs and solar cycles-dependent geomagnetic field fluctuations are capable of altering expression of genes related to function of NF-κB, hormones and other biological regulators. Notably, NF-κB, along with its significant role in immune response, also participates in differential regulation of influenza virus RNA synthesis. Presented data suggests that in the case of global application (example—geomagnetic field), MF-mediated regulation may have epidemiological and other consequences.

Trends in excess winter mortality (EWM) were investigated from the winter of 1900/01 to 2019/20. During the 1918-1919 Spanish flu epidemic a maximum EWM of 100% was observed in both Denmark and the USA. During the Spanish flu epidemic in the USA 70% of excess winter deaths were coded to influenza. EWM steadily declined from the Spanish flu peak to a minimum around the 1970’s to 1980’s. There is evidence that this decline was accompanied by a shift in deaths away from the winter, and that the EWM calculation shifted from a maximum around April to June in the early 1900’s to around March since 1967. EWM has a good correlation with the number of estimated influenza deaths, but in this context influenza pandemics after the Spanish flu only had an EWM equivalent to that for seasonal influenza. Using data from 1980 onward the effect of influenza vaccination on EWM was examined using a large international data set. No effect of increasing influenza vaccination could be discerned; however, there are multiple competing forces influencing EWM which will obscure any underlying trend, e.g., increasing age at death, multimorbidity, dementia, polypharmacy, diabetes, and obesity – all of which either interfere with vaccine effectiveness or are risk factors for influenza death. After adjusting the trend in EWM in the USA influenza vaccination can be seen to be masking higher winter deaths among a high morbidity US population. Winter deaths are clearly the outcome of a complex system of competing long-term trends.

No abstract