Since 2020 COVID-19 has caused serious mortality around the world. Given the ambiguity in es-tablishing COVID-19 as the direct cause of death we first investigate the effects of age and sex upon all-cause mortality during 2020 and 2021 in England and Wales. Since infectious agents have their own unique age profile for death, we explore several methods to adjust single year of age deaths in England and Wales during 2019 (the pre-COVID-19 base year) to a pathogen-neutral single year of age baseline. This adjusted base year is then used to confirm the widely reported higher deaths in males for most ages above 43 years in both 2020 and 2021. During 2020 (+ COVID-19 but no vac-cination) both male and female population-adjusted deaths were significantly increased above age 35. A significant reduction in all-cause mortality among both males and females aged 75+ could be demonstrated in 2021 during widespread COVID–19 vaccination, however, below age 75 deaths progressively increased. This finding arises from a mix of vaccination and year of age profiles of deaths for the different SARS-CoV-2 variants. In addition, specific effects for age around puberty were demonstrated where females had higher deaths rather than males. There is evidence that year-of-birth cohorts may also be involved, indicating that immune priming to specific pathogen outbreaks in the past may lead to lower deaths for some birth cohorts. To specifically identify the age profile for the COVID-19 variants in 2020 to 2023, we employ the proportion of total deaths at each age which are potentially due to or ‘with’ COVID-19. The original Wuhan strain, and the Alpha variant show somewhat limited divergence in the age profile with the Alpha variant shifted to a moderately higher proportion of deaths below age 84. The Delta variant specifically targeted persons below age 65. The Omicron variants showed significantly lower proportion of overall mortality, with markedly higher relative proportion of deaths above age 65 steeply increasing with age to a maximum around 100 years of age. A similar age profile for the variants can be seen in the age-banded deaths in US states – although slightly obscured by using age bands rather than single year of age. However, the US data shows that higher male deaths are greatly dependent on age and the COVID-variant. Deaths determined as ‘due to’ COVID-19 (as opposed to ‘involving’ COVID-19) in England and Wales were especially over-estimated in 2021 relative to the change in all-cause mortality. This arose as a by-product of an increase in COVID-19 testing capacity in late 2020. Potential structure-function mechanisms for the year of age specificity of SARS-CoV-2 var-iants are discussed. The question is posed as to whether vaccines based on different variants carry the specific age profile through into the vaccine.

All vaccines exhibit both specific and non-specific effects. The specific effects are measured by the efficacy against the target pathogen, while the non-specific effects can be detected by the change in all-cause mortality . All-cause mortality data (gender, age band, vaccination history, month of death) between January 2021 and May 2022 was compiled by the Office for National Statistics. COVID–19 vaccination gave good protection on many occasions but less so for younger ages. Each gender and age group shows its own unique vaccination benefit/disbenefit time profile. Individuals are free to make vaccination decisions. For example, women aged 18-39 show a cohort who do not progress beyond the first or second dose. The all-cause mortality outcomes for the Omicron variant showed a very poor response to vaccination with 70% of sex/age/vaccination stage/month combinations increasing all-cause mortality, probably due to unfavorable antigenic distance between the first-generation vaccines and this variant, and additional non-specific effects. The all-cause mortality outcomes of COVID–19 vaccination is far more nuanced than have been widely appreciated, and virus vector appear better than the mRNA vaccines in this specific respect. The latter are seemingly more likely to increase all-cause mortality especially in younger age groups. An extensive discussion/literature review is included to provide potential explanations for the observed unexpected vaccine effects.

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.