COVID-19 vaccination and short-term mortality risk: a nationwide self-controlled case series study in The Netherlands

COVID-19 vaccination and short-term mortality risk: a nationwide self-controlled case series study in The Netherlands | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search COVID-19 vaccination and short-term mortality risk: a nationwide self-controlled case series study in The Netherlands View ORCID Profile Isabel AL Slurink , View ORCID Profile Annemarijn R de Boer , View ORCID Profile Marc JM Bonten , View ORCID Profile Miriam CJM Sturkenboom , View ORCID Profile PCJL Bruijning-Verhagen doi: https://doi.org/10.1101/2024.12.11.24318790 Isabel AL Slurink 1 Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University , Utrecht, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Isabel AL Slurink For correspondence: I.A.L.Slurink{at}umcutrecht.nl Annemarijn R de Boer 1 Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University , Utrecht, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Annemarijn R de Boer Marc JM Bonten 1 Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University , Utrecht, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Marc JM Bonten Miriam CJM Sturkenboom 1 Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University , Utrecht, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Miriam CJM Sturkenboom PCJL Bruijning-Verhagen 1 Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University , Utrecht, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for PCJL Bruijning-Verhagen Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Excess mortality during the COVID-19 pandemic partly exceeded COVID-19-related deaths, indicating that other causes may have contributed. We conducted a retrospective data-linkage study including all Dutch inhabitants to investigate the impact of COVID-19 vaccination on excess mortality using a modified self-controlled case series method. We found a 44% lower relative incidence of all-cause deaths in the first three weeks after the primary vaccination compared to more than three weeks after vaccination (IRR 0.56, 95%CI 0.54-0.57). This lower incidence was consistent across vaccine types, doses, genders, age groups, and individuals with or without prior SARS-CoV-2 infection or comorbidities, and for non-COVID-19 related deaths. For booster vaccinations, the relative incidence was similar (IRR 0.49, 95%CI 0.49-0.50). In comparison, we observed a 16-fold higher incidence of all-cause deaths in the three weeks following a registered positive SARS-CoV-2 infection compared to more than three weeks after infection (IRR 16.19, 95%CI 15.78-16.60). A lower relative incidence of short-term deaths following COVID-19 vaccination support that COVID-19 vaccination is not associated with the observed excess mortality. Introduction The COVID-19 pandemic has significantly impacted global mortality rates, leading to an estimated 14.83 million excess deaths, which is 2.74 (2.44-3.06) times higher than the 5.42 million reported COVID-19 deaths 1 . This excess mortality could be due to both the direct effects of SARS-CoV-2 infections, and indirect effects such as disruptions in healthcare systems and economic instability. In the Netherlands, three periods of excess mortality were observed in 2020 and 2021, each period having around 10% higher mortality than expected 2 . The first two periods coincided with waves of COVID-19-reported deaths. However, during the third period of excess mortality in the fourth quarter of 2021, the excess mortality exceeded the COVID-19-reported deaths. This suggests that other causes of death may have contributed to the excess mortality. The difference was most pronounced for individuals aged 65 to 80. COVID-19 vaccination has shown to be highly effective against symptomatic SARS-CoV2 infections in randomized clinical trials, as well as in observational studies showing reduced risk of severe illness and deaths from COVID-19 3 - 7 . In response to vaccination, the immune system is activated to generate an immune response. This temporary activation can, in rare cases, be accompanied by severe side effects. Several severe side effects of COVID-19 vaccination have been reported to occur in the weeks following vaccination. These include myocarditis and pericarditis, thrombosis and other rare cardiovascular events, as well as neurological complications 8 - 12 . Whether COVID-19 vaccination contributed to excess mortality has been studied in several countries, consistently showing no increased risk for non-COVID-19 related mortality and a protective effect for COVID-19-related mortality 5,6,13-15 . Nevertheless, these studies could not exclude the possibility of several forms of bias, which may occur due to prognostic differences between vaccinated and unvaccinated subjects 2 , 15 . In this context, the self-controlled case series (SCCS) design complements the current evidence by performing within-person comparisons, using each case (a person who died) as their own control. This automatically controls for time-fixed confounding, thus accounting for factors that vary by vaccination status such as frailty, comorbidities and socio-economic factors. An extension of the SCCS design was developed to quantify short-term mortality following COVID-19 vaccinations 16 , which has been previously used in COVID-19 vaccine safety studies 17 - 21 . This design focuses on the immediate period after vaccination, during which immune activation may increase the risk of severe side effects, resulting in death. Nevertheless, these studies consistently show a lower risk of death from any cause following vaccination compared to non-vaccination periods. Considering the protective effect of vaccination on COVID-19 mortality, assessment of non-COVID-19 mortality will further elucidate the causative role of COVID-19 vaccination in the observed excess deaths. Furthermore, the impact of previous SARS-CoV-2 infection, and presence of comorbidities, on these associations, remains understudied. This study investigates the association between COVID-19 vaccine administration and (short-term) deaths from any cause using a SCCS approach, to assess if COVID-19 vaccination can explain the observed excess mortality during the COVID-19 pandemic. Furthermore, associations with non-COVID related deaths were assessed. Differences in type of COVID-19 vaccination (mRNA or non-mRNA), dose-effect and impact of sex, age, previous SARS-CoV-2 infection, and comorbidities were investigated. The latter is especially important due to potential lower vaccine effectiveness and higher risk of mortality among populations with comorbidities 22 . The analysis was repeated for the associations between a SARS-CoV-2 infection and each of the outcomes. Methods Study design and population We performed an retrospective study using a SCCS design and record linkage approach in the general Dutch population. The study included Dutch inhabitants registered in the General population Personal Records Database (BPR) governed by Statistics Netherlands (CBS). For the analysis on the effect of primary COVID-19 vaccination, all subjects who died between January 6, 2021, the first day of vaccine administration in the Netherlands, and November 18, 2022, the start of the booster campaign were included. For the analysis on the effect of booster vaccinations, we additionally included subjects who died until April 30, 2023, the last recorded date in the mortality database at time of the study. For the analysis on the effect of a positive registered SARS-CoV-2 infection, inhabitants who died between June 1, 2020 and December 31, 2021 were selected, during the period when tests were registered. All data sources were linked by an unique pseudonymized identifier. CBS is bound by the European General Data Protection Regulation. In addition, CBS adheres to the privacy stipulations in the Statistics Netherlands Act, the European Statistics Code of Practice, and its own Code of conduct. Informed consent is not feasible for this study since all research data is pseudonymized. This study falls within the exceptions mentioned in section 5 of the code of conduct for medical research. This study was conducted according to ‘gedragscode gezondheidsonderzoek’, the principles of the Declaration of Helsinki (World Medical Association, 2013) and in accordance with the EU GDPR (General Data Protection Regulation). This study does not fall under the scope of the Dutch Medical Research Involving Human Subjects Act (WMO). It therefore does not require approval from an accredited medical ethics committee in the Netherlands. However, in the UMC Utrecht, an independent quality check has been carried out to ensure compliance with legislation and regulations (regarding Informed Consent procedure, data management, privacy aspects and legal aspects). Outcomes The primary outcome of this study was death from any cause. As a secondary outcome, non-COVID-19 related death was examined. Notification of the cause, time and location of death is mandatory by Dutch law. Death certificates are processed and coded by CBS into The National Cause of Death Registry (1995-2023). From this registry, the date and cause of death were extracted. The event or disease that initiated the process of events that led to death is registered according to the International Statistical Classifications of Diseases and Related Health Problems, 10th revision (ICD-10) of the World Health Organization (WHO) 23 . COVID-19 deaths were defined based on the ICD-10 codes for proven (U07.1) or suspected COVID-19 (not tested or virus not identified; U07.2). Non-COVID-19 related causes of death were grouped into six umbrella categories as used by Statistics Netherlands including neoplasms; circulatory system; respiratory system; mental, behavioral, and nervous system; external (non-natural) causes; and other natural causes 2 . COVID-19 vaccination COVID-19 vaccination data was obtained from the COVID-vaccinatie Informatie-en Monitoringssysteem (CIMS) (2020-2023) governed by the National Institute for Public Health and the Environment (RIVM). CIMS contains information on individuals who have consented to be registered in the vaccine registry. The COVID-19 vaccination campaign for the primary series started on 6 January 2021 in the Netherlands according to priority groups. The booster series started on 18 November 2022. Vaccination uptake was 87.4% among people aged 12 and over at the end of 2021 24 . Permission for registering vaccine administrations in the database was granted by 93% of participants for the primary series, 95% for the booster series, and 99% for the repeated dose. From this registry, the date of vaccination, vaccine batch, type of vaccination, vaccine dose, and administrator was extracted. The type of vaccine was categorized as mRNA (Pfizer/BioNTech, and Moderna) and non-mRNA or unknown (AstraZeneca, Janssen, Novavax, Valneva, Sanofi Pasteur, HIPRA, or vaccine type unknown). SARS-CoV-2 infection Information about reported SARS-CoV-2 infections to the Dutch municipal health services were obtained from a database governed by the municipal health services [HPZone Lite van de gemeentelijke gezondheidsdiensten, GGDCOVID19BM] (2020-2021). At the time of the study-period, COVID-19 was a notifiable disease in the Netherlands meaning that all positive SARS-CoV-2 infections had to be reported to a municipal health service. From this registry, the registration date of a SARS-CoV-2 infection and type of SARS-CoV-2 test were extracted. A positive reporting within 90 days of a previous positive report was assumed to belong to the previous SARS-CoV-2 infection episode and excluded 25 . At the start of 2021, the SARS-CoV-2 wildtype dominated in the Netherlands, the Alpha variant dominated in Spring 2021, and Delta dominated from June 2021 onwards until Omicron BA.1 replaced Delta at the end of the year. The primary series was considered completed and effective 14 days after a subject received two or three (only indicated for immunocompromised individuals) primary vaccinations with either Spikevax® (Moderna), Comirnaty® (Pfizer-BioNTech), Nuvaxovid® (Novavax), or Vaxzevria® (AstraZeneca), or as a single dose of the Janssen COVID-19 Vaccine, as per national guidelines at the time 26 . Alternatively, a completed primary series could be defined as a single vaccine dose of the Moderna, Pfizer, Novavax or AstraZeneca vaccine in subjects with a documented prior SARS-Cov2 infection. Covariates Sex and age group (10-20 years band) were extracted from the population registry governed by Statistics Netherlands. Comorbidities before the date of first vaccination or SARS-CoV-2 infection were defined on the basis of hospital admission information were extracted from the Dutch Hospital Discharge Registry (DHDR) governed by the Dutch Hospital Data (DHD) foundation. The hospital admission and discharge data, institutions number (pseudonymized), admission number (pseudonymized), and diagnoses recorded as ICD-10 code (as of 2014) and ICD-9 code (1995-2013) were extracted from this database 23 , 27 . The comorbidities were specified according to the ECDC core protocol for COVID-19 vaccine effectiveness studies including asthma, immunodeficiency (including HIV infection) and organ transplant, cancer, mellitus, heart disease (excluding hypertension), hypertension, lung disease (excluding asthma), obesity, anemia, asplenia, chronic liver disease, neuromuscular disorders, renal diseases, dementia, stroke, rheumatologic diseases and tuberculosis 28 . Statistical analysis Data linkage and statistical analyses were conducted using R version 4.4.4. A modified SCCS method was used to estimate the incidence rate ratio (IRR) and 95% confidence intervals (CI) of death in a predefined risk interval compared to a predefined control interval 16 . This modification is designed to handle multiple event-dependent exposures, such as COVID-19 vaccine administrations, in relation to death as the event of interest. With death as the event of interest, the key assumptions of a standard SCCS are violated, as death precludes subsequent exposures and observation periods. This modified SCCS compares the risk of death during a predefined risk period following exposure to a reference period, defined as all observation time during which subsequent exposures could have occurred. This makes the end of the observation period independent of events. The model is estimated by iteratively reweighting observations to align with a counterfactual scenario in which no exposures can occur after death, ensuring that death does not censor exposures, as there are no exposures in this counterfactual scenario. The SCCS models were fitted using a conditional Poisson regression model using a pseudo-likelihood method on a person-week level dataset 16 , 29 , 30 . The IRRs for deaths in the risk interval relative to the control interval were estimated. The 95% CI for the parameters were obtained using the sandwich estimator in which the inverse Jacobian matrix surrounds the observed covariance matrix of the estimating functions 31 , 32 . The length of each week in days was included as an offset in the model, as some weeks are not complete (such as if a vaccination occurs part way through a week). The risk interval was defined as day 1 to 21 days following COVID-19 vaccine administration, excluding day 0 from analyses, or as day 0 to 21 following a registered positive SARS-CoV-2 infection. We examined the first three weeks combined, and for each of the three weeks individually. The control interval was defined as all the following weeks to the end of the study. For vaccination, the risk weeks were further categorised by dose or considered for all doses combined. Due to the within-person comparison, time-invariant confounding, such as sociodemographic factors, comorbidities and health-seeking behaviour, is automatically controlled for. To account for time trends in mortality incidence due to seasonality and fluctuating SARS-Cov-2 infection rates, calendar time in two-week intervals was included as a covariate in the analysis. This time-trend adjustment is independent of vaccination status and thus included cases with no registered vaccine administration or infection to avoid bias 16 . Subgroup analyses Analyses were stratified by sex, age group at start of the observation period (12-29, 30-39, 40-49, 50-59, 60-69, 70-79, 80-89, ≥90) and presence of comorbidities (none, one, multiple). The subgroup aged <12 was removed from analyses to comply with privacy regulations of Statistics Netherlands. Analyses for the primary series were additionally stratified for vaccine type (mRNA or non-mRNA/unknown), and a prior registered positive SARS-CoV-2 infection before vaccination (yes/no). The analyses of each vaccine type included all individuals who received at least one dose of the vaccine type of interest. The doses were renumbered to correspond to the first, second, and third dose of the vaccine type of interest, while doses of other vaccine types were excluded by setting them as missing. Analyses for positive registered SARS-CoV-2 infection were additionally stratified by vaccination status at time of registration. Sensitivity analyses Multiple sensitivity analyses were performed to assess robustness of findings or to test relevant secondary hypothesis. First, individuals with a positive SARS-CoV-2 infection in the 8 weeks before vaccination or during the exposure period were excluded. Second, calendar time adjustment was done using a restricted cubic spline to test whether this was a more realistic representation of confounding by calendar time effects. Third, we repeated the analysis without adjustment for calendar time, to evaluate its impact. Third, a 12-week risk periods was used to assess sensitivity to the specification of the risk period. Fourth, analyses were stratified according to administrator (municipal health services, general practitioner, or other) to account for possible difference in patient populations and to identify potential inconsistencies in data registration. Lastly, a, 2-, 4-, 7- and 14-day induction interval before the registration date of positive SARS-CoV-2 was applied (excluding observation time immediately preceding the index date) to account for potential delays in test registration. Results A total of 493,382 deaths were registered among Dutch inhabitants of all ages between June 1, 2020 and December 31, 2023. The number of deaths each week by main cause of death is shown in Figure 1 . COVID-19 related mortality was highest in January-February 2021, decreasing during the summer months, and surged again in November 2021. Mortality from other causes of deaths remained relatively stable throughout the study period. Trends in COVID-19 related mortality were more pronounced in older age groups and individuals with multiple comorbidities ( Supplemental figure 1A&C ). Download figure Open in new tab Figure 1. Number of deaths each week by main cause, among individuals who died between June 1, 2020 to April 30, 2023 ( n = 493,382). Relative incidence of deaths following primary COVID-19 vaccination A total of 75,421 individuals had received one or more doses of the primary COVID-19 vaccination and died between January 6, 2021, and November 18, 2022 ( Supplemental figure 2 ). The mean age was 79.8 ± 11.8 years and 51.2% were female ( Table 1 ). Most individuals received two doses (78.9%), the majority were mRNA vaccines (90.7%). More than half had more than one chronic condition (57.6%), with CVD, hypertension, cancer and lung disease being the most common. Characteristics according to the risk period after vaccination compared to individuals without registered vaccine administration are shown in Supplemental table 1 . Differences between individuals who died within three weeks after vaccination and those who died in the period thereafter were minor. The distribution of primary vaccine administrations over time in the study population is shown in Supplemental figure 3a . View this table: View inline View popup Download powerpoint Table 1. Characteristics of individuals in the general Dutch population who received at least one COVID-19 vaccination and died from any cause between January 6, 2021 and November 18, 2021. The relative incidence of all-cause deaths in the three-weeks following any dose of the primary vaccination, compared with the period thereafter, was 0.56 (95%CI 0.54-0.57) ( Table 2 ). The relative incidence varied within the risk interval from 0.33 (95%CI 0.31-0.34) in week one, to 0.56 (95%CI 0.54-0.58) in week two, to 0.73 (95%CI 0.70-0.75) in week three. The relative incidence was comparable across different vaccine doses of the primary series (range 0.55–0.61) and across sexes (0.55–0.56), age groups (0.48–0.64), presence of comorbidities (0.51–0.57), and prior COVID-19 infection (0.56–0.61). A slightly lower relative incidence was found for non-mRNA or unknown vaccine types (IRR 0.40, 95%CI 0.37-0.43) compared to mRNA vaccine types (IRR 0.53, 95%CI 0.51-0.54). This was only evident for the first dose (IRR 0.34, 95%CI 0.31-0.37) and not for the second and third dose (IRR 0.54, 95%CI 0.48-0.60 and IRR 0.69, 95%CI 0.24-1.97, respectively). Associations were similar considering non-COVID-19 related deaths as outcome. View this table: View inline View popup Download powerpoint Table 2. Relative incidence of all-cause and non-COVID-19 related deaths in the 3-week risk period following primary series vaccination, by risk period and subgroup Relative incidence of deaths following booster series COVID-19 vaccination Between January 6, 2021, and April 30, 2023, a total of 396,765 deaths were registered, linked to 299,935 records of individuals who received at least one vaccine ( Supplemental figure 4 ; Supplemental table 2) . The first booster dose was administered starting November 2021, the second starting January 2022, the third in April and the fourth started in September 2022 ( Supplemental figure 3b ). Consistent with main analysis, the relative incidence of all-cause deaths was significantly lower for all doses combined (IRR 0.49, 95%CI 0.49-0.50) and stratified per primary or booster dose (IRR ranging from 0.46-0.51) ( Table 3 ). The relative incidence was similar across men and women, and for age groups, and was consistent for non-COVID-19 related deaths. View this table: View inline View popup Download powerpoint Table 3. Relative incidence of all-cause deaths in the 3-week risk period following primary and booster series vaccination Relative incidence of deaths following a registered positive SARS-CoV-2 infection Between June 1, 2020, and December 31, 2021, a total of 263,518 deaths were registered which were linked to 34,066 registered positive SARS-CoV-2 infections among 33,875 unique individuals ( Supplemental figure 5 ). For 36.6% of these individuals, a vaccine administration was registered, and COVID-19 was the main cause of death (65.9%) ( Table 4 ). More men, at higher age and with more comorbidities died within three weeks after infection, compared to those who died in the period thereafter or had no infection registered ( Supplemental table 3 ). The numbers of registered infections over time in the study population are shown in Supplemental figure 6 . There were peaks in infections in November 2020, January 2021 and in November-December 2021. Most individuals had one registered infection. View this table: View inline View popup Download powerpoint Table 4. Characteristics of individuals in the general Dutch population with a registered positive SARS-CoV-2 infection and who died from any cause between June 1, 2020 and December 31, 2021. A higher relative incidence of all-cause deaths was observed in the three-weeks after a registered positive SARS-CoV-2 infection, compared to the period thereafter (IRR 16.19, 95%CI 15.78-16.60) ( Table 5 ). The relative incidence was highest in the second week (IRR 22.63, 95%CI 21.97-23.31) and decreased in the third week (IRR 9.92, 95%CI 9.57-10.28). The relative incidence was lower for individuals with a registered vaccination within 6 months before infection (IRR 6.09, 95%CI 5.47-6.78) than individuals without registered vaccination or a vaccination longer than 6 months before infection (16.90, 95%CI 16.47-17.33). The relative incidence increased with age, ranging from 2.69 (95%CI 1.74-4.16) in those aged 12-29, to 20.60 (95%CI 19.77-21.46) in individuals aged 80-89. Furthermore, the relative incidence was slightly higher in men (IRR 18.00, 95%CI 17.37-18.65) compared to women (IRR 14.43, 95%CI 13.92-14.96), and in individuals with multiple comorbidities (IRR 17.34, 95%CI 16.73-17.97) compared to one (IRR 14.29, 95%CI 13.52-15.11) or none (IRR 15.26, 95%CI 14.57-15.98). The associations were substantially weaker when non-COVID-19 related deaths were used as the outcome. View this table: View inline View popup Download powerpoint Table 5. Relative incidence of all-cause deaths in the 3-week risk period following a registered positive SARS-CoV-2 infection, by risk period, vaccination status, and subgroups Sensitivity analyses The results were robust in sensitivity analysis without adjustment for calendar time, when using a restricted cubic spline for calendar time adjustment, and when excluding individuals who had a registered positive SARS-CoV-2 infection in the 8 weeks before vaccination or during the exposure period ( Supplemental table 4 ). The relative incidence was slightly stronger for individuals vaccinated by municipal health services (IRR 0.46, 95%CI 0.44-0.48) or general practitioners (IRR 0.55, 95%CI 0.52-0.59), compared to those vaccinated by other administrators (IRR 0.77, 95%CI 0.74-0.80). The relative incidence was slightly reduced to 0.71 (95%CI 0.70-0.72) when considering a twelve-week risk period for all vaccine doses combined, compared to 0.56 (95%CI 0.54-0.57) in the three-week risk period analysed in the main analysis. Similarly, the relative incidence in the twelve-week risk period after a registered positive SARS-CoV-2 infection was reduced compared to main analysis (8.28, 95%CI 8.05-8.51 versus 16.19, 95%CI 15.78-16.60). Furthermore, setting the induction interval to 2, 4, 7 or 14 days before the registration date attenuated the relative incidence (IRR 14.79, 13.02, 9.91 and 2.54, respectively). Discussion In this registry-based, nation-wide study in the Netherlands, a 44% lower incidence of all-cause and non-COVID-19 related deaths was observed in the first three weeks after any dose of the primary series vaccine administration compared to subsequent periods. This reduced incidence of all-cause deaths was most pronounced in the first week after vaccine administration and was slightly greater for non-mRNA or unknown vaccine types compared to mRNA vaccine types. The reduction was consistent across different vaccine doses, by sex, age groups, presence of comorbidities and registered prior COVID-19 infection. A lower relative incidence of deaths was also found following booster doses, consistent across different doses, as well as by sex and age groups. By contrast, we observed a 16-fold higher incidence of all-cause deaths after a registered positive SARS-CoV-2 infection, most notable in older age groups, and slightly higher in men and those with multiple comorbidities. The relative incidence ratios were slightly attenuated with a longer 12-week risk period. Results in context Our results align with other SCCS studies conducted between 2020 and 2022, all reporting lower relative incidences of deaths shortly after vaccination compared with subsequent periods, consistent across demographic groups, vaccine doses, and types 17 - 21 . A US cohort study ( n = 18,000) found a substantial lower relative incidence of all-cause and non-COVID-19 deaths in the 14-day or 28-day risk interval following first or second vaccination (IRR range 0.23-0.55) 18 . In a nation-wide registry in Italy ( n = 2,167), the relative incidence of all-cause deaths within 30-days following vaccination was 0.76 (95%CI 0.70-0.83) 19 . Using registry data in an urban city of Japan ( n = 126), mRNA vaccination was associated with lower relative incidence of all-cause deaths within 3 weeks following the first and second dose (IRR 0.38, 95%CI 0.29-0.49 and 0.43, 032-0.56, respectively) 20 . In a nationwide registry study in adult Singaporeans ( n = 3,137,210), the relative incidence of all-cause deaths 31-days after any mRNA booster dose was 0.44 (0.40–0.48) 17 . Furthermore, in a registry-study among 12 to 29 year-old individuals in England ( n = 3,807), death rates were lower in the twelve weeks post-vaccination period for three doses combined (IRR 0.88, 95%CI 0.80-0.97) 21 , with stronger associations for the second and third doses compared to the first, and for males compared to females. Jointly, the evidence consistently points towards reduced mortality in the weeks following vaccination. This is a reassuring finding in the context of the observed and still partly unexplained excess mortality during the COVID-19 pandemic. If vaccination was causally related to an increase in mortality, the risk of death would be expected to peak shortly after vaccination and decline thereafter. In our study we observed the opposite; the risk of death was lowest shortly after vaccination. The lower death rate shortly after vaccination can be partly attributed to a time-varying ‘healthy vaccinee effect’ 33 , such as the tendency for vaccinations to be administered during periods without illness, especially as fever is a contra-indication for vaccination 34 . This unmeasured time-varying confounding is not fully addressed in SCCS designs, which also explains the similar low relative incidence rates for non-COVID-19 deaths. This healthy vaccinee effect may overestimate the reduction in deaths after vaccination to some extent and point estimates should therefore be interpreted with some caution. We observed a slightly more pronounced incidence rate reduction for the first dose of non-mRNA or unknown vaccine types compared to mRNA vaccines, although this comparison is limited as only few people received these vector vaccines. Vector vaccines are no longer administered in the Netherlands due to high effectiveness of mRNA vaccines with lower incidence of adverse events, and logistic considerations. Prior studies have not demonstrated differences in all-cause 19 , 21 , or excess mortality 35 , by vaccine type. Our findings of high relative incidence of deaths following SARS-CoV-2 infection are also consistent with SCCS studies from Singapore and England 17 , 21 . In our study, the relative incidence of deaths was highest in the second week after infection, in line with the typical clinical course of severe COVID-19 caused by SARS-CoV-2 wildtype, Alpha and Delta variants in the initial waves of the pandemic 36 , 37 . This course typically begins with respiratory symptom onset in the initial phase, followed by a dramatic worsening due to a cytokine storm, leading to hospitalization and death within one to two weeks from symptom onset. The relative incidence of deaths following a positive SARS-CoV-2 infection was substantially lower among vaccinated individuals compared to unvaccinated individuals. A still somewhat higher incidence of deaths after a positive registered infection compared to control weeks in vaccinated individuals may reflect incomplete vaccine effectiveness and potential waning immunity from the primary series, particularly in older adults or those with pre-existing conditions 38 , as well as selection bias, as testing might have been associated with higher severity of infections. Nevertheless, only a slight proportion of all infections was among vaccinated individuals, mostly registered in November 2021, coinciding with a peak in all-cause mortality. Strength and limitations Strengths of our study include the nation-wide coverage of vaccination and mortality records, inclusion of data on previous SARS-CoV-2 infections and chronic medical conditions across all age groups, providing considerable sample size and generalizable findings. The results should be interpreted considering the following limitations. First, while the date of death registration in the Netherlands is highly accurate, there is uncertainty in the reliability of the recorded primary cause of death 39 . In a proportion of non-COVID-19 related deaths, SARS-CoV-2 infection may have had an unrecognized role in the causal pathway to death. Misclassification of non-COVID-19 related deaths could occur in both directions, potentially attenuating the observed associations. Despite, the associations with non-COVID-19 related death as the outcome remained substantial, suggesting that this misclassification is unlikely to have significantly altered our findings. Second, the national vaccination database is not complete as 7% of the primary series and 5% of the booster recipients did not give consent for registration. As a result, some cases without registered vaccine administration were, in fact, vaccinated. While this may have resulted in exclusion of some vaccinated subjects in our case series, this misclassification does not influence the IRR estimates, as cases without registered vaccine administrations are not part of the analysis. Routine procedure was to ask for consent for registration before the vaccine was administered, and therefore the probability of non-registration is unrelated to the likelihood of death following vaccination. Nevertheless, the associations between SARS-CoV-2 infection and mortality in individuals without a registered vaccine administrations are likely to be biased towards the null 15 , 35 . Third, the median duration between the first and second primary vaccine was 5 weeks (IQR 4 - 5.1 weeks), limiting the longer-term risk assessment following the first dose. The duration of the risk interval affects the associations, as shown in sensitivity analyses with a 12-week risk interval. Lastly, routine testing for SARS-CoV-2 upon hospital admission could have inflated the associations, particularly during the first week after infection. The exact onset date of the infection is often unclear, complicating correct specification of the risk period. However, the results were robust in sensitivity analyses including induction days varying between 2 and 14 days. Conclusion Taken together, our results provide additional evidence for absence of increased risk of death after COVID-19 vaccination, thereby excluding vaccination as a cause of observed excess mortality between January 2021 up to April 2023. The results indicate that for both all-cause and non-COVID-19-related deaths, the relative incidence in the three weeks following vaccination is lower compared to the period more than three weeks after vaccination. The reduced risk of death remained evident for up to 12 weeks post-vaccination. In comparison, the relative incidence of all-cause death in the three weeks following a SARS-CoV-2 infection was higher compared to the period more than three weeks after infection. Our findings can inform communication strategies about safety of COVID-19 vaccination, emphasizing consistency across demographic groups, vaccine types, and doses. Data Availability All data are available within CBS Microdata and can be made available under strict conditions: Microdata: Conducting your own research https://www.cbs.nl/en-gb/our-services/customised-services-microdata/microdata-conducting-your-own-research#:~:text=Microdata%20are%20linkable%20data%20at,strict%20conditions%20for%20statistical%20research https://github.com/isabelslurink/SCCS_COVID19_mortality_paper References 1. ↵ Msemburi , W. , et al. The WHO estimates of excess mortality associated with the COVID-19 pandemic . Nature 613 , 130 – 137 ( 2023 ). OpenUrl PubMed 2. ↵ Rijksinstituut voor Volksgezondheid en Milieu . Sterfte en oversterfte in 2020 en 2021 . (ed. Centraal Bureau voor de Statistiek, Den Haag/Heerlen/Bonaire ) ( 2022 ). 3. ↵ Al Kaabi , N. , et al. Effect of 2 Inactivated SARS-CoV-2 Vaccines on Symptomatic COVID-19 Infection in Adults: A Randomized Clinical Trial . JAMA 326 , 35 – 45 ( 2021 ). OpenUrl PubMed 4. Zeng , B. , Gao , L. , Zhou , Q. , Yu , K. & Sun , F. Effectiveness of COVID-19 vaccines against SARS-CoV-2 variants of concern: a systematic review and meta-analysis . BMC medicine 20 , 200 ( 2022 ). OpenUrl PubMed 5. de Gier , B. , et al. Effect of COVID-19 vaccination on mortality by COVID-19 and on mortality by other causes, the Netherlands, January 2021-January 2022 . Vaccine 41 , 4488 – 4496 ( 2023 ). OpenUrl PubMed 6. Zheng , C. , et al. Real-world effectiveness of COVID-19 vaccines: a literature review and meta-analysis . International journal of infectious diseases 114 , 252 – 260 ( 2022 ). OpenUrl CrossRef PubMed 7. ↵ Watson , O.J. , et al. Global impact of the first year of COVID-19 vaccination: a mathematical modelling study . Lancet Infect Dis 22 , 1293 – 1302 ( 2022 ). OpenUrl CrossRef PubMed 8. ↵ Bozkurt , B. , Kamat , I. & Hotez , P.J. Myocarditis with COVID-19 mRNA vaccines . Circulation 144 , 471 – 484 ( 2021 ). OpenUrl CrossRef PubMed 9. Sharifian-Dorche , M. , et al. Vaccine-induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis post COVID-19 vaccination; a systematic review . Journal of the Neurological Sciences 428 , 117607 ( 2021 ). OpenUrl CrossRef PubMed 10. Patone , M. , et al. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection . Nature Medicine 28 , 410 – 422 ( 2022 ). OpenUrl PubMed 11. Fazlollahi , A. , et al. Cardiac complications following mRNA COVID-19 vaccines: A systematic review of case reports and case series . Reviews in medical virology 32 , e2318 ( 2022 ). OpenUrl CrossRef PubMed 12. ↵ Patone , M. , et al. Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection . Nature Medicine 27 , 2144 – 2153 ( 2021 ). OpenUrl PubMed 13. Xu , S. COVID-19 vaccination and non–COVID-19 mortality risk—seven integrated health care organizations, United States, December 14, 2020–July 31, 2021 . MMWR. Morbidity and Mortality Weekly Report 70 ( 2021 ). 14. Xu , S. , et al. A safety study evaluating non-COVID-19 mortality risk following COVID-19 vaccination . Vaccine 41 , 844 – 854 ( 2023 ). OpenUrl PubMed 15. ↵ Rijpkema , C. , et al. Oversterfte tijdens de COVID-19-pandemie: onderzoek onder mensen met en zonder COVID-19 vaccinatie . Utrecht: Nivel , 2024 . 59 p. 16. ↵ Ghebremichael-Weldeselassie , Y. , et al. A modified self-controlled case series method for event-dependent exposures and high event-related mortality, with application to COVID-19 vaccine safety . Stat Med 41 , 1735 – 1750 ( 2022 ). OpenUrl PubMed 17. ↵ Wee , L.E. , et al. Risk of death and cardiovascular events following COVID-19 vaccination or positive SARS-CoV-2 test amongst adult Singaporeans during omicron transmission . Vaccine 42 , 126356 ( 2024 ). OpenUrl PubMed 18. ↵ Xu , S. , et al. Mortality risk after COVID-19 vaccination: A self-controlled case series study . Vaccine 42 , 1731 – 1737 ( 2024 ). OpenUrl PubMed 19. ↵ Stivanello , E. , et al. Short-term mortality following COVID-19 vaccination in Bologna, Italy: a one-year study . Vaccine 40 , 5709 – 5715 ( 2022 ). OpenUrl PubMed 20. ↵ Takeuchi , Y. , et al. A post-marketing safety assessment of COVID-19 mRNA vaccination for serious adverse outcomes using administrative claims data linked with vaccination registry in a city of Japan . Vaccine 40 , 7622 – 7630 ( 2022 ). OpenUrl PubMed 21. ↵ Nafilyan , V. , et al. Risk of death following COVID-19 vaccination or positive SARS-CoV-2 test in young people in England . Nat Commun 14 , 1541 ( 2023 ). OpenUrl CrossRef PubMed 22. ↵ Ciabattini , A. , et al. Vaccination in the elderly: the challenge of immune changes with aging . in Seminars in immunology , Vol. 40 83 – 94 ( Elsevier , 2018 ). OpenUrl 23. ↵ World Health Organisation . International Statistical Classification of Diseases Related Health Problems 10th Revision Geneva: WHO ; 2019 [Available from: https://icd.who.int/browse10/2019/en ]. 24. ↵ Valk , A. , et al. Vaccinatiegraad COVID-19 vaccinatie Nederland, 2021 . ( 2022 ). 25. ↵ Rijksinstituut voor Volksgezondheid en Milieu . COVID-19 Richtlijn 2022 [updated 31-10-2023]. ( 2022 ). 26. ↵ Rijksinstituut voor Volksgezondheid en Milieu . Ministerie van Volksgezondheid, Welzijn en Sport. COVID-19-vaccinatie Uitvoeringsrichtlijn . Professionele standaard voor COVID-19-vaccinatie 2021 . Versie 5 februari 2021. ( 2024 ). 27. ↵ World Health Organization . International classification of diseases, injuries, and causes of death . Ninth Revision (ICD-9) . Geneva : World Health Organization ( 1987 ). 28. ↵ European Centre for Disease Prevention and Control . Core protocol for ECDC VEBIS studies of COVID-19 vaccine effectiveness against hospitalisation with Severe Acute Respiratory Infection laboratory-confirmed with SARS-CoV-2 or seasonal influenza - Version 3.0 . Stockholm : ECDC ; 2024 . 29. ↵ Farrington , C.P. , Whitaker , H.J. & Hocine , M.N. Case series analysis for censored, perturbed, or curtailed post-event exposures . Biostatistics 10 , 3 – 16 ( 2009 ). OpenUrl CrossRef PubMed Web of Science 30. ↵ Whitaker , H.J. , Paddy Farrington , C. , Spiessens , B. & Musonda , P. Tutorial in biostatistics: the self-controlled case series method . Statistics in medicine 25 , 1768 – 1797 ( 2006 ). OpenUrl CrossRef PubMed Web of Science 31. ↵ Farrington , P. , Whitaker , H. & Ghebremichael-Weldeselassie , Y. Self-controlled case series studies: a modelling guide with R , ( Taylor & Francis , 2018 ). 32. ↵ Jesus , J. & Chandler , R.E. Estimating functions and the generalized method of moments . Interface focus 1 , 871 – 885 ( 2011 ). OpenUrl CrossRef PubMed 33. ↵ Remschmidt , C. , Wichmann , O. & Harder , T. Frequency and impact of confounding by indication and healthy vaccinee bias in observational studies assessing influenza vaccine effectiveness: a systematic review . BMC infectious diseases 15 , 1 – 15 ( 2015 ). OpenUrl CrossRef PubMed 34. ↵ Rijksinstituut voor Volksgezondheid en Milieu . Ministerie van Volksgezondheid, Welzijn en Sport . COVID-19-vaccinatie Uitvoeringsrichtlijn . Versie 2 september 2024 (versie 7.0). ( 2024 ). 35. ↵ Rijpkema , C. , Ramerman , L. , Hek , K. , Bos , I. & Verheij , R. Oversterfte tijdens de COVID-19-pandemie in Nederland nader onderzocht: de associatie met medische voorgeschiedenis, sociaaleconomische en demografische kenmerken . NIVEL . ( 2023 ). 36. ↵ Hu , B. , Huang , S. & Yin , L. The cytokine storm and COVID-19 . Journal of medical virology 93 , 250 – 256 ( 2021 ). OpenUrl CrossRef PubMed 37. ↵ Harrison , E.M. , Docherty , A. & Semple , C. COVID-19: time from symptom onset until death in UK hospitalised patients . URL: https://assets.publishing.service.gov.uk , Accessed November 30, 2020 ( 2020 ). 38. ↵ Wright , B.J. , et al. Comparative vaccine effectiveness against severe COVID-19 over time in US hospital administrative data: a case-control study . The Lancet Respiratory Medicine 10 , 557 – 565 ( 2022 ). OpenUrl PubMed 39. ↵ Dekkers , O.M. & Groenwold , R.H. Doodsoorzaken: de onzekerheid achter de cijfers . Ned Tijdschr Geneeskd . 2024 ; 168 : D8059 . OpenUrl PubMed View the discussion thread. Back to top Previous Next Posted December 11, 2024. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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