The profile of the COvid-19 VACcination register SAFEty study in Sweden (CoVacSafe-SE)

Background The coronavirus disease 2019 (COVID-19) vaccines have been rapidly implemented in national vaccination programs world-wide after accelerated approval processes. The large population exposure achieved in very short time requires systematic monitoring of safety. The Swedish Medical Products Agency has launched a project platform for epidemiological surveillance to detect and characterise suspected adverse effects of COVID-19 vaccines in Sweden. Methods The platform includes all individuals 12 years or older in Sweden in 2021 and will be updated annually. Data, including vaccine and COVID-19 disease data, socioeconomic and demographic data, comorbidity, prescribed medicines and healthcare utilisation outcomes, are obtained from several national registers in collaboration with other Swedish Government agencies. Data from 2015 to 2019 are used as a historical comparison cohort unexposed to both the COVID-19 pandemic and to the COVID-19 vaccines. Results The primary study cohort includes 8,305,978 adults 18 years and older permanently residing in Sweden on 31 December 2020. The historical control cohort includes 8,679,641 subjects. By 31 July 2021, around 50% of those 18 years and older and two-thirds of those 50 years and older were vaccinated with at least one dose, 90% of those 70 years or older had two doses. Conclusions The nationwide register-based study cohort created by the Swedish Medical Products Agency with regular updates of individual level linkage of COVID-19 vaccination exposure data to other health data registers will facilitate both safety signal detection and evaluation and other pharmacoepidemiological studies.


Introduction
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared as a Public Health Emergency of International Concern by the World Health Organization on 30 January 2020. Symptoms of COVID-19 are highly variable, ranging from none to life-threatening critical illness, and COVID-19 is related to more than 4.9 million deaths as of 21 October 2021 (1).
Several COVID-19 vaccines have demonstrated efficacy as high as 95% in preventing symptomatic COVID-19 infections. As of June 2021, two mRNA vaccines (Comirnaty ® and Spikevax ® ) and two viral vector vaccines (Vaxzevria ® and COVID-19 Vaccine Janssen) have been granted marketing authorisation in the European Union (EU). Several other vaccines are under evaluation for marketing approval.
Sweden implemented a phased vaccine distribution plan prioritising vaccination of those at highest risk of COVID-19 complications and those at high risk of exposure and transmission, e.g. healthcare workers, but at present (August 2021), all 16 years and older are eligible for vaccination. The Swedish Medical Products Agency participates in the assessment of marketing authorisation applications as well as the monitoring of safety of COVID-19 vaccines within the EU. The Marketing Authorization Holder has responsibility for monitoring safety post-marketing, and this is supervised by the European Medicines Agency.
In addition to the regular pharmacovigilance activities in place for all medicines, the Swedish Medical Products Agency has launched a project for epidemiological surveillance to detect and characterise suspected adverse effects of COVID-19 vaccines in Sweden. This study set-up is partly based on the valuable experience from the studies of narcolepsy undertaken following the nationwide vaccination campaign during the 2009-2010 H1N1 influenza pandemic (2)(3)(4)(5)(6)(7)(8). Narcolepsy as a serious adverse event of H1N1 influenza vaccine was first observed in Finland and Sweden and proved initially more difficult to detect in other countries, highlighting the importance of studies in national settings. Information on individual vaccination exposure was not directly available in a national vaccine register during the Pandemrix ® vaccination campaign in 2009-2010, leading to cumbersome efforts to retrieve this information from local authorities and regions (5). With the recent inclusion of COVID-19 vaccine data into the national vaccination register, individual level vaccination exposure data linked to other health data registers will facilitate extended possibilities for safety signal detection and evaluation, as well as other pharmaco-epidemiological studies. An in-depth safety surveillance is not only motivated by the concern for individual and population health but also to maintain the trust in national vaccination programs in general.
The overall aim of the present work is to describe the study design, major objectives and data sources, used for a nationwide, population-based, pharmaco-epidemiological surveillance system.

Major objectives of COvid-19 VACcination register SAFEty study in Sweden (CoVacSafe-SE)
The major objectives of the CoVacSafe-SE are to study effectiveness and safety of vaccines for COVID-19 with a special focus on early detection and characterisation of suspected adverse events.
Specific aims are to: • Study the occurrence of specific diagnoses, conditions and symptoms in vaccinated compared to non-vaccinated and historical cohorts. • In in-depth analysis study the occurrence of suspected serious adverse events. • Study mortality amongst vaccinated and non-vaccinated. • Follow-up of vaccine effectiveness. • Study the coverage of vaccination uptake.

Study base
The study base comprises all individuals 12 years and older and alive and registered as permanently residing in Sweden on 31 December any year from 31 December 2014 to 31 December 2020. The study is comprised of three cohorts (Figure 1).

Study cohort during the COVID-19 vaccination in 2021
The cohort comprises all individuals 12 years and older permanently residing in Sweden, as registered on 31 December 2020 and consists of 8,305,978 adults (Table 1). This study cohort residing in Sweden during the COVID-19 vaccination in 2021 is the main cohort under study. For this cohort, information on COVID-19 diagnosis and exposure to COVID-19 vaccines is continuously collected, and the population is followed for subsequent outcomes of suspected adverse events.
Occurrence of different diseases in vaccinated is compared to occurrence of diseases in non-vaccinated and to occurrence in the Swedish population in previous years (the historical cohort permanently residing in Sweden 2015-2019, and to the pandemic cohort permanently residing in Sweden in 2020 and exposed to the SARS-CoV-2 pandemic, see below). The vaccination campaign started in Sweden on 27 December 2020. Vaccination status as of 31 July 2021 is presented in Table 2, and positive COVID-19 status as of 1 January 2021 is presented in Table 1

Data collected
The cohort is continuously updated with information on exposure to COVID-19 vaccines, covariates and outcomes during 2021 (see below). All data collected are on individual level with a unique personal identifier, making it possible to link data from all registers to the same individual. For the health data registers below, it is mandatory by law for healthcare providers to report to the respective registers, and patients cannot decline such registration.

Data on COVID-19 diagnosis and exposure to COVID-19 vaccines
The national vaccination register The national vaccination register contains information on vaccination for COVID-19 since 1 January 2021. The information includes personal identifier and date of vaccination. The vaccine products are specified by a unique identifier based on a combination of brand name, substance, formulation, additionally batch number and dose number (for repeated doses). The completeness of registration within the child immunisation program is high, where 98.4% of children had at least one vaccination recorded; however, completeness for vaccination for COVID-19 has not been published (9). The register is held by the Public Health Agency of Sweden.

Register on surveillance of notifiable communicable diseases (SmiNet)
SmiNet contains information on notifiable diseases, which must be reported by the laboratories and the physician treating the patient, or performing an autopsy, in accordance with the Swedish Communicable Diseases Act. SmiNet includes personal identifier, date of disease occurrence, date of testing, date of positive test and diagnosis of notifiable infectious disease (10). The register is held by the Public Health Agency of Sweden.

Data on comorbidity and health outcome
Previous hospitalisation and specialised outpatient care up to 5 years before cohort entry are collected. Also filled prescriptions 1 year before cohort entry are collected.

The Swedish patient register
The Swedish patient register comprises information on all inhospital care and out-patient specialist care in Sweden. The information includes personal identifier, admission and discharge dates, whether hospitalisation was planned or acute, codes for discharge diagnoses and surgical procedures, whether discharged as deceased, to own private residence or other healthcare facilities, and type of department and hospital. It has nation-wide coverage regarding in-patient care since 1987 and specialised outpatient care since 2001 (11,12). The register is a discharge register; hence, the admission is reported at time of discharge, also, there is no information on admission diagnoses. There is no information on primary care. During the study period, diagnoses were recorded according to the Swedish clinical modification of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10-SE). CoVacSafe-SE includes all main and secondary diagnoses, and surgical procedures except those of the chapter O, P and Z in ICD-10-SE. These diagnoses are omitted, but the admission or visit is reported. The register is held by the National Board of Health and Welfare.
The Swedish cancer register The Swedish Cancer Register was set up in 1958. Every clinician, pathologist and cytologist in Sweden must report a new primary malignancy. The Cancer Register includes primary malignancies and certain benign tumours and precancerous lesions (13,14). In comparison to the National Patient Register, the proportion of non-reporting to the National Cancer Registry was estimated to be 3.7% in 1998 (13). The register is held by the National Board of Health and Welfare.

Data on socioeconomic and demographic factors
The Total Population Register The Total Population Register contains information on personal identifier, date of birth, country of birth, place of residence, marital status, date of death and date of immigration and emigration (20). The register is held by Statistics Sweden.

The longitudinal integrated database for health insurance and labour market studies
The longitudinal integrated database for health insurance and labour market studies (LISA) contains information on a wide range of socioeconomic factors. Information on mother's and father's country of birth, educational level, socioeconomic position and occupation was retrieved from the register (21). The register is held by Statistics Sweden.

Register on persons in nursing homes
The register contains information on elderly and persons with physical, psychiatric or intellectual disabilities, given nursing care in nursing homes, their own homes or other institutions. For this study, the register is solely used to define elderly aged 65 years and older living in nursing homes (22). The register is held by the National Board of Health and Welfare.

Definition and classification of some socioeconomic variables
Definition and classification of persons living in elderly nursing homes, marital status, country of birth (23), highest attained educational level and socioeconomic position are described in Appendix A. The distribution of marital status, country of birth and highest attained education level in the population is presented in Tables 3 and 4.

Database updates
The project will run at least until

Quality assurance and quality control
Most of the registers used are of high or very high quality, including very high or complete coverage, high completeness and high validity of registered information (11)(12)(13)(14)(15)(16)(18)(19)(20)(21)(22). Together with the Swedish Medical Products Agency, the Public Health Agency of Sweden and the National Board of Health and Welfare continuously monitor the data used in this study. Registration of COVID-19 vaccines is new to the national vaccination registry; hence, initial lag in registration by healthcare vaccinators has been anticipated. The coverage and completeness of COVID-19 vaccination registration in the register is, however, high or very high (personal communication with the Public Health Agency of Sweden). For some suspected adverse events, it may be important to validate the recorded diagnoses, foremost using the patient register.

Strength and limitations
The main strengths of the CoVacSafe-SE include the populationbased cohort design with full nationwide coverage of the adult population, and complete follow-up. Other advantages include the availability and regular updates of complete data on positive COVID-19 PCR test and complete data on COVID-19 vaccination, and health outcomes and covariates from complete and valid nationwide Swedish registers. The main limitations concern the nature of register data. Outcomes that are not severe enough to require healthcare utilisation in terms of hospitalisation or specialised outpatientcare will not be reliably captured. COVID-19 infections are only captured if a laboratory test is performed. The availability of testing has varied over time, and likelihood of being tested may also depend on factors such as severity of symptoms, age, socioeconomic factors and vaccination status. Hence, capture of mild disease is hampered by lacking testing capacity. There is no information on lifestyle factors, laboratory data or patient clinical parameters, apart from what is registered for those treated in ICU in the SIR register. Also, this study does not collect any data on pregnancies or conditions related to childbearing (chapter O in the ICD, and also not on Chapters P and Z). In the comparison of disease occurrence after vaccination in 2021 to previous disease occurrence, the historical cohort 2015-2019 is

Marital status* Married
Marital status* Married used as reference. The year 2020 is not included as during the pandemic, a large drop in non-acute healthcare utilisation was noticed. For some specific analyses, foremost those of complications to COVID-19, the cohort residing in 2020 under the pandemic has been used. For some of the variables reflecting socioeconomic position, there is a possibility of misclassification. Marital status does not take into account those cohabitating without marriage. Thus, there is an underestimation of persons sharing household.
Not all persons have information on their own country of birth or that of their parents. Persons born in Sweden with one of their parents born in Sweden and the other where country of birth is unknown, or both of unknown country of birth, have been categorised as born in Sweden by Sweden born parents. For the older generation, this is probably true, as they may well have been born in Sweden by parents born in Sweden, but where that information is missing. However, for the younger population, this is probably an overestimation of parents born in Sweden.
The proportion of those with more than compulsory education level has increased over time in Sweden. Hence, analyses on education level must take birth year into account. For this study, where we at present have information on educational level in 2018, we only categorised those 35 years or older in 2021 as before that age not all have reached their highest attained education level.
The classification of socioeconomic groups is today a bit outdated as educational requirements for several occupations have changed in the last decades. However, it is used to measure socioeconomic position in the adult working age population in the 80s and 90s. For this study, it will only be used for those born in Sweden and 70 years or older in 2021, i.e. born 1951 or earlier, and hence 39 years or older in the 1990 Census.

Discussion on the research potential and regulatory use
The current pandemic situation and introduction of new vaccines stimulated the need for new register-based regulatory tools for follow-up of their effectiveness and safety and facilitate non-interventional studies. In such studies, signals on possible side effects may be evaluated and support regulatory decisionmaking. Signals originating from the spontaneous reporting system can also more timely be further evaluated, compared to the situation during the 2009-2010 H1N1 influenza pandemic (4).
CoVacSafe-SE will foremost focus on studies of potential short-and long-term adverse events of special interest, vaccination coverage and effectiveness of vaccines. The longitudinal design with regular updates of both exposure and outcome will enable product-specific studies of all vaccines approved for use against COVID-19. Additionally, the linkage of health data to information on sociodemographic and socioeconomic factors enables studies on inequalities in health. If suspected adverse events arise where the evaluation of a potential causality requires additional data not currently available in CoVacSafe-SE, e.g. laboratory data or in-depth data on specific medical conditions, the CoVacSafe-SE can be linked to such information. Thus, CoVacSafe-SE will facilitate the study of many important research questions by using the large potential of population-based register research in settings with nationwide registers of high completeness and validity (20,27,28).

Ethics considerations
CoVacSafe-SE contains sensitive data on individuals in the whole adult Swedish population. Hence, high security in the management of data is crucial. Sweden has implemented a phased distribution vaccination plan of the whole adult population. An in-depth safety surveillance, detecting and characterising potential side effects of vaccines, is not only motivated by the concern for individual and population health but also important in order to maintain the trust in national vaccination programs in general. Hence, a well-functioning systematic monitoring of the safety of vaccines is highly important. The sensitive data on individuals are pseudonymised with only a few persons within the project group having access to the data. All data are stored in a designated server area without connection to the internet, only used for analyses of sensitive data and with highly restricted and monitored access.
The study is approved by the Swedish Ethical Review Authority (2020-06859 and 2021-02186) and has conformed to the principles embodied in the Declaration of Helsinki. Consent to participate is not applicable as this is a register-based study (29,30).

Concluding remarks
The Swedish Medical Products Agency has launched a project platform with the dual purpose of epidemiological surveillance to detect and characterise suspected adverse events of COVID-19 vaccines in Sweden and scientific research. The nationwide study, COvid-19 VACcination register SAFEty study in Sweden (CoVacSafe-SE), using the newly implemented national register on individual level COVID-19 vaccination exposure data linked to other health data registers with high completeness and regular updates will facilitate extended possibilities for signal detection and evaluation, as well as other pharmaco-epidemiological studies.

Data access and collaboration
Access to similar data requires permission. Apart from ethical approval from the Swedish Ethical Review Authority (29), researchers will also need approval from each register holder. The Swedish Medical Products Agency will consider proposals for research collaboration. The CoVacSafe-SE may only be used for studies related to vaccine safety, vaccine effectiveness, vaccine coverage, COVID-19 disease and for assessment of quality and validity of data included in the register. Enquiries can be submitted to the agency (registrator@lakemedelsverket.se with a copy to the corresponding author rickard.ljung@ lakemedelsverket.se).