1. Introduction

Mass vaccination against COVID-19 is a prerequisite for controlling the pandemic of a new coronavirus infection worldwide. Nevertheless, population hesitancy to vaccinate (HV), which is defined as "delay in deciding to vaccinate or deciding not to vaccinate despite vaccine availability," remains a major public health problem [1]. In 2019, the World Health Organization declared HV one of the top ten global health threats associated with misinformation on vaccine effectiveness and safety [2]. At the same time, published data on the efficacy and safety of vaccines to prevent COVID-19 in the population are available [3]. Thus, vaccination of healthcare providers in Argentina with the Russian vaccine Gam-COVID-Vac (Sputnik V) was associated with rare serious adverse events, although the overall incidence of adverse events was high [4].

Fear of possible side effects of vaccines is the most common reason for HV in various population groups. In this regard, increasing public awareness of vaccine effectiveness, honesty, and objectivity about their side effects become crucial for positive perceptions of vaccination [5]. In a Polish cross-sectional study, the domestic vaccine Sputnik V ranked last in terms of credibility among all non-approved vaccines in the European Union (EU) [6]. The practice of 'cutting corners' reported during the approval of the Sputnik V vaccine [7], as well as the methodological errors identified in the results of phase III clinical trials publication [8], which was also noted in subsequent critical publications [9, 10], may have contributed to this.

Public health systems now face a new and unique challenge because of the diversity of vaccine manufacturers and the high level of public awareness of these manufacturers and their marketing strategies [11]. Given the expected seasonality of SARS-CoV-2 transmission and the increasing number of its variants (mutations), vaccine manufacturers have initiated trials of booster doses that are expected to be available to the population in the fall of 2021 [12-14]. Independent, non-sponsored studies using evidence-based methods to evaluate vaccine efficacy and safety can successfully drive non-biased pharmacovigilance efforts for COVID-19 vaccines worldwide [15, 16].

Thus, a harmonized and cross-country adapted study design, independent comparative evaluation of the efficacy and safety of available vaccines against COVID-19 will contribute to rising public confidence in vaccines and increasing vaccination rates, which will reduce the social and economic burden of disease at all levels (country, regional and global).

1.1. Aims and objectives

The aim of the international project is to survey and compare the effectiveness and side effects of COVID-19 vaccines. Canada, Croatia, Czech Republic, Estonia, Ethiopia, Germany, Ghana, Mexico, Poland, Portugal, Russian Federation (RF), Serbia, Slovenia, USA will participate in the project. The international version of the study protocol is published by A. Riad et al. in 2021 [17].

The main objectives of the project include the following:

(a) assessment of the prevalence of both local and systemic short- and long-term side effects of each COVID-19 vaccine in the target populations: healthcare providers, teachers, and researchers, elderly (≥ 65 years) and minors (< 18 years);

(b) evaluation of the association of demographic and health risk factors with the frequency and severity of adverse effects of COVID-19 vaccines.

Additional objectives include:

(a) a comparative analysis of the efficacy and safety of different vaccines against COVID-19;

(b) evaluating the effect of medications used by vaccinated individuals to manage the short-term side effects of vaccines.

2. Materials and methods

2.1. Design

The study consists of three main phases to evaluate the efficacy and safety of COVID-19 vaccines: (a) A one-stage cross-sectional study of short-term side effects; (b) a prospective cohort study of booster doses; (c) a long-term prospective cohort study.

2.1.1. Phase A

A self-completed online questionnaire developed and validated by healthcare professionals in the Russian Federation will be used to assess the short-term side effects of COVID-19 vaccines. The questionnaire contains questions about short-term side effects after administering the first, second, or both doses of a COVID-19 vaccine. Side effects are classified into local and systemic. The onset, duration, and intensity of side effects are self-evaluated by study participants. This phase is planned to last until 31 December 2021.

2.1.2. Phase B

The study will include a fully vaccinated population that has also received booster doses of vaccines and has consented to record and communicate both the long-term side effects of COVID-19 vaccines (Phase A and C study participants) and the short-term side effects of their booster doses. A self-completed online questionnaire will be used during the study. This phase is expected to last from October 2021 till April 2022.

2.1.2. Phase C

A long-term 5-year prospective cohort study to evaluate the efficacy and safety of COVID-19 vaccines is scheduled to begin in January 2022.

2.2. Study population

Phase A will utilize a pragmatic approach to tracking each target population. In the Russian Federation, the survey questionnaires are aimed at healthcare providers, teachers, researchers, the elderly, and minors.

Based on the results of the participants included in the Phase A studies, samples of participants in the Phase B and C studies will be generated.

Since in RF, according to the pilot questionnaire, more than 25 % of participants in Phase A were healthcare providers who also agreed to participate in further phases of the study, additional recruitment of this target group to participate in Phase B will not be required.

2.2.1. Inclusion criteria

— Target study groups: healthcare providers (doctors and nursing staff); teachers (teaching staff in primary, secondary and tertiary education, researchers); the elderly (≥ 65 years) and minors 16 to 18 years of age vaccinated against COVID-19 with vaccines produced in the Russian Federation within the previous 30 days or earlier.

— Age of participants: adult study participants (≥ 18 years of age) will be asked to give their informed, voluntary consent; for underage participants (< 18 years), informed consent will be required from the legal representative, parent, or guardian.

2.2.2. Exclusion criteria

— Individuals who received the COVID-19 vaccine as part of a Phase III clinical trial.

2.2.3. Sample size

The pragmatic sample size for each target group in each country was calculated by the organizers using Epi Info TM build 7.2.4 (CDC, Atlanta, GA, 2020). This population survey formula will be used to achieve an acceptable margin of error of 5 % and a confidence level of 95–99 %. Expected incidence (possibility of systemic side-effects after COVID-19 vaccination) based on data from a pilot set of 200 respondents is assumed to be 55 % [17]. Population size: the total number of healthcare providers in Russia in 2019, according to Rosstat, was 2,205,900 [18]. Acceptable margin of error: 5 % for all CoVaST-RU groups. The design effect and number of clusters are defined as 1 according to CDC guidelines for simple sample. The pragmatic sample size was 380-657 respondents to achieve a confidence interval (CI) of 95–99 %.

The sample size of other target groups (teachers in primary, secondary, and tertiary education, researchers, the elderly aged 65 and over, and 16-18-year-old minors) is assumed to be the same: 380–657 (CI 95–99 %) based on a calculation determined by the size of each target population in the Russian Federation [19].

2.3. Development of the Russian version of the questionnaire

Questionnaires including information on adverse reactions to COVID-19 vaccines will be used to survey the target population. The questionnaire includes four categories of questions: (a) Demographics (age, sex, height, weight, occupation, and geographic region); (b) medical history (chronic diseases, medications, smoking, and alcohol use); (c) History related to COVID-19 (type of vaccine, number of vaccine doses, dates of vaccination, previous COVID-19 illness and date of diagnosis); (d) COVID-19 vaccine side effects (local and systemic side effects, their onset and duration) (see appendix).

The Russian version of the questionnaire was developed based on the translation of the English version of the questionnaire developed at Masaryk University (Czech Republic) [17] and its adaptation to the cultural specifics of the population. Current versions of the questionnaire have been developed and validated for healthcare providers, teachers and researchers. An English-language version of the questionnaire for minors (< 18 years old) is under development and is also subject to adequate qualified translation into Russian.

The translation of the original version of the questionnaire into Russian was made by native Russian speakers with high level of English proficiency in the field of professional communication (health care). Subsequently, a group of experts consisting of two professional translators and a native Russian speaker with experience in biomedical research in public health, epidemiology, with foreign language proficiency of C1 (according to the Common European Framework of References for Languages), reviewed the translated versions and eliminated inconsistencies between them to create a final agreed version. The working version of the questionnaire was repeatedly tested for reliability. When ten volunteers were retested, the questionnaire was completed twice at an interval of 2 weeks.

2.4. Target populations

Data in RF will be collected in two stages using an online self-completed questionnaire. As data collection strategies may differ from country to country, target groups in the RF are planned to be approached through federal and regional governmental agencies, professional and scientific communities.

2.4.1. Phase A

Healthcare providers, teachers, researchers, the elderly aged 65 years and over, and 12-18-year-old minors will participate in the study.

A.1. The group will include healthcare professionals (doctors and nursing staff) who will be approached by academic and medical organizations and professional associations. The organizers chose the "snowball" method to recruit participants for the study. However, due to the geographical location and administrative divisions of the Russian Federation, the quotas approach according to the region code will be attempted to use.

A.2. The elderly (≥ 65 years old) will be approached by members of the federal project "Older Generation", professional medical associations and public organizations of seniors. "Snowball" method and quota assignment according to the region code will also be used.

A.3. Educational institutions staff. School teachers will be approached by the project coordinators through the regional ministries of education and educational networks, and university teachers will be approached by the councils of rectors of the constituent units of the Russian Federation. The researchers will be approached through the Russian Academy of Sciences.

The QR code and address of the questionnaire for self-completion by education specialists and researchers in RF are shown in the Figure.

QR code of the questionnaire for self-completion by teachers and researchers in the Russian Federation (https://ee.kobotoolbox.org/single/2ba5ee0ca449e6cbe909bf50975f8d1c)

A.4. Minors (from 12 to 18 years old) will be approached by the organizers through the regional ministries of education and educational networks, mainly through their schools, where parents (guardians) will be asked to fill in the questionnaire on behalf of their children.

2.4.2. Phases B and C

Respondents in groups A1, A2, A3, A4 who have expressed an interest in providing results of tracking their long-term side effects will be approached again. Phase B will study vaccine efficacy and side effects after booster vaccination. The Phase C study for the same respondents will be conducted over five years, starting in 2022.

Phase B and Phase C questionnaires will be developed in line with Phase A findings and emerging data on the safety and efficacy of COVID-19 vaccines.

2.5. Study schedule

The timing of the study in RF depends on the conditions prevailing in the country regions during the third wave of a new coronavirus pandemic and on regional plans for vaccine distribution and administrative work. The CoVaST-RU progress schedule is expected to be generally consistent with the of global CoVaST progress (see Table).

Planned schedule of the Russian CoVaST-RU study

2.6. Ethical considerations

The study was initially reviewed and approved by the Ethics Committee of the Faculty of Medicine at Masaryk University on May 19, 2021 (ref. 26/2021) (Brno, Czech Republic).

In the Russian Federation, the study was approved by the Biomedical Ethics Committee of the Irkutsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences, Minutes No. 61 of July 3, 2021.

Electronic informed consent will be obtained from each participant before the study begins. Respondents will have the opportunity to withdraw the consent and discontinue the study at any time without giving a reason. No data will be saved until the participant has provided their answers complete. Electronic informed consent will be obtained again from respondents to participate in phases B and C of the study.

2.7. Data analysis

Descriptive statistics will be used to test the normality of the data distribution and to represent the frequency and percentage of dependent variables (side effects) and independent variables (demographics, medical history, and history related to COVID-19). Regression analysis will be used to assess the potential association of each side effect with concerning demographic and medical risk factors. Statistical processing will be done using SPSS 27 or Statistica. The threshold level of significance will be set at p≤0.05.

3. Registration of the study project

The study protocol is registered in the US National Library of Medicine registry (ClinicalTrials.gov) under the identifier NCT04834869. The ClinicalTrials.gov entry is regularly updated by the project's principal investigator. Deviations from the protocol will be noted and justified in the electronic record and manuscript of the final study. The participation of the Russian Federation in the project is recorded and approved in the updated version dated 26.07.2021 [20].

4. Discussion

Post-approval evaluation of vaccine safety is usually based on voluntary reporting of side effects by healthcare professionals, vaccinated persons and caregivers. Analysis of the vaccination process and the status of vaccinated citizens requires different from traditional passive forms of surveillance and monitoring. Despite the obvious call of the time, "active" surveillance systems have not been established in most countries [21].

The results of post-approval studies of COVID-19 vaccines may differ from their Phase III results, which usually enroll nearly healthy volunteers according to strict criteria.

A. Riad et al. (2021) [22] found that the overall prevalence of side effects of the Pfizer-BioNTech vaccine against COVID-19 among vaccinated healthcare providers in the Czech Republic was relatively higher than reported by the manufacturer. On the other hand, side-effects of Pfizer-BioNTech and Oxford-AstraZeneca vaccines against COVID-19 occurred much less frequently among the large cohort of vaccinated individuals in the UK than those reported in Phase III studies of these vaccines [23].

In the ROCCA study, preliminary results from the vaccination of 2558 recipients comprising the population of the Republic of San Marino aged 18–89 years showed that Sputnik V had a high tolerability profile, and the incidence of systemic adverse reactions after vaccination was 53.0 %, including 0.8 % of severe complications [24].

There is evidence that coronavirus infection in fully vaccinated healthcare professionals is generally asymptomatic [25]. This observation needs to be confirmed in additional studies.

Demographic and health risk factors for the frequency and intensity of side effects are not usually specified in Phase III studies. Consequently, post-approval studies of vaccine efficacy and safety involving large study participant groups are needed to look for suspected risk factors for adverse reactions [26, 27].

More COVID-19 vaccines are now in the clinical trial and approval stage. Therefore, additional research and available technology will be needed to reduce the post-approval surveillance period to actively monitor vaccinated individuals. The safety of booster doses should be assessed over relatively shorter periods to reduce the workload for healthcare systems. Thus, the international CoVaST project, including CoVaST-RU, will be a tool for the global public healthcare system to actively survey the side effects of booster doses, long-term safety, and efficacy of COVID-19 vaccines [17].

5. Conclusion

Side effects of COVID-19 vaccines require active survey as they could potentially influence the decision to vaccinate. The Russian part of the international CoVaST-RU study aims to evaluate the short- and long-term side effects and efficacy of COVID-19 vaccines used in the Russian Federation versus other countries and regions of the world. The authors invite healthcare and scientific organizations, readers of the journal, and interested individuals to participate in the study.

Appendix. Questionnaire for healthcare professionals and teachers/researchers

Author roles:

Study concept and design — A. Riad, M. Klugar;

Data collection and processing — K. Apartsin, N. Sverdlova, V. Kireeva;

Statistical processing of the data — K. Apartsin, A. Riad, M. Klugar;

Text writing — K. Apartsin, N. Sverdlova, V. Kireeva, A. Riad, M. Klugar;

Editing — K. Apartsin, N. Sverdlova, V. Kireeva, A. Riad, M. Klugar.

The authors declare no conflict of interest.