ABSTRACT
Background In the absence of a specific treatment for COVID-19, preventive measures have been implemented to control this pandemic and vaccination is one of them. However, it is crucial to verify the safety and efficiency of every vaccine. The aim was to determinate the predictive factors of side effects and reinfection after COVID-19 vaccine. Methods A cross-sectional study was conducted in February 2022 among Tunisians infected with COVID-19 between March 2020 and February 2022, using an online self-administered questionnaire. We conducted univariate and multivariate analyses using binary stepwise logistic regression. Results A total of 1541 was selected from 1911 individuals. Comorbidities affected a quarter of the population (22.3%). Before the initial infection, 39.3% had received full vaccination, and 8.7% had received partial vaccination. By February 2022, the majority (82.9%) had received at least two vaccine doses. The reinfection rate was 30.6%. All vaccines prior to the first infection was identified as a protective factor against reinfection. Inactivated virus vaccinations were less likely to induce adverse effects. Conclusion ach vaccine has its own set of advantages and disadvantages: mRNA-based vaccines had a higher incidence of side effects but all vaccines provided better protection against reinfection.
Introduction
COVID-19 was declared a global pandemic on March 11, 2020Citation1 and continues to persist.Citation2,Citation3 From its emergence until August 31, 2023, the world health organization (WHO) has recorded more than 770 million confirmed cases of COVID-19 and 7 million deaths worldwide. In the absence of a specific treatment for COVID-19, preventive public health measures such as mask-wearing, physical distancing, good hand hygiene, isolation of confirmed cases and vaccination have been implemented to reduce COVID-19.Citation4,Citation5 However, the most effective alternative to curb the virus’s spread, reduce severe illness and death, and enable society to return to normalcy, is a safe and effective vaccine with minimal side effects.Citation6 Vaccines are a crucial tool, though none are 100% effective in controlling this pandemic.Citation7 Multiple vaccine has been developed worldwide using various technologies, including mRNA, viral vector, protein subunit, and inactivated virus.Citation7–9 The first COVID-19 vaccines were granted emergency use authorization in the United States by the end of 2020,Citation10,Citation11 marking a significant turning point in the battle against the pandemic. Globally, 13 billion vaccine doses have been administered, contributing to achieving herd immunity and reducing the virus’s ability to spread. Post-vaccination monitoring systems continuously track vaccine safety, and any adverse events are thoroughly investigated.Citation12,Citation13 Nevertheless, it is well understood that each vaccine comes with its own set of advantages and side effectsCitation14,Citation15 but the benefits of vaccination far outweigh the risks. While COVID-19 vaccination is highly effective in preventing infection and reducing the severity of the disease, the possibility of reinfection exists, particularly in the context of emerging variants and waning immunity. Reinfection can occur due to an insufficient initial immune response to the virus or a decline in neutralizing antibody responses over time.Citation16 As of June 20, 2023, Tunisia has administered 13 million vaccine doses.Citation17 The Tunisian government has approved various vaccines, including Pfizer-BioNTech, Moderna, AstraZeneca, Sputnik V, Janssen, Sinopharm and Sinovac, and has made them available to the entire population.Citation18 Our study aims to determine the side effects and the incidence of reinfection following COVID-19 vaccination and identify their predictive factors.
Methods
Study design
A cross-sectional study was conducted in February 2022 among the Tunisians population infected with COVID-19 between March 2020 and February 2022.
Study population
All Tunisians who had been infected with COVID-19, confirmed by either a rapid test or PCR at least once, and who agree to participate in the study were included.
The sample size needed was estimated using the formula: n=[(Zα/2)2 × p × (1–p)]/i2. The rate of side effects considered was 70%Citation19 and the prevalence of reinfection ranges from 0.3% to 31.4%.Citation20–24 To optimize the sample size, a proportion (p) of 70% was selected, a precision (i) of 5% and a risk error (α) of 5% were evaluated, resulting in a necessary sample size of at least 288 individuals and a loss of 30% due to non-eligible participants (not being a Tunisian, under 18 years of age, ect.) were considered, resulting in a required sample size of at least 375 participants. We excluded individuals under the age of 18, Tunisians residing abroad, non-Tunisian residents in Tunisia, those who were unvaccinated at the time of the study, and those who had received mixed vaccines. In Tunisia, the population was vaccinated with three types of vaccines: mRNA vaccines including Pfizer and Moderna; viral vector including Sputnik, Janssen & Janssen and AstraZeneca; and inactivated virus vaccines including Sinovac Coronavac and Sinopharm.Citation25,Citation26
The determination of COVID-19 Variants Of Concern (VOC) typically involves genetic sequencing of the virus. This process can be more complex in certain countries, such as Tunisia, due to several challenges, including limited resources and a scarcity of national laboratories equipped for such procedures. Consequently, the sequencing efforts have focused on specific clusters or severe cases. According to the Tunisian Ministry of Health, the predominant circulation of VOCs during the study period was the Alpha variant from December 2019 to April 2021, the Delta variant from May 2021 to December 2021, and the Omicron variant starting from January 2022.Citation27
Data collection
Data was collected using an online self-administered questionnaire in both French and Arabic through Google Forms. The questionnaire was shared on Facebook, which is considered as the most popular social media in Tunisia,Citation28 as well as on radio, and television channels for one month in February 2022, with weekly reminders. Respondents were questioned about their socio-demographic factors, COVID-19 infection history, reinfection, its impact on their health, post-COVID infection symptoms, vaccination and side effects.
Data analysis
Data entry and analysis using the Statistical Package for Social Sciences (SPSS) version 21.0. Quantitative variables were presented as mean and standard deviations if the distribution is normal and compared by the t-test Student. Qualitative variables were presented as frequencies and percentages and compared by chi-square test. Univariate after multivariate logistic regression was used. All variables with a p value less than or equal to 20% were included in the univariate analysis. The significance threshold was set at 5%, and the strength of association was estimated by calculating the odds ratio (OR) and its 95% confidence interval. The rate of menstrual disorders was calculated in the sub-population of women of childbearing age.Citation29
Variables’ definitions
Reinfection was defined as patients who had two positive tests confirmed by either rapid test or PCR, taken more than 90 days apart and who had recovered clinically.Citation30,Citation31 Long COVID was defined as the persistence of current symptoms or the emergence of new symptoms within three months after onset, lasting at least two months, and having no differential diagnosis.Citation32 Safety was defined by presence or absence of post-vaccination adverse effects.Citation33
Ethics approval and consent to participate
The Farhat Hached University Hospital’s Ethical Committee (Institutional Review Board code:00008931) approved this study, and it was carried out in accordance with the ethical principles the Declaration of Helsinki (CER:34–2022 is the reference number for the committee’s opinion). The Google form’s two sections were preceded by an introductory paragraph that described the study’s goals and methodology. Responses’ anonymity was emphasized. The first element of the Google form required participants to indicate their agreement to participate in the study by selecting “yes” in response to the following question: “Do you agree to participate in the study?” This action was required in order for them to access the questionnaire. The user of the link was not given the questionnaire if they selected “No” as their response. Full names and e-mail addresses were not collected to ensure anonymity and confidentiality.
Results
General characteristics of the population
Among the 1911 participants, 1541 were selected. The sex ratio F/M was 3.98 with an average age of 37.27 ± 9.25 years, which serves as the population’s cutoff point. The Tunis governorate had the highest participation (19.4%), followed by the Sousse governorate (16.1%), Ariana governorate (10.8%), Ben Arous governorate (8.8%), and Sfax governorate (6.4%). Regarding participants’ lifestyle habits, 18.6% were active smokers and 11.8% were alcohol consumers. About 39.1% of the population was overweight and 18.8% were obese. Comorbidities affected a quarter of the population (22.3%), with respiratory problems (6%), hypertension (5.4%), thyroid disorder (5.5%), and diabetes (3.8%). A total of 937 (60.8%) people received the mRNA Pfizer-BioNTech vaccine, 221 (14.3%) received the mRNA Moderna vaccine, 180 (11.7%) received the adenovirus vector AstraZeneca vaccine, 75 (4.9%) received the adenovirus vector Janssen & Janssen vaccine, 77 (5.0%) received the inactivated Sinopharm vaccine and 51 (3.3%) received the inactivated Sinovac Coronavac vaccine. We did not identify any subjects vaccinated exclusively with Sputnik, as all of them had a mixed vaccination schedule (and were excluded from the study) because those exclusively vaccinated solely with Sputnik had not received their vaccine pass.
Side effects following COVID-19 vaccination
Side effects were reported by 76.8% of participants (n = 1184) at the time of the study. Regarding local side effects, redness was the most frequent (34.1%). Fatigue (47.6%), headache (45.5%), fever (32.1%), and arthralgia (30.5%) were the most common systemic adverse symptoms ().
Table 1. Side effects of vaccine.
In the univariate analysis, females were more susceptible to developing side effects (p = .003; OR = 1.51[1.14–2.00]). The use of mRNA-based and adenovirus vector vaccines significantly increased the likelihood of experiencing side effects compared to inactivated virus vaccine (p = .002, OR = 1.51 [1.16–1.96]). For individuals aged 37 and above, who were smokers, alcohol consumers, obese, and had at least one comorbidity, the difference was statistically insignificant. Respiratory comorbidities (p = .102), hypertension (p = .742), diabetes (p = .600), and thyroid disorder (p = .236) also showed no statistical significance ().
Table 2. Univariate analysis of the side effect.
Table 3. Multivariate analysis of the side effect.
Reinfection
More than half (52%) had been infected with the virus prior to vaccination. Before the initial infection, 39.3% had received full vaccination and 8.7% had received partial vaccination against COVID-19. A total of 528 (34.2%) received mRNA vaccine, 141 (9.1%) received adenovirus vector vaccine and 71 (4.6%) received inactivated vaccine. The rate of reinfection was 30.6%. Among the 472 participants who underwent a second infection, the majority (82.4%) were not reinfected by the same VOC. A small percentage reported a third infection (5.1%), with 88.6% of these cases associated with a different VOC compared to their initial infection.
In the univariate analysis, vaccination with two doses prior to the first infection was a protective factor against reinfection (p = .001; OR = 0.49 [0.31–0.76]), all types of vaccine were protective against reinfection. Obesity (BMI ≥ 30) was also a predictive factor of reinfection (p = 0.020; OR = 1.37 [1.05–1.80]). Among individuals aged 37 and older who were smokers, alcohol consumers, obese, and had at least one comorbidity, there was no statistically significant difference. Respiratory comorbidities (p = .905), hypertension (p = .728), diabetes (p = .758), and thyroid disorder (p = .199) similarly exhibited no statistical significance ().
Table 4. Univariate analysis of the reinfection.
Table 5. Multivariate analysis of the reinfection.
Long COVID
Complete vaccination protects against long COVID (p ≤ 10−3; OR = 0.49[0.31–0.76]). Reinfection is considered a risk factor for long COVID (p = .002; OR = 1.32[1.04–1.66].
Discussion
While COVID-19 vaccines have demonstrated a high level of safety in clinical trials, there is less statistical data comparing their safety in real world usage.Citation13 To our knowledge, few studies worldwide such as in the Middle East (Iraq, Jordan, Bahrain) and IndiaCitation19,Citation34–39 have compared the side effects among the three types of COVID-19 vaccines in the general population and none of them have been conducted in North Africa except for one study that focused on Algerian athletes.Citation40 However, side effects are considered reactogenicity symptoms which are a consequence of the expected immune response to immunization. In fact, the extent of reactogenicity, whether local or systemic, is influenced by a multitude of factors, including host characteristics (such as age and gender), vaccine features and various other elements.Citation41 In this study we found that 76.8% of participants reported side effects regardless of the type of vaccine. Fatigue (47.6%), headache (45.5%), fever (32.1%), and arthralgia (30.5%) were the most common systemic adverse symptoms. These findings align with those reported in numerous other studies regarding the most prevalent side effects.Citation13,Citation15,Citation42–46 Initially, mRNA vaccines were believed to carry no risk of reactivation and were thought to be safer than inactivated vaccines.Citation46,Citation47 However, the findings of our study revealed that side effects were more common among mRNA vaccines than adenovirus vector vaccines and inactivated vaccines. Other studies support our results when comparing mRNA and inactivated vaccinesCitation35,Citation36,Citation43 or mRNA and adenovirus vector vaccineCitation13,Citation35,Citation37,Citation42 or adenovirus vector and inactivated vaccine,Citation19,Citation35,Citation48,Citation49 but no study has compared all three types of vaccine. For most vaccines, these reactions are mild to moderate and temporary,Citation26,Citation43,Citation44 with no serious adverse event.Citation50–52 Another noteworthy finding is the considerable variation in side effects based on gender, with a higher prevalence of events in females compared to male as reported in the majority of the studies worldwide,Citation34,Citation39–42,Citation43,Citation53–56 which is consistent with our results. Additionally, other predictive factors for side effects have been reported in previous studies, such as age,Citation34,Citation55 comorbidities as diabetes, hypertension, asthma, thyroid disorder,Citation34,Citation43 or weight status,Citation45 but no significant association were found in our study. The lack of statistical significance regarding the age variable in our sample may be attributed to older subjects having limited access to the internet compared to younger subjects. At the present, the precise reason for the presence or the absence of association between chronic diseases and side effects is still unclear. Nonetheless, it is suggested that additional forward-looking studies with a larger sample size are needed to confirm or infirm this correlation. It is well established that vaccines do not provide immunity to all vaccinated individuals.Citation57 The reasons for this variability are numerous, ranging from genetic and immunological factors to the quality of the vaccines themselves and their administration.Citation26 Despite significant disparities in the prevalence and severity of side effects among these vaccinations, statistical analysis suggested that vaccines may offer similar protection against severe forms of COVID-19.Citation19 Hence, the importance of studying these factors in the Tunisian population and identifying their specific characteristics. Indeed, the reinfection rate found in our study was 30.6% falling within the range reported in the literature (which ranges from 0.3% to 31.4%).Citation20–24 This variation can be attributed to various factors, including the absence of a consensus definition of reinfection,Citation58 the presence of different virus variants (such as Omicron, which is the most activeCitation59), vaccination rates, population herd immunity level, infection prevention strategies and recipient characteristics.Citation60–62 In our survey, receiving two vaccine doses prior to the first infection was a protective factor against reinfection. This finding is supported by several studies that have demonstrated that full vaccination provides additional protection against reinfection.Citation63–67 While full vaccination does not completely eliminate the risk of reinfection, it contributes significantly to controlling the pandemic by reducing the incidence symptomatic cases, critical cases, and fatalities.Citation68 Researchers have reported high vaccine efficacy levels, with Pfizer, Moderna and Sputnik V exceeding 90%, AstraZeneca and Janssen & Janssen above 70% and Sinopharm reaching an efficacy of 79%.Citation34,Citation44,Citation69,Citation70 When comparing the three types of COVID-19 vaccine, mRNA-based vaccination showed a more significant decrease in the risk of reinfection compared to adenovirus vector. This observation is consistent with findings in the literature, which confirm that individuals vaccinated with Pfizer or Moderna are less likely to develop severe symptoms upon reinfection, experience fewer hospitalizations, and have lower mortality rates.Citation66,Citation67,Citation71–73 Another notable finding in this study was that obese individuals were more susceptible to reinfection. Vaccine effectiveness appears to be reduced in individuals with obesityCitation74–78 due to the inappropriate immune response. Prioritizing strategies to achieve and maintain a healthy weight could potentially increase vaccine efficacy and reduce the risk of severe COVID-19 infections in this population.Citation74,Citation79 Encouraging healthy eating habits, physical activity, and weight reduction should be emphasized.Citation80 The low rate of reinfection among vaccinated individuals in our study indicates that immunity produced by vaccination remains effective despite the ongoing mutation of the COVID-19 virus and the emergence of new VOCs. While there is controversy, one meta-analysis reported that certain variants (Beta, Gamma and Delta) may have the ability to evade immunity induced by vaccination.Citation81 Nevertheless, overall, study results indicate that vaccination conferred immunity is likely to protect against severe forms of the disease, and that the vaccine remains effective against the majority of VOCs.Citation81 This survey also revealed that individuals suffering from long-COVID syndrome were more vulnerable to reinfection. However, studies have primarily explored the other aspect of this relationship between long COVID and reinfection to ascertain that reinfection could have significant consequences in terms of morbidity and could be further complicated by long COVID.Citation82–86
Limits of the study
While online questionnaires are convenient tools with benefits such as access to a diverse population and rapid responses, certain issues may arise during the completion of the questionnaire. Additionally, we relied on self-reported data for weight and height, the reliability and validity of which have been found to be inconsistent in previous investigations. Moreover, given the anxiety associated with this emerging pandemic, the side effects experienced by each individual, regardless of gender and age, are a highly individualized experience with specific psychological implications for each person. Therefore, the findings should be evaluated and analyzed while considering all the factors mentioned above.
Strengths of the study
This study can be considered representative of the general Tunisian population, particularly because the participants were from all 24 governorates of Tunisia. Furthermore, to the best of our knowledge, this is the first North African study that has compared the rates of side effects and reinfection and their predictive factors for the three types of vaccines (mRNA, adenovirus vector, and inactivated vaccines) in the same general population, with a large sample size.
Identifying factors predictive of side effects and reinfection after vaccination with COVID-19 is imperative for improving the vaccine’s safety and efficacy. It also helps to strengthen public confidence in vaccination. Vaccination recommendations based on individual characteristics reinforce safety measures and promote personalized vaccination strategies. Large-scale population studies on side effects are essential for effective communication, promoting transparency and trust in vaccination programs, and increasing adherence to vaccination campaigns. Analysis of viral reinfection also provides important information for decisions on booster injections and long-term efficacy. The vaccine also protects against long COVID. Taking population-specific factors into account is essential for tailoring vaccination strategies, and contributes to global health equity.
Conclusion
Although the rapid development of vaccinations represents an exceptional scientific achievement, it has raised significant concerns regarding safety and efficacy, contributing to vaccine hesitancy. Our study revealed that each vaccine has its own set of advantages and disadvantages: mRNA-based vaccines were associated with more side effects but offered greater protection against reinfection. Nevertheless, all vaccines appear to be effective in preventing severe reinfection and are generally considered safe.
Declaration
Ethical approval and consent to participate
The Farhat Hached University Hospital’s Ethical Committee (Institutional Review Board code:00008931) approved this study, and it was carried out in accordance with the ethical principles the Declaration of Helsinki (CER:34-2022 is the reference number for the committee’s opinion). Participants gave informed consent via an online form at the beginning of the survey, which was approved by the ethics committee.
Authors’ contributions
The authors SC and SJ designed the work. SC, MT, SS and SJ participated in data analysis and interpretation. SC, SJ, AA, OE and MM drafted the work. SC and ND revised it. SC, MM and MN supervised all the steps of the manuscript editing. All authors approved the final version of the manuscript, agreed to be personally accountable for their own contributions and ensure that questions related to the accuracy or integrity of any part of the work, are appropriately investigated and resolved. All authors read and approved the final manuscript.
Acknowledgments
We would like to express our gratitude to all the individuals and groups who have shared the questionnaire link on Facebook. We also extend our thanks to all the radio and TV channels that have allowed us to distribute the questionnaire.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Additional information
Funding
References
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