Side Effects of COVID-19 Vaccines Primer Doses: Experience of Saudi Healthcare Workers Participating in CoVaST-SA

Background: Side effects emerging after COVID-19 vaccines may adversely impact public confidence in vaccines. Therefore, this study was designed to explore the short-term side effects of COVID-19 vaccines as a part of the COVID-19 Vaccines Safety Tracking (CoVaST) study. Methods: A cross-sectional survey-based study was carried out to collect data from healthcare workers (HCWs) in Saudi Arabia. The study was initiated between June and December 2021. A validated questionnaire was used in this study consisting of four categories, including demographic characteristics and medical anamnesis of the participants, COVID-19-associated anamnesis, and side effects of vaccine uptake. Results: The study included 1039 participants, of which 70.2% were females, and their median age was 34. About 82.9% and 52.3% of the participants reported a minimum of both one local and systemic side effect, respectively. Females, young participants (≤34 years old), and non-obese participants had more potential to disclose post-vaccination side effects than their counterparts. Heterologous schedules and viral vector-based vaccines were linked with a greater rate of systemic side effects, whereas homologous vaccination schedules and mRNA-based vaccines were linked with a greater rate of local side effects. Conclusion: Future studies on COVID-19 vaccines should focus on the role of BMI, previous infection, and vaccination schedule in terms of vaccine safety and reactogenicity.


Introduction
The worldwide burden related to the COVID-19 virus remains a serious public health issue [1,2]. Hence public health institutions such as the World Health Organization (WHO) regularly issue regulations to help protect people, preventing and slowing down the SARS-CoV-2 spread [3]. Moreover, the U.S. Centres for Disease Control and Prevention (CDC) have advocated various policies to reduce the spread of coronavirus disease [4]. Current evidence shows that one of the most effective measures that can reduce the risk of infection is by using vaccinations [5].
The rapid COVID-19 vaccine development and wide availability have given a ray of hope to humanity to control the ongoing global pandemic of COVID-19. However, the success of the vaccination programs depends on the population's understanding of the risks and benefits of the vaccine and their belief in the benefit of the vaccines. Researchers found that refusal or indecision towards immunisation results from a lack of knowledge about the balance between the benefits and risks of vaccination [6,7], which is defined as vaccine hesitancy (VH) by the WHO; it refers to the "delay in acceptance or refusal of vaccines despite the availability of vaccine services" [8]. Recent studies in the Middle East revealed that COVID-19 VH was as high as 20% in Qatar and 26.2% in Kuwait [9,10]. In 2019, WHO recognised vaccine hesitancy as a major global public health threat driven by misleading and incorrect information regarding vaccines' effectiveness and safety [11].
In September 2020, the WHO announced the introduction of several COVID-19 vaccines [12], and by the start of the year 2021, several international health regulations declared many vaccines eligible for emergency use authorisation (EUA) [13,14]. The initial vaccines authorised and launched in Saudi Arabia were Pfizer-BioNTech and Oxford-AstraZeneca vaccines. The Pfizer vaccine's effectiveness reached 95%, and the effectiveness of the As-traZeneca vaccine was 70% [15,16]. The initial authorisation for this vaccine was given over three phases. Phase I targeted healthcare workers (HCWs) at greater risk for exposure to the virus and people over 65 years of age and older. Phase II targeted other frontline workers (healthcare workers, military and security in critical locations) and people over 50. Lastly, phase III was directed at the Saudi population, excluding children and pregnant women [17].
As a result of widely used COVID-19 vaccines, many questions and concerns were raised about obtaining COVID-19 vaccines among some people globally. For example, in Saudi Arabia, questions were raised by the general population regarding the COVID-19 vaccine programs concerning the safety of the approved vaccines. However, common side effects demonstrated by clinical trials after getting COVID-19 vaccines tend to be mild to moderate, such as fever, headache, fatigue (tiredness), redness, and pain or swelling at the site of injection [15,18]. The recent reports of some rare cases of severe side effects, such as thrombosis following COVID-19 vaccines [19], may also affect the acceptance of COVID-19 vaccines among some populations. Furthermore, there is limited data and literature reviews concerning each vaccine's side effects. Therefore, ongoing monitoring of COVID-19 vaccines is vital to promote reassurance and acknowledgement of COVID-19 vaccines amongst the public by doing independent post-marketing studies to understand the side effects of COVID-19 vaccines better.
The primary objective of this study was to reveal the prevalence of COVID-19 vaccineassociated side effects among vaccinated healthcare workers (HCWs) by either Oxford-AstraZeneca or Pfizer BioNTech vaccines, which are currently used in Saudi Arabia. The secondary objective was to investigate the potential demographic characteristics and medical anamnesis for the intensity and frequency of side effects after taking the vaccines.

Design
A cross-sectional survey-based study was carried out between June and December 2021 to collect data on the side effects of the COVID-19 vaccine among recruited healthcare workers (HCWs) in all regions of Saudi Arabia. The study used a validated multiple-choice self-administered online questionnaire digitally designed using KoBoToolbox version 2.021.03 (Harvard Humanitarian Initiative, Cambridge, MA, USA, 2021) written in Arabic and English [20]. The questionnaire asked about the short-term side effects after either the first, second, or both doses of the COVID-19 vaccine. The side effects are classified as local or systemic, and their onset, duration, and intensity are self-reported. After the ethical review, an invitation to participate was sent to the target groups (HCWs) online, mainly via social media platforms (namely WhatsApp mobile applications).

Participants
The inclusion criteria for this study were HCWs who received the COVID-19 vaccine in the post-approval phase and those recently vaccinated who received their vaccine dose within the last 30 days were prioritised for study invitation. However, the study was not limited to recently vaccinated individuals. Eligible participants were preferably at least 18 years of age and able to provide consent independently. HCWs who received the COVID-19 vaccines as part of phase III clinical trials were excluded from the study.

Instrument
The standardised questionnaire focused on adverse events and side effects of COVID-19 vaccines and was previously validated in several countries. The questionnaire consisted of four categories: i.
Demographic characteristics (age, gender, height, weight, profession, and geographic region). ii. Medical anamnesis (chronic diseases, medication, smoking and alcohol consumption). iii. COVID-19-related medical histories (type of vaccine, number of vaccine doses, dates of vaccine doses, previous infection, and date of diagnosis). iv. Vaccine side effects (local side effects, systemic side effects, onset, and duration).

Ethics
The Institutional Review Board (IRB) of King Fahad Specialist Hospital reviewed and approved the study on 1 July 2021. All investigators have also earned the Collaborative Institutional Training Initiative (CITI) certificate. The first page of the electronic survey contained a description of the study and a statement of informed consent, which was obtained from each participant prior to participation. Participants could withdraw from the study at any time without explanation, and no data was stored until the participant finally submitted their answers.

Analyses
The categorical variables were summarised using frequencies and percentages, while the numerical variables were summarised using means and standard deviations. The association between local and systemic side effects and their sociodemographic and anamnestic predictors was tested using the Chi-square test, Fisher's exact test, and the Mann-Whitney test. A significance level of <0.05 (two-tailed) was used to indicate statistical significance. All data analyses were performed using Statistical Packages for Software Sciences (SPSS) Version 28.
While injection site pain was significantly more common with mRNA-based vaccines than viral vector-based vaccines after the first dose (82.2% vs. 71.8%; sig. < 0.001) and the second dose (81.5% vs. 74.2%; sig. = 0.053), injection site swelling and redness were not significantly different between mRNA-and viral vector-based vaccines.

Onset and Duration of Post-Vaccination Side Effects
Most participants (65.6%) reported injection site pain after both doses, while only 49.2% and 31.3% reported injection site swelling and redness after both doses. All local side effects tended to be associated with the first dose rather than the second dose, as injection site pain was reported 25.6% more often after the first dose only, compared to only 8.8% after the second dose. Dyspnoea (45.5%), headache (43.5%), fatigue (42.4%) and myalgia (37%) were the most common systemic adverse reactions reported after both doses. While diarrhoea (50%), fever (37.3%), nausea (36.5%), dyspnoea (31.8%) and myalgia (30%) were reported more frequently only after the first dose, chills (45.2%), nausea (41.9%), arthralgia (41.4%) and diarrhoea were reported more frequently after the second dose Figure 1.

Post-Vaccination Medications
Fewer than two-thirds (62.5%) of participants reported taking post-vaccination medication to control their side effects, with acetaminophen being the most common (91.5%), followed by ibuprofen (9.2%) and diclofenac (1.5%). No statistically significant differences were found among participants in post-vaccination medication use in terms of gender, age, BMI, and medical history. Participants who received viral vector-based vaccines were significantly more inclined to stop drugs after the first (73.6% vs. 58.4%; sig. < 0.001) and second doses (78.8% vs. 60.3%; sig. < 0.001). Heterologous vaccination schedules were more significantly (72.7% vs. 61.2%; sig. = 0.010) associated with post-vaccination drug intake. Participants who reported local side effects (sig. < 0.001) or systemic side effects (sig. < 0.001) used medications more often (Table 3).   Chi-squared (χ 2 ) and Fisher's exact (*) test were used with a significance level (sig.) < 0.05. The significant values are in bold font.

Discussion
The current study was conducted to assess the side effects experienced by Saudi healthcare workers (HCWs) after getting primer doses of COVID-19 vaccines. Up to 82.9% and 52.3% of the participants reported a minimum of one local and one systemic side effect, respectively. The most reposted local side effect was pain at the sight of infection (79.4%), while the most common systemic adverse reaction was fatigue (36.1%), followed by myalgia (26%), headache (25.2%), and fever (17.8%). Females, young participants (≤34 years old), and non-obese respondents had more potential to disclose post-vaccine side effects in comparison to their counterparts. Homologous vaccination schedules and mRNA vaccines were associated with a greater frequency of local adverse reactions, while heterologous schedules and viral vector-based preparations were associated with a greater frequency of systemic side reactions.
In our study, females reported more local (84.6% vs. 78.7%) and systemic (53.5% vs. 49.4%) side effects than males, which is consistent with what had been previously reported among Saudi and non-Saudi populations. El-Shitany et al., 2021 discussed a cross-sectional study of the immediate adverse effects experienced by Saudi residents after receiving an mRNAbased vaccine (BNT162b2) and found that females (58%) were significantly more likely to report post-vaccine side effects than males (28.1%) [21]. Females' susceptibility was evident in several studies conducted in Saudi Arabia, such as that by Ahsan et al., 2021, who found that female HCWs were more likely to report side effects (93.1% vs. 57.4%; sig. < 0.001) than males [22]. Likewise, Darraj et al., 2022 reported Saudi female HCWs' susceptibility after receiving a viral vector-based vaccine (ChAdOx1-S) [23]. Additionally, Mohammed et al., 2021 [24], Alghamdi et al., 2021 [25], and Alzarea et al., 2022 [26] found a phenomenon of females' predisposition among the general Saudi population. Among children aged between 12 and 18, female participants reported more side effects after receiving an mRNAbased vaccine (BNT162b2) than their male counterparts in Saudi Arabia [27].
Green et al., 2022 analysed four cross-sectional studies that were carried out after disseminating two and three doses of BNT162b2, and they found females' predisposition consistently among all age groups [35]. One of the proposed explanations for this phenomenon is that females may have a more enhanced immune response which can be evident through their lower COVID-19 case-fatality rates [36]. Moreover, females exhibit higher levels of type IFN I and innate immune responses, which are believed to be subjected to modulation by X chromosome-linked and ChrY gene polymorphisms [37][38][39].
Our young participants (≤34 years old) experienced more local (87.5% vs. 78.2%) and systemic (52.9% vs. 51.5%) side effects than older participants (>34 years old), which is consistent with what was reported among Saudi and non-Saudi populations. According to Ahsan et al., 2021, younger Saudi adults (≤36 years old) experienced more side effects than their older counterparts (>36 years old) after receiving BNT162b2 and ChAdOx1-S [22]. Likewise, Alzarea et al., 2022 revealed that younger Saudi adults (≤35 years old) experienced more side effects than their older counterparts (>35 years old) after receiving BNT162b2 and ChAdOx1-S [26]. A recent systematic review of clinical trials found that younger adults were more likely to have neurological and muscular adverse effects, such as headache and myalgia, than their older counterparts after receiving COVID-19 vaccines [40]. The age-related differences in side-effect incidence can be explained by the varying levels of binding antibodies, which were reportedly lower among seniors and older adults [41,42].
The lower BMI levels were associated with higher frequencies of local (84.1% vs. 78%) and systemic (52.9% vs. 49.5%) side effects among our participants. Likewise, a Spanish cross-sectional study found that non-obese status was significantly associated with a greater frequency of post-vaccine side effects [43]. In Iran, headache was significantly more common among non-obese individuals, while flu-like symptoms were more common among the obese ones [44]. Pellini et al., 2021 evaluated levels of antibody titers after BNT162b2 among HCWs and found that non-obese participants had a more efficient humoral response compared with obese participants [45].
While mRNA-based vaccines recipients reported more local side effects after the first (85.6% vs. 75.4%) and second doses (84.9% vs. 79.5%), viral vector-based vaccines recipients reported more systemic side effects after the first (59.6% vs. 49.5%) and second doses (57.6% vs. 51.8%). Similarly, Klugar et al., 2021 revealed that local reactions were more associated with mRNA vaccines, while systemic adverse effects were associated with viral vector-based vaccines among German HCWs [30]. In Poland, Andrzejczak-Grządko et al., 2021 indicated that BNT162b2 was associated with more frequent local adverse effects, i.e., injection site pain and arm pain and less frequent systemic side effects (headache, myalgia, headache, fever, and chills) [46].
The homologous schedules were associated with a greater frequency of local adverse effects and a lower frequency of systemic side effects compared with heterologous schedules in our study. Rzymski et al., 2022 revealed that homologous schedules of mRNAbased vaccines had significantly higher levels of post-vaccination side effects [47]. In Brazil, heterologous vaccination schedules produced more robust immune responses than homologous schedules, and they were associated with more side effects [48]. Likewise, Schmidt et al., 2021 found that local and systemic adverse effects were less common in post-homologous schedules (vector-vector) than in heterologous schedules (mRNA-vector) among German adults [49].
Fewer than two-thirds (62.5%) of our participants reported using medications after vaccination to control their side effects, with acetaminophen being the most common (91.5%), followed by ibuprofen (9.2%), and diclofenac (1.5%). However, there is a paucity of evidence about the interference of analgesics/antipyretics with the vaccine-elicited immune response; it is unlikely that these medications might have any significant impact on vaccine effectiveness [50]. Moreover, there is a lack of evidence about the benefits of these medications against serious adverse reactions, even though public health authorities recommend using these medications to control post-vaccination side effects [50]. Iguacel et al., 2021 found that 62.7% of Spanish vaccinees reported using analgesics such as acetaminophen and ibuprofen to control/relieve their side effects [43]. The same finding was reported in Nepal [51] and Ghana [52].

Strengths
This study used a validated instrument (questionnaire) that had been broadly used by a series of cross-sectional studies in multiple countries, thus facilitating comparisons. The identity of participants was kept anonymous to reduce information bias. The present study attempted to evaluate the role of various demographic and anamnestic risk factors in terms of post-vaccine side effects emergence, onset, and duration. This study employed HCWs as the target population because they supposedly retain the highest levels of health literacy within their respective communities.

Limitations
Firstly, the cross-sectional design deprived us of following the adverse reactions that might remain longer than the standard period. The number of participants was not equally or proportionately distributed among geographic regions, age groups, or sex. Given the current sample size, very rare side effects cannot be captured or validated.

Implications
Future studies on COVID-19 vaccines should focus on the role of BMI and previous infection in vaccine safety and reactogenicity. The differences between homologous and heterologous vaccination schedules should be further evaluated through various scenarios. The older participants had fewer side effects; possibly implying that they could be protected through prioritisation schemes of booster doses.

Conclusions
The present study found that 82.9% and 52.3% of the participants reported a minimum of one local and systemic side effect, respectively. Females, young participants (≤34 years old), and non-obese participants had more potential to disclose post-vaccine side effects than their counterparts. Future studies on COVID-19 vaccines should focus on the role of BMI, previous infection, and vaccination schedule in terms of vaccine safety and reactogenicity.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/vaccines10122137/s1, Table S1. Anamnestic Characteristics of Saudi Healthcare Workers Responding to CoVaST-SA. Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Data Availability Statement:
The data that support the findings of this study are available from the corresponding author upon reasonable request.