Follow-Up of Side Effects throughout the Entire Course of Coronavirus Vaccination

Vaccines are considered the best protective means against coronavirus infection. There is increasing interest in reporting the side effects of vaccines, especially for individuals younger than 18 years old. Accordingly, this analytical cohort study aims to report on the side effects of adult and young individuals who received vaccination within 24 h, 72 h, 5 days, and 1 week through the entire course of vaccination (ECoV). A validated online survey was used to collect information. In total, 1069 individuals were completely followed. Most individuals received the Pfizer vaccine (59.6%). Most individuals had received two doses (69.4%). Very strong and statistically significant associations with side effects (p < 0.05, Phi (Φ) > 0.25) throughout the ECoV were reported for the type of vaccine and female gender. Non-smokers reported weak statistically significant associations. Fatigue and localized pain were the most commonly reported side effect, with onset within 24 h and duration of less than 72 h. The prevalence of reported side effects was statistically significantly higher among young individuals (<18 years old) than among adults (X2 (1) =7.6, p = 0.006. Phi φ = 0.11).


Introduction
Coronavirus disease 2019 (COVID- 19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which mainly affects the respiratory system [1]. The first recorded case was in Wuhan, China, in December 2019 [2]. The World Health Organization (WHO) declared COVID-19 a pandemic in March 2020 [2]. Thereafter, developing a vaccine became a high priority to confront this pandemic. Pfizer-BioNTech and Oxford-AstraZeneca are nucleic acid vaccines based on messenger ribonucleic acid (mRNA) and double-stranded deoxyribonucleic acid (dsDNA), respectively [3]. Sinopharm, on the other hand, is an inactivated coronavirus vaccine [4].
In January 2021, the Jordanian ministry of health launched the national vaccination program, which was set to include all children over 12 years old in the vaccination process. The most used vaccines in Jordan are Pfizer-BioNTech, Sinopharm, and Oxford-AstraZeneca. In July 2022, more than four million adults had been vaccinated with two doses, while more than 500,000 had received three doses [5].
Despite the efficacy of COVID-19 vaccines, there are many common side effects [6,7]. The incidence may differ greatly depending on the type of given vaccine. Sinopharm has shown the mildest side effects, such as pain at the injection site, fatigue, headache, lethargy, and muscle pain. In rare situations, however, vaccine-induced immune thrombotic thrombocytopenia (VITT) has been recorded as a life-threatening side effect [8,9]. The Oxford-AstraZeneca vaccine has shown comparatively more serious side effects, which The questionnaire had the following sections: (1) demographics; (2) comorbidities, allergies, and medication; (3) the profile of side effects (symptoms of the side effect, onset, duration, severity-impact on daily life, data for which were collected after each injection throughout the ECoV). The categories for side effects [19] were classified as mild (i.e., does not interfere with daily activity such as general tasks, mood, mobility, and normal work), moderate (i.e., interferes with daily activity, but no hospitalization), or severe (cases involving hospitalization).
Before enrollment, participants received a full description of the study, they were informed that their vaccination number would be recorded for follow-up and would be used as their ID number. No specific personal data were collected, and data would be treated as confidential in all cases. Subjects were also informed that participation is totally voluntary, and they could withdraw at any stage without the need to clarify reasons for their request. The study protocol was approved by the institutional review board (IRB) committee at Hashemite University (No. 13/1/2021/2022).
In Jordan, almost 3.53 million people were fully vaccinated by Nov 2021 [5,25]. Based on this number, a sample size of minimum of 385 participants was considered representative as recommended by Taherdoost [26] and carried out by the sample size calculator [27] considering a confidence level of 95% and a margin of error of 5%.
Data were coded and transferred to SPSS for Windows, version 25, for statistical analysis (SPSS Inc., Chicago, IL, USA). For data analysis, descriptive analysis was first conducted to present participant characteristics. The chi-squared test (X 2 ) for association was used (Fisher's exact test was used in cases where the expected count was less than 5). To measure the strength of the association of a nominal-by-nominal relationship (which is a measure of effect size), the Phi (Φ) coefficient factor was also calculated and illustrated, with a strength of association value of 1 indicating complete association, "0" indicating no association, >0.25 indicating a very strong relationship, >0.15 indicating a strong relationship, >0.1 indicating a moderate relationship, and >0.05 indicating a weak relationship [28]. The degrees of freedom for the chi-square between practices were illustrated using the formula df = (r − 1)(c − 1), where r is the number of categories within the demographic variable and c is the number of options related to item options. For all tests in the present study, a p-value of <0.05 is considered to indicate a statistically significant difference [29].

Results
Results are presented within the following sections: Section 3.1 Descriptive results for the participant and comorbidities. Section 3.2 Descriptive for side effect types, onset, duration, and impact. Section 3.3 Analysis of the relationship and association within and between variables. Table 1 shows the characteristics of the 1069 individuals who were enrolled in our study. In all, 542 (50.7%) were male and 527 (49.3%) were female. The majority were young, between 18 and 40 years old (63.7%), living in Amman (701, 65.6%), and non-smokers (874, 81.8%). Regarding the highest educational level, 685 (64.1%) of participants held a bachelor's degree, 104 (9.7%) held a diploma degree, 49 (4.6%) held a master's/PhD degree, 52 (4.9%) had attended primary school, and 179 (16.7%) had attended secondary school. Most participants were non-HCWs (662 or 62% compared with 406 or 38% who worked in healthcare). The majority of participants received the Pfizer-BioNTech vaccine (637, 59.6%), followed by Sinopharm (387, 36.2%) and AstraZeneca (45, 4.2%).  Table 2 shows that spring (seasonal) allergies were the most common, affecting 25.26% of total participants, with the least common allergy found to be walnut fruit allergy. Among chronic diseases, hypertension was the most common, followed by diabetes and coronary artery disease, while only eight individuals reported liver disease and neurological disease. The most common medication type was painkiller (NSAID and others), followed by hypertension and anti-coagulant.  Table 3 shows the incidence of side effects according to the number of doses that the individual received. The majority of individuals suffer from fatigue, fever, headache, localized pain, and myalgia. Other individuals suffered from arthralgia, chills, and localized redness. A small minority of individuals suffered from side effects such as dizziness, diarrhea, cough, rhinorrhea, nasal congestion, sneezing, shortness of breath, nausea, vomiting, sore throat, facial swelling, ageusia, anosmia, and neurological symptoms.

Severity of Reported Side Effects
Most individuals suffer side effects with mild impact, with less than 3% requiring hospitalization for complications ( Figure 1).

Severity of Reported Side Effects
Most individuals suffer side effects with mild impact, with less than 3% requiring hospitalization for complications ( Figure 1).

Side Effects and 1-Week Follow-Up
The majority of individuals suffered from side effects within 24 h of vaccination. Other individuals suffered from side effects 1-3 days after vaccination. A small minority of individuals suffered from side effects later than 1 week after vaccination. As seen in Table 4, almost 14% of those who received three doses suffered from minor side effects for periods longer than 1 week.

Side Effects and 1-Week Follow-Up
The majority of individuals suffered from side effects within 24 h of vaccination. Other individuals suffered from side effects 1-3 days after vaccination. A small minority of individuals suffered from side effects later than 1 week after vaccination. As seen in Table 4, almost 14% of those who received three doses suffered from minor side effects for periods longer than 1 week. a : Pfizer-BioNTech, n = 46 (64.8%), Sinopharm, n = 21 (29.6%), AstraZeneca, n = 4 (5.6%). b : Pfizer-BioNTech, n = 410 (55.3%), Sinopharm, n = 303 (40.9%), AstraZeneca, n = 28 (3.8%). c : Pfizer-BioNTech, n = 181 (70.4%), Sinopharm, n = 63 (24.5%), AstraZeneca, n = 13 (5.1%). d : X 2 The Chi-squared test (p-value) for single dose shot to multi shots in two doses. e : X 2 The Chi-squared test (p-value) and for single dose shot to multi shots in three doses. Table 5 shows the frequency of reported side effects and their association with different variables after each injection of vaccine throughout the entire course of vaccination.

Individuals Who Received a Single Dose
The profiles of side effects show no statistically significant differences across all tested variables (gender, age, smoking status, and vaccines).

Individuals Who Received Two Doses
After the first shot for those who received two doses of vaccines, individuals receiving the Pfizer vaccine reported a statistically significant higher percentage of side effects compared with those receiving Sinopharm and AstraZeneca vaccines (64.7% vs. 28.8% and 6.5%, respectively, X 2 (4) = 50.8, p < 0.001), and the association was very strong (Phi ϕ = 0.26). Females reported statistically significant side effects more than males (57.6% vs. 42.2%, X 2 (1) = 164.5, p < 0.001, and the association was very strong (Phi ϕ =0.53). Non-smokers reported statistically significant side effects compared with smokers (X 2 (1) = 4.2, p = 0.042); however, the association strength was weak (Phi ϕ = 0.08). In line with the results from the first shot, variables such as gender, smoking, and the type of vaccine maintained their statistically significant association with the side effect profile. However, at this stage, a new variable "age" was also reported to be statistically significantly associated. Patients receiving the Pfizer vaccine reported a statistically significant higher percentage of side effects compared with Sinopharm and AstraZeneca (70.7% vs. 24.3% and 5.1%, respectively, X 2 (4) = 54.7, p < 0.001), and the association was very strong (Phi ϕ =0.27). Significantly more females than males reported side effects (58% vs. 42%, X 2 (1) =21.3, p < 0.001, and the association was very strong (Phi ϕ = 0.38). Non-smokers reported a higher percentage of side effects, but the association was weak (Phi ϕ = 0.08). After the second shot for those who received two doses of vaccines, the prevalence of reported side effects versus no side effects among young individuals (<18 years old) was higher than for the elderly (>18 years), and this difference was statistically significant (X 2 (1) =7.6, p = 0.006, and the association strength was moderate (Phi ϕ = 0.11.)

Individuals Who Received Three Doses of Vaccine
After the first shot for those who received three doses of vaccines, a statistically significant higher percentage of side effects was reported for patients receiving the Pfizer rather than Sinopharm and AstraZeneca vaccines (76.9% vs. 15.7% and 7.4%, respectively, X 2 (4) = 16.2, p = 0.002), and the association was strong (Phi ϕ =0.25). Significantly more females than males reported side effects (63.6% vs. 36.4%, X 2 (1) = 4, p = 0.045). However, the strength of the association was weaker than that reported for those who had received two doses (Phi ϕ = 0.13 vs. Phi ϕ = 53).

Discussion
The present study showed that after the first shot of those who received two doses of vaccines, individuals that received the Pfizer vaccine reported a statistically significant higher percentage of side effects compared with those receiving Sinopharm and AstraZeneca vaccines. This finding contradicts the conclusion of two studies that were conducted to compare different types of vaccines against COVID-19, which found more side effects resulting from the AstraZeneca vaccine compared with Pfizer and Sinopharm vaccines [30,31]. This can be attributed to the lower number of participants who received the AstraZeneca vaccine in our study.
Similar to the findings of several published studies in Jordan or worldwide [8,[31][32][33][34][35][36][37], the most commonly reported side effects following COVID-19 vaccination, regardless of the type of vaccine, are fatigue, fever, headache, localized pain, and myalgia. In the present study, the severity of side effects was assessed by the questionnaire. Most responders (nearly 90%) reported a mild to moderate impact on life, while less than 3% required hospitalization. This is in agreement with similar studies conducted in the same region [8,32,33,38]. Moreover, our study showed that the majority of vaccine recipients had vaccination side effects for less than 3 days' duration, which is in line with the results of a study conducted in India illustrating that vaccination side effects tend to resolve within 48 hours of vaccine administration [39].
There are many studies that demonstrate the variety of vaccine side effects based on gender [40]. The present study shows that females experienced more side effects compared with males [40,41], and the variation between males and females is attributed to sex hormones, including estrogen, progesterone, and testosterone, which can bind to the surface of immune cells and influence how they work. Exposure to estrogen causes immune cells to produce more antibodies in response to the vaccine in general [42]. Some studies reported no difference between males and females [43]. Nevertheless, there are others showing that more males suffer from side effects than females [44]. Our results support those studies and scientific explanations reporting females having a higher sensitivity to side effects. In the present study, differences in side effect profiles based on gender had diminished in those who received three doses of vaccines.
The present results highlight that non-smokers are more susceptible to experiencing more significant side effects in comparison with smokers. This finding is in agreement with the results of studies by Abukhalil et al. and Hatmal et al. [45,46]. However, in the study of Al-Hanawi et al., a higher prevalence of moderate adverse effects among smokers in contrast to non-smokers was demonstrated [47]. Historically, the influence of smoking on vaccination has been studied. A study conducted in the Netherlands showed a greater response of antibodies toward the influenza vaccine in smokers compared with non-smokers, which might indicate a modulatory role of smoking over the immune system that in turn affects the body's response toward vaccination [48].
The present study evaluated the implications of the Pfizer-BioNTech vaccine in participants aged <18 years old. After the second shot of those who received two doses of the vaccine, the prevalence of reported side effects versus no side effects was higher among young individuals (<18 years old) than among adults (>18 years old). Such results are similar to those reported in other studies [17,19]. This might be explained by increased reactogenicity and increased vaccine-induced immunogenicity, which may lead to more intense inflammatory responses in younger people [19,49]. Most side effects described after the second dose of the Pfizer-BioNTech vaccine in young participants (<18 years old) are transient mild-to-moderate side effects (predominantly injection site pain, fatigue, headache, fever, and myalgia) as confirmed by Robert and colleagues [17].
Similar to the findings of our study, there is increasing evidence confirming that females and younger people tend to report more side effects from COVID-19 vaccines [50]. Nevertheless, nocebo effects [51,52] of COVID-19 vaccines should be considered [53,54]. The incidence of nocebo response to COVID-19 vaccines was reported to be high (16.4%) in a recent meta-analysis [55]. Earlier systematic reviews found little evidence for a gender effect [56], with females observed to be more vulnerable to nocebo effects [57]. While nocebo effects are driven more by misinformation (verbal manipulation) in males, they are found to be driven by conditioning and previous experience in females [58]. This lagged effect is further documented by Hoffman and colleagues [59], who reported that COVID-19 vaccine side effects decreased across waves for males but increased for females. Accordingly, the association between wave one and wave two side effects (wave one following a second Pfizer dose, wave two after their booster) was more robust in females. They also reported no association across the waves between side effects and age. Such results are strongly linked with the findings of the present study.

Strengths
This study has numerous strengths. It follows the side effect profile after each vaccine injection despite the number of doses, and information is then presented for each injection and dose of vaccine. Such presentation went hand-in-hand with related statistical analysis. For the present study, the recruited participants amounted to a very robust sample size, especially for individuals younger than 18 years who received the vaccination.

Limitations
The present study has some limitations, for example, we could not access the hospital admissions after vaccination to validate the causality association between vaccine and admission. Information in the present study is mainly dependent on participants' selfassessment, which may differ from one person to another. In addition to the standard bias are the participants' recall bias [60] and the Hawthorne effect [61].

Conclusions
The profile of side effects in terms of prevalence, severity, onset, and duration of action was almost constant across the entire course of vaccination. Most side effects, regardless of the type of vaccine, were mild and disappeared 3 days after injections. One week after vaccination was the period corresponding to being totally free of side effects. Mainly females and, to a lesser extent, non-smokers were more sensitive to side effects and reported consistent claims across the entire course of vaccination. In the present study, the Pfizer-BioNTech vaccine was the most used vaccine, followed by Sinopharm and AstraZeneca. Individuals younger than 18 years of age reported a higher prevalence of side effects compared with older individuals.

Informed Consent Statement:
Written informed consent has been obtained from individuals to publish this paper.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.

Conflicts of Interest:
The authors declare no conflict of interest.