As information about the COVID-19 vaccine continues to evolve, and with the FDA approval for human use, post-marketing studies are necessary to ensure safety, efficacy, and use. Therefore, this study was conducted as a post-marketing survey of the Pfizer-BioNTech vaccine in Palestinian society. First, we investigated the incidence of side effects and reinfection rates following the administration of the Pfizer-BioNTech vaccine, then compared the incidence of these side effects between the first, second, and third doses. In addition, we predict the post-vaccination side effects based on predisposing factors.
Adverse effects were reported in more than two-thirds of the study participants. Most of the side effects were experienced within 12 h of vaccination and persisted for 1–3 days. This finding is similar to a systemic review of Pfizer-BioNTech COVID-19 Vaccine side effects and other COVID-19 vaccines, where participants suffered from post-vaccination adverse effects after the three doses, and to an Egyptian study where adverse events resolved a couple of days after onset [14, 19,20,21]. These side effects are related to the normal immune system’s response to the vaccine constituents resulting in the transient production of cytokines that cause inflammation in the muscles, blood vessels, and other tissues.
A wide range of common side effects, including fever, chills, headache, fatigue, pain and swelling at the injection site, muscle pain, and joint pain, were reported by participants. In addition, some side effects were reported less commonly, such as increased blood pressure, increased heart rate, vomiting, diarrhea, swollen armpit glands, swollen ankles and feet, and others. These findings are consistent with those reported in the Pfizer-BioNTech factsheet by the Food and Drug Administration (FDA) and many other studies [22, 23]. Myocarditis was reported in many published case reports, case series, and retrospective studies following COVID-19 mRNA immunization in young people (18–25 years) after receiving the second vaccination dose; however, the incidence was rare [24, 25]. Many factors must be considered when assessing the risk of myocarditis, including patient factors, medical history, and SarsCov2 infection history [26]. The Centers for Disease Control and Prevention (CDC) reported that infection with the Sars-cov2 virus increases the risk for myocarditis; therefore vaccine’s benefits in preventing COVID-19 infection, hospitalization, and intensive admissions and death exceed the potential risk of myocarditis [27]. The localized lymphadenopathy (enlarged axillary nodes) reported in this study aligns with the first Therapeutic Goods Administration’s COVID vaccine safety report of 2022, which is more common in the mRNA booster dose [28, 29]. Enlarged axillary nodes are a normal response caused by a robust vaccine-elicited immune response due to the proliferation of rapidly activated immune cells (residual effector cells) from previous doses [30, 31].
The severity of most experienced side effects reported after each of the three vaccine doses was mild to moderate and self-limiting, similar to the published results of the phase III Pfizer clinical trial, with the majority occurring after the second dose [22, 23, 32]. Interestingly, some side effects after the third dose were reported more frequently, including fatigue, pain at the injection site, myalgia, and arthralgia, which is inconsistent with the Food and Drug Administration (FDA) report on the booster dose [3].
Specific Side effects types and severity reported by participants differed slightly from the CDC, the FDA, or other studies. For example, as shown in Fig. 7, there is an increase in the occurrence of fever (35.7%, and 33.1% for first and second doses, respectively) compared to the CDC (3.7% and 15.8%). Furthermore, study participants reported less injection site pain and redness (30.1%, 25.8%) than what is reported on the Pfizer-BioNTech factsheet (83.1%, 77.8%) and other regional studies [6, 14, 33]; a similar finding was reported in a Bahraini study where the incidence of fever and pain at the injection site after the first dose (25%, 43%).
A considerable percentage (13%) of the participants experienced at least one type of allergic reaction after receiving the Pfizer BioNTech vaccine (skin rash, persistent cough, shortness of breath, angioedema, swelling of the tongue or lips) (Fig. 3d). However, anaphylactic reactions associated with vaccines are rare, and it has been reported at a rate of 1:125,000 doses for the Pfizer/BioNTech COVID-19 vaccine, perhaps due to PEGylated nanoparticles (PEG2000) as excipients [32].
Participants with a history of allergy or anaphylaxis prior to vaccination had a significantly higher tendency for post-vaccination allergic reactions and side effects caused by a stronger immune response. The injection of foreign materials triggers a non-specific inflammation caused by the activation of macrophages, dendritic cells, eosinophils, basophils, and especially innate type 2 lymphoid cells and the decreased activation threshold of effector cells (mast cells among them) to non-IgE activating factors [34]. In a cohort study to investigate the association of high-risk allergy history with allergy symptoms post COVID-19 vaccination, subjects with food and drug allergies were more susceptible to experiencing a post-vaccination allergic reaction [35].
Therefore, healthcare providers and institutions are encouraged to follow the CDC’s COVID-19 vaccination guidance, including pre-vaccination screening forms, enforcing the recommended 15-min post-vaccination observation periods, and having the necessary reserves available to handle severe allergic reactions.
The participants’ demographic data revealed a significant percentage of females, young, non-smokers, and individuals of normal weight. These findings refer to the large percentage of student participation and a higher percentage of female vs. male students at Birzeit University (62% vs. 38%, respectively) [36].
Females experienced a higher incidence of side effects after receiving the Pfizer-BioNTech vaccine. These gender variations were also found in previous vaccines, as reported by a 2019 study on allergic reactions following the 2009 flu vaccine [37]. Gender biological variations, including hormones, genes, immunologic distinctions, pharmacokinetics, and pharmacodynamics, affect vaccine response [19, 38]. The difference in immune response between males and females was demonstrated in a study by Yale University in 2020, in which the blood samples of females taken following COVID-19 infection showed a higher t-cell response than male blood samples [39]. Therefore, vaccine manufacturers should consider the higher female immune response and offer a reduced vaccine dose for females, reducing the side effects and maintaining the same efficacy or considering a later booster dose [40].
Many studies have addressed smoking, vaccinations, and the risk of COVID-19 infections. The CDC developed its recommendation for the necessity of smoker vaccination based on smokers' high risk of COVID infections. Smokers who participated in the study experienced a lower prevalence of post-COVID-19 vaccination side effects than non-smokers. This finding is supported by other studies where nonsmokers who received the COVID-19 vaccine experienced a higher incidence of pain and swelling at the injection site after the first dose than smokers [15]. Smoking could affect immunological responses, but further investigations are needed to define the effects of smoking on vaccinations and immunologic responses. A systematic review of the effect of smoking on humoral immunity to vaccine P. Ferrara demonstrated that antibody titers dropped rapidly in COVID-19 vaccinated smokers [41].
Elderly patients and patients with comorbid diseases prioritized vaccinations according to many vaccine protocols owing to a higher risk of COVID-19 infections and complications. Participants with comorbidities are assumed to have depleted responses to immunogens; thus, they are more susceptible to experiencing reduced side effects following any Vaccination [42]. In this study, participants with comorbid diseases were at higher risk of developing post-vaccination side effects, including increased blood pressure, heart rate, shortness of breath, voice hoarseness, dizziness, nausea, diarrhea, abdominal pain, and myalgia (muscle pain). These findings support the results of studies from the Arab region by Ma’mon M. Hatmal [31] and Saudi Arabia by Alghamdi et al. [43], which showed that chronic diseases are associated with developing post-vaccination side effects. However, further studies are needed to explain the causes of increased side effects following different COVID-19 vaccinations in comorbid people.
Regarding pre-vaccination COVID-19 infection, there was a significant association between previous COVID-19 infection and post-vaccination adverse effects. Participants who had COVID-19 infection before vaccination experienced higher post-vaccination side effects. This result was consistent with a multinational study among Arab populations and an Italian study [15, 32]. In this scenario, the natural vaccine infection of COVID-19 simulates the first vaccination dose, and side effects are more common after the second dose of the vaccine in patients who have never been infected. Thus, the first dose of the vaccine may serve as a booster dose in previously infected COVID-19 patients, causing an ADR to occur more frequently.
The CDC has developed training modules for healthcare workers (HCW) delivering the Pfizer-BioNTech (COMIRNATY®) COVID-19 vaccine to ensure good HCW practice, professional vaccine administration, and storage, as well as to provide HCWs with scientific data regarding vaccine safety and efficacy [44]. Adherence to vaccine protocols in administration, counseling, and patient assessments and providing patients with vaccine information sheets are essential to prevent complications and allergic reactions and ensure patient safety. Unfortunately, many HCWs did not implement the COVID-19 vaccination guidance designed by vaccine manufacturers, increasing the risk of improper vaccination techniques of intramuscular percutaneous injection into the patient’s arm [45]. However, Reports of SIRVA with the mRNA COVID-19 vaccines are rare, and it is hard to specify how common SIRVA is with the COVID-19 vaccine [46].
Nonetheless, this finding suggests that the healthcare field should be more attentive to vaccine-related training and education for HCWs to guarantee vaccine administration safety and good clinical practice. Furthermore, prevent complication that leads to missed days of work or school. In this study, 23% of participants reported work or school absence for a couple of days due to Pfizer-BioNTech vaccine side effects, which could influence the economy in the long term. A similar finding was reported in a US survey “AstraZeneca and Pfizer COVID vaccine shots lead to missed work days.” [47].
Strengths
With increasing studies on the side effects of COVID-19 vaccines worldwide, our study is the first to evaluate the side effects of the Pfizer-BioNTech vaccine among Palestinians with a large sample size (N = 1137) and high educational level. Furthermore, our study’s main strength was the lack of opportunity for non-response bias because most questionnaires were filled based on face-face interviews. In addition, open-ended responses were primarily used in the survey, while close-ended answers (Yes/No) were rarely used, expanding the participants’ information.
Limitations
As the study was conducted at a university, a higher percentage of responses were received from young people aged 18–23 year old (students) compared to older people aged > 30 year old (university staff), the age groups were unevenly distributed, causing the participant proportions in different groups to be biased. Second, although only a tiny percentage of questionnaire responses were collected online via Google Forms, differences resulted from exposure, interpretation, or misclassification of side effects. Third, this study was a self-reported study based on participant perception of adverse events, which was not clinically evaluated or confirmed, and could be related to other factors besides the vaccine; therefore, this study was unable to make a causality assessment of serious events as recommended by the WHO. Furthermore, uncovering severe side effects and establishing a direct causal relationship will require further research and studies. Therefore, further studies are recommended to cover the entire country, including the occupied Palestinian territories, to confirm the initial results of this study.