The safety concern of candidate vaccines has loomed large over the past months. Providing robust data regarding possible side effects after SARSCoV-2 vaccine administration is crucial to provoke trust and confidence in any type of vaccine [14]. In this multicenter questionnaire-based survey among dental students and dental practitioners, we have investigated adverse effects following the administration of the four available SARSCoV-2 vaccines in Iran; ChAdOx1 nCoV-19, Gam-COVID-Vac, BBV152, and BBIBP-CorV and report that the most common reactions, in our community analysis, were fatigue, local pain in the hand, and malaise which affected 79.0%, 77.4%, and 73.0% of cases, respectively.

Individuals vaccinated with the ChAdOx1 nCoV-19 vaccine (AZD1222) were more likely to experience the aforementioned side effects compared with other groups; the mean±standard deviations were 6±3, 6±4, 5±3, and 5±3, respectively.

The most common adverse events reported for both doses of Gam-COVID-Vac were in line with another trial on health care workers [16] (pain at the injection site, fever, and muscle pain).

The incidence of events attributed to the Gam-COVID-Vac was 64.7% in phase 3 clinical trial [10].

Comparing with phase 3 clinical trial of the Gam-COVID-Vac, which reported 94% of adverse events (a total of 7966 events) as mild (10), our study population experienced higher intensity for unserious side effects (Figs. 1 and 2).

93.2% of vaccinated population experienced at least one side effect. 7 cases of thrombosis and blood clotting (1.64%) and 4 mild allergic reactions (0.93%) were reported after Gam-COVID-Vac administration.

In the phase 3 clinical trial, 0.3% of the vaccinated group had serious adverse events, although no serious side effect was considered related to the vaccine administration [10]. There was a significant discrepancy between the thrombosis rate reported in phase 3 (three cases of renal colic and deep vein thrombosis associated with pre-existing comorbidities in 21,977 included cases) and our findings (7 cases of thrombosis in 426 cases). Phase 3 suggested no association between serious adverse events and vaccine administration, but our results do not support this and further clinical assessments are highly recommended.

The ChAdOx1 nCoV-19 vaccine (AZD1222) was administered by 578 of 1205 cases of which 100.0% received only the first injection. 98.6% of ChAdOx1 nCoV-19 vaccinated population experienced at least one side effect.

10 cases of mild and one case of moderate thrombosis and blood clotting were reported. Also, 6 cases reported mild and one reported moderate levels of allergic reaction. In phase 3 clinical trial of this candidate vaccine [17] 88% of participants, aged 18–55, administered prime vaccine reported incidence of systemic adverse effects. Meanwhile, a prospective observational study in the UK reported a significantly lower rate of adverse effects (33.7%) [18].

In our study, the data for BBV152, also known as COVAXIN®, as a purified inactivated whole virion was scarce. 100% of the vaccinated population experienced at least one side effect. 16 out of 25 cases received two doses of BBV152. Individuals who received BBV152 were less likely to experience moderate levels of side effects compared with Gam-COVID-Vac and ChAdOx1 nCoV-19 group (Figs. 1 and 2). Upon cell entry, the adenovirus-vector vaccines (Gam-COVID-Vac and ChAdOx1 nCoV-19) risen the release of cytokines and chemokines causing higher levels of side reactions after vaccination compared with inactivated vaccines (BBIBP-CorV and BBV152) [19].

Among the reported side effects, the most intense and most common side effect was local pain in the hand. The interim results of phase 2 of BBV152 reporting pain at the injection site as the most common adverse event (11 of 380 patients) followed by headache, fatigue, and fever [20] although the data for phase 3 trial have not yet been published/available. Same as phase 2, in our study, no serious event was reported after BBV152 vaccination. Our initial experience is similar to currently limited literature suggesting that BBV152 is a safe and tolerable candidate vaccine with minimal and minor adverse events profile [20, 21].

The Chinese inactivated vaccine candidate, BBIBP-CoV (Beijing,China), was administered to merely 9% of our study population. 88.2% received a single dose of BBIBP-CoV. 87.3% of the vaccinated population experienced at least one side effect. The phase 2 trials reported side effects were mild in severity with no serious adverse event (21) [22]. In our study, 3 cases of thrombosis and blood clotting were reported. The current literature regarding the BBV152 is not powered to address safety and adverse events; therefore, we were unable to draw a solid conclusion.

We have concerns with the number of serious adverse effects reported: 20 cases of thrombosis and blood clotting, 12 ChAdOx1 nCoV-19, 7 Gam-COVID-Vac, and 3 BBIBP-CorV groups, were reported. The Phase 3 of Gam-COVID-Vac suggested no association between serious adverse events and vaccine administration (10). Likewise, phase 3 trials of BBIBP-CorV have not yet been published/available [21].

In April 2021, 86 potential cases of thrombosis and clots, out of 25 million vaccinated people, were reported. The blood clots have been tentatively linked to a syndrome causing unwanted immune response against platelet factor 4 after administration of adenoviral vector vaccines. There is a possibility that phase 3 reports of clotting are susceptible to biases and higher numbers of reports are expected in the near future [23]. Despite the fact that the findings of a questionnaire-based survey is not powered to address serious side effects after vaccination, it necessitates the need for further clinical assessments with large sample sizes.

The duration of side effects based on the type of administered vaccine is as below:

Most cases in groups of ChAdOx1 nCoV-19, Gam-COVID-Vac, and BBV152 experienced adverse events for a duration of 1–3 days, 66.3%, 49%, and 57%, respectively, while 53.8% of BBIBP-CorV group experienced side effects for only a few hours.

Also, the onsets of side effects were mostly 0–12 h after vaccine administration for both genders and the durations of side effects were mostly 1–3 days for both males and females.

Individuals expressing a history of SARS-CoV-2 infection, in ChAdOx1 nCoV-19, Gam-COVID-Vac, and BBIBP-CorV groups experienced some non-serious side effects more intense than those without known past SARS-CoV-2 infection. This finding is similar to the results of an observational study with more than 600,000 cases reporting a correlation between the history of SARS-CoV-2 infection and the systemic side effects.

The results from small preprints suggest that higher reactogenicity and clear antibody response, peaked almost 7 to 14 days after vaccine administration in individuals with pre-existing immunity causes higher frequencies of systemic side effects such as chills, fever, fatigue, headache, and muscle or joint pains compared to cases exposed to SARS-CoV-2 spike protein for the very first time [24, 25].

1.5% of cases (17 cases) reported a history of EBV (mononucleosis) infection. Some studies suggested the possibility of EBV reactivation in SARS-CoV-2 patients which might alter the clinical characteristics of SARS-CoV-2 infection and cause over-activation of the cellular immune system [26]. In our study, though, no significant relation between EBV previous infection and the levels of side effects was found. Larger sample sizes are warranted to assess the relationship.

336 cases (27.8%) reported a history of MERS or influenza or EBV before vaccine administration. In total, patients who reported history of previous viral infections (MERS, Influenza, or EBV) had significantly higher rates for cellulitis warmth and swollen armpit glands and faint (P value <0.001) and for the following side effects (P value<0.05):

Headache, chest pain, cough, and shortness of breath

Reports have suggested a possibility that EBV reactivation might occur in SARSCoV-2 patients which might alter the clinical characteristics and cellular immune response leading to increased inflammation and fever [26]. Due to the limited number of reports in current study, any association between a history of EBV/MERS infection and the side effects of candidate vaccines remained unknown. Further studies with larger sample sizes are therefore warranted.

The results of this survey should be interpreted in the context of shortcomings. Due to the limited number of cases receiving multiple doses of candidate vaccines (7.0%), we were unable to compare the probability and intensity of side effects between the first and second doses of each group.

The number of cases reporting a previous viral infection, history of SARSCoV-2 or infections other than SARSCoV-2, was limited. Nevertheless, the history of SARSCoV-2 infection was considered based on symptoms and the capture of data on SARS-CoV-2 RT-PCR/lateral flow test results was not available in this survey.

Due to the limited number of cases receiving the second dose of each vaccine, the timing was not considered in the analyses. Even the most efficient questionnaire is unlikely to capture all the thromboembolic events. Therefore, the true incidence rate of thromboembolic events might be unknown.

This survey conducted a comparison between vector-based and inactivated candidate vaccines, although a comparison with common mRNA candidates was not available.

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