Adverse Events Following Immunization (AEFI) with CoronaVac COVID-19 Vaccine among Clinical Clerkship

: Objective: Clinical clerkship students, as adolescent health workers, have been first recipients of the COVID-19 vaccination programme. The success rate and trust of recipients in the program have been impacted by adverse events following immunization (AEFI). This study aims to determine the AEFI of the CoronaVac vaccine among clinical clerkship students at the Faculty of Medicine, State Islamic University, Jakarta. Material and Methods: This study used cross sectional methods with a total of 225 subjects completing a questionnaire. The CoronaVac vaccine was administered twice with 2 week interval. AEFI was evaluated after 30 minutes, 24 hours, and on the third day. Results and discussion : 73.3% of the participants were female, 20-25 years old. AEFIs were found in 57.8 % of all participants in the first and second doses vaccination. The most common local AEFI was pain at the site injection, accounting 27.1 % which occurred 30 minutes after second dose vaccination. The most common systemic AEFI was drowsiness, accounting for 18 % which occurred 24 hours after first dose vaccination. Other systemic AEFIs were headache, fatigue, and chills. There was significant association between AEFIs and females but no significant association with history of allergy, comorbidities, and history of previous COVID-19 . AEFIs were mild, no special treatment or hospitalization were required. Conclusion: The AEFIs of the CoronaVac vaccine among students were mild and had significant association with females. The study is expected to increase the public’s confidence in the COVID-19 vaccination program and to create awareness of its safety.

treatments have been developed, but they are not all effective to cure critical cases 2,3 . The development of a COVID-19 vaccine is required to create new hope for communities 4 . Vaccination programmes must be implemented with consideration of their effectiveness, immunogenicity and safety.
Around 170 vaccines have been developed up to phase 3 clinical trials and a few are already being used 5,6 The Beijing-based pharmaceutical company Sinovac Ltd produced the third vaccine called CoronaVac. The main ingredient of the vaccine is the inactivated SARS-CoV-2 virus 7 . It was approved by Brazil, Chile, Turkey, and Indonesia after clinical trials, and received Emergency Use Authorization (EUA) on May 7, 2021 from SAGE (Strategic Advisory Group of Experts) at WHO 5,6 . Preliminary reports show the CoronaVac vaccine is well tolerated and able to activate humoral immunity to eliminate the virus. Study results from Turkey, Chile, and Brazil showed an efficacy of 84 %, 67 %, and 50.7 % respectively 7,8,9 . The third phase of the clinical trial in Indonesia showed 65.3% of efficacy 10 . The EUA of the CoronaVac vaccine was announced by the Food and Drug Supervisory Agency (BPOM) on January 13, 2021 and it also received a Halal Fatwa from the Indonesian Ulema Council (MUI) 11,12 .
Vaccines are products using modern biotechnology that build specific antibodies against infection. Vaccines should be good quality, safe and effective, although they may have adverse events. Therefore, the implementation of the vaccine needs evaluation of adverse events following immunization (AEFI) 13 . AEFI is any untoward medical event which takes place after immunization and does not have a causal relationship with use of the vaccine. The classification of AEFI includes vaccine productrelated reactions, vaccine procedural errors, vaccine quality defects, immunization-anxiety reactions or coincidental events. AEFI could be common, mild, or severe with serious symptoms, accounting for 10% and <0.01% of cases, respectively. Management of mild AEFI is based on the symptoms present, while severe cases require specific medical treatment or hospitalization 13,14 . AEFI is divided into local and systemic symptoms that occurred quickly or slowly 13 . Many studies have shown AEFI from the CoronaVac vaccine were mild, such as pain, redness and swelling at the injection site as local symptoms meanwhile headache, fatigue, drowsiness, myalgia, chills, fever, nausea, and vomiting as systemic symptoms [15][16][17][18][19][20][21][22][23] .
The Indonesian government has the responsibility to ensure that immunization coverage reaches around 70% of the population, called herd immunity. Therefore, vaccination of 189 million out of the 270 million Indonesian population is needed 2,14 . Information about AEFI had an impact on public confidence in terms of benefits and support for the programme's implementation. Elnaem, et al study showed uncertainty regarding vaccine safety was the most common reported reason for vaccine hesitancy 16 . Generally, a lack of vaccine knowledge especially the benefits and risks leads to refusal or delay in terms of vaccination 14 . A study in Indonesia found that the majority neither supported nor rejected the mass vaccination programme 24 .
The immunization programme covered approximately 1 million Indonesians in January-February 2021 15 . Health workers and older people were first priority while adolescents who have better immunity and low risk of comorbidity are next priority 25 . Meanwhile clinical clerkship students as adolescent health workers represent an ideal population group could take part in the vaccination program and to provide information about the vaccine's benefits and the safety of the community and environment, due to their high level of health literacy and scientific interest 15 . Therefore, this study aims to determine the adverse events of COVID-19 vaccination in clinical clerkship students at the Faculty of Medicine, State Islamic University, Syarif Hidayatullah, Jakarta, Indonesia.

Material and Methods:
The study was cross sectional that conducted between February and March 2021. The collection of data made using a validated questionnaire that covered the subjects characteristics and adverse events after administration of the vaccine. The inclusion criteria were clinical clerkship students from the Faculty of Medicine, State Islamic University in Jakarta, who had received two doses of the CoronaVac vaccine and completed the questionnaire. The vaccine was administered twice, with an interval 2 weeks 17 . Adverse events were evaluated after 30 minutes, 24 hours, and on the third day after the administration of the two doses. The data were analysed statistically using Microsoft Excel 2019 and SPSS 24.0. The Chisquare statistical analysis test was used to determine association between AEFIs and sex, history of allergy, comorbidities and history of COVID-19 previous 3 month , which p-value < 0.05 were statistically significant. The questionnaire included the reason and benefits of the study also informed consent document.
Ethical clearance: Ethical clearance was obtained from the Ethics Committee of the Faculty of Medicine, Syarif Hidayatullah State Islamic University, with registry number B-027/F12/KEPK/TL.00/04/2021. All the research data were used solely for the study and remained confidential.

Results:
A total of 225 students who met the inclusion criteria comprised 73.3% females within the age range of 20 to 25. There were 35. 6 % had a history of allergy history and 5.8 % had history of COVID-19 positive in the previous 3 months as shown in Table 1.  Table 2.     Local and systemic AEFI occur because vaccines contain antigens that recognised as potential pathogens which found on peripheral circulating immune cells resulting in the synthesis and release of pyrogenic cytokines such as interleukin (IL)-1, IL-6, TNF-α, prostaglandin-E2, and chemokines. These inflammatory events lead to the development of symptoms at the injection-site, such as pain, redness and swelling within the first hours after administration. Pain sensation is transmitted through fast-conducting myelinated neurons. Those components may enter the bloodstream and produce systemic symptoms such as fatigue, headaches, myalgia and drowsiness. Intracerebral prostaglandin E2 activates neuronal circuits, which create autonomic and behavioural responses, such as metabolic heat production, chills and elevated body temperature 29 .
Our study showed females had significant association with AEFIs than males, that was similar with Riad et al, reported females were more likely to have vaccine-related side effects, apart from fever, which slightly more common in males 19 . Kaya et al, showed that females complained more of severe adverse events than males because they have stronger immune responses and less susceptible to viral infection however there were no significant differences in the adverse events found between males and females 23 . But Supangat study found that AEFIs was not correlated with gender 19 . Our study showed the systemic AEFI had no significant association with history of allergies, comorbidities and history of COVID-19 previous 3 month which similar with Beg et al found no relationship between the previous COVID-19 infection, comorbidities and systemic AEFI 36 . Meanwhile Tosun study reported history of allergy had a higher rate of AEFIs 20 . A case series study identifying individuals who had been infected with COVID-19 showed that there was no increase in the risk of myocarditis/pericarditis, Bell's Palsy, stroke, or myocardial infarction in the 21 days following either dose of the CoronaVac vaccine, apart from arrhythmia 35 . The study was also similar to the Indonesia Ministry of Health report that adverse events after the CoronaVac vaccine were mild, with no history of anaphylactic shock 23 .
This study showed pain at the site injection being the most common local symptom and most systemic reactions were felt 24 hours after vaccination which similar with other studies. All symptoms were mild and none needed specific treatment or hospitalization.
Implementation of the vaccination programme is intended to protect people from the high risk of infection, especially health workers. Furthermore, the target group was clinical clerkship students, an adolescent group who were expected to spread information about the benefits and safety of the vaccination to the community.
This study had the limitations that the respondents were homogenous, and that it only assessed up to three days after the vaccinations. Long-term followup is needed to assess late symptoms of vaccination.

Conclusion:
The most common local AEFI after administering the CoronaVac vaccine in the clinical clerkship students at the Faculty of Medicine Syarif Hidayatullah State Islamic University Jakarta was pain at the injection site after 30 minutes while the most common systemic AEFI was drowsiness after 24 hours of the first and second doses vaccination. Other common adverse events were fatigue, chills and headache. There were significant association between females and AEFIs, but no significant differences history of allergy, comorbidities and history of COVID previous 3 month. Generally, the AEFIs were mild and people were released without any specific treatment or hospitalization. Clinical clerkship students, represent an adolescent population group to take part in active surveillance studies due to their high level of health literacy and scientific interest. Therefore, this study is expected to increase public confidence in the vaccination program and create awareness of its safety. Future studies of the AEFI of CoronaVac vaccination should explore more of its risk factors.