Adverse event following immunisation of adsorbed-inactivated Coronavac (Sinovac) and ChAdOx1 nCOV-19 (Astra Zeneca) of COVID-19 vaccines

Abstract

Introduction:
Countries around the world organised mass vaccinations using various types of vaccines against COVID-19, like inactivated viruses and mRNA. The study aimed to look at adverse events following immunisation (AEFI) of Coronavac® (SIN) and ChAdOx1 nCOV-19 ® (AZ) COVID-19 vaccines in Indonesia.

Materials and methods:
Subjects who received SIN or AZ vaccines were sent questionnaires twice: after they received the first and the second doses of vaccine, respectively. AEFI data on the first- and second-day post-vaccination were collected and analyzed descriptively.

Results:
A total of 1547 people vaccinated with SIN vaccine, 529 (33.3%) responded to the first-dose and 239 (47%) to the second-dose questionnaires, whereas 936 people vaccinated with AZ vaccine, 483 (51.6%) answered the firstdose and 123 (25%) to the second-dose questionnaires. Some important AEFIs on the first- and second-day post receiving SIN vs. AZ vaccination were as follows: fever 4% vs 59%; pain at the injection site 27% vs 87%; redness and swelling at the injection site 4% vs 18%; nausea 5% vs 30%; diarrhea 1.8% vs 5.7%, respectively.

Conclusion:
SIN seemed to have fewer AEFIs than AZ. Apart from different vaccine materials and excipients, the gap in AEFIs between SIN and AZ could be caused by the distinct population where AZ recipients were more exposed to COVID-19.

Full text

Med J Malaysia Vol 79 No 5 September 2024 507
ABSTRACT
Introduction: Countries around the world organised mass
vaccinations using various types of vaccines against
COVID-19, like inactivated viruses and mRNA. The study
aimed to look at adverse events following immunisation
(AEFI) of Coronavac® (SIN) and ChAdOx1 nCOV-19 ® (AZ)
COVID-19 vaccines in Indonesia.
Materials and Methods: Subjects who received SIN or AZ
vaccines were sent questionnaires twice: after they received
the first and the second doses of vaccine, respectively. AEFI
data on the first- and second-day post-vaccination were
collected and analyzed descriptively.
Results: A total of 1547 people vaccinated with SIN vaccine,
529 (33.3%) responded to the first-dose and 239 (47%) to the
second-dose questionnaires, whereas 936 people
vaccinated with AZ vaccine, 483 (51.6%) answered the first-
dose and 123 (25%) to the second-dose questionnaires.
Some important AEFIs on the first- and second-day post
receiving SIN vs. AZ vaccination were as follows: fever 4%
vs 59%; pain at the injection site 27% vs 87%; redness and
swelling at the injection site 4% vs 18%; nausea 5% vs 30%;
diarrhea 1.8% vs 5.7%, respectively.
Conclusion: SIN seemed to have fewer AEFIs than AZ. Apart
from different vaccine materials and excipients, the gap in
AEFIs between SIN and AZ could be caused by the distinct
population where AZ recipients were more exposed to
COVID-19.
KEYWORDS:
AEFI, COVID-19, real-world evidence
INTRODUCTION
Numerous instances of pneumonia with an unknown
eatiology were reported to the World Health Organisation
(WHO) on December 31, 2019, in Wuhan City, Hubei
Province, China. The SARS-CoV-2 new coronavirus was
identified as the culprit. The distinctive illness-causing virus
has been given the name COVID-19, which was declared
pandemic in March 2020. Since then, the disease has
expanded, having a significant negative influence on the
health and welfare of people and populations around the
world. The pandemic has caused major disruptions to the
society and the economy across the globe. SARS-CoV-2
vaccines have been produced by numerous nations,
organizations, and pharmaceutical firms.1 The Food and
Drug Administration (FDA), Centers for Disease Control and
Prevention (CDC), and WHO were compelled to grant
Emergency Use Authorization (EUA) of the vaccinations
because to the urgent necessity for vaccination.2 It is
beneficial to get immunised against the COVID-19 pandemic
to stop the disease’s spread and transmission. The present
emphasis across all nations, including Indonesia, is on
planning large immunization campaigns for their
populations. Indonesia originally selected Sinovac, a
vaccination based on inactivated viruses rather than the
mRNA vaccine, from among the several vaccines that were
already in use and those that were being developed. The
Sinovac vaccine is developed with inactivated virus.
Its phase III clinical trials have been conducted in Indonesia,
Brazil and China, with good efficacy results.3,4 Aside from the
vaccine’s effectiveness, adverse event following
immunisation (AEFI) is also crucial as it often happens within
24 to 72 hours of receiving the shot. Sometimes, reactions
persisted for as long as 14 days.5
The Sinovac vaccine contains 3 ug/0.5 mL (equivalent to 600
SU per dose) of inactive viruses with aluminium hydroxide
adjuvant (Al2OH3), which can also give a crossroads effect.6,7
Astra Zeneca vaccine, like Sputnik and Johnson & Johnson is
based on genetically engineered viral vector (adenovirus).8
An extremely concerning side effect that can occur during
vaccine development is thrombo-embolism, which can occur
with or without bleeding and have a variety of symptoms,
including cerebral venous sinus thrombosis and pulmonary
embolism.9 Some European countries like Germany, Finland
and Denmark have suspended the use of this vaccine. After
listening to the WHO Strategic Advisory Group of Experts on
Adverse event following immunisation of adsorbed-
inactivated Coronavac (Sinovac) and ChAdOx1 nCOV-19
(Astra Zeneca) of COVID-19 vaccines
Abraham Simatupang, MD1,Yunita RMB Sitompul, Occupational Health Specialist2, Bona Simanungkalit,
Dr.PH2, Kurniyanto Kurniyanto, Internist3, Luana Natingkaseh Achmad, Psychiatrist4, Fransiska Sitompul,
MFarm1, Salaheddin M Mahmud PhD5, Eva Suarthana, PhD6
1Department of Pharmacology & Therapy, Faculty of Medicine, Universitas Kristen Indonesia, 2Department of Public Health,
Faculty of Medicine, Universitas Kristen Indonesia, 3Department of Internal Medicine, Faculty of Medicine, Universitas Kristen
Indonesia, 4Department of Psychiatry and Mental Health, Faculty of Medicine, Universitas Kristen Indonesia, 5Vaccine and Drug
Evaluation Centre, Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada,
6Department of Obstetrics and Gynecology, McGill University, Montreal, Canada
ORIGINAL ARTICLE
This article was accepted: 19 August 2024
Corresponding Author: Abraham Simatupang
Email: abraham.simatupang@uki.ac.id
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508 Med J Malaysia Vol 79 No 5 September 2024
Immunisation (SAGE) opinion, WHO finally approved the
use of Astra Zeneca vaccine.10
In accordance with the national vaccination program;
Sinovac, Astra Zeneca and Moderna vaccines have been used
and given to the people through many public and private-
sectors. The aim of the study was to assess and compare AEFIs
between Sinovac and Astra Zeneca vaccines, as real-world
evidence.11,12
MATERIALS AND METHODS
Universitas Kristen Indonesia organised a mass vaccination
program. The vaccine was supplied by the Community
Health Center of Kramat Jati, Jakarta. Vaccination was
carried out in March to April 2021.
Two sets of questionnaires were developed to assess the AEFIs,
each of which was developed for the first and second dose of
vaccination.
AEFI data included symptoms on the first- and second-day
post vaccination (fever, pain and swelling at the injection
site, headache, vomiting, bloating, and/or diarrhea); as well
as actions taken by the respondents if they experienced
adverse events (i.e., pain-killers, consultation to health care
workers, etc.).
Indonesian FDA approved the vaccination with SIN and AZ,
which was carried out in accordance with the protocols
outlined in the product description. Two separate 0.5 ml
doses of Sinovac were administered; the second dose were
given four weeks after the first dose.13 The AZ vaccination
consists of two separate doses of 0.5 mL each; where the
second dose were administered between 4 and 12 weeks (28
to 84 days) after the first dose.14
The survey was ethically approved by the Ethical Committee:
No. 15/Etik Penelitian/FKUKI/2021. An online questionnaire
using Microsoft Form was distributed to all vaccine recipients
recorded by the committee via WhatsApp (WA). The
questionnaire consists of 14 questions for Sinovac
respondents and 17 questions for Astra Zeneca respondents
consisting of (1) demographics information (gender, age), (2)
adverse effects, which were divided into nervous system and
brain, skin, digestive system, and other adverse effects and (3)
Actions taken by respondents if they experienced adverse
effects. In the questionnaire for AZ respondents, we added
questions on whether they were diagnosed or have had
thrombose and had or were receiving blood thinning
therapy.
The first questionnaire was sent to all first dose vaccine
recipients and those who responded were sent the second
questionnaire following the second dose. To increase response
rate, each questionnaire was sent three times with one-week
interval. Data were extracted from the MS forms.
Distributions of the demographics, AEFIs and actions taken
by the respondents were analysed descriptively. Analysis was
done using SPSS version 25 (IBM, Armonk, NY, USA).
RESULTS
There was a total of 1574 subjects who were vaccinated with
SIN and 936 subjects with AZ vaccines. In the SIN group 529
subjects responded (response rate 33%), whereas in the AZ
group there were 483 respondents (response rate 51.6%). The
response rate for the second questionnaire was lower in the
AZ group. The low response rate could have occurred due to
the delivery of the questionnaire through the WhatsApp
application, in which people could receive hundreds of
notifications per day. This could have made respondents did
not pay attention to notifications of the questionnaire sent to
them, despite our effort to send each questionnaire three
times with one-week interval. This study was not a clinical
trial with strict protocols that should be followed by subjects
to increase adherence to the treatment. In this study, subjects
were voluntarily asked to fill-out the questionnaire sent to
them. Although web-based survey has many advantages
such as: wider spread of distribution, lower cost, and efficient,
comparison studies between web-based versus paper-based
survey showed that response rate of wed-based or internet-
based survey were lower up to 10-20% than paper-based.15
Vaccinated subjects Coronavac (SIN) ChAdOx1 nCOV-19 (AZ) Total
NSIN = 1547 NAZ = 936
First dose Second dose First dose Second dose First dose Second dose
n = 530 n = 239 n = 483 n = 123 n = 1013 n = 372
f (%) f (%) f (%) f (%) f (%) f (%)
Female* 322 (61) 131 (55) 224 (46) 64 (52) 546 (53.9) 195 (52.4)
Male* 208 (39) 108 (45) 259 (54) 59 (48) 467 (46.1) 167 (44.9)
Fever 1st day 22 (4.2) 6 (2.4) 285 (59.0) 20 (16.3) 307 (30.3) 26 (7.0)
Fever 2nd day 5 (0.9) 3 (1.2) 155 (32.1) 8 (6.5) 160 (15.8) 11 (3.0)
Took pain killer 6 (1.1) 0 (0) 293 (60.7) 20 (16.3) 299 (29.5) 20 (5.4)
Pain at injection site 147 (27.7) 79 (33) 420 (87.0) 70 (56.9) 567 (56.0) 149 (40.1)
Bump at injection site 22 (4.2) 8 (3.3) 86 (17.8) 14 (11.4) 108 (10.7) 22 (5.9)
Drowsiness 112 (21,1) 28 (11,7) 30 (6.2) 12 (9.8) 142 (14.0) 40 (10.8)
Headache 3 (0.6) 6 (2.5) 311 (64.4) 35 (28.5) 314 (31.0) 41 (11.0)
Nausea 30 (5.7) 18 (7.5) 143 (29.6) 8 (6.5) 173 (17.1) 26 (7.0)
Vomit 6 (1.1) 2 (0.8) 19 (3.9) 1 (0.8) 25 (2.5) 3 (0.8)
Bloating 35 (6.6) 16 (6.4) 100 (20.7) 10 (8.1) 135 (13.3) 26 (7.0)
Diarrhea 10 (1.9) 5 (2.0) 27 (5.6) 9 (7.3) 37 (3.7) 14 (3.8)
Table I: Demographics and list of adverse events following immunization
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Adverse event following immunisation of adsorbed-inactivated
Med J Malaysia Vol 79 No 5 September 2024 509
The AEFI is shown in Table I, the most prominent adverse
event in both vaccine groups was pain at the injection site,
whereas the percentage was higher in the AZ than the SIN
group (58.6% vs 20.5%, respectively). Fever both on the first
day and the next day is also more prominent in the Astra
Zeneca group. Overall, the percentages of AEFIs appeared to
decrease after the second-dose compared to the first-dose of
the vaccine. In contrast, drowsiness was more prominent in
the SIN group than AZ. While the headaches were more in
the AZ group. According to the Centers for Disease Control
and Prevention (CDC), pain at the injection site was the most
commonly reported local reaction among Pfizer-BioNTech
COVID-19 vaccine users aged 18 to 55 years, and the
percentage decreased after the second injection.16,17
Out of 483 AZ first dose vaccine recipients, 28 acknowledged
that prior to vaccination they were diagnosed with symptoms
of thrombo-embolism and 12 of them taking blood thinning
Fig. 1: Respondents’ recruitment and number of subjects who responded to questionnaire.
Fig. 2: Percentages of actions taken to the adverse effects experienced by the COVID-19 vaccine recipients (numbers represent
percentages of respondents within each group of vaccine). SIN: Sinovac; AZ: Astra Zeneca.
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510 Med J Malaysia Vol 79 No 5 September 2024
drugs such as Aspilet® or Ascardia®, which contains
acetylsalicylic acid (n = 3); clopidogrel (n = 4), Plavix® (a
brand name of clopidogrel, n = 1), or other blood-thinning
medications (n = 4). No vaccine-induced immune thrombotic
thrombocytopenia (VITT), or anaphylaxis reaction reported
by recipients in both vaccine groups. Although it is possible
that thromboembolism may occur. However, with the
national integrated AEFI reporting system, if a vaccine
recipient subject reports a severe AEFI, the local vaccine
injection centre will be informed.
Figure 2 demonstrated actions taken by the vaccine recipients
in the presence of adverse effect. Only a few respondents
(≤3%, not shown in the figure) who consulted their concern to
the nearest public health center, doctor, or hospital. None
reported a severe adverse effect that required further
treatment in the hospital. In the implementation of this mass
immunization, the government established a tiered reporting
system. If there are complaints that are directly felt by the
subject after vaccination, can be directly handled by the
doctors who serve at the vaccination sites. Interestingly, 60%
respondents in AZ group (first dose) and 55% (second dose),
whereas, in SIN group only 22% (first dose) and 19% (second
dose) who took self-medication. It is certainly shown that
more respondents in the SIN group did not take action for the
side effects. This suggests that most of the adverse events in
the SIN group were milder than AZ group (Table I). This also
in accordance with a meta-analysis study by Chen at al., the
AEFI report due to inactivated vaccines was lower than other
types of vaccines.18
DISCUSSION
In general, the results of our analysis of the data from the AZ
group were generally consistent with those of Jeon et al, who
observed that the two AEFIs that were most frequently
reported were tenderness at the injection site (94.5%) and
fatigue (92.9%). Both the severity and number of AEFI were
lower in the older age group. Sultana no significant incidents
necessitated further medical treatment, and the majority of
AEFIs subsided within a few days.19 Recent report on safety of
AZ (EudraVigilance) has added information that 28 people
consisting of 19 women and nine men were diagnosed with
AEFI associated with thrombosis problem, such as deep vein
thrombosis (DVT), pelvic vein thrombosis, pulmonary
embolism, etc. Three people died and six did not recover.20 In
our study, none reported VITT nor anaphylaxis reaction. As
is stated elsewhere, the aetiology of AEFI due to inactivated
virus could be from its vaccine material or its excipients.
While the problem of thrombosis that appeared in the group
of subjects who were vaccinated with Astra Zeneca triggered
the expression of antiplatelet antibodies.21 In contrast to our
study, Hyun et al discovered that patients who got the
ChAdOx1 nCOV-19 (AstraZeneca) vaccination experienced
substantial adverse effects after just one dosage, including
polyarthralgia and myalgia syndrome that lasted up to 47
days.22 Other non comparison study by Jain et al (2022)
showed AEFI with ChAdOx1 nCOV-19 vaccine was generally
mild and moderate, although one case of severe allergic
reaction was obtained ( mild – 31 [83.7%]; moderate – 5
[13.5%] and severe – 1 [2.7%]), respectively.23 Although our
study showed higher AEFI in AZ group than SIN, which may
be due to differences in vaccine ingredients and excipients,
no severe AEFI was found as other studies reported. In our
center, AZ vaccine was administered to anyone, not limited
to healthcare workers (HCWs). Profession with higher
exposure to COVID-19 such as HCWs might pose higher risk
of AEFIs.24 However, unfortunately data on occupation
(health care workers vs non health care worker) was not
available.
CONCLUSION
This study focuses on the adverse events following
immunisation (AEFI) of the Sinovac and Astra Zeneca
COVID-19 vaccines and presents real-world evidence.
Sinovac appeared to have fewer AEFI than ChAdOx1 nCOV-
19 (Astra Zeneca), according to this investigation. No major
adverse event, such vaccine-induced immune thrombotic
thrombocytopenia or anaphylactic reaction, occurredA total
of 60% respondents from the SIN group did not take any
action concerning the adverse effect they experienced. On the
contrary, 60% AZ vaccine recipients at least took pain-killer
to reduce the pain at the injection site and their fever. To
overcome AEFI, especially fever, respondents preferred self-
medication. The limitation of this study is that the response
given by respondents was not confirmed by medical
examination. The response rate is small, especially the
response obtained from the second dose of vaccination.
ACKNOWLEDGEMENTS
Authors would like to thank Ms. Ayu Sibuea, Ms. Okta
Hutabarat for collecting and supplementing raw data to the
research team. Special thanks to Ms. Dr.rer.pol. Ied V. Sitepu,
MA the head organiser of the UKI’s Vaccination Program in
collaboration with Alumni Association, UKI’s General
Teaching Hospital and Public Health Service – Kramat Jati,
East Jakarta.
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