key: cord-1010687-21p3q4xo
authors: Watcharananan, Sirapat Arthur; Nadee, Chalermlap; Kongsuwattanaleart, Patis; Sangthong, Nussara; Ngorsakun, Punpen; Vimonvattaravetee, Pornpimon; Phuphuakrat, Angsana; Udomsubpayakul, Umaporn
title: Rate, Type and Associated factor of Acute Adverse Effects after the First Dose of ChAdOx1 nCoV-19 Vaccine Administration in Thailand
date: 2021-11-27
journal: IJID Regions
DOI: 10.1016/j.ijregi.2021.11.008
sha: 8b13d3bc0025afdd229f0076e54a34d3ef270569
doc_id: 1010687
cord_uid: 21p3q4xo

Objective Effective vaccines are prioritized to curtail the transmission and burden of coronavirus disease 2019. Nevertheless, monitoring the safety of vaccines is crucial. As Thailand began the ChAdOx1 nCoV-19 vaccination, we aimed to study the acute adverse effects and the associated factors after the first dose of vaccination. Methods We performed a survey using a mobile self-report questionnaire to assess the rate and type of side effects within three days after the first dose of ChAdOx1 nCoV-19 vaccine administration. Risk factors associated with side effects were analyzed. Results A total of 774 participants participated in the survey. Their mean (±standard deviation) age was 49.5 (±17.2) years old. The majority (57.8%) were females, and 59.1% were anxious before the vaccination. Side effect(s) after the vaccination commonly occurred (65.2%) and but most (42.6%) were mild. Side effect was significantly associated [odds ratio (95% confidence interval)] with younger age [4.32 (2.26-8.23), p <0.001; age <30 VS. ≥60 years old], female sex [1.66 (1.19-2.30), p=0.003], anxiousness [2.10 (1.06-4.13), p=0.033; moderate-severe anxiousness VS. none] and allergic disease [2.60 (1.07-6.31), p=0.035). Conclusions After the ChAdOx1 nCoV-19 vaccination, most acute adverse effects were mild and often noted among participants with younger age, females, anxiousness, and allergic disease.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was declared a pandemic by WHO on March 11, 2020 (World Health Organization, 2020 , resulting in devastating medical, economic, and social consequences worldwide. Safe and effective vaccines are therefore very crucial and urgently needed in order to contain the pandemic. Because COVID-19 spreads swiftly, newer vaccine platforms, including mRNA and adenovirus vectorbased, were developed quickly and distributed worldwide. In Thailand, the Food and Drug Administration (FDA) has granted emergency use approval for the ChAdOx1 nCoV-19 (AstraZeneca) vaccine since January 2021, and the country's mass COVID-19 vaccination program has begun in June 2021. After introducing the ChAdOx1 nCoV-19 vaccine, there has been a variable rate of vaccine acceptance in many parts of the world (Sallam, 2021 ) and uncertainty about vaccine safety (Lin et al., 2020 , Megget, 2020 . As the acceptance of a public community towards vaccination appears to have a decisive role in the successful pandemic control, a study that determines and reassures the new vaccine's safety is highly desirable. We aimed to explore the rate and type of acute adverse effects after the first dose of ChAdOx1 nCoV-19 vaccine in Thailand. We also analyzed factors associated with acute adverse effects (AAEs) after the vaccination.

We included adults >18 years of age who were healthy or had stable chronic medical conditions. These participants were scheduled to receive the first dose of the ChAdOx1 nCoV-19 vaccine between June 8, 2021, and July 8, 2021, at two vaccination sites. One site was hosted by Praram 9 hospital, Bangkok, Thailand, and another was co-operated by Praram 9 hospital, The Street Ratchada, and the Bangkok Metropolitan Administration. We excluded individuals with a history of severe allergic reactions to the components of the COVID-19 vaccine. Before the vaccination, we educated all participants about the possible side effects after the vaccination. We administered the vaccine according to the manufacturers' instructions. Participants were also observed at the site for 30 minutes after the vaccination procedure and asked to record any adverse events using electronic surveys during the 3-day (acute) follow-up period. The survey was created to collect data, including participants' demography, underlying disease/chronic medical condition, and clinical symptoms after the vaccination.

We put clinical parameters in the questionnaire. AAEs were divided into two types, mild and severe. Mild AAEs included any of the following symptoms; local site reactions (injection site pain, tenderness, warmth, redness, swelling, induration, and itch), feverishness (i.e., a selfreported feeling of having a fever), headache, nausea/vomiting, and fatigue. Severe AAEs included palpitation, high-grade fever, chills, chest tightness, severe headache, facial weakness, limb weakness, skin lesion (i.e., spots/bleb/blister), bleeding spots, facial/body swelling, muscle ache, joint pain, >3 episodes of vomiting, diarrhea, altered mental status, and seizure. During the morning and evening of every day, the data of participants' side effects submitted through the mobile survey were reviewed. The study was approved by the Institutional Review Board (IRB) of the Praram 9 hospital. Written or verbal consent was waived from the participants because the study was observational, and we also concealed patient identifiers before the analysis.

We entered all data into Microsoft Excel and crosschecked for the presence of any errors to ensure their accuracy. Descriptive statistics were used to present and summarize the categorical variables by frequency (n) and percentage (%). Inferential statistics were performed to assess the association between factors and side effects using the chi-squared test (χ2), and logistic regression analysis was conducted to identify statistically significant factors associated with different outcome variables (any side effects). A p-value of less than 0.05 was considered statistically significant. Statistical analysis was performed using the STATA software package, version 16.1 (StataCorp, College Station, TX, USA).

Between June 8, 2021, and July 8, 2021, we identified 774 participants who received the first dose of the ChAdOx1 nCoV-19 vaccine. Their mean (range) age was 49.5 (18-91) years old.

There were 447 (57.8%) females. The majority (65.1%) of the participants did not have an underlying disease. The majority (59.1%) were anxious before the vaccination. Between the group of participants who had and did not have the AAEs (Table 1) , the group with AAEs were predominantly (62.6 %) female and were younger than the group without the AAEs (46.5+15 vs. 55.1+15.6 years old, p <0.001). The rate of AAEs was higher among patients with the allergic disease compared to those without (8.7% vs. 2.2%, p <0.001), but it was less among participants with diabetes mellitus compared to the non-diabetic group (7.9% vs. 13.8%, p=0.010). Among the group with allergic disease, common AAEs were arm pain (84.1%), low-grade fever (52.3%), fatigue (52.3%), headache (47.7%), joint/muscle pain (20.5%), chills (18.2%) and high-grade fever (13.6%). Less common symptoms were numbness (4.5%) and palpitation (4.5%). One (2.3%) reported a skin lesion. The rate and intensity of anxiousness differed between participants who had and did not have AAEs (p=0.001). AAEs (Table 2) after the vaccination commonly occurred (65.2%), and ranged from mild (42.6%) to severe (22.6%). Common symptoms included arm pain (48.2%), low-grade fever (30.9%), fatigue (27.5%), headache (27.4%), chills (10.7%) and joint/muscle pain (9.4%). Severe AAEs that were considered serious seldom occurred. These included muscle weakness (0.5%), limb weakness (1.0%), skin lesions (0.6%), multiple bleed spots (0.3%). There was no case of concurrent bleeding spots and limb weakness.

There was no report of facial weakness, alteration of consciousness, or seizure. Local numbness (1.6%) was all transient. Table 3 describes and compares characteristics between the participants who had mild, severe, and those who did not have AAEs. The mean age (years old, + standard deviation; SD) of participants with no side effects were highest, followed by the group with mild AAEs and severe AAEs (55.1+15.6 VS. 48.8+15.1 VS. 42.3+13.8, respectively). The female proportion was highest in the group with severe AAEs, followed by mild and no AAEs (69.7% VS. 58.8% VS.

48.7%). The highest rate of severe AAEs (12.2%) was observed among the participants who had moderate to severe anxiousness before vaccination. The highest rate (47.1%) of participants who did not have AAEs was among participants without anxiousness.

We further analyzed the significance of clinical parameters associated with AAEs after the vaccination (Table 4 ). Age (years old) were further categorized into five groups; <30, 30-39, 40-49, 50-59 and >60, respectively. We used participants >60 years old as a reference group for univariate and multivariate analysis. Diabetes mellitus showed an association with the occurrence of AAEs after the vaccination only in univariate analysis. From the multivariate analysis ( p=0.021 for mild degree and 2.10 (1.06-4.13), p=0.033 for moderate to severe degree, respectively]. The crude odds ratio of any AAEs conversely increased with every ten years' reduction in age, and the crude odds ratio (95% CI) was highest [5.59 (3.09-10.11)] among the group participant with <30 years old.

The present study reported the type and rate of acute side effects among Thais who received the first dose of the ChAdOx1 nCoV-19 vaccine. This information is crucial, as the global COVID-19 vaccination is a priority to end the pandemic. Doubt or uncertainty about vaccine safety is a major contributing factor to vaccine hesitancy, negatively impacting public health. Our study reemphasizes that the benefits of the COVID-19 vaccine outweigh the risks of AAEs.

We showed that side effects commonly occurred, especially in a group of younger adults, but most of the symptoms were mild. Our finding of a higher rate of side effects among females and younger age is concurrent with other previous pieces of literature (Bae et al., 2021 , Ramasamy et al., 2021 . Although severe symptoms were noted in about one-fifth of our cases, most of them were not serious (chills, joint/muscle pains, and high-grade fever), and most were subsequently resolved in a few days (Bae et al., 2021 , Ramasamy et al., 2021 . Although symptoms compatible with serious AAEs were seldom, two cases of multiple bleeding spots and eight cases of limb weakness have been self-reported. It was unclear if such reports were eventually confirmed with clinical significance and the underlying etiologies among these cases were also unknown. It was therefore uncertain if these symptoms occurred as a result of bleeding or clotting disorder.

In early 2021, after the rollout of the ChAdOx1 nCoV-19 vaccine, concern about the increased thrombosis risk had led many European countries to temporarily suspend the ChAdOx1 nCoV-19 vaccine (Wise, 2021) . A recent study on a cohort of 1.7 million ChAdOx1 nCoV-19 vaccinees in Scotland revealed an increased risk of idiopathic thrombocytopenic purpura and arterial thromboembolic events at 0-27 days after vaccination [adjusted rate ratio (aRR) 5.77, 95% CI 2.41-13.83, and 1.22, 95% CI 1.12-1.34, respectively]. For hemorrhagic events, the aRR was 1.48, 95% CI 1.12-1.96 at 0-27 days after vaccination (Simpson et al., 2021) . The statistically significance of these rate ratios was noticed after day 7 of vaccination.

Another study on 19.6 million first dose ChAdOx1 nCov-19 vaccinees in England reported increased risk of thrombocytopenia and increased risk of venous thromboembolism at 8-14 days after ChAdOx1 nCoV-19 vaccination (incidence rate ratio 1.33, 95% CI 1.19-1.47, and 1.10, 95% CI 1.02-1.18, respectively). Importantly, the study also showed a greater and prolonged increased risk of hematological events after SARS-CoV-2 infection than after vaccination (Hippisley-Cox et al., 2021) . The increased risk of cerebral venous thrombosis after ChAdOx1 nCoV-19 was seen at 8-14 days after vaccination (Hippisley-Cox et al., 2021 , Hwang et al., 2021a . Later, the European Medicines Agency (EMA) investigation has concluded that this blood disorder following the vaccination was deemed a very rare adverse event (Mahase, 2021) .

In Thailand, during the preparation of this manuscript, four (one definite and three probable) cases of vaccine-induced immune thrombotic thrombocytonenia (VITT) have been reported after vaccination with more than 35 million doses of ChAdOx1 nCoV-19 (Department of Disease Control, Ministry of Public Health, 2021). Of these, two cases with probable VITT died. Albeit extremely rare, this adverse event should be advised to the vacinees, and those who was diagnosed VITT should be closely monitored and evaluated to provided timely treatment (Hwang et al., 2021b) . Taken together, we underscore benefits of ChAdOx1 nCoV-19 vaccination still outweigh the risks of adverse events.

Nevertheless, a limited number of studies have found an association between allergic disease and adverse reactions (Kaur et al., 2021) . Almost all of the side effects that occurred in the allergic disease group were not serious. Only one had skin lesions and joint/muscle pain. The

ChAdOx1 containing the gene that encodes the glycoprotein spike (S) antigen of SARS-CoV-2.

It also contains polysorbate 80, which can trigger an allergic reaction. Although the allergic reaction can occur, recent data has noted that the incidence was rare. The only contraindication for administering this vaccine is a previous history of allergic reactions to any component contained in the vaccine (Novak et al., 2021 , Sokolowska et al., 2021 .

The strength of this study included a mobile self-report questionnaire was used to assess the side effects within three days; which could avoid interviewer and recall biases. However, there are some limitations of our study. First, the type and severity of adverse reactions may have been biased (overestimated or underestimated) due to the nature of the self-reporting survey.

Second, the final diagnosis among cases with acute adverse effects, especially those with severe symptoms, was not determined. Third, the adverse effects that occurred later, especially VITT, were unknown, as the self-report period was only within an acute period (three days) after the vaccination.

The acute adverse effects after one dose of ChAdOx1 nCoV-19 vaccination commonly occurred, but they were primarily mild and unlikely serious. The adverse reactions were more commonly reported in females, those in the younger age groups, those who reported anxiousness, and those with allergic diseases. However, the rare but fatal adverse effects, especially VITT, should be advised to ChAdOx1 nCoV-19 vaccinees for the vigilance.

All authors declare no conflict of interest.

This research received no specific grant from any funding agency.

This study was approved by the Institutional Review Board (IRB) of the Praram 9 hospital. Tables   Table 1 Characteristics between participants who had and did not have acute adverse effect(s) after the 

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