Adverse events of special interest and mortality following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines in Hong Kong: A retrospective study.

BACKGROUND: Safety monitoring of coronavirus disease 2019 (COVID-19) vaccines is crucial during mass vaccination rollout to inform the choice of vaccines and reduce vaccine hesitancy. Considering the scant evidence directly comparing the safety profiles of mRNA and inactivated SARS-CoV-2 vaccines, this territory-wide cohort study aims to compare the incidence of various adverse events of special interest (AESIs) and all-cause mortality between CoronaVac (inactivated vaccine) and BNT162b2 (mRNA-based vaccine). Our results can help vaccine recipients make an informed choice. METHODS AND
FINDINGS: A retrospective, population-based cohort of individuals who had received at least 1 dose of BNT162b2 or CoronaVac from 23 February to 9 September 2021 in Hong Kong, and had data linkage to the electronic medical records of the Hong Kong Hospital Authority, were included. Those who had received mixed doses were excluded. Individuals were observed from the date of vaccination (first or second dose) until mortality, second dose vaccination (for first dose analysis), 21 days after vaccination, or 30 September 2021, whichever came first. Baseline characteristics of vaccinated individuals were balanced between groups using propensity score weighting. Outcome events were AESIs and all-cause mortality recorded during 21 days of post-vaccination follow-up after each dose, except anaphylaxis, for which the observation period was restricted to 2 days after each dose. Incidence rate ratios (IRRs) of AESIs and mortality comparing between CoronaVac and BNT162b2 recipients were estimated after each dose using Poisson regression models. Among 2,333,379 vaccinated individuals aged 18 years or above, the first dose analysis included 1,308,820 BNT162b2 and 955,859 CoronaVac recipients, while the second dose analysis included 1,116,677 and 821,560 individuals, respectively. The most frequently reported AESI among CoronaVac and BNT162b2 recipients was thromboembolism (first dose: 431 and 290 per 100,000 person-years; second dose: 385 and 266 per 100,000 person-years). After the first dose, incidence rates of overall AESIs (IRR = 0.98, 95% CI 0.89-1.08, p = 0.703) and mortality (IRR = 0.96, 95% CI 0.63-1.48, p = 0.868) associated with CoronaVac were generally comparable to those for BNT162b2, except for Bell palsy (IRR = 1.95, 95% CI 1.12-3.41, p = 0.018), anaphylaxis (IRR = 0.34, 95% CI 0.14-0.79, p = 0.012), and sleeping disturbance or disorder (IRR = 0.66, 95% CI 0.49-0.89, p = 0.006). After the second dose, incidence rates of overall AESIs (IRR = 0.97, 95% CI 0.87-1.08, p = 0.545) and mortality (IRR = 0.85, 95% CI 0.51-1.40, p = 0.516) were comparable between CoronaVac and BNT162b2 recipients, with no significant differences observed for specific AESIs. The main limitations of this study include residual confounding due to its observational nature, and the possibility of its being underpowered for some AESIs with very low observed incidences.
CONCLUSIONS: In this study, we observed that the incidences of AESIs (cumulative incidence rate of 0.06%-0.09%) and mortality following the first and second doses of CoronaVac and BNT162b2 vaccination were very low. The safety profiles of the vaccines were generally comparable, except for a significantly higher incidence rate of Bell palsy, but lower incidence rates of anaphylaxis and sleeping disturbance or disorder, following first dose CoronaVac versus BNT162b2 vaccination. Our results could help inform the choice of inactivated COVID-19 vaccines, mainly administered in low- and middle-income countries with large populations, in comparison to the safety of mRNA vaccines. Long-term surveillance on the safety profile of COVID-19 vaccines should continue.

Introduction

Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, an unprecedented number of SARS-CoV-2 vaccines using different platforms and with varying efficacy have been developed, namely inactivated virus, mRNA, viral vector, and protein subunit vaccines [1]. While rapid and mass vaccination of individuals is essential to reducing COVID-19-related hospitalizations, disease severity, and associated deaths, vaccine hesitancy has been observed owing to fear of adverse reactions following immunization [2]. Accordingly, continuous monitoring of vaccine safety via active and passive surveillance is crucial to providing up-to-date evidence about any potential safety signals over the rollout period, especially those concerning adverse events of special interest (AESIs).

In Hong Kong SAR (Special Administrative Region), China, the government initiated a territory-wide vaccination program with CoronaVac (inactivated SARS-CoV-2 vaccine) on 23 February 2021, and with BNT162b2 (mRNA-based vaccine, equivalent to Comirnaty) on 6 March 2021; individuals can choose to get vaccinated with either platform. Adopting the traditional approach, CoronaVac was developed as an inactivated whole-virion SARS-CoV-2 vaccine using the adjuvant aluminum hydroxide, and its tolerability has been demonstrated in several clinical trials [3-5]. Two cross-sectional studies conducted among healthcare workers in Turkey and China reported that the prevalence of local and systemic side effects for CoronaVac was significantly lower than for mRNA vaccines, and all adverse effects, including allergic reaction and lymphadenopathy, were mild and transient [6,7]. Upon the rollout of CoronaVac in multiple countries, case reports of AESIs have emerged in the literature, for example, thyroiditis, Kounis syndrome, and kidney diseases [8-11]. Nevertheless, systematic evaluation of the incidence of various AESIs possibly associated with this inactivated vaccine—compared to other platforms, unvaccinated individuals, or background incidence rates in the population—is profoundly lacking.

BNT162b2 vaccine was the first SARS-CoV-2 vaccine approved by the US Food and Drug Administration (FDA) for COVID-19 prevention in adults [12]. Despite the novel mRNA platform, substantial evidence on its safety and effectiveness is accumulating, given the rapid deployment and massive number of doses administered across different populations worldwide. While vaccine reactogenicity was transient, with mainly mild to moderate adverse effects, serious adverse events such as lymphadenopathy, arrhythmia, and leg paresthesia were recorded among BNT162b2 recipients in the clinical trial [13]. Also, strong pharmacoepidemiological data have suggested an excess risk of myocarditis and pericarditis [14-16], lymphadenopathy, herpes zoster infection, and potentially appendicitis with this mRNA vaccine [14]. Concurrently with mass vaccination, several AESIs in close temporal relationship with BNT162b2 have been identified for further detection of safety signals, including anaphylaxis [15,17], myocarditis and pericarditis [18], kidney diseases [19,20], Bell palsy [14,21,22], Guillain-Barré syndrome (GBS) [17], seizure [15,17], transverse myelitis (TM) [15,17], venous thromboembolism, thrombosis, and thrombocytopenia [15,23].

Inactivated and mRNA vaccines are both associated with risks of serious adverse events comparable to placebo control [24-27], yet there is a lack of direct comparison of the safety profiles of these 2 vaccine platforms widely used around the world. A nested case–control study conducted in Hong Kong has suggested an elevated risk of Bell palsy following CoronaVac vaccination, which was not evident with BNT162b2 vaccination [28]. This is in line with a disproportionality analysis that used the World Health Organization (WHO) pharmacovigilance database and concluded that a signal of facial paralysis had not been displayed for mRNA COVID-19 vaccines compared to other viral vaccines [29]. While the WHO pharmacovigilance database may be used for generating safety signals for further testing and confirmation, it relies on the spontaneous reporting of suspected adverse drug reactions by patients and health professionals of participating countries, which has been extensively performed for BNT162b2 but not as much for CoronaVac [30]. In view of the very limited evidence comparing the safety profile of mRNA and inactivated SARS-CoV-2 vaccines, our population-based, retrospective cohort study aims to evaluate and compare the incidences of AESIs following the first and second doses of each vaccine type, with reference to the lists recommended for continuous monitoring of COVID-19 vaccine safety [31]. The findings of this study could inform the public in decision-making on the choice of COVID-19 vaccines, reduce vaccine hesitancy by addressing safety concerns, and inform governments about the allocation of healthcare resources for AESI surveillance and monitoring.

Methods

Study design and study population

A territory-wide cohort study was conducted to compare the incidence rates of AESIs and all-cause mortality between CoronaVac (supplied by Sinovac) and BNT162b2 (supplied by Fosun Pharma as Comirnaty vaccines, manufactured by BioNTech in Germany) [32] vaccination after the first and second doses.

The mass COVID-19 vaccination program in Hong Kong was launched on 23 February 2021 for CoronaVac and 6 March 2021 for BNT162b2. Certain patient groups were prioritized to receive vaccination at the start and during specific periods of the community vaccination program. However, there were no guidelines recommending that certain individuals or patient groups receive a particular vaccine or different service delivery. Individuals remained free to choose their preferred type of vaccine at their first dose, but were unable to switch vaccine type for their second dose (except for rare instances of anaphylaxis following the first dose, where switching between vaccine types is allowed on a case-by-case basis). People aged 18 years or above who had received at least 1 dose of CoronaVac or BNT162b2 vaccine in Hong Kong SAR, China, between 23 February and 9 September 2021 were included in the study (Fig 1). People who had received BNT162b2 as the first dose followed by CoronaVac as the second dose (or vice versa) were excluded from the second dose analysis.

Fig 1

Inclusion and exclusion criteria for the analysis of individuals who received a first or second dose of BNT162b2 or CoronaVac from 23 February to 9 September 2021 in Hong Kong SAR, China.

Data sources

Anonymized, population-wide COVID-19 vaccination records obtained from the Department of Health and electronic medical records retrieved from the Hong Kong Hospital Authority (the statutory body managing public healthcare services in the region) were linked using a unique mapping key (Hong Kong Identity Card number or foreign passport number). Vaccination records included the brand of vaccine, venue for vaccination, and date of administration. Centralized electronic medical records included patient demographics, date of registered death (including both hospital and non-hospital deaths), drug dispensing records, diagnoses, procedures, and laboratory tests. The validity of disease diagnoses identified from electronic medical records has been shown to be high [33-38]. These 2 linked sources of data have been extensively used for pharmacovigilance and COVID-19 vaccine safety studies [18,28,39-45].

Ethics approval

Ethical approval for this study was granted by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 21–149 and UW 21–138) and the Department of Health Ethics Committee (LM 21/2021). A waiver of participant consent was granted for this retrospective cohort study using anonymized data.

Exposure period of the first and second doses

For individuals who received the first dose of BNT162b2 or CoronaVac from 23 February to 9 September 2021, the follow-up period was from the date of first dose vaccination (baseline date) until mortality, second dose vaccination, 21 days after the first dose, or the data cutoff date (30 September 2021), whichever came first. For those who received the second dose of either vaccine within the inclusion period, their observation period was stratified into 2 exposure risk periods, namely follow-up windows for the first and second doses. The follow-up period for those who received a second dose was from the date of second dose vaccination (baseline date) until mortality, 21 days after the second dose, or the data cutoff date, whichever came first. Vaccinated individuals had at most 21 days of post-vaccination follow-up after each dose, to make the follow-up periods comparable for the first and second doses and between vaccines, since approximately two-thirds of BNT162b2 recipients had their second dose administered 21 days after their first dose, which is the recommended dosing interval for this mRNA vaccine [46].

Outcomes

Our study outcomes adapted the full list of AESI outcomes endorsed by the WHO Global Advisory Committee on Vaccine Safety, which has been widely used for the safety surveillance of COVID-19 vaccines; a range of events suggested by the European Medicines Agency–funded vACCine covid-19 monitoring readinESS (ACCESS) project; and “subacute thyroiditis,” “pancreatitis,” and “rhabdomyolysis,” as updated by the Coalition for Epidemic Preparedness Innovations–funded Safety Platform for Emergency vACcines (SPEAC) project [31,47,48]. These last 3 AESI outcomes have not yet been endorsed by the WHO but were included in this study following discussion and consensus reached between co-investigators and the Department of Health. All of the AESI outcomes have been identified as events potentially related to existing marketed vaccines, events related to vaccine platforms or adjuvants, or events that may be associated with COVID-19.

Our study outcomes consisted of various AESIs including autoimmune diseases, cardiovascular system diseases, circulatory system diseases, hepato-renal system diseases, nerve and central nervous system diseases, and respiratory system diseases. The list of AESIs investigated in this study is shown in S1 Table, where cases are defined by International Classification of Diseases–9th Revision, Clinical Modification (ICD-9-CM) diagnosis and procedure codes and laboratory parameters. Previous research validating ICD-9-CM diagnostic codes in Hospital Authority data estimated the positive predictive value at >85% [33]. The Hospital Authority database has previously been used extensively for COVID-19 vaccination safety and pharmacovigilance studies, one of which quantified risks of AESIs following COVID-19 vaccination [39,40]. Outcome events were recorded during the 21 days of post-vaccination follow-up, except for anaphylaxis, for which the observation period was restricted to 2 days after each vaccine dose. The secondary outcome of interest was all-cause mortality.

Covariates

Various demographic and clinical characteristics of the vaccinated individuals were considered in this analysis. As reported by previous studies [40,45,49-51], baseline covariates that were potential risk factors of AESIs were chosen. The following covariates were weighted between BNT162b2 and CoronaVac recipients for each dose (as elaborated the “Statistical analyses” section below): age, sex, any previous SARS-CoV-2 infection (defined as ever a positive result on the SARS-CoV-2 reverse transcription polymerase chain reaction [RT-PCR] test before COVID-19 vaccination), pre-existing comorbidities documented from 2018 (myocardial infarction [MI], peripheral vascular disease, cerebrovascular disease, coronary artery disease [CAD], chronic obstructive pulmonary disease, dementia, paralysis, diabetes with and without chronic complications, hypertension, chronic renal failure, mild and moderate-severe liver disease, ulcers, rheumatoid arthritis or other inflammatory polyarthropathy, acquired immune deficiency syndrome, malignancy, and metastatic solid tumor), medication use in the past 90 days (including renin–angiotensin-system agents, beta blockers, calcium channel blockers, diuretics, lipid-lowering agents, insulin, antidiabetic drugs, anticoagulants, antiplatelets, hormonal agents, antidepressants, non-steroidal anti-inflammatory drugs, drugs for gout, antiepileptic drugs, antiviral drugs, antibacterial drugs, and immunosuppressants), venue for vaccination (community vaccination center, clinic, or other), and the time interval between the administration of the first and second doses. Patients who had recovered from a previous SARS-CoV-2 infection were recommended to receive BNT162b2 at least 90 days after hospital discharge or CoronaVac at least 180 days after discharge [52]. There were no missing values in covariates, under the assumption that the absence of a medication record implies that the specific medication had neither been prescribed using the electronic prescribing system nor dispensed by the Hospital Authority. Similar to other database studies, the absence of a disease diagnosis in an individual’s lifetime records from the Hospital Authority database was treated as the individual being without that specific disease.

Statistical analyses

This study is based on a regulatory pharmacovigilance program set up by the regulatory authority (Department of Health) to monitor the safety of COVID-19 vaccine emergency use. A prospective study protocol or analysis plan was not separately developed in the design of this study; however, this study was part of an overall research program that was assessed by the regulatory authority (Department of Health), clinical data custodian (Hospital Authority), institutional review board, and funding body (Food and Health Bureau). We developed a protocol (S1 Protocol) when designing this study, which was followed and used for independent double checking of data analysis to ensure data quality and reproducibility. Statistical analyses were planned in November 2021 and conducted in November 2021 and March 2022.

The variables considered in the propensity score (PS) model were potential risk factors for AESI after vaccination, including age, sex, Charlson Comorbidity Index, pre-existing comorbidities, history of medication use, and history of AESI. History of AESI was defined as a history of any of the conditions, except mortality, listed in S1 Table from 2005 to the date of first dose COVID-19 vaccination. The background rate of AESIs would influence both the vaccination rate and risk of AESI; hence, it was added to the PS model. The probability of receiving either CoronaVac or BNT162b2 was estimated by the PS model. Inverse probability of treatment weighting (IPTW) using the PS was applied, followed by truncation of the 1st and 99th percentiles of the observed PS weighting distribution to account for extreme weights [53] (S1 Fig). Standardized mean differences (SMDs) of baseline covariates between CoronaVac and BNT162b2 recipients were calculated, with SMD < 0.1 indicating covariate balance [54].

Inverse-probability-of-treatment-weighted Poisson regression models with person-years as an offset term were fitted to estimate the incidence rate ratios (IRRs) and corresponding 95% confidence intervals (CIs) of AESIs comparing between CoronaVac and BNT162b2 recipients after each vaccine dose. For patient confidentiality and robustness of the results, IRRs were estimated only when there were at least 5 events for a specific AESI in both the BNT162b2 and CoronaVac groups. A sensitivity analysis was performed on the study outcomes excluding people with previous SARS-CoV-2 infection, who might have had an increased risk of various disease diagnoses in association with SARS-CoV-2 infection. The goodness of fit of the Poisson regression models was assessed by deviance chi-squared tests and overdispersion tests, which were conducted during the revision following referees’ comments [55].

All statistical analyses were performed using STATA version 16.0 (StataCorp, College Station, TX). A two-sided significance level of p < 0.05 was considered statistically significant.

This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist).

Results

Baseline characteristics

A total of 2,333,379 individuals had data linkage to electronic medical records of the Hong Kong Hospital Authority, and received at least 1 dose of BNT162b2 or CoronaVac from 23 February to 9 September 2021 (Fig 1). The first dose analysis included 1,308,820 BNT162b2 and 955,859 CoronaVac recipients. After excluding 22 recipients with mixed vaccine doses, 1,116,677 (85.3%) and 821,560 (85.9%) individuals were fully vaccinated with BNT162b2 and CoronaVac, respectively. BNT162b2 recipients were generally younger and healthier than CoronaVac recipients (Table 1). The distribution of PSs in the 2 vaccine groups after each dose greatly overlapped after weighting (S2 Fig). All baseline characteristics were balanced between groups, with SMD < 0.1 after PS weighting. Among fully vaccinated individuals, the mean (standard deviation) dosing interval was 22.8 (4.3) and 29.2 (5.2) days for the BNT162b2 and CoronaVac groups, respectively.

Table 1

Baseline characteristics of individuals who had received a first or second dose of BNT162b2 or CoronaVac from 23 February to 9 September 2021 in Hong Kong SAR, China.

Baseline characteristic	First dose recipients				Second dose recipients
	Before weighting			After weighting	Before weighting			After weighting
	Mean ± SD or N (%)		SMD	SMD	Mean ± SD or N (%)		SMD	SMD
	BNT162b2(N = 1,308,820)	CoronaVac(N = 955,859)			BNT162b2(N = 1,116,677)	CoronaVac(N = 821,560)
Age, years	45.7 ± 16.0	55.3 ± 14.1	0.63	0.02	45.9 ± 15.7	54.8 ± 13.9	0.59	0.02
Sex			0.03	0.00			0.03	0.00
Male	584,158 (44.6%)	439,928 (46.0%)			502,740 (45.0%)	383,164 (46.6%)
Female	724,662 (55.4%)	515,931 (54.0%)			613,937 (55.0%)	438,396 (53.4%)
Dosing interval, days	NA	NA	NA	NA	22.8 ± 4.3	29.2 ± 5.2	NA	NA
Venue for vaccination			NA	NA			NA	NA
Community vaccination center	1,264,703 (98.5%)	463,815 (50.3%)			1,099,211 (98.4%)	428,794 (52.2%)
Clinic	0 (0.0%)	441,526 (47.9%)			0 (0.0%)	378,865 (46.1%)
Other	19,249 (1.5%)	17,198 (1.9%)			17,377 (1.6%)	13,497 (1.6%)
Previous SARS-CoV-2 infectiona	4,642 (0.4%)	1,690 (0.2%)	0.03	0.00	422 (0.0%)	263 (0.0%)	0.00	0.00
Pre-existing comorbidities
Charlson Comorbidity Index	1.4 ± 1.5	2.2 ± 1.5	0.56	0.01	1.4 ± 1.5	2.1 ± 1.5	0.52	0.01
History of AESI	395,232 (30.2%)	382,549 (40.0%)	0.21	0.02	340,006 (30.4%)	323,326 (39.4%)	0.19	0.01
Myocardial infarction	1,662 (0.1%)	2,238 (0.2%)	0.03	0.00	1,347 (0.1%)	1,688 (0.2%)	0.02	0.00
Peripheral vascular disease	657 (0.1%)	881 (0.1%)	0.02	0.00	513 (0.0%)	653 (0.1%)	0.01	0.00
Cerebrovascular disease	11,591 (0.9%)	17,638 (1.8%)	0.08	0.00	9,374 (0.8%)	13,259 (1.6%)	0.07	0.00
Coronary artery disease	253,883 (19.4%)	343,413 (35.9%)	0.00	0.00	210,140 (18.8%)	274,353 (33.4%)	0.00	0.00
Chronic obstructive pulmonary disease	11,837 (0.9%)	11,324 (1.2%)	0.03	0.00	9,817 (0.9%)	8,954 (1.1%)	0.02	0.00
Dementia	251 (0.0%)	607 (0.1%)	0.02	0.00	203 (0.0%)	261 (0.0%)	0.01	0.00
Paralysis	321 (0.0%)	525 (0.1%)	0.02	0.00	252 (0.0%)	359 (0.0%)	0.01	0.00
Diabetes without chronic complication	75,440 (5.8%)	98,194 (10.3%)	0.17	0.00	62,113 (5.6%)	77,702 (9.5%)	0.15	0.00
Diabetes with chronic complication	2,366 (0.2%)	3,135 (0.3%)	0.03	0.00	1,832 (0.2%)	2,350 (0.3%)	0.03	0.00
Hypertension	177,913 (13.6%)	225,107 (23.6%)	0.08	0.00	148,978 (13.3%)	182,379 (22.2%)	0.07	0.00
Chronic renal failure	3,498 (0.3%)	4,901 (0.5%)	0.04	0.00	2,720 (0.2%)	3,708 (0.5%)	0.04	0.00
Mild liver disease	631 (0.0%)	708 (0.1%)	0.01	0.00	502 (0.0%)	568 (0.1%)	0.01	0.00
Moderate-severe liver disease	380 (0.0%)	426 (0.0%)	0.01	0.00	305 (0.0%)	326 (0.0%)	0.01	0.00
Ulcers	4,585 (0.4%)	6,086 (0.6%)	0.04	0.00	3,779 (0.3%)	4,953 (0.6%)	0.04	0.00
Rheumatoid arthritis or other inflammatory polyarthropathy	2,514 (0.2%)	2,061 (0.2%)	0.01	0.00	1,997 (0.2%)	1,647 (0.2%)	0.00	0.00
Malignancy	12,695 (1.0%)	12,068 (1.3%)	0.03	0.00	10,253 (0.9%)	9,386 (1.1%)	0.02	0.00
Metastatic solid tumor	1,094 (0.1%)	1,108 (0.1%)	0.01	0.00	840 (0.1%)	802 (0.1%)	0.01	0.00
Medication use in the past 90 days
Renin–angiotensin system agent	82,760 (6.3%)	101,285 (10.6%)	0.15	0.00	66,641 (6.0%)	78,660 (9.6%)	0.14	0.00
Beta blocker	46,915 (3.6%)	57,279 (6.0%)	0.11	0.00	37,359 (3.3%)	43,334 (5.3%)	0.10	0.00
Calcium channel blocker	124,214 (9.5%)	158,884 (16.6%)	0.21	0.00	101,220 (9.1%)	125,113 (15.2%)	0.19	0.00
Diuretic	11,455 (0.9%)	14,847 (1.6%)	0.06	0.00	8,929 (0.8%)	10,863 (1.3%)	0.05	0.00
Nitrate	7,081 (0.5%)	9,705 (1.0%)	0.05	0.00	5,550 (0.5%)	7,200 (0.9%)	0.05	0.00
Lipid-lowering agent	119,105 (9.1%)	146,738 (15.4%)	0.19	0.00	96,959 (8.7%)	114,869 (14.0%)	0.17	0.00
Insulin	7,284 (0.6%)	8,406 (0.9%)	0.04	0.00	5,527 (0.5%)	6,031 (0.7%)	0.03	0.00
Antidiabetic drug	63,170 (4.8%)	80,903 (8.5%)	0.15	0.00	50,403 (4.5%)	62,001 (7.5%)	0.13	0.00
Antiarrhythmic drug	579 (0.0%)	599 (0.1%)	0.01	0.00	445 (0.0%)	421 (0.1%)	0.01	0.00
Cardiac glycoside	739 (0.1%)	1,049 (0.1%)	0.02	0.00	560 (0.1%)	689 (0.1%)	0.01	0.00
Oral anticoagulant	2,924 (0.2%)	4,028 (0.4%)	0.03	0.00	2,167 (0.2%)	2,772 (0.3%)	0.03	0.00
Parenteral anticoagulant	396 (0.0%)	340 (0.0%)	0.00	0.00	261 (0.0%)	215 (0.0%)	0.00	0.00
Antiplatelet	32,943 (2.5%)	43,862 (4.6%)	0.11	0.00	26,140 (2.3%)	32,890 (4.0%)	0.09	0.00
Antifibrinolytic or hemostatic	4,946 (0.4%)	3,540 (0.4%)	0.00	0.00	4,116 (0.4%)	2,912 (0.4%)	0.00	0.00
Hormonal agent (contraceptive, HRT, SERM)	6,485 (0.5%)	4,039 (0.4%)	0.01	0.00	5,202 (0.5%)	3,045 (0.4%)	0.01	0.00
Glucocorticoid	6,252 (0.5%)	4,790 (0.5%)	0.00	0.00	4,784 (0.4%)	3,637 (0.4%)	0.00	0.00
Antidepressant	31,259 (2.4%)	26,354 (2.8%)	0.02	0.00	25,771 (2.3%)	21,280 (2.6%)	0.02	0.00
Bevacizumab	32 (0.0%)	23 (0.0%)	0.00	0.00	24 (0.0%)	13 (0.0%)	0.00	0.00
Tranexamic acid	4,921 (0.4%)	3,526 (0.4%)	0.00	0.00	4,093 (0.4%)	2,905 (0.4%)	0.00	0.00
Intravenous immunoglobulin	47 (0.0%)	28 (0.0%)	0.00	0.00	33 (0.0%)	15 (0.0%)	0.00	0.00
NSAID	72,371 (5.5%)	54,715 (5.7%)	0.01	0.00	62,948 (5.6%)	46,969 (5.7%)	0.00	0.00
Drug for gout	11,084 (0.8%)	12,782 (1.3%)	0.05	0.00	9,167 (0.8%)	10,295 (1.3%)	0.04	0.00
Antiepileptic drug	12,728 (1.0%)	10,132 (1.1%)	0.01	0.00	10,171 (0.9%)	7,498 (0.9%)	0.00	0.00
Drug for control of epilepsy	12,722 (1.0%)	10,125 (1.1%)	0.01	0.00	10,163 (0.9%)	7,493 (0.9%)	0.00	0.00
Antiviral drug	8,342 (0.6%)	8,192 (0.9%)	0.03	0.00	6,845 (0.6%)	6,587 (0.8%)	0.02	0.00
Antibacterial drug	38,297 (2.9%)	28,903 (3.0%)	0.01	0.00	31,342 (2.8%)	23,029 (2.8%)	0.00	0.00
Immunosuppressant	3,634 (0.3%)	2,336 (0.2%)	0.01	0.00	2,701 (0.2%)	1,772 (0.2%)	0.01	0.00
Adrenaline	91 (0.0%)	132 (0.0%)	0.01	0.00	60 (0.0%)	77 (0.0%)	0.00	0.00
Oral contraceptive	1,162 (0.1%)	388 (0.0%)	0.02	0.00	943 (0.1%)	320 (0.0%)	0.02	0.00
HRT	2,947 (0.2%)	1,711 (0.2%)	0.01	0.00	2,407 (0.2%)	1,374 (0.2%)	0.01	0.00
Hormonal agent in malignant disease	2,463 (0.2%)	1,960 (0.2%)	0.00	0.00	1,912 (0.2%)	1,372 (0.2%)	0.00	0.00

AESI, adverse event of special interest; HRT, hormone replacement therapy; NSAID, non-steroidal anti-inflammatory drug; SD, standard deviation; SERM, selective estrogen receptor modulator; SMD, standardized mean difference.

aPrevious SARS-CoV-2 infection was defined as ever having a positive result on the SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) test before COVID-19 vaccination.

AESIs and all-cause mortality after the first dose

Overall AESI and mortality rates per 100,000 doses were 65 and 3 cases, respectively, for the first dose of BNT162b2 administered, and 90 and 6 cases for the first dose of CoronaVac administered. There were 861 (1,566 per 100,000 person-years) and 850 (1,162 per 100,000 person-years) AESI cases within 21 days after the first dose of CoronaVac and BNT162b2, respectively (Table 2). The cumulative incidence rate of overall AESIs was very low relative to the number of first vaccine doses administered, i.e., 0.06% for BNT162b2 and 0.09% for CoronaVac. Frequently reported AESIs among CoronaVac and BNT162b2 recipients after the first dose were thromboembolism (431 and 290 per 100,000 person-years), anaphylaxis (134 and 376 per 100,000 person-years), CAD (271 and 157 per 100,000 person-years), arrhythmia (236 and 168 per 100,000 person-years), MI (180 and 104 per 100,000 person-years), and sleeping disturbance or disorder (131 and 167 per 100,000 person-years).

Table 2

Cumulative incidence and crude incidence rate of AESIs among first dose recipients of CoronaVac or BNT162b2 from 23 February to 9 September 2021 in Hong Kong SAR, China.

Outcome	BNT162b2 (N = 1,308,820)				CoronaVac (N = 955,859)
	Cumulative incidence(events/100,000 doses)		Crude incidence rate(events/100,000 person-years)		Cumulative incidence(events/100,000 doses)		Crude incidence rate(events/100,000 person-years)
	Cases with event	Rate	Estimate	95% CI	Cases with event	Rate	Estimate	95% CI
Overall AESIs	850	64.94	1,162	1,085.02, 1,242.63	861	90.08	1,566	1,463.42, 1,674.52
Guillain-Barré syndrome	2	0.15	2.73	0.33, 9.87	—	—	—	—
Acute disseminated encephalomyelitis	—	—	—	—	—	—	—	—
Sleeping disturbance or disorder	122	9.32	166.71	138.44, 199.05	72	7.53	130.93	102.45, 164.89
Acute aseptic arthritis	28	2.14	38.26	25.42, 55.30	34	3.56	61.83	42.82, 86.40
Type 1 diabetes	1	0.08	1.37	0.03, 7.61	1	0.10	1.82	0.05, 10.13
(Idiopathic) thrombocytopenia	10	0.76	13.66	6.55, 25.13	5	0.52	9.09	2.95, 21.22
Subacute thyroiditis	1	0.08	1.37	0.03, 7.61	—	—	—	—
Microangiopathy	3	0.23	4.10	0.85, 11.98	1	0.10	1.82	0.05, 10.13
Heart failure	21	1.60	28.69	17.76, 43.86	54	5.65	98.20	73.77, 128.12
Stress cardiomyopathy	—	—	—	—	—	—	—	—
Arrhythmia	123	9.40	168.08	139.69, 200.54	130	13.60	236.41	197.52, 280.71
Carditis	10	0.76	13.66	6.55, 25.13	3	0.31	5.46	1.13, 15.94
Thromboembolism	212	16.20	289.70	252.01, 331.43	237	24.79	431.01	377.88, 489.52
Coronary artery disease	115	8.79	157.14	129.74, 188.63	149	15.59	270.96	229.20, 318.13
Myocardial infarction	76	5.81	103.85	81.82, 129.98	99	10.36	180.03	146.32, 219.18
Venous thromboembolism	16	1.22	21.86	12.50, 35.50	10	1.05	18.18	8.72, 33.44
Arterial thromboembolism	104	7.95	142.11	116.12, 172.19	134	14.02	243.68	204.17, 288.61
Hemorrhagic disease	43	3.29	58.76	42.52, 79.14	47	4.92	85.47	62.80, 113.65
Single organ cutaneous vasculitis	2	0.15	2.73	0.33, 9.87	—	—	—	—
Acute liver injury	13	0.99	17.76	9.46, 30.38	11	1.15	20.00	9.99, 35.79
Acute kidney injury	95	7.26	129.81	105.03, 158.69	120	12.55	218.22	180.92, 260.93
Acute pancreatitis	17	1.30	23.23	13.53, 37.19	15	1.57	27.28	15.27, 44.99
Generalized convulsion	57	4.36	77.89	58.99, 100.91	42	4.39	76.37	55.04, 103.24
Meningoencephalitis	9	0.69	12.30	5.62, 23.34	1	0.10	1.82	0.05, 10.13
Transverse myelitis	—	—	—	—	—	—	—	—
Bell palsy	22	1.68	30.06	18.84, 45.51	37	3.87	67.28	47.37, 92.74
Acute respiratory distress syndrome	16	1.22	21.86	12.50, 35.50	16	1.67	29.09	16.63, 47.25
Erythema multiforme	2	0.15	2.73	0.33, 9.87	1	0.10	1.82	0.05, 10.13
Chilblain-like lesions	—	—	—	—	—	—	—	—
Anosmia, ageusia	—	—	—	—	—	—	—	—
Anaphylaxis	27	2.06	376	248.11, 547.77	7	0.73	134	53.73, 275.35
Multisystem inflammatory syndrome	—	—	—	—	—	—	—	—
Sudden death	9	0.69	12.30	5.62, 23.34	13	1.36	23.64	12.59, 40.42
Rhabdomyolysis	7	0.53	9.56	3.85, 19.71	6	0.63	10.91	4.00, 23.75
All-cause mortality	42	3.21	57.39	41.36, 77.57	53	5.54	96.38	72.19, 126.06

AESI, adverse event of special interest; CI, confidence interval. The cumulative incidence and crude incidence rate of some AESIs were not reported because the number of events for that AESI was 0.

AESIs and all-cause mortality reported after the first dose of CoronaVac were compared to BNT162b2 as a reference group (Table 3). Goodness-of-fit tests demonstrated adequate model fit for all Poisson regression models (S2 Table). Despite the slightly higher crude incidence rate of overall AESIs among first dose CoronaVac recipients than among BNT162b2 recipients, the incidence rates of overall (IRR = 0.98, 95% CI 0.89–1.08, p = 0.703) and specific AESIs during 21 days post-vaccination were generally comparable for the first dose of CoronaVac and BNT162b2 after weighting, except for Bell palsy (67 versus 30 per 100,000 person-years; IRR = 1.95, 95% CI 1.12–3.41, p = 0.018), anaphylaxis (IRR = 0.34, 95% CI 0.14–0.79, p = 0.012), and sleeping disturbance or disorder (IRR = 0.66, 95% CI 0.49–0.89, p = 0.006). Despite the slightly higher incidence rate of sleeping disturbance or disorder among BNT162b2 recipients than among CoronaVac recipients, the occurrence of this AESI was not concentrated in the days shortly after the first dose of BNT162b2 vaccination (S3 Fig). Hence its occurrence might not be correlated with initial reactogenicity. Meanwhile, no significant differences were identified for all-cause mortality comparing the first dose recipients of CoronaVac and BNT162b2 (IRR = 0.96, 95% CI 0.63–1.48, p = 0.868).

Table 3

Incidence rate ratio of AESIs among first dose and second dose recipients of CoronaVac versus BNT162b2 as the reference category (after weighting).

Outcome	First dose recipients			Second dose recipients
	IRR	95% CI	p-Value	IRR	95% CI	p-Value
Overall AESIs	0.98	0.89, 1.08	0.703	0.97	0.87, 1.08	0.545
Sleeping disturbance or disorder	0.66	0.49, 0.89	0.006	0.91	0.66, 1.27	0.586
Acute aseptic arthritis	1.33	0.79, 2.24	0.281	1.13	0.68, 1.90	0.636
(Idiopathic) thrombocytopenia	0.72	0.24, 2.16	0.555	—	—	—
Heart failure	1.59	0.94, 2.70	0.083	1.45	0.76, 2.74	0.256
Arrhythmia	0.90	0.69, 1.16	0.412	0.96	0.72, 1.27	0.764
Thromboembolism	0.94	0.78, 1.14	0.543	0.93	0.75, 1.15	0.501
Coronary artery disease	1.13	0.88, 1.44	0.354	1.13	0.86, 1.47	0.376
Myocardial infarction	1.18	0.87, 1.60	0.287	0.91	0.65, 1.28	0.603
Venous thromboembolism	0.58	0.26, 1.29	0.180	—	—	—
Arterial thromboembolism	1.02	0.79, 1.34	0.857	1.12	0.84, 1.50	0.446
Hemorrhagic disease	1.02	0.66, 1.57	0.932	0.63	0.38, 1.04	0.070
Acute liver injury	1.31	0.57, 2.98	0.523	0.59	0.21, 1.66	0.317
Acute kidney injury	1.09	0.82, 1.45	0.545	0.82	0.60, 1.11	0.194
Acute pancreatitis	1.08	0.51, 2.30	0.837	1.62	0.81, 3.24	0.173
Generalized convulsion	1.41	0.92, 2.17	0.117	0.73	0.43, 1.25	0.250
Bell palsy	1.95	1.12, 3.41	0.018	0.88	0.51, 1.51	0.641
Acute respiratory distress syndrome	0.81	0.40, 1.66	0.571	1.27	0.76, 2.13	0.360
Anaphylaxis	0.34	0.14, 0.79	0.012	—	—	—
Sudden death	0.97	0.39, 2.38	0.944	1.80	0.69, 4.73	0.232
Rhabdomyolysis	1.48	0.46, 4.79	0.513	—	—	—
All-cause mortality	0.96	0.63, 1.48	0.868	0.85	0.51, 1.40	0.516

AESI, adverse event of special interest; CI, confidence interval; IRR, incidence rate ratio. IRR was estimated only when there were at least 5 events for a specific AESI in both the BNT162b2 and CoronaVac groups.

AESIs and all-cause mortality after the second dose

Overall AESI and mortality rates per 100,000 doses were, respectively, 66 and 3 cases for the second dose of BNT162b2 administered and 88 and 4 cases for the second dose of CoronaVac administered. There were 720 (1,524 per 100,000 person-years) and 733 (1,141 per 100,000 person-years) AESI cases within 21 days after the second dose of CoronaVac and BNT162b2, respectively (Table 4). Similar to the results for the first dose, the cumulative incidence rates of overall AESIs were very low relative to the number of second vaccine doses administered, i.e., 0.07% for BNT162b2 and 0.09% for CoronaVac. Again, despite the slightly higher crude incidence rate of overall AESIs among second dose CoronaVac versus BNT162b2 recipients, the incidence rates of overall AESIs (IRR = 0.97, 95% CI 0.87–1.08, p = 0.545) and all-cause mortality (IRR = 0.85, 95% CI 0.51–1.40, p = 0.516) were comparable between recipients of CoronaVac and BNT162b2 after weighting (Table 3). Frequently reported AESIs after second dose CoronaVac and BNT162b2 vaccination were thromboembolism (385 and 266 per 100,000 person-years), CAD (271 and 157 per 100,000 person-years), arrhythmia (220 and 157 per 100,000 person-years), anaphylaxis (67 and 212 per 100,000 person-years), MI (148 and 107 per 100,000 person-years), and sleeping disturbance or disorder (146 and 142 per 100,000 person-years), consistent with results of the first dose. In contrast to the significant differences observed for Bell palsy (higher incidence rate for CoronaVac) and anaphylaxis and sleeping disturbance or disorder (higher incidence rates for BNT162b2) following the first dose, none of the AESIs investigated had demonstrated significant differences in incidence rate for second dose CoronaVac versus BNT162b2 (Table 3).

Table 4

Cumulative incidence and crude incidence rate of AESIs among second dose recipients of CoronaVac or BNT162b2 from 23 February to 9 September 2021 in Hong Kong SAR, China.

Outcome	BNT162b2 (N = 1,116,677)				CoronaVac (N = 821,560)
	Cumulative incidence(events/100,000 doses)		Crude incidence rate(events/100,000 person-years)		Cumulative incidence(events/100,000 doses)		Crude incidence rate(events/100,000 person-years)
	Cases with event	Rate	Estimate	95% CI	Cases with event	Rate	Estimate	95% CI
Overall AESIs	733	65.64	1,141	1,060.15, 1,226.98	720	87.64	1,524	1,414.58, 1,639.37
Guillain-Barré syndrome	—	—	—	—	—	—	—	—
Acute disseminated encephalomyelitis	—	—	—	—	1	0.12	2.12	0.05, 11.79
Sleeping disturbance or disorder	91	8.15	141.65	114.05, 173.91	69	8.40	145.98	113.59, 184.75
Acute aseptic arthritis	31	2.78	48.25	32.79, 68.49	31	3.77	65.59	44.56, 93.09
Type 1 diabetes	2	0.18	3.11	0.38, 11.25	—	—	—	—
(Idiopathic) thrombocytopenia	7	0.63	10.90	4.38, 22.45	1	0.12	2.12	0.05, 11.79
Subacute thyroiditis	—	—	—	—	—	—	—	—
Microangiopathy	2	0.18	3.11	0.38, 11.25	1	0.12	2.12	0.05, 11.79
Heart failure	15	1.34	23.35	13.07, 38.51	30	3.65	63.47	42.82, 90.61
Stress cardiomyopathy	—	—	—	—	—	—	—	—
Arrhythmia	101	9.04	157.21	128.05, 191.03	104	12.66	220.04	179.79, 266.62
Carditis	16	1.43	24.90	14.23, 40.44	2	0.24	4.23	0.51, 15.28
Thromboembolism	171	15.31	266.18	227.78, 309.21	182	22.15	385.09	331.17, 445.28
Coronary artery disease	101	9.04	157.21	128.05, 191.03	128	15.58	270.82	225.94, 322.00
Myocardial infarction	69	6.18	107.40	83.57, 135.93	70	8.52	148.10	115.45, 187.12
Venous thromboembolism	10	0.90	15.57	7.46, 28.62	4	0.49	8.46	2.31, 21.67
Arterial thromboembolism	82	7.34	127.64	101.51, 158.43	111	13.51	234.85	193.20, 282.82
Hemorrhagic disease	37	3.31	57.59	40.55, 79.38	29	3.53	61.35	41.09, 88.12
Single organ cutaneous vasculitis	1	0.09	1.56	0.04, 8.67	—	—	—	—
Acute liver injury	11	0.99	17.12	8.55, 30.64	6	0.73	12.69	4.66, 27.63
Acute kidney injury	91	8.15	141.65	114.05, 173.91	83	10.10	175.60	139.87, 217.69
Acute pancreatitis	14	1.25	21.79	11.91, 36.56	21	2.56	44.43	27.50, 67.92
Generalized convulsion	44	3.94	68.49	49.76, 91.94	22	2.68	46.54	29.17, 70.47
Meningoencephalitis	2	0.18	3.11	0.38, 11.25	1	0.12	2.12	0.05, 11.79
Transverse myelitis	—	—	—	—	1	0.12	2.12	0.05, 11.79
Bell palsy	34	3.04	52.92	36.65, 73.95	24	2.92	50.78	32.53, 75.55
Acute respiratory distress syndrome	25	2.24	38.91	25.18, 57.44	38	4.63	80.40	56.89, 110.35
Erythema multiforme	2	0.18	3.11	0.38, 11.25	2	0.24	4.23	0.51, 15.28
Chilblain-like lesions	—	—	—	—	—	—	—	—
Anosmia, ageusia	1	0.09	1.56	0.04, 8.67	—	—	—	—
Anaphylaxis	13	1.16	212	113.12, 363.30	3	0.37	67	13.74, 194.74
Multisystem inflammatory syndrome	1	0.09	1.56	0.04, 8.67	—	—	—	—
Sudden death	8	0.72	12.45	5.38, 24.54	13	1.58	27.50	14.64, 47.03
Rhabdomyolysis	4	0.36	6.23	1.70, 15.94	6	0.73	12.69	4.66, 27.63
All-cause mortality	34	3.04	52.92	36.65, 73.95	33	4.02	69.82	48.06, 98.05

AESI, adverse event of special interest; CI, confidence interval. The cumulative incidence and crude incidence rate of some AESIs were not reported because the number of events for that AESI was 0.

Sensitivity analysis

Results of the sensitivity analysis excluding vaccinated individuals with previous SARS-CoV-2 infection are presented in S3 Table. Overall, they were consistent with those of the main analysis, suggesting a comparable safety profile between the 2 vaccines, alongside a significantly higher incidence rate of Bell palsy, but lower incidence rates of anaphylaxis and sleeping disturbance or disorder, following first dose CoronaVac versus BNT162b2 vaccination.

Discussion

In this territory-wide cohort study, the risks of AESIs and all-cause mortality in temporal association with the first and second doses of CoronaVac and BNT162b2 were observed to be very low. Despite the slightly higher crude incidence rates of overall AESIs among CoronaVac recipients than among BNT162b2 recipients, the incidence rates of overall AESIs and all-cause mortality were comparable between the 2 vaccines after weighting, except for a significantly higher incidence rate of Bell palsy identified over the 21 days of post-vaccination follow-up for first dose CoronaVac versus BNT162b2 recipients, and lower incidence rates of anaphylaxis and sleeping disturbance or disorder observed for first dose CoronaVac versus BNT162b2 recipients. Notably, these significant associations did not persist during the follow-up period of the second dose vaccination. Also, the wider confidence intervals in the results of the sensitivity analysis for acute kidney injury suggested the difference was not significant, possibly caused by the small number of events following COVID-19 vaccination.

As with any vaccines and pharmaceutical products, anaphylaxis is a potential adverse event of major concern given its severe and life-threatening nature. Regarding the 2 different vaccine platforms in this study, the inactivated virus and fragments, as well as the adjuvant aluminum hydroxide, of CoronaVac have been suggested as possible allergens, while a possible allergen of BNT162b2 could be its polyethylene glycol (PEG) excipient [56,57]. Proposed mechanisms of allergic reactions to these 2 COVID-19 vaccines include IgE- and non-IgE-mediated reactions, mast cell and complement activation, and delayed hypersensitivity [56,57]. Compared to an estimated rate of anaphylaxis of 2.2 per million doses of CoronaVac [57], the administration of BNT162b2 was associated with higher rates of anaphylaxis, ranging from 4.7 to 13.7 per million doses, which could vary depending on the priority groups for vaccination [15,58,59]. Consistent with previous observations that anaphylaxis was clinically manifested more frequently after the first dose of either vaccine [57,59], it remains to be determined if these events would be considered anaphylaxis with previous sensitization to specific components of the vaccines, or anaphylactoid reactions occurring on their first exposure [60]. In line with the current literature, our results suggested a higher incidence rate of anaphylaxis after first dose BNT162b2 versus CoronaVac vaccination. While no fatal anaphylaxis with either vaccine has been reported so far, several cases of mortality in close temporal relationship with COVID-19 vaccination have raised major public concern, such as death possibly due to intracranial hemorrhage or myocarditis following BNT162b2 vaccination [61,62]. Nevertheless, autopsy and postmortem findings have not established a causal link between COVID-19 vaccination and death, given the multimorbidity status and relatively older ages of those who died, where decompensation could result from common side effects of immunization [63].

With respect to several neurological AESIs, our study was able to replicate the results of a case series and nested case–control study demonstrating a significantly higher incidence rate and odds of Bell palsy following the administration of CoronaVac versus BNT162b2, especially after the first vaccine dose [28]. Despite an imbalance in the number of cases found in COVID-19 mRNA vaccine trials [64], the risk of Bell palsy was not significantly increased with BNT162b2 vaccination compared to unvaccinated controls or across different risk intervals in surveillance studies [14,15,21,22]. Apart from an association with herpes zoster infection, autoimmunity might play a role in the development of Bell palsy, hence calling for an investigation into the immunomodulatory effects of viral antigens and adjuvants of different vaccine platforms [14,22,28].

Over the last decade, autoimmune/inflammatory syndrome induced by adjuvants (ASIA) has been proposed to collectively include a variety of post-vaccination phenomena associated with adjuvants and subsequent clinical manifestations of autoimmune diseases, for example, GBS, TM, and subacute thyroiditis [65,66]. In this study, IRR estimation for GBS, TM, and subacute thyroiditis were not performed owing to the very few cases recorded in our dataset. In fact, while both GBS and TM have not been investigated among CoronaVac recipients, BNT162b2 vaccination has not been shown to be associated with an elevated risk of either AESI, as other risk factors such as concomitant infections and autoimmunity might play a more prominent role in these 2 neurological disorders [15,21,67]. Regarding subacute thyroiditis, case reports have suggested that the aluminum adjuvant of CoronaVac, and cross-recognition between the SARS-CoV-2 spike protein of BNT162b2 and thyroid cell antigens, may induce this endocrine disorder [9,68]. Regarding the higher incidence rate of sleeping disturbance or disorder following a first BNT162b2 dose than following a first CoronaVac dose, there is a lack of evidence suggesting a correlation with initial reactogenicity. Based on our best knowledge and the current literature, we are unable to identify any biological or immunological mechanisms to explain sleeping disturbances following COVID-19 vaccination; hence, further investigation is needed.

Since the rollout of mass vaccination and continuous safety monitoring, numerous studies have concluded that BNT162b2 is potentially associated with an increased risk of myocarditis, especially among males under the age of 30 years and within the first week following second dose vaccination [14-16,69]. Despite the small number of cases and without an estimation of IRR in this study, higher crude incidence rates of carditis were consistently demonstrated among BNT162b2 versus CoronaVac recipients for both vaccine doses, and in particular after the second dose. The small number of carditis cases in this study may be attributed to our exclusion of vaccinated individuals under the age of 18 years old, as a significantly increased risk of acute myocarditis or pericarditis has been identified among male adolescents following BNT162b2 vaccination in local studies, especially after the second dose [18,70,71]. Based on the above observations, several mechanisms have been proposed regarding the development of myocarditis and pericarditis following COVID-19 mRNA vaccination, for instance, robust antibody response in younger recipients, hypersensitivity upon second exposure to the viral antigen, as well as cardiac inflammation mediated through cross-reactivity, molecular mimicry, or bystander activation [16,72]. Regarding arrhythmia, CAD, and MI, no significant differences in their incidence rates were identified between CoronaVac and BNT162b2 recipients in our cohort. For the mRNA vaccine, previous studies have shown comparable risks of these cardiac events in vaccinated individuals and unvaccinated controls, and across different risk intervals [14,15,23]; their incidences following the inactivated vaccine are yet to be evaluated, apart from 1 case of CAD and 1 case of coronary atherosclerosis reported in 1 of the clinical trials for CoronaVac [4].

Among the numerous COVID-19 vaccines administered worldwide, adenoviral vector vaccines have been associated with rare AESI of thromboembolism, thrombocytopenia, and hemorrhagic events [73,74], while the relationship of these AESIs with mRNA vaccines remain inconclusive. Studies have found no association between BNT162b2 vaccination and thromboembolic events compared to unvaccinated controls, a marginally increased risk of venous thromboembolism with COVID-19 mRNA vaccines during days 1–21 versus days 22–42 after vaccination, as well as increased IRR for arterial thromboembolism, cerebral venous sinus thrombosis, and ischemic and hemorrhagic stroke during post-vaccination follow-up in comparison to baseline periods of self-controlled case series [14,15,21,23]. While these events could be mediated by systemic inflammation in response to vaccination and immune responses of free-floating spike proteins interacting with angiotensin-converting enzyme 2 (ACE2) to promote platelet aggregation, BNT162b2 vaccination does not seem to favor these outcomes, nor does the inactivated vaccine CoronaVac [73-75]. Overall, the IRRs for the above AESIs were not statistically significant comparing between CoronaVac and BNT162b2 recipients of either dose.

The strengths of this population-based study included the large sample size of vaccinated individuals, and capturing the occurrence of rare AESIs after both the first and second doses of COVID-19 vaccines. Also, the small proportion of vaccinated individuals with previous SARS-CoV-2 infection would have minimized any effects of long COVID on specific AESIs. This territory-wide cohort study provided substantial evidence comparing the incidence rates of various AESIs and all-cause mortality following vaccination with an inactivated COVID-19 vaccine (CoronaVac) and an mRNA vaccine (BNT162b2, Comirnaty), which could be useful in safety monitoring comparing different vaccine platforms, and complementary to the current literature comparing vaccinated individuals to unvaccinated controls. Nevertheless, several study limitations of this analysis should be addressed. First, similar to all epidemiological studies, even though the demographic and clinical characteristics of vaccine recipients were balanced with PS weighting at baseline, residual confounding could still exist. Second, certain events might have been missed if patients were managed under the private healthcare system and without data linkage to the Hospital Authority; however, there is no reason why recipients of one type of vaccine would be more likely to use private care than recipients of the other type, and, consequently, use of private care is unlikely to affect the interpretation of our results. Third, the observed incidences of some AESIs were very low in this cohort, and our study might be underpowered to draw any definite conclusions about these AESIs; however, it is also reassuring that recipients of either vaccine were very unlikely to experience these serious AESIs. Lastly, our electronic medical records did not allow access to the free text, or contact with doctors or patients; therefore, we were unable to assess cases using the Brighton case definition of anaphylaxis and level of certainty [76].

By evaluating and comparing the safety profile of CoronaVac against BNT162b2 (Comirnaty), the first FDA-approved SARS-CoV-2 vaccine for COVID-19 prevention, this study could help inform the choice of inactivated COVID-19 vaccines, mainly administered in low- and middle-income countries with large populations, in comparison to the safety of mRNA vaccines. Despite the slightly higher crude incidence rates of overall AESIs among CoronaVac recipients than among BNT162b2 recipients, the 2 vaccine platforms had a similar safety profile after adjusting for baseline characteristics. As currently done for mRNA vaccines, clinical data and observational reports of COVID-19 vaccines should continue to be made publicly available for all vaccine platforms in a timely manner [77,78], as a means of facilitating the continuous monitoring of vaccine safety via pharmacovigilance and pharmacoepidemiology. Further research comparing the safety and efficacy of different novel COVID-19 vaccine platforms—as well as homologous versus heterologous boosting regimens and different numbers of booster doses administered—is urgently needed.

In this territory-wide cohort study, the incidence rates of AESIs (cumulative incidence rate of 0.06%–0.09%) and all-cause mortality following the first and second doses of CoronaVac and BNT162b2 vaccination were very low. The safety profiles of CoronaVac (inactivated COVID-19 vaccine) and BNT162b2 (mRNA vaccine) were generally comparable regarding various AESIs and all-cause mortality following the first and second doses, except for a significantly higher incidence rate of Bell palsy, and lower incidence rates of anaphylaxis and sleeping disturbance or disorder, among first dose CoronaVac recipients than among first dose BNT162b2 recipients. Long-term surveillance of the safety profile of COVID-19 vaccines should continue.

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.

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Definitions of adverse events of special interest (AESIs).

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Goodness-of-fit test for Poisson regression models.

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Sensitivity analysis of the study outcomes excluding people with previous SARS-CoV-2 infection.

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The observed propensity score weighting distribution after truncation of the 1st and 99th percentiles, by the first and second vaccine dose.

IPTW, inverse probability of treatment weighting.

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Distribution of propensity score density by the first and second vaccine dose before and after weighting.

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Distribution of the occurrence of sleeping disturbance or disorder within 21 days after the first dose of BNT162b2.

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Study protocol.

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7 Jan 2022

Dear Dr Wong,

Thank you for submitting your manuscript entitled "Adverse Events of Special Interest and mortality following the mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by Jan 11 2022 11:59PM.

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine

2 Mar 2022

Dear Dr. Wong,

Thank you very much for submitting your manuscript "Adverse Events of Special Interest and mortality following the mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines" (PMEDICINE-D-21-05271R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to three independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

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We expect to receive your revised manuscript by Mar 23 2022 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

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Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

1. From the academic editor: Please include additional high-level contextualization of the data in the Abstract, Results, and Discussion sections. Specifically, please discuss that less than 1% of vaccine doses were associated with an AESI, with the overall AESI rate slightly higher in CoronaVac compared to BNT162b2.

2. Title: Please revise your title according to PLOS Medicine's style. Your title must be nondeclarative and not a question. It should begin with main concept if possible. "Effect of" should be used only if causality can be inferred, i.e., for an RCT. Please place the study design ("A randomized controlled trial," "A retrospective study," "A modelling study," etc.) in the subtitle (ie, after a colon).

3. Data availability statement: Please clarify the availability of vaccination record data owned by the Department of Health in Hong Kong. If the data are owned by a third party but freely available upon request, please note this and state the owner of the data set and contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data.If the data are not freely available, please describe briefly the ethical, legal, or contractual restriction that prevents you from sharing it. Please also include an appropriate contact (web or email address) for inquiries (again, this cannot be a study author).

4. Competing Interests: Several authors report research funding or grants from Pfizer, the makers of the BNT162b2 vaccine. For authors with ties to industry, please indicate whether any of the interests has a financial stake in the results of the current study.

5. Abstract: Background: Please provide an additional sentence of context of why the study is important.

6. Abstract: Methods and Findings: Please also present some of the specific AESI and mortality results for first and second doses of each vaccine (e.g rates overall for AESI and mortality, and for some of the more common AESIs such as thromboembolism). Please also present results for some of the AESIs for which the two vaccines were generally comparable and more frequently reported.

7. Abstract: Conclusion: We suggest beginning the first sentence with: "In this study, we observed ..." and we suggest including a sentence to address the study implications.

8. Author summary: At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

9. Throughout: In-text citations: Please place in-text citations within square brackets, placed before the sentence punctuation, for example [1]. Where multiple references are cited, please do not include spaces within brackets.

10. Methods: Please ensure that the study is reported according to the STROBE guideline. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."

The STROBE guideline can be found here: http://www.equator-network.org/reporting-guidelines/strobe/

11. Methods: Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

12. Methods: Line 131: Please clarify as (Figure 1) here.

13. Methods: Line 172-175: Please explain here exactly how the AESI outcomes were adapted from the WHO Global Advisory Committee on Vaccine Safety list of AESI (e.g. the specific rationale for adding to the conditions listed in Table 4 of reference 28).

14. Methods: Line 185: Previous SARS-CoV-2 infection: Please provide some information as to how this covariate was assessed. In Table 1, this variable is indicated by “COVID-19 survivor” and it may help to provide a clear description of the definition of this measure.

15. Methods: Line 197: Please provide more specific information on how covariates “were taken into account” here.

16. Methods: Line 203: Please clarify how “history of AESI” is defined (for example, does this indicate a history of any of the conditions listed in Table S1, over the same time period over which other covariates/comorbidities were considered?).

17. Results: Line 272: “Nevertheless, none of the AESI investigated had demonstrated significant differences in the incidence rate comparing between second dose CoronaVac and BNT162b2 (Table 4).” It may be useful here to point out the results for comparisons for Bell’s palsy, anaphylaxis, and sleeping disturbance/disorder (those AESIs that differed significantly for the first dose).

18. Discussion: Please present and organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion.

19. References: Please use the "Vancouver" style for reference formatting, and please check each reference for NLM abbreviations for journal titles. Please see our website for other reference guidelines https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references

20. Table 1: Please provide numbers in addition to percentages. Please clarify if “Overall AESI” under “Pre-existing comorbidities” refers to the history of AESI conditions, prior to vaccination.

21. Tables 2 and 3: Please describe in the legend, the rationale for unreported incidence (for example, for ADEM).

22. STROBE Checklist: Thank you for including the STROBE Checklist. Please revise the checklist, referring to locations within the text by section and paragraph numbers, rather than page numbers (for example, Methods, Paragraph 1).

Comments from the reviewers:

Reviewer #1: This is an extremely original article, given the fact that comparison of the coronavac and BNT162b2 Covid vaccine safety can only be done in a very few countries, among which Hong Kong has the lead. I have the following comments:

* Introduction. Among the different tools to compare Covid vaccines's safety, disproportionallity analysis on the WHO pharmacovigilance database is a non specific way to generate safety signals. Please introduce the fact that this cannot be done to date for the Coronavac given that there is an incomplete and selective pharmacovigilance signals reporting Coronavac, which is not the case for the mRNA vaccines (Lancet Infect Dis. 2021 Nov; 21(11): 1490-1491. doi: 10.1016/S1473-3099(21)00646-0.).

* Page 5, line 99 to 110 needs complete rewriting. Here, there is an heterogenous mixture of signal detection and signal confirmation. We have very strong pharmacoepidemiological data for BNT162b2 Covid supporting lymphadenopathy, myocarditis, pericarditis, herpes zoster infections, and potentially appendicitis, but not the other (http://www.nejm.org/doi/10.1056/NEJMoa2110475).

* Page 6, line 128. Please specify the source of BNT162b2 vaccines, are those tozinameran?

* The nature of the sleeping disturbances following the first BNT162b2 dose is intriguing and not previously reported, could you check whether this is correlated to the initial reactogenicity?

* One major interest of the study is the population based cohort, and the ability to try to take into account a larger variety of confounding biais. However, residual biais are still likely given that the initial population strickingly differs. The authors ackowledged that in the discussion. I do not need to see E-values here

* Overall, the study adds few to the numerous data already available for BNT162b2 Covid vaccine safety. The major interest is the comparison with Coronavac, for which data are new. I think that the discussion could briefly introduce the fact that publicly available reports of continuous monitoring of vaccine's safety through pharmacovigilance and pharmacoepidemiology, as done for mRNA vaccines is mandatory for all vaccines platforms.

Jean-Luc Cracowski, Univ Grenoble Alpes, FR

Reviewer #2: Thanks for the opportunity to review your manuscript. My role is as a statistical reviewer so my comments focus on the study design, data and analysis presented in the manuscript. I have put general comments first, and followed these with queries relevant to a specific section of the manuscript (with a page/line reference).

This is a retrospective cohort study based in the Hong Kong SAR in China, comparing AESI and mortality between people who received the Pfizer-BioNTech to those that received the CoronoVac/Sinovac Covid-19 vaccine. The temporal window for risk of the outcomes was examined for several definitions - the main being from data of either first or second vaccination. Propensity scores were estimated and then used to weight the cohort to balance on the observed covariates. The outcomes were a list of particular vaccine safety AESIs, and all-cause mortality. Poisson regression was used to estimate IRRs for the AESIs and mortality. The study included data from Feb 2021 to- September 2021 - the data is very fresh. The IRR showed similar overall rates of the selected AESIs between vaccines (and can exclude any large or medium differences) with some differences for particular AESIs. In theory mortality is a competing outcome for the AESIs, but mortality was rare enough over the study period it would be highly unlikely to bias the results. The sensitivity analysis showed broadly similar results - I note that AKIs in in the sensitivity analysis showed a difference between groups but these were uncommon and the IRR CI interval is quite wide.

One thing I would like clarified - there introduction states the choice of vaccine was up to the individual, but where there any guidelines that some people should get a particular vaccine or differences in service delivery that might lead to a difference in availability?

Was a protocol or statistical analysis plan developed for the study? If so, can this be made available as part of the review?

P6, L137. Was the unique mapping key a health insurance ID or similar?

P8, L173. Were the adaptions made to exclude conditions unlikely to be recorded from the EHR data available?

P9, L201. What criteria was used to decide which of the covariates should be included in the PS model?

P9, L205. What were the observed weights of these 1/99 percentiles of the weighting distribution?

P9, L208. Was common-support (sufficient overlap in PS scores) between the two groups apparent? Could a visualisation of this be included in the supplementary materials please?

P9, L210. Were any assessments of model goodness of fit included of the Poisson regression models?

Supp Appendix, Table 2 (and throughout the main tables). Even with a population-based study, 2 decimal places for the IRRs and 95% CI should be ok.

Reviewer #3: This is an impressive paper worthy of publication.

I was struck by the statement that there were no missing data in the covariates (line 199).

In the Methods it was stated that the ICD 9th Revision (ICD-9-CM) was used for definitions of AESI (line 176). Is this a more flexible definition of anaphylaxis than the Brighton criteria?

You may wish to consider a statement in the Methods or Discussion that clarifies this.

Any attachments provided with reviews can be seen via the following link:

[LINK]

24 Mar 2022

Submitted filename: PMEDICINE-D-21-05271R2 Response to reviewers 20220321.docx

Click here for additional data file.

28 Apr 2022

Dear Dr. Wong,

Thank you very much for re-submitting your manuscript "Adverse Events of Special Interest and mortality following the mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines: A retrospective study" (PMEDICINE-D-21-05271R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by two reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by May 05 2022 11:59PM.

Sincerely,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

1. Title: Please use sentence capitalization for the title, and please update the title in both the manuscript submission system and the manuscript document. Please also revise the title to: “Adverse events of special interest and mortality following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines in Hong Kong: A retrospective study”

2. Abstract: Methods and Findings: Lines 57-64: Please also report the associated p values, in addition to the 95% CIs, for comparisons between CoronaVac and BNT162b2.

3. Abstract: Methods and Findings: Please move the study limitations sentence to the end of the Methods and Findings paragraph, deleting the break at line 65.

4. Abstract: Line 77: Please use “low and middle income countries” instead of “developing countries” if this is what is meant.

5. Line 119: Please remove “Manuscript Text” from the document.

6. Results: Line 362: Please re-word this as “AESI and all-cause mortality reported after the first dose of CoronaVac were compared to BNT162b2 as a reference group (Table 3).” if this is accurate.

7. Discussion: Line 443: We suggest “ in view of the multimorbidity status and relatively older ages of the deceased” if this is accurate.

8. Discussion: Line 476: We suggest that “younger” is not needed in the sentence “...especially among younger males under the age of 30…”

9. Discussion: Line 538: Please use “low and middle income countries” instead of “developing countries” if this is what is meant.

10. Line 562: Please remove the Ethical Approval description from this location. Please ensure that the study approvals, information on data anonymization, and participant consent waiver are completely described in the relevant place in the Methods (line 216).

11. Line 568: Availability of data and materials: Please remove this section from this location in the text. Please ensure that this information is completely and accurately entered into the data availability section of the manuscript submission metadata. In the event the article is accepted for publication, this information will be included.

12. Line 581: Competing Interests: Please remove this section from this location in the text. Please ensure that this information is completely and accurately entered into the competing interests section of the manuscript submission system. In the event the article is accepted for publication, this information will be included.

13. Line 609: Funding: Please remove this section from this location in the text. Please ensure that this information is completely and accurately entered into the funding section of the manuscript submission system. In the event the article is accepted for publication, this information will be included.

14. Line 615: Author contributions: Please remove this section from this location in the text. Please ensure that this information is completely and accurately entered into the author contributions section of the manuscript submission system. In the event the article is accepted for publication, this information will be included.

15. References: Please check each reference for formatting, including the NLM abbreviations for journal titles. Please use the "Vancouver" style for reference formatting, and see our website for other reference guidelines https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references

Please update references 45, 50,69, 70 with complete information.

16. S1 Figure: Please define IPTW in the legend.

Comments from Reviewers:

Reviewer #1: The authors answered all queries. I have no further comment

Reviewer #2: Thanks for the revised manuscript and responses to my initial queries. This is an excellent study and I recommend it should be published. Just one small change to the abstract (below).

The extra information about the study plan makes sense - that this is part of a wider surveillance study. There is clearly common support - this could be used as an example in teaching of appropriate amount of overlap of the PS. The weights looks reasonable with the trimming applied - no extreme weights indicating issues with PS estimation. The Poisson distribution clearly fits well from the extra info in S2_table.

L67. I would just clarify slightly "..possibility of being underpowered for some AESI with very low observed incidences" as for many of the important AESI you are very well powered!

Any attachments provided with reviews can be seen via the following link:

[LINK]

29 Apr 2022

Submitted filename: PMEDICINE-D-21-05271R2 Rebuttal letter 20220429.docx

Click here for additional data file.

9 May 2022

Dear Dr Wong,

On behalf of my colleagues and the Academic Editor, Amitabh Bipin Suthar, I am pleased to inform you that we have agreed to publish your manuscript "Adverse events of special interest and mortality following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines in Hong Kong: A retrospective study" (PMEDICINE-D-21-05271R3) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process.

Please also address the following editorial requests:

-Data availability statement: In the last sentence, please also mention that Hospital Authority data access inquiries can be directed to hacpaaedr@ha.org.hk.

-Line 91: We suggest “A territory-wide, retrospective cohort study of individuals who had received at least one dose of BNT162b2 (mRNA-based vaccine, Comirnaty) or CoronaVac (inactivated SARS-CoV-2 vaccine) from 23rd February to 9th September 2021 in Hong Kong was conducted to compare the occurrence…”

-Line 108-109: We suggest revising to: “...which adds to the real-world evidence on the safety of both COVID-19 vaccines, and may help reduce vaccine hesitancy by addressing safety concerns.”

-Line 110: We suggest changing “would inform” to “may inform” in this sentence.

-References: Please correct the formatting of each reference, including the NLM abbreviations for journal titles. For example, please use “Nat Rev Immunol” for reference 1. Please use “Lancet” for reference 3. Please use “Lancet Infect Dis” for reference 5. Please correct throughout.

PRESS

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To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper.

Sincerely,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine