Estimation of Vaccine Effectiveness of CoronaVac and BNT162b2 Against Severe Outcomes Over Time Among Patients With SARS-CoV-2 Omicron

Key Points Question Does vaccine effectiveness against hospitalization and mortality due to the SARS-CoV-2 Omicron variant change over time? Findings In this case-control study with 164 151 participants, the CoronaVac and BNT162b2 vaccines were generally estimated to be effective against severe outcomes due to SARS-CoV-2 Omicron infection, but protection among older individuals was more likely to wane 6 months after the second dose. Meaning These findings suggest that a booster dose should be recommended to older individuals to restore immunity, and this is especially urgent for a setting like Hong Kong, where third-dose coverage is still insufficient among older residents.


Introduction
7][8] Unfortunately, the rapidity and scale of the Omicron outbreak became uncontrollable in Hong Kong in early 2022.The daily COVID-19 death rate was among the highest ever recorded. 9,10In early 2021, the Hong Kong government authorized the free distribution of COVID-19 vaccines BNT162b2 mRNA vaccine (Pfizer-BioNTech) and CoronaVac inactivated vaccine (Sinovac) to the resident population.Approximately 85% of the population had received the second dose of the COVID-19 vaccine by June 5, 2022. 11 To date, few studies have assessed the waning of protection against severe outcomes caused by SARS-CoV-2 Omicron infection.In this study, we used the official linked data to estimate how vaccine effectiveness (VE) against hospitalization and mortality changed over time after vaccination in patients with SARS-CoV-2 Omicron in Hong Kong, where the population had minimal protection against infections before the Omicron variant emerged.

Methods
This is a case-control study using the linked administrative data.The Department of Health (DH) of the Government of the Hong Kong Special Administrative Region (HKSAR) permitted us to use the database in this investigation.All study data were completely anonymized.Ethics approval was obtained from the Survey and Behavioral Research Ethics Committee, The Chinese University of Hong Kong.Because this study was a retrospective analysis using secondary data with no personal information, the requirement for obtaining informed consent was waived.This study followed Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines for case-control studies.

Data Sources
The data on registered patients with COVID-19 obtained from DH were linked to the vaccination database, which centralized population-based electronic vaccination records, including the date and type of each dose for Hong Kong residents who had been vaccinated.We also linked the hospital admissions database for patients with infection.The admission database was provided by the Hong Kong Hospital Authority, a statutory body managing all public hospitals in Hong Kong.

Case-Control Design
The risk of hospitalization and death due to the SARS-CoV-2 Omicron variant was estimated using a case-control design in the vaccinated population vs the unvaccinated population.Data analysis was limited to an Omicron-predominant period spanning January 1 to June 5, 2022.
We used all registered patients with COVID-19 during the study period as our primary study Omicron status of patients with PCR-confirmed COVID-19 was determined by genomic sequencing based on the defining mutations (N501Y and E484A).Due to laboratory capacity being overwhelmed by the rapid and massive increase in cases from no infections to more than 50 000 cases daily, the DH launched a self-registration system for PCR test and RAT results in mid-February 2022, a period dominated by the SARS-CoV-2 Omicron variant.While the variant status of all patients was not confirmed by genomic sequencing, subsampling revealed more than 99% of the specimens sequenced carried the mutated strain of the Omicron variant.Imported cases were excluded from the analysis.Aside from all registered patients, we included all patients aged 18 years or older who were hospitalized in public hospitals and were diagnosed with a COVID-19 infection by PCR test as a secondary study population.

Study Outcomes
We used hospitalization or COVID-19 death, defined as the death episode with a positive test result, as a proxy for severe outcomes in the primary study population.The mortality data were corroborated by the birth and death records of HKSAR government, representing a complete coverage of deaths in Hong Kong.In the analysis of the hospitalization outcome, we excluded patients with COVID-19 who became infected during their hospital stay by excluding those whose PCR confirmation date was more than 3 days after admission.The data for this analysis did not include those admitted before week 6 in 2022; during that period, all confirmed cases were hospitalized regardless of clinical status following the government's COVID-19 patient management policy.After the Omicron outbreak, the admission policy was changed, and only patients in severe or critical condition were admitted to hospitals. 12The number of days from the last dose (second or third dose) to the hospitalization or death date was used to calculate the time from vaccination to hospitalization or death.For the analyses of the hospitalized population, only COVID-19 death was used as the study outcome.

Case and Control Groups
In the analysis of all the registered patients, case participants were the patients with COVID-19 who had the defined study outcomes (ie, hospitalization and death or death), and control participants were patients infected with SARS-CoV-2 who did not experience the study outcomes before the cutoff date.Because of the scarcity of individual-level data available for the community control population, case and control participants were only matched by age, sex, and the calendar date of COVID-19 infection.
In the analysis of the hospitalized patients, case participants were the patients with COVID-19 who had a positive PCR test on admission and died while hospitalized.Patients with SARS-CoV-2 who were hospitalized and alive before the cutoff date served as control participants.Given that clinical information could be linked to the hospitalization database, case and control participants were matched by the covariates of age, sex, chronic conditions or cancer, and use of oral COVID-19 treatment drugs (molnupiravir or paxlovid) or other coronavirus medications.
The propensity score method was performed for all case-control matches in a 1:4 ratio by using the nearest neighbor method without replacement, and the scores were determined by the logit link model regressing on the matching variables.We tested the robustness of the results by setting the matching ratio to 1:1 or 1:2.

Exposure Assessment
Only individuals who received the BNT162b2 or CoronaVac vaccines were included in the analysis.
Given the latency between vaccine ingestion and full development of immune responses, only a dose taken within 14 days of infection was considered a completed dose in the study.

JAMA Network Open | Public Health
Estimated Effectiveness of CoronaVac and BNT162b2 Over Time Among Patients With SARS-CoV-2 Omicron

Statistical Analysis
The baseline characteristics of the case participants and matched control participants in the 2 study populations were descriptively compared.The adjusted odds ratio (AOR) for the association between vaccination and death was estimated using conditional logistic regression controlling for covariates.VE against the severe outcome was calculated as 1 − AOR.The 95% CIs of VE estimates were constructed by bootstrapping with 1000 resampled data sets with replacement.VE was compared across age groups (ie, 18-49, 50-64, 65-79, and Ն80 years), vaccine types, and number of doses.To assess the change in effectiveness over time, we estimated the VE of each vaccine for each period following vaccination (ie, 0-3, 4-6, and >6 months) using conditional logistic regression.

Results
In all registered patients, 9362 deaths and 37 488 matched controls were included in the analysis of death outcome, whereas 32 832 case participants with death or hospitalization and 131 328 matched controls were included in the analysis of the death or hospitalization outcome (Figure 1).In the hospitalized population, 6602 deaths and 24 513 matched controls were included in the analysis of death outcome.To control for confounding by exposure risk during the Omicron epidemic, case and control participants were matched by calendar week (eFigure 1 in Supplement 1).
The characteristics of the case and control participants were generally balanced within each of the matching groups (Table 1).In the case group (n = 32 832) of the 164 160 registered patients in the analysis of the hospitalization or death outcome, 3149 (9.6%), 4137 (12.6%), 9104 ( 95% CI, 59.7%-64.7%)were preserved at 6 months and longer after the last dose in all registered patients (Table 2).The changes in VE of the 3 doses over time were similar across vaccine types (Figure 2).Specifically, the VE of CoronaVac, BNT162b2, and the mixed doses against death at 4 to 6 Across age groups, both types of vaccines were less effective in older groups (eFigure 2 in Supplement 1).In registered patients, VE against death in patients aged 18 to 49 years was 86.4% (95% CI, 85.8%-87.0%)and 92.9% (95% CI, 92.6%-93.2%)for those receiving 2 doses of CoronaVac and BNT162b2, respectively, while for patients aged 80 years or older, it lowered to 61.4% (95% CI, 59.8%-63.2%)and 52.7% (95% CI, 50.2%-55.6%),respectively.Furthermore, there was a pronounced decline in VE for older individuals in the hospitalized population even after controlling for covariates (Figure 3).The median survival time of the protection against death for 2 doses of CoronaVac and BNT162b2 in hospitalized patients aged 80 years or older was 323 days (95% CI, 313-330 days) and 330 days (95% CI, 315-341 days), respectively.Nonetheless, vaccine effectiveness for a 3-dose schedule remained greater than 90.0% for all vaccine types in the total sample (eg, mixed vaccines: vaccine effectiveness, 92.2%; 95% CI, 89.2%-95.1%),greater than 80.0% for all vaccine types in each age group, and there was no discernible difference in the decline of vaccine protection following the third dose across age groups (eFigure 3 in Supplement 1).b VE was calculated as 1 − the adjusted odds ratio, which was obtained using a conditional logistic regression model adjusted with the covariates.The unvaccinated group was used as the reference level compared with the vaccinated group in a specific subgroup (ie, vaccine type and time after dose).Time after dose (in months) is defined as the time since the last dose (second or third) to hospitalization or death for vaccinated individuals.One thousand bootstrapped samples were used to construct the 95% CI around the mean estimates.
c The estimates cannot be drawn due to insufficient size of outcome.

Discussion
The sudden influx of infections caused by the Omicron variant in early 2022 overwhelmed the health system and depleted critical care resources in Hong Kong.In this study using linked administrative data, we found that the VE of 2 or 3 doses of mRNA or inactivated vaccine was estimated to remain durable over time.The results are generally consistent with other studies, [13][14][15][16] including one in Qatar where the VE of BNT162b2 against severe Omicron outcomes was estimated to be 77.5% in 7 months The survival probability was determined by using the conditional Cox proportional hazard model adjusted with the covariates.Time from vaccination to an event was calculated as the number of days between the date of the last dose and the date of an event.The shaded areas represent 95% CIs. after 2 doses and 90.1% in 7 weeks after 3 doses. 13Similarly, a study from England found that the VE of mRNA vaccines against severe outcomes caused by Omicron infection was greater than 80% 14 days after the second dose in patients aged 18 to 64 years and greater than 90% 7 to 104 days after the booster dose in patients aged 65 years and older. 14r study assessed VE in the hospitalized population.In a cohort study of hospitalized older patients with COVID-19 infections during the Omicron wave in Israel, 3 doses of BNT162b2 did not The survival probability was determined by using the conditional Cox proportional hazard model adjusted with the covariates.Time since vaccination to an event was calculated as the number of days between the date of the second dose and the date of an event.The shaded areas represent 95% CIs.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 2.

Additional Contributions:
We thank Hospital Authority and Department of Health, Hong Kong government, for providing the data for this study.The Centre for Health Systems and Policy Research funded by the Tung Foundation is acknowledged for the support throughout the conduct of this study.
population.Patients with COVID-19 aged 18 years or older with a positive result from a polymerase chain reaction (PCR) test or rapid antigen test (RAT) were included.Before mid-February 2022, the JAMA Network Open | Public Health Estimated Effectiveness of CoronaVac and BNT162b2 Over Time Among Patients With SARS-CoV-2 Omicron Vaccine protection over time, defined as the time from the last dose (second or third) to hospitalization or death for vaccinated individuals, was examined using the conditional Cox proportional hazard model adjusted for the covariates and is presented using the adjusted survival curves with an estimate of the median survival time of protection.Time from the last dose to infection was adjusted in the Cox model to control the temporal variation of coverage of the 2 vaccine types.A cutoff date of June 19, 2022, was used as the right censoring of the death outcome.R version 3.6 (R Project for Statistical Computing) was used for all the statistical analyses.Because this study used a large official administrative database with a high study power, no hypothesis testing was carried out.

Figure 2 .
Figure 2. Survival Distribution of Time Since the Second and Third Doses of Vaccination to an Event by Vaccine Type

Figure 3 .
Figure 3. Survival Distribution of Time After the Second Dose of Vaccination to an Event by Age Group

Table 1 .
Characteristics of Cases and ControlsEstimated Effectiveness of CoronaVac and BNT162b2 Over Time Among Patients With SARS-CoV-2 Omicron Abbreviations: NA, not applicable; PCR, polymerase chain reaction; RAT, rapid antigen test.a All registered patients included those aged 18 years or older who were diagnosed with a positive PCR test or RAT during the study period.b Hospitalized patients included all local patients aged 18 years or older who were hospitalized and diagnosed with Omicron infection by genomic sequencing.Their hospitalization records were linked with the test results to provide details on comorbidities and inpatient treatment received.JAMA Network Open | Public Health JAMA Network Open.2023;6(2):e2254777.doi:10.1001/jamanetworkopen.2022.54777(Reprinted) February 3, 2023 6/13 Downloaded From: https://jamanetwork.com/ on 09/28/2023

Table 2 .
Estimated VE Against Severe Outcomes of SARS-CoV-2 Omicron Infection by Vaccine Type, Number of Doses, and Time After Dose There were 5813 deaths among 19 651 unvaccinated patients and 15 304 hospitalizations among 44 360 unvaccinated patients in all registered patients.There were 4605 deaths among 16 040 unvaccinated patients in the hospitalized group. a