Assessment of Effectiveness of 1 Dose of BNT162b2 Vaccine for SARS-CoV-2 Infection 13 to 24 Days After Immunization

IMPORTANCE The BNT162b2 vaccine showed high efficacy against COVID-19 in a phase III randomized clinical trial. A vaccine effectiveness evaluation in a real-world setting is needed. OBJECTIVE Toassesstheshort-termeffectivenessofthefirstdoseoftheBNT162b2-vaccineagainst SARS-CoV-2 infection 13 to 24 days after immunization in a real-world setting. DESIGN, SETTING, AND PARTICIPANTS This comparative effectiveness study used data from a 2.6 million-member state-mandated health care system in Israel. Participants included all individuals aged 16 years and older who received 1 dose of the BNT162b2 vaccine between December 19, and January 15, 2021. Data were analyzed in March 2021. EXPOSURE Receipt of 1 dose of the BNT162b2 vaccine. MAIN OUTCOMES AND MEASURES Information was collected regarding medical history and positive SARS-CoV-2 polymerase chain reaction test and COVID-19 symptoms from 1 day after first vaccine to January 17, 2021. Daily and cumulative infection rates in days 13 to 24 were compared with days 1 to 12 after the first dose using Kaplan-Meier survival analysis and generalized linear models. RESULTS Data for 503875 individuals (mean [SD] age, 59.7 [14.7] years; 263228 [52.4%] women) were analyzed, of whom 351897 had follow-up data for days 13 to 24. The cumulative incidence of SARS-CoV-2 infection was 2484 individuals (0.57%) during days 1 through 12 and 614 individuals (0.27%) in days 13 through 24. The weighted mean (SE) daily incidence of SARS-CoV-2 infection in days 1 through 12 was 43.41 (12.07) infections per 100000 population and 21.08 (6.16) infections per 100000 with 25.3 doses per 100 capita. 7 The aim of this study is to assess the short-term effectiveness of 1 dose of BNT162b2 in reducing infection with SARS-CoV-2 in real-world settings. In light of the RCT results, our hypothesis was that the cumulative incidence of SARS-CoV-2 infection among individuals who received the BNT162b2 vaccine would decline after 12 days after immunization compared with the incidence during the preceding 12 days.


Introduction
The recently authorized BNT162b2 COVID-19 vaccine (BioNTech, Pfizer) has demonstrated 95% efficacy in preventing COVID-19 with the 2-dose regimen in a phase III placebo-controlled randomized clinical trial (RCT), 1 with the second dose given 21 days after the first vaccine dose. The European Medicines Agency has approved the BNT162b2 vaccine, as 2 doses separated by at least 21 days, for emergency use. 2 In light of the peaking outbreak of COVID-19, UK authorities decided to vaccinate a large number of people with high risk in the shortest possible time by postponing the second dose toward the maximal recommended vaccine dosing schedule (12 weeks). 3 The same immunization approach is also being considered in other countries and by the World Health Organization in view of limited doses of vaccine currently available for mass vaccination. 4 Accordingly, there is a global need to understand the real-world short-term effectiveness of the vaccine after the first dose.
The BNT162b2 RCT 1 showed vaccine efficacy of 52% (95% CI, 29.5%-68.4%) between the first dose and the second dose, with reduction in risk compared with the placebo starting as soon as 12 days after the first dose. This is comparable with the minimal acceptable level of efficacy of 50% in preventing COVID-19 as indicated by the World Health Organization 5 and by the US Food and Drug Administration 6 as one of the essential criteria to confer emergency use approval to COVID-19 candidate vaccines. However, the effectiveness of the new vaccine in protecting against infection is difficult to assess in phase III RCTs. Instead, it requires large phase IV studies in real-world settings where the vaccine is widely deployed. 5 Furthermore, assessment of the vaccine effectiveness in real life outside of clinical trial settings is warranted, especially given the complex and unusual storage and handling requirements of BNT162b2 vaccine.
In Israel, vaccination against SARS-CoV-2 using the BNT162b2 mRNA vaccine started on December 19, 2020, with priority given to individuals aged 60 years or older, health care workers, and individuals with high risk. On January 15, 2021, Israel was ranked first in vaccination doses, with 25.3 doses per 100 capita. 7 The aim of this study is to assess the short-term effectiveness of 1 dose of BNT162b2 in reducing infection with SARS-CoV-2 in real-world settings. In light of the RCT results, our hypothesis was that the cumulative incidence of SARS-CoV-2 infection among individuals who received the BNT162b2 vaccine would decline after 12 days after immunization compared with the incidence during the preceding 12 days.

Methods
This comparative effectiveness study obtained ethical approval from Maccabi Healthcare Services Ethics Committee and was granted a waiver from informed consent for analysis of deidentified data.
This study followed the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) reporting guideline.

Study Design and Data Sources
This comparative effectiveness study was conducted using data from a single health care system to estimate the short-term effectiveness associated with the first dose of the BNT162b2 vaccine against SARS-2-CoV-2 infection in a real-world setting. Data sources were the central databases of Maccabi Healthcare Services (MHS), a 2.6 million-member state-mandated, nonprofit, health maintenance organization (HMO) in Israel, representing one-quarter of the population of Israel. Membership in HMOs is compulsory in Israel, and by the National Health Insurance Law of 1994, all citizens must freely choose 1 of 4 national HMOs that are prohibited by law from denying membership to any Israel resident. The data set included extensive demographic data, anthropometric measurements, clinic and hospital diagnoses, medication dispensed, and comprehensive laboratory data from a single central laboratory. In Israel, everyone is assigned a unique person-specific alphanumeric identifier, called a National Health Index Number, which is used across all health systems, including in these data sets, thereby enabling data linkage.

JAMA Network Open | Infectious Diseases
We used data linkage to assign vaccine exposure, collect information regarding medical history and positive results in a SARS-CoV-2 polymerase chain reaction (PCR) test. 8

Study Population and End Point
Our study population consisted of all MHS members aged 16 years or older who were vaccinated during a mass immunization program from December 19, 2020, through January 15, 2021. We used as reference the results of the phase III RCT 1 that provided experimental evidence that the BNT162b2 vaccine conferred no or little protection against SARS-CoV-2 infection until 12 days after vaccination with the first dose. Therefore, we calculated cumulative incidence of infection during a 12-day period (days 13-24 after first dose) compared with days 1 to 12 after vaccination with the first dose. Index day was thus defined as day 1 after the first dose for the day 1 to 12 period and day 13 for the day 13 to

Additional Variables
Individual-level clinical and demographic data were collected from MHS central data sets. Data included age at index date, sex, and body mass index, as well as information on underlying diseases from computerized registries, including cancer, immunocompromised conditions, diabetes, 9 cardiovascular diseases, 10 and hypertension. 11 The socioeconomic status (SES) index of each member's enumeration area was based on several parameters, including household income, educational qualifications, household crowding, material conditions, and car ownership. Further information on participants' residential areas, including characterization of ultraorthodox Jewish or Arabic communities was collected. These variables were selected based on the local epidemiological characteristics of COVID-19 in Israel showing higher incidence in ultraorthodox Jewish and Arabic communities compared with the general population and in low vs high SES communities.

Statistical Analysis
Continuous variables were expressed as means with SDs and medians with ranges. Categorical variables were summarized as counts and percentages. Cumulative incidence plots of SARS-Cov-2 infection were created using Kaplan-Meier survival analysis and compared with the log-rank test. The comparison of the incidence of PCR-confirmed SARS-CoV-2 infection between days 1 through 12 and days 13 through 24 after immunization with 1 dose of the BNT162b2 vaccine was first estimated using a generalized linear models, applying a negative-binomial distribution with a log-link and log-timeat-risk as an offset. The offset was used to scale the counts of SARS-CoV-2 infections to daily incidence, expressed as cases per 100 000 population. The dependent variable was the number of SARS-CoV-2 cases per day during 12 days of follow-up for each group. Independent variables were sex and age category. Vaccine effectiveness (VE) was defined as infection relative risk reduction (RRR) and calculated as (1 -relative risk) × 100. We also calculated VE against infections with   age and sex groups, as well as among individuals with chronic conditions (Figure 2)

Discussion
In this comparative effectiveness study using real-world data, we found that the BNT162b2 mRNA vaccine was associated with 51% reduced risk of PCR-confirmed SARS-CoV-2 infection and symptomatic COVID-19 during days 13 to 24 after immunization with the first dose, compared with the preceding 1 to 12 days. While our effectiveness estimate was comparable with the 52% efficacy in Our study has several strengths. The automated data collection of vaccination status and laboratory results that are offered to all citizens free of charge allowed us to comprehensively explore vaccine effectives with minimal threat of the information bias that characterizes studies relying on

Conclusions
In this comparative effectiveness study, a single dose of the BNT162b2 COVID-19 vaccine was associated with a 51% reduction in the incidence of SARS-CoV-2 infection during 13 to 24 days after immunization compared with the preceding 12 days. This estimate was consistent across age, sex,