The primary objective of this study is to determine the vaccine effectiveness of 2 doses of Pfizer-BioNTech BNT162b2 vaccine against COVID-19-associated hospitalization. There will be a large retrospective database study using two parallel study designs: a test-negative case-control design and a retrospective cohort design. VE estimates by various strata and strain type will be conducted.

The primary objective of the study is to estimate vaccine effectiveness (VE) of 2 doses of Pfizer's BNT162b2 vaccine against acute respiratory illness (ARI) requiring hospitalization due to SARS-CoV-2 infection among KPSC members eligible for vaccination. VE will be evaluated using a test-negative design (TND), including all KPSC patients eligible for vaccination who are admitted to the hospital with (ARI) after 14 December 2020 (date of first vaccinations at KPSC), and who receive a PCR test for SARS-CoV-2. Secondary and exploratory objectives may examine VE for 1 dose vaccination, at least 1 dose, >2 doses, monovalent, bivalent or mixed dosing schedules as well as against ED admission, specific variants, mixed dosing schedules, durability, age cut-offs to align with regulatory authorizations/approvals and other populations of interest. Additionally, we will estimate VE using a full cohort design, including all KPSC members eligible for vaccination.

To assess VE, we propose a large retrospective database study using two parallel study de-signs: a test-negative case-control design and a retrospective cohort design. The TND will assess VE against COVID-19 hospitalization (primary endpoint) and ED admission. The retrospective cohort analysis may assess VE against COVID-19 hospitalization (primary), ICU admission, death, ED admission, and outpatient disease (with no subsequent hospitalization within 14 days). The BNT162b2 BA.4/BA.5 bivalent vaccine effectiveness will only be assessed via a test negative design due to the limitations regarding testing bias. As the pandemic evolved PCR-confirmed testing and reporting became less routine and differences in health care seeking behaviors were seen based on vaccination status.

VE for the XBB1.5-adapted monovalent vaccine will be defined as receipt of Pfizer -BioNTech XBB1.5-adapted monovalent vaccine with greater than or equal to 14 days between receipt of vaccine and the event date.

We will further conduct additional analyses of VE estimates by various patient characteristics and strain types.

Inclusion Criteria for Test Negative Design

• KPSC patients eligible to receive BNT162b2 who are admitted to the hospital (primary objective and some secondary objectives) with acute respiratory infection (ARI; International Classification of Diseases (ICD) codes) after 14 December 2020 (date of first vaccinations at KPSC), and who receive a PCR test for SARS-CoV-2.
• For secondary objectives estimating VE against ED admission, the TND will include KPSC patients eligible to receive BNT162b2 who present to the ED with ARI after 14 December 2020, and who receive a PCR test for SARS-CoV-2.
• We will include membership requirement of 1 year prior to index date, which is defined as the date of hospitalization or ED admission (allowing 31-day administrative gap), to facilitate accurate capture of comorbid conditions.

Inclusion Criteria for Cohort Design-

• All KPSC members as of 14 December 2020 (date of first Pfizer vaccination at KPSC) eligible to receive BNT162b2.
• For the cohort study, patients must have at least 1 year of membership (allowing 31-day administrative gap) prior to 14 December 2020 (index date, date vaccinations first began at KPSC) to facilitate accurate capture of comorbid conditions.

Exclusion Criteria Test Negative Design Patients who receive only another newly licensed or investigational SARS-CoV-2 vaccine or COVID-19 prophylactic agent other than Pfizer's COVID-19 vaccine prior to hospitalization (or ED, for secondary objective) will be excluded from the study population When estimating VE for BNT162b2 vaccination, patients receiving another newly licensed or investigational SARS-CoV-2 vaccine or COVID-19 prophylactic agent other than Pfizer's COVID-19 vaccine prior to hospitalization or ED will be excluded from the analysis. Patients will also be excluded if the index date is within certain time windows from vaccination date, outlined further in the exposure section below.

Exclusion Criteria for Cohort Design There will be no exclusion criteria for the cohort design, however patients will be censored for receiving any other newly licensed or investigational SARS-CoV-2 vaccine or COVID-19 prophylactic agent other than Pfizer's COVID-19 vaccine

XBB.1.5-adapted monovalent vaccine eligibility analyses:

Inclusion Criteria:

• KPSC membership for a minimum of 1 year prior to index date, allowing a 30-day gap in membership to allow for delays in renewal. Participants <1 year did not have a membership requirement.≥6 months of age as of index date
• Admitted to the hospital or had an encounter in the ED, UC, or OP setting with a diagnosis of acute respiratory infection (ARI; defined based on International Classification of Diseases (ICD) codes listed in Appendix Table 1) after 25 September 2023
• Received a SARS-CoV-2 PCR or rapid antigen test

Exclusion criteria:

• Individuals who received a non-Pfizer-BioNTech XBB.1.5-adapted monovalent vaccine
• Individuals with an index event <14 days after vaccination with Pfizer-BioNTech XBB.1.5-adapted monovalent vaccine
• Individuals receiving a mRNA bivalent BA4.5 booster ≤ 8 weeks (≤ 56 days) since receiving last wild type dose
• Individuals with <28 days between a second and subsequent wild type dose
• Individuals receiving a XBB.1.5-adapted monovalent vaccine ≤ 8 weeks (≤ 56 days) since receiving a mRNA bivalent BA4.5 booster
• Individuals receiving oral COVID-19 antiviral OP treatments within 30 days of index event (will be excluded for primary analysis, but included in sensitivity analyses)

All members of KPSC who are eligible based on vaccination status and age.

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.