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Comparative Performance of BNT162b2 and mRNA-1273 Vaccines in U.S. Veterans

Specification of the Target Trials

We built this observational assessment to emulate a concentrate on trial (i.e., a hypothetical pragmatic trial that would have answered the causal issue of desire) of BNT162b2 as in comparison with mRNA-1273 for the prevention of Covid-19 outcomes in the VA health and fitness treatment system. The essential elements of the protocol are summarized in Table S1 in the Supplementary Appendix, out there with the complete textual content of this posting at NEJM.org.

Eligibility requirements bundled veteran standing, an age of at minimum 18 several years among January 4 and May possibly 14, 2021, no formerly documented SARS-CoV-2 an infection, no prior Covid-19 vaccination, and a identified household deal with exterior of a very long-phrase treatment facility, as perfectly as regarded cigarette smoking standing and physique-mass index recorded inside the earlier year. Members wanted to have made use of the VA wellbeing care system for the duration of the preceding yr (outlined as receiving treatment at a station qualified to administer the vaccines beneath analyze and getting at the very least one main care stop by) having said that, they had to have experienced no interactions with the well being care program in the past 3 times (which may perhaps have indicated the start off of symptomatic disease and precluded vaccination).

The interventions of fascination were vaccination with either the BNT162b2 vaccine or the mRNA-1273 vaccine, with a next dose scheduled 21 days afterwards for the BNT162b2 vaccine and 28 days later for the mRNA-1273 vaccine. To guarantee equilibrium of essential qualities across groups, eligible veterans in the focus on trial would be randomly assigned to a single of these two vaccine groups inside strata defined in accordance to calendar date (5-working day bins), age (5-12 months bins), sex (male or female), race (White, Black, other, or unfamiliar), urbanicity of home (urban or not urban), and geographic place (coded as 1 of 19 types of the Veterans Built-in Solutions Network).

The five results of fascination ended up documented SARS-CoV-2 infection, documented symptomatic Covid-19, healthcare facility admission for Covid-19, ICU admission for Covid-19, and demise from Covid-19. For every single eligible participant, stick to-up started off on the day the first dose of vaccine was acquired (baseline) and finished on the working day of the consequence of fascination, dying, 168 days (24 weeks) just after baseline, or the stop of the analyze time period (July 1, 2021), whichever occurred 1st.

This focus on demo was intended to examine the comparative performance of the vaccines in a period of time in the course of which the SARS-CoV-2 alpha variant was predominant. Even so, the alpha variant experienced reduced to a share of 26% of circulating variants in the United States as of June 26, 2021, as it was speedily displaced by the delta variant, which rose from a 68% share as of July 3, 2021, to 99% as of September 18, 2021.11 To assess the comparative efficiency of the vaccines in a period of time with delta-variant predominance, we regarded a next focus on demo that was similar to the initially trial except that the recruitment time period was July 1 to September 20, 2021, and the only outcome of interest was documented SARS-CoV-2 infection (mainly because the period of time was as well small to accumulate a sufficient range of rarer results, such as hospitalization and dying).

Emulation of the Concentrate on Trials

We emulated the over pragmatic focus on trials applying the VA health treatment databases, which are described in the Supplementary Procedures 1 part in the Supplementary Appendix. Table S2 provides thorough definitions of all analyze variables. Vaccination was determined with the use of data in the Immunization area and procedures recorded in the Outpatient or Inpatient area of the databases. SARS-CoV-2 bacterial infections were being determined with the use of the VA Covid-19 Nationwide Surveillance Device,12 which integrates info on polymerase-chain-response (PCR) laboratory checks with all-natural language processing of medical notes to seize diagnoses inside of and outside the VA health care technique. Symptomatic Covid-19 was defined as at minimum one of the following signs documented inside of the VA wellness treatment method in just 4 times prior to or soon after documentation of SARS-CoV-2 an infection: fever, chills, cough, shortness of breath or issues respiratory, sore throat, decline of flavor or odor, headache, myalgia, diarrhea, and vomiting. Signs or symptoms had been ascertained with the use of records in the Outpatient, Inpatient, Important Signals, Overall health Components, and Price domains in the databases. Hospitalization for Covid-19 was outlined as a hospitalization in 21 times soon after documentation of SARS-CoV-2 an infection (ascertained with the Inpatient domain), ICU admission for Covid-19 was outlined as an ICU admission through hospitalization for Covid-19 (ascertained with the Inpatient area and specialty transfer codes), and dying from Covid-19 was outlined as a demise inside 30 days immediately after documentation of SARS-CoV-2 infection (ascertained working with the Patient domain).

To mimic the stratified randomization of the concentrate on trial, we matched qualified folks who were vaccinated with BNT162b2 in a 1:1 ratio to qualified people who have been vaccinated with mRNA-1273. The matching things (calendar day, age, sexual intercourse, race, urbanicity of residence, and geographic location) are associated with the likelihood of acquiring a certain vaccine, as very well as with the hazard of SARS-CoV-2 infection or significant Covid-19. (Added details on the matching algorithm are furnished in the Supplementary Techniques 2 section in the Supplementary Appendix.)

To examine the probability of residual confounding (e.g., by fundamental health and fitness status or wellness care–seeking conduct), we utilised two detrimental outcome controls that are not specifically affected by vaccination but for which the impact of vaccination may well be similarly confounded.13 Initially, we evaluated the hazard of symptomatic Covid-19 in the initial 10 days after the initial vaccine dose, throughout which no big difference in threat between the vaccines is expected.1,2 Next, we evaluated the hazard of demise from leads to other than Covid-19 through the adhere to-up period.

Statistical Examination

Covariate balance immediately after matching was evaluated by plotting the indicate discrepancies between variable values (standardized for continual variables) for the vaccination groups, with a variation of .1 or considerably less viewed as to be suitable.14 Cumulative incidence (threat) curves for the vaccination groups ended up estimated with the Kaplan–Meier estimator.15 We thought of the period of time from the working day of the initial dose of vaccine until the conclude of adhere to-up. We employed the Kaplan–Meier estimator with day-to-day result activities to compute the probability (hazard) of the end result in the course of the period. We then calculated 24-7 days risk differences and danger ratios involving the vaccination groups. We done subgroup analyses according to age (<70 or ≥70 years) and race (Black or White). Nonparametric bootstrapping with 500 samples was used to calculate percentile-based 95% confidence intervals for all estimates.

Analyses were performed with R software, version 3.6.0 (R Foundation for Statistical Computing), and SAS software, version 8.2 (SAS Institute). Information on authors’ contributions to the study is provided in the Supplementary Methods 3 section in the Supplementary Appendix. The first and last authors vouch for the accuracy and completeness of the data presented in this report.