Comparative effectiveness of third doses of mRNA-based COVID-19 vaccines in US veterans

Comparative effectiveness of third doses of mRNA-based COVID-19 vaccines in US veterans

Specification of goal trials

We designed an observational evaluation to emulate a hypothetical pragmatic trial of a 3rd dose of BNT162b2 versus mRNA-1273 and the dangers of COVID-19 outcomes within the VA healthcare system. Supplementary Desk 3 summarizes the principle elements of the protocol.

Eligibility standards included veteran standing; age ≥65 years or 18-64 years with excessive danger of extreme COVID-19 between October 20 and November 18, 2021 (primarily based on the presence of at the very least one coexisting situation listed in Desk 1)8 or ≥18 years outdated between November 19, 2021 and February 8, 2022 (primarily based on nationwide tips for third dose deployment)9.10; obtained the second dose of a major collection of mRNA vaccines at the very least 6 months earlier (primarily based on the identical tips); recognized residential handle outdoors of a long-term care facility; and recognized smoking standing and recognized physique mass index within the earlier yr. People have been required to have used the VA healthcare system up to now yr (outlined as receiving care at a station eligible to manage examine vaccines and having at the very least one major care go to) however not up to now yr. 3 days earlier (which can point out the onset of symptomatic sickness).

The interventions of curiosity have been a 3rd dose of BNT162b2 vaccine or mRNA-1273 vaccine. To make sure steadiness of essential traits between the teams, eligible veterans within the goal trial can be randomly assigned to one in all these two vaccines in strata outlined by the calendar date of the third dose (5 days), the calendar month of second dose of mRNA vaccine, age (5-year bins), gender (male, feminine), race (White, Black, different, unknown), urbanity of residence (city, non-urban), geographic location ( coded into 19 Veterans Built-in Companies Community classes) and variety of SARS-CoV-2 assessments carried out up to now 12 months (0, 1, ≥2).

The 5 outcomes of curiosity have been documented SARS-CoV-2 an infection, documented symptomatic hospital admission with COVID-19 and COVID-19, ICU admission, and demise. For every eligible particular person, follow-up started on the day the third dose of vaccine was obtained (baseline) and ended on the day of the result of curiosity, demise, 112 days (16 weeks) after baseline or the tip of the examine interval (February 15, 2022), whichever comes first.

Our goal trial assesses the comparative efficacy of a 3rd dose of the vaccines over a interval spanning durations when SARS-CoV-2 Delta and Omicron variants have been circulating. The Delta variant had declined to a 26% share of variants in circulation in america as of December 25, 2021, because it was shortly changed by the Omicron variant, which rose to 100% as of February 12, 202211. To evaluate comparative efficacy throughout a interval of Omicron variant dominance, we thought-about a second goal trial that was an identical to the primary trial, besides that the enrollment interval was January 1 to March 1, 2022, and the one consequence of curiosity was documented SARS-CoV-2 an infection as a result of the time interval was too brief to build up a ample variety of rarer and extra extreme outcomes.

Emulation of goal trials

We emulated the 2 goal trials utilizing VA Healthcare databases3. Vaccination was recognized utilizing information from the Enterprise Information Warehouse and the VA COVID-19 Shared Information Useful resource. SARS-CoV-2 infections have been recognized utilizing the nationwide VA COVID-19 surveillance software3.12, which integrates lab check knowledge with pure language processing of medical notes to seize documented diagnoses inside and outdoors of the VA healthcare system. Symptomatic COVID-19 was outlined as ≥ 1 of the next signs documented inside 4 days of SARS-CoV-2 an infection: fever, chills, cough, shortness of breath or problem respiratory, sore throat, lack of style or scent, headache, myalgia/muscle ache, diarrhea and vomiting. Hospitalization for COVID-19 was outlined as hospitalization inside 21 days of documented SARS-CoV-2 an infection, ICU admission for COVID-19 was outlined as ICU admission throughout hospitalization for COVID-19 and COVID-19 demise was outlined as demise inside 30 days of documented SARS-CoV-2 an infection. Supplementary Desk 4 supplies detailed info on all examine variables and their dedication.

We tried to imitate the stratified randomization of the goal trial by matching individuals who obtained a 3rd dose of BNT162b2 and mRNA-1273 primarily based on the calendar date of the third dose, the calendar month of the second dose , age, gender, race, urbanity of residence, geographic location, and variety of SARS-CoV-2 assessments carried out up to now 12 months, utilizing the identical matching algorithm described in our earlier examine3.

To discover the potential for residual confounding (e.g., by underlying well being standing or healthcare-seeking conduct), we integrated two destructive consequence controls7. First, we assessed the danger of symptomatic COVID-19 within the first 7 days after the third vaccine dose. Second, we assessed the danger of demise from causes apart from COVID-19 through the follow-up interval.

statistical analyzes

Covariate steadiness after matching was assessed by plotting the imply variations between variable values ​​(standardized for steady variables) for the vaccination teams, with a distinction of 0.1 or much less thought-about acceptable.13.

The cumulative incidence (danger) curves for the vaccinated teams have been estimated utilizing the Kaplan-Meier estimator14. We then calculated the 16-week dangers of every consequence and in contrast them between the vaccinated teams by way of variations and ratios. We carried out subgroup analyzes by age (<70 or ≥70 years), race (black or white), time since completion of major COVID-19 vaccine collection (6-7, 8 or ≥9 months) and first collection vaccine sort (BNT162b2 or mRNA-1273). We carried out sensitivity analyzes that excluded eligible people who (1) had beforehand documented SARS-CoV-2 an infection, (2) had not obtained a homologous third dose to the first collection of vaccines COVID-19 and (3) had obtained a 3rd dose which couldn't be recognized as a booster dose primarily based on accessible process codes within the “Inpatient” and “Outpatient” domains, to match vaccine recipients to recognized doses, the dose of mRNA-1273 being totally different for the booster doses (50 μg) vs. the third major collection (100 μg).

We used a nonparametric bootstrapping process (together with each pairing and post-analyzes) with 500 iterations to calculate percentile-based 95% confidence intervals for all estimates.

Analyzes have been carried out utilizing R software program model 3.6.0 (R Basis for Statistical Computing) and SAS Enterprise Information model 8.2 (SAS Institute).

Abstract of reviews

Additional info on the analysis design might be discovered within the abstract of Nature portfolio reviews linked to this text.


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