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Association Between 3 Doses of mRNA COVID-19 Vaccine and Symptomatic Infection Caused by the SARS-CoV-2 Omicron and Delta Variants

E.K. Accorsi et al, Journal of the American Medical Association (JAMA), January 2022

Questions

  1. How was the study designed?
  2. How was the exposure defined in this study?
  3. What was the primary outcome of this study?
  4. What were the adjusted odds ratios (OR) when comparing three doses of the COVID-19 vaccine with unvaccinated and with two doses?
  5. What were some limitations of the study?

Explanations

  1. This was a case-control study on samples collected from 12/10/2021 to 1/1/2022 among adults (at least 18 years of age) with symptomatic COVID-like illness. A test-negative design was used, in which participants with positive test results were defined as cases and those with negative test results were defined as controls.
  2. The exposure was self-reported COVID-19 vaccination with three doses of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) (included mixed vaccination) versus unvaccinated versus any two doses of BNT162b2 or mRNA-1273.
  3. The primary outcome was symptomatic SARS-CoV-2 infection (Omicron or Delta variant).
  4. The adjusted OR for three doses of COVID-19 vaccine compared with unvaccinated was 0.33 (95% confidence interval [CI], 0.31-0.35) for Omicron and 0.065 (95% CI, 0.059-0.071) for Delta. The adjusted OR for three doses versus two doses was 0.34 (95% CI, 0.32-0.36) for Omicron and 0.16 (95% CI, 0.14-0.17) for Delta.
  5. Exposure was self-reported and may have been misclassified. Individuals may have been counted more than once, because tests (not individuals) were analyzed. People who received three doses may differ from those who were unvaccinated or received two doses even after adjusting for confounders (residual confounding). Some potential confounders (e.g., masking, social distancing) were not evaluated. Certain subgroups of US adults may have had greater access to booster shots due to recommendations. S-gene target failure (SGTF) was used as a marker of Omicron infection. The time since people received the first two vaccine doses was at least six months, during which immunity may have already waned. Time since the last vaccine dose may influence the association between vaccination and infection.

Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial

A.P.S. Munro et al, Lancet, December 2021

Questions

  1. Which first and second dose COVID-19 vaccines did the participants receive?
  2. Which third dose (booster) COVID-19 vaccines did the participants receive?
  3. For participants who received two doses of the Pfizer-BioNTech vaccine followed by a third full dose of the Pfizer-BioNTech vaccine versus the control, what was the geometric mean ratio (GMR) in the SARS-CoV-2 anti-spike IgG antibody response?
  4. For participants who received two doses of the Pfizer-BioNTech vaccine followed by a third full dose of the Janssen vaccine versus the control, what was the GMR in the SARS-CoV-2 anti-spike IgG antibody response?
  5. For participants who received two doses of the Pfizer-BioNTech vaccine followed by a third full dose of the Moderna vaccine versus the control, what was the GMR in the SARS-CoV-2 anti-spike IgG antibody response?

Explanations

  1. Two doses of AstraZeneca or two doses of Pfizer-BioNTech
  2. AstraZeneca (full dose), Novavax (full and half dose), Pfizer-BioNTech (full and half dose), Valneva (full and half dose), Janssen (full dose), Moderna (full dose), or Curevac (full dose)
  3. Pfizer-BioNTech third full-dose booster: GMR 8.11 (95% confidence interval [CI], 6.59 to 9.99). See Table 6 in the article under “Prime with BNT/BNT” heading, then “BNT” subheading.
  4. Janssen third full-dose booster: GMR 5.63 (95% CI, 4.55 to 6.97). See Table 6 in the article under “Prime with BNT/BNT” heading, then “Ad26” subheading.
  5. Moderna third full-dose booster: GMR 11.49 (95% CI, 9.36 to 14.12). See Table 7 in the article under “Prime with BNT/BNT” heading, then “m1273” subheading.

Myocarditis after Covid-19 Vaccination in a Large Health Care Organization

G. Witberg et al, New England Journal of Medicine (NEJM), October 2021

Questions

  1. What was the goal of this study?
  2. How was the study designed?
  3. What were the main findings?
  4. What were some limitations of this study?

Explanations

  1. The goal of this study was to assess the frequency and severity of myocarditis after at least one dose of the Pfizer–BioNTech (BNT162b2) Covid-19 vaccine.
  2. The investigators conducted a retrospective cohort study using a large health care organization database in Israel. Patients who received at least one dose of the Covid-19 vaccine were followed for the diagnosis of myocarditis. The incidence of myocarditis up to 42 days after the first dose of vaccine was evaluated using Kaplan-Meier analysis.
  3. The estimated incidence of myocarditis was 2.13 cases (95% confidence interval [CI], 1.56-2.70) per 100,000 persons receiving at least one vaccine dose. Males ages 16-29 years had the highest incidence (10.69 cases [95% CI, 6.93-14.46] per 100,000 persons). Regarding myocarditis severity, 76% was mild and 22% was intermediate.
  4. Definitive diagnosis of myocarditis using endomyocardial biopsy was only performed on one patient. Diagnoses not noted in the health record that the investigators analyzed would have been missed. There were missing data for the clinical course. No comparator group was available, so no conclusions about the vaccine causing myocarditis can be made. The study design did not call for collecting information about myocarditis incidence after Covid-19.

Association Between COVID-19 Diagnosis and In-Hospital Mortality in Patients Hospitalized With ST-Segment Elevation Myocardial Infarction

M. Saad et al, Journal of the American Medical Association (JAMA), October 2021

Questions

  1. How did the investigators conduct the study?
  2. What did the investigators find for the primary outcome?
  3. What were some weaknesses of the study?

Explanations

  1. The investigators performed a retrospective cohort study using a deidentified patient database of numerous medical centers. They restricted the time period of patient admission between January 2019 and December 2020. Patients included in the study were hospitalized with STEMI at a percutaneous coronary intervention (PCI)–capable center. Details about the inclusion and exclusion criteria are under “Study Population” in Methods. Patients who had COVID-19 infection at the same encounter were considered active. The primary outcome was all-cause in-hospital mortality. Secondary outcomes are detailed under “Outcomes” in Methods. Propensity-matching was used to account for potential confounders.
  2. In the out-of-hospital STEMI group, in-hospital mortality rates for with vs without COVID-19 were 15.2% vs 11.2%, respectively (absolute difference, 4.1% [95% CI, 1.1%-7.0%]; P = .007). In the in-hospital STEMI group, in-hospital mortality rates for with vs without COVID-19 were 78.5% vs 46.1%, respectively (absolute difference, 32.4% [95% CI, 29.0%-35.9%]; P < .001). Therefore, patients with out-of-hospital or in-hospital STEMI and COVID-19 had significantly higher rates of in-hospital mortality compared with those without COVID-19.
  3. Given the observational study design, residual confounding and bias may remain. The findings cannot be generalized beyond US academic medical centers. Miscoding may be a possibility. Data were not collected on cause of death or on how COVID-19 was diagnosed. There were numerous measurements that were not available in the database, for example, vital signs and laboratory test results. In the in-hospital STEMI group, the timing of PCI in relation to the timing of STEMI diagnosis could not be determined. In-hospital outcomes were mainly examined, not long-term outcomes.

REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19

D.M. Weinreich et al, New England Journal of Medicine (NEJM), September 2021

Questions

  1. What was the purpose of this study?
  2. How was the study designed?
  3. What was the primary end point of this study?
  4. What did the researchers find for the primary end point?
  5. Who supported this study?

Explanations

  1. The purpose of this study was to evaluate the efficacy of REGEN-COV (combination therapy of monoclonal antibodies casirivimab and imdevimab) for reducing the risk of COVID-19-related complications in outpatients.
  2. This was a phase 3 adaptive randomized controlled trial. Adaptive clinical trials modify the trial protocol during the trial. Patients were randomized to receive REGEN-COV or saline placebo.
  3. The percentage of patients with at least one Covid-19-related hospitalization or death from any cause through day 29 was selected as the primary end point.
  4. For REGEN-COV 2400 mg versus placebo, the primary end point (Covid-19-related hospitalization or death) occurred in 1.3% (18/1355) patients in the treatment group versus 4.6% (62/1341) patients in the placebo group. This was a relative risk reduction (1 – relative risk) of 71.3% (95% confidence interval, 51.7 to 82.9; P<0.001). For REGEN-COV 1200 mg versus placebo, the primary end point (Covid-19-related hospitalization or death) occurred in 1.0% (7/736) patients in the treatment group versus 3.2% (24/748) patients in the placebo group. This was a relative risk reduction (1 – relative risk) of 70.4% (95% confidence interval, 31.6 to 87.1; P=0.002).
  5. This study was supported by Regeneron Pharmaceuticals, F. Hoffmann–La Roche, and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response.

Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial

E. López-Medina et al, Journal of the American Medical Association (JAMA), March 2021

Questions

  1. How did the researchers investigate the research question?
  2. What did the researchers find for the primary outcome?
  3. What were some strengths and weaknesses of the study?

Explanations

  1. The researchers conducted a double-blind, randomized controlled trial of ivermectin (300 μg/kg of body weight per day for 5 days) (n=200) vs placebo (daily for 5 days) (n=200) in Cali, Colombia. Participants had confirmed positive SARS-CoV-2 tests. They were identified by simple random sampling from the state’s electronic database. Inclusion and exclusion criteria are in the third paragraph of the Study Design and Patients section under Methods. Allocation concealment is mentioned under the Randomization section of Methods. Follow-up and adherence are noted in the Procedures section of Methods. The primary outcome was “time from randomization to complete resolution of symptoms within the 21-day follow-up period.” An 8-point ordinal scale was used to score symptom severity. Secondary outcomes are detailed in the second paragraph of Outcome Measures under Methods. Post-hoc analyses are described in Methods. The primary outcome was assessed with Kaplan-Meier analysis and a log-rank test.
  2. Participants were median (interquartile range [IQR]) age of 37 (29-48 years), with 231 women and 167 men. The ivermectin group took median (IQR) 10 days (9-13) for resolution of symptoms, while the placebo group took median (IQR) 12 days (9-13). The hazard ratio for resolution of symptoms was 1.07 (95% confidence interval, 0.87 to 1.32), P=0.53 by log-rank test. In conclusion, a 5-day course of ivermectin vs placebo did not significantly improve the time to resolution of symptoms among adults with mild COVID-19.
  3. Strengths: The study was double-blinded, randomized, and placebo-controlled. It had sufficient power to detect a statistical difference. Weaknesses: The study recruited relatively young and healthy participants, so it may not be generalizable to the whole population. The study design was changed during the clinical trial. The study may be underpowered to detect smaller differences. There were no virological assessments. Some of the placebo differed in taste and smell from ivermectin. The ordinal scale may be subjective. There were no ivermectin plasma levels collected.