Comparison of test-negative and syndrome-negative controls in SARS-CoV-2 vaccine effectiveness evaluations for preventing COVID-19 hospitalizations in the United States.

Background: Test-negative design (TND) studies have produced validated estimates of vaccine effectiveness (VE) for influenza vaccine studies. However, syndrome-negative controls have been proposed for differentiating bias and true estimates in VE evaluations for COVID-19. To understand the use of alternative control groups, we compared characteristics and VE estimates of syndrome-negative and test-negative VE controls.
Methods: Adults hospitalized at 21 medical centers in 18 states March 11-August 31, 2021 were eligible for analysis. Case patients had symptomatic acute respiratory infection (ARI) and tested positive for SARS-CoV-2. Control groups were test-negative patients with ARI but negative SARS-CoV-2 testing, and syndrome-negative controls were without ARI and negative SARS-CoV-2 testing. Chi square and Wilcoxon rank sum tests were used to detect differences in baseline characteristics. VE against COVID-19 hospitalization was calculated using logistic regression comparing adjusted odds of prior mRNA vaccination between cases hospitalized with COVID-19 and each control group.
Results: 5811 adults (2726 cases, 1696 test-negative controls, and 1389 syndrome-negative controls) were included. Control groups differed across characteristics including age, race/ethnicity, employment, previous hospitalizations, medical conditions, and immunosuppression. However, control-group-specific VE estimates were very similar. Among immunocompetent patients aged 18-64 years, VE was 93 % (95 % CI: 90-94) using syndrome-negative controls and 91 % (95 % CI: 88-93) using test-negative controls.
Conclusions: Despite demographic and clinical differences between control groups, the use of either control group produced similar VE estimates across age groups and immunosuppression status. These findings support the use of test-negative controls and increase confidence in COVID-19 VE estimates produced by test-negative design studies.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors have completed and submitted the International Committee of Medical Journal Editors (ICMJE) disclosure form. Funding for this work was provided to all participating sites by the United States Centers for Disease Control and Prevention. Samuel Brown reports grants from National Institutes of Health (NIH) and Department of Defense (DoD), participation as the DSMB chair for Hamilton Ventilators, and participation as a member of the DSMB for New York University COVID clinical trials. Jonathan Casey reports funding from NIH and DoD. Steven Chang reports consulting fees from La Jolla Pharmaceuticals, PureTech Health, and Kiniska Pharmaceuticals, payment/honoraria from La Jolla Pharmaceuticals, and participation on a DSMB for an investigator-initiated study conducted at UCLA. James Chappell reports grants and other support from NIH. Abhijit Duggal reports consulting fees from ALung technologies. Matthew Exline reports payment/honorariua from Abbott Lab for sponsored talks. D. Clark Files reports consulting fees from Cytovale and participation on a DSMB for Medpace. Anne Frosch reports grants from NIH. Manjusha Gaglani reports grants from Centers for Disease Control and Prevention (CDC), CDC-Abt Associates, CDC-Westat, and Janssen, and a leadership role as co-chair of the Infectious Disease and Immunization Committee of the Texas Pediatric Society, Texas Chapter of American Academy of Pediatrics. Kevin Gibbs reports funding from NIH/ National Heart, Lung, and Blood Institute (NHLBI) for the ACTIV-4HT NECTAR trial. Nicholas Mohr reports grants from the CDC (funded 2 other multicenter COVID-related projects separate from this work through payments to author’s institution). Adit Ginde reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals. Michelle Gong reports grants from NIH/NHLBI and Agency for Healthcare Research and Quality (AHRQ), consulting fees from Endpoint, a leadership role on the American Thoracic Society (ATS) executive committee and board as well as support from ATS for meeting travel expenses, and participation on a DSMB for Regeneron. Carlos Grijalva reports grants from NIH, CDC, Food and Drug Administration (FDA), AHRQ, Sanofi, and Syneos Health and consulting fees from Pfizer, Merck, and Sanofi. David Hager reports grants from NIH/NHLBI for the ACTIV-4HT NECTAR trial and Incyte Corporation and participation as a DSMB chair for the SAFE EVICT Trial of vitamin C in COVID-19. Jennifer Wilson reports grants from the CDC and NIH (ARREST Pneumonia Trial UH3HL141722, ACTIV3a and 3b trials, and ACTIV4a trial), and membership on the American Board of Internal Medicine Critical Care Medicine exam committee. Natasha Halasa reports grants from NIH, Quidel, and Sanofi and honoraria for speaking at the American Academy of Pediatrics (AAP) conference. Nicholas Johnson reports grants from NIH/NHLBI/NINDS and the University of Washington Royalty Research Fund and payment for expert testimony for the Washington Department of Health. Akram Khan reports grants from United Therapeutics, Gilead Sciences, and 4D Medical and a leadership role on the guidelines committee for Chest. Jennie Kwon reports grants from NIH/NIAID. Adam Lauring reports grants from CDC, NIH/NIAID, and Burroughs Wellcome Fund and consulting fees from Sanofi and Roche. Christopher Lindsell reports grants from NIH, DoD, CDC, bioMerieux, Entegrion Inc., Endpoint Health, and AbbVie, patents for risk stratification in sepsis and septic shock, participation on DSMBs for clinical trials unrelated to the current work, a leadership role on the executive committee for the Board of Directors of the Association for Clinical and Translational Science, and stock options in Bioscape Digita. Emily Martin reports grants from Merck, CDC, and NIH and payment/honoraria from the Michigan Infectious Disease Society. Tresa McNeal reports payment/honoraria from the Society of Hospital Medicine. Ithan Peltan reports grants from NIH, Janssen, Regeneron, and Asahi Kasei Pharma. Todd Rice reports grants from AbbVie Inc., consulting fees from Cumberland Pharmaceuticals, Inc. and Cytovale, Inc., membership on a DSMB for Sanofi, Inc., a leadership role as immediate past president of the American Society of Parenteral and Enteral Nutrition, and stock options in Cumberland Pharmaceuticals, Inc. Wesley Self reports receiving the primary funding for this project from the United States Centers for Disease Control and Prevention, and research funding from Merck and Gilead Sciences. William Stubblefield reports grants from the NIH/NHLBI.
(Published by Elsevier Ltd.)