Impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination and Booster on Coronavirus Disease 2019 (COVID-19) Symptom Severity Over Time in the COVID-OUT Trial

Clin Infect Dis. 2023 Feb 8;76(3):e1-e9. doi: 10.1093/cid/ciac772.


Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has decreasing protection from acquiring any infection with emergence of new variants; however, vaccination continues to protect against progression to severe coronavirus disease 2019 (COVID-19). The impact of vaccination status on symptoms over time is less clear.

Methods: Within a randomized trial on early outpatient COVID-19 therapy testing metformin, ivermectin, and/or fluvoxamine, participants recorded symptoms daily for 14 days. Participants were given a paper symptom diary allowing them to circle the severity of 14 symptoms as none (0), mild (1), moderate (2), or severe (3). This is a secondary analysis of clinical trial data on symptom severity over time using generalized estimating equations comparing those unvaccinated, SARS-CoV-2 vaccinated with primary vaccine series only, or vaccine-boosted.

Results: The parent clinical trial prospectively enrolled 1323 participants, of whom 1062 (80%) prospectively recorded some daily symptom data. Of these, 480 (45%) were unvaccinated, 530 (50%) were vaccinated with primary series only, and 52 (5%) vaccine-boosted. Overall symptom severity was least for the vaccine-boosted group and most severe for unvaccinated at baseline and over the 14 days (P < .001). Individual symptoms were least severe in the vaccine-boosted group including cough, chills, fever, nausea, fatigue, myalgia, headache, and diarrhea, as well as smell and taste abnormalities. Results were consistent over Delta and Omicron variant time periods.

Conclusions: SARS-CoV-2 vaccine-boosted participants had the least severe symptoms during COVID-19, which abated the quickest over time. Clinical Trial Registration. NCT04510194.

Keywords: COVID-19; SARS-CoV-2; symptoms; vaccine.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19 Vaccines
  • COVID-19* / prevention & control
  • Humans
  • SARS-CoV-2*
  • Vaccination


  • COVID-19 Vaccines

Supplementary concepts

  • SARS-CoV-2 variants

Associated data