On September 12, 2023, the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices recommended that all persons aged ≥6 months receive 2023–2024 COVID-19 vaccination [1]. These monovalent vaccines contained a component from the SARS-CoV-2 Omicron XBB.1.5 lineage and, unlike previous COVID-19 vaccines, did not contain the ancestral SARS-CoV-2 strain. Several studies of COVID-19 vaccines have shown effective protection against severe illness [2–4]; however, little research has been done in the United States on the frequency of reported symptoms by vaccination status among those who test positive for SARS-CoV-2 [5,6]. Previous research investigated presentation of symptoms based on a single combined category of fever or chills, which may fail to account for the variety of symptoms associated with COVID-19, among small sample sizes (approximately 200 individuals). To investigate the association between 2023–2024 COVID-19 vaccination and symptomatic infections, we evaluated the frequency of 12 self-reported symptoms among 6966 vaccinated and unvaccinated individuals who tested positive for SARS-CoV-2.

Increasing Community Access to Testing, Treatment, and Response (ICATT) is a CDC program that contracts with pharmacy chains and laboratories at selected sites nationwide to provide no-cost SARS-CoV-2 testing to people who are uninsured. This analysis includes ICATT tests, as well as cash- and insurance-paid tests, performed at Walgreens locations using methods previously described for vaccine effectiveness studies [7]. Self-reported information was collected from individuals aged ≥18 years who registered for SARS-CoV-2 testing online, including COVID-19 vaccination history, sex, race, ethnicity, age, state of residence, presence or absence of symptoms, date of symptom onset, prior SARS-CoV-2 infections, and underlying health conditions. Records for SARS-CoV-2 tests conducted from September 21, 2023 through August 22, 2024, were included in this analysis. Records for each individual’s first positive test result during the study period were analyzed. Tests from individuals with self-reported or laboratory-confirmed positive SARS-CoV-2 tests within three months before the first positive test within the study period were excluded to avoid analyzing multiple tests from the same episode of illness. Further, tests from individuals who reported symptom onset more than 14 days prior to the test were excluded. Vaccination was defined as the receipt of at least one 2023–2024 COVID-19 vaccine dose, at least 7 days prior to date of testing. The referent group included tests from people who did not receive a 2023–2024 COVID-19 vaccine dose, regardless of prior COVID-19 vaccination history.

During the SARS-CoV-2 testing registration process, individuals were able to report up to 12 symptoms they were experiencing (e.g., cough, fever, chills, congestion/runny nose, muscle pain, headache, fatigue, sore throat, shortness of breath, vomiting, recent loss of sense of smell or taste, and diarrhea). Adjusted odds ratios (aOR) with 95 % confidence intervals (95 % CI) were calculated to estimate associations between each of the 12 symptoms and 2023–2024 COVID-19 vaccination. Multivariable logistic regression models adjusted for age (continuous), sex, race and ethnicity, length of time in days from symptom onset to test date (continuous), social vulnerability index score of pharmacy site census tract, U.S. Department of Health and Human Services (HHS) region² of ICATT pharmacy site, calendar week of test (categorical variable), and underlying conditions (presence of one or more vs. absence of any).

Statistical analyses were performed in R (version 4.4.2 R Foundation for Statistical Computing, Vienna, Austria). This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy (see e.g., 45C.F.R. part 46; 102(l) (2), 21C.F.R. part 56; 42 U.S.C. §241(d), 5 U.S.C. §552a, 44 U.S.C. §3501 et seq.).

A total of 6966 records of positive SARS-CoV-2 tests from 2965 sites across 48 states, Puerto Rico and Washington, D.C. met the inclusion criteria, including 643 (9 %) tests from those who received 2023–2024 COVID-19 vaccination and 6323 (91 %) from those who did not receive a 2023–2024 COVID-19 vaccine dose (Table 1). Of those who received 2023–2024 COVID-19 vaccination, 313 (49 %) were White, non-Hispanic, while 2088 (33 %) of those who did not receive a 2023–2024 COVID-19 vaccine dose were White, non-Hispanic. Additionally, 48 % of individuals who received the vaccine reported at least one underlying medical condition, compared to 33 % of those who did not receive it. Individuals with receipt of 2023–2024 COVID-19 vaccination arrived for testing a median of 2 days after symptom onset, while individuals who did not receive a 2023–2024 COVID-19 vaccine arrived for testing a median of 3 days after symptom onset.

The most commonly reported symptoms were cough (79 %), congestion or runny nose (75 %), headache (67 %), sore throat (67 %), and fatigue (62 %) (Fig. 1). The proportions of individuals reporting each of the 12 symptoms were consistently lower among those who received 2023–2024 COVID-19 vaccination compared with those who did not receive a 2023–2024 COVID-19 vaccine dose (range of differences: 2 % to 19 %). When estimating the associations between symptom reporting and vaccination status, those with receipt of 2023–2024 vaccination had significantly lower adjusted odds of reporting each of the symptoms other than congestion/runny nose, sore throat, and vomiting compared to the those who did not receive 2023–2024 COVID-19 vaccination. The significantly lower odds of symptoms among those who received 2023–2024 COVID-19 vaccination ranged from 61 % for recent loss of sense of smell or taste (aOR: 0.39; 95 % CI: 0.29–0.53) to 30 % for fatigue (aOR: 0.70; 95 % CI: 0.58–0.83). Notably, the odds of reporting of chills (aOR: 0.52; 95 % CI: 0.43–0.62) or fever (aOR: 0.51; 95 % CI: 0.42–0.61) were similarly lower among those who received 2023–2024 COVID-19 vaccination compared to those who did not receive a 2023–2024 COVID-19 vaccine.

In this analysis of national pharmacy testing data and persons with positive SARS-CoV-2 results, the odds of reporting most of the common symptoms of COVID-19 [8] were significantly lower for those who had received 2023–2024 COVID-19 vaccination compared with those who had not. The odds of reporting chills or fever were almost 50 % lower for those who received 2023–2024 COVID-19 vaccination compared to those who did not. This finding aligns with previously published data, showing a reduction in risk of febrile conditions (defined as fever, feverishness, chills, or a measured temperature higher than 38 °C) among those who received a full or partial primary series of original monovalent mRNA COVID-19 vaccines compared to those who were unvaccinated in a population with SARS-CoV-2 [5,6].

This analysis had several limitations. First, the sample comprises individuals who were administered SARS-CoV-2 tests at pharmacy locations. Differences in testing behaviors, such as reliance on over-the-counter (at-home) tests instead of utilizing tests administered at pharmacy locations that may be related to symptoms or vaccination history, could have introduced selection bias. Test-negative design studies lessen this potential selection bias by only including tests from persons who had at least one symptom, thereby only including people arriving for testing for the same reasons. Second, both recent vaccination status and previous infection histories were self-reported, raising the possibility of recall bias and potential misclassification errors. However, we only compared those with recent 2023–2024 COVID-19 vaccination to those without 2023–2024 COVID-19 vaccination rather than relying on recall of previous doses. Furthermore, the frequency of past infections is likely underestimated [9] As of December 2023, research has shown that 87.2 % of US adults have experienced a SARS-CoV-2 infection [10], yet only 58 % of this ICATT sample reported a prior infection. To reduce bias, we excluded tests from individuals with a self-reported or lab-confirmed positive SARS-CoV-2 test within three months before the first positive test within the study period and consider all adults in this sample to have had at least one prior illness. Third, this study did not measure protection against progression to infection, as it only includes those who were both symptomatic and SARS-CoV-2-positive. Fourth, approximately 11 % of the data were missing information to determine vaccination status and were not included in the analysis. Of the sample that had determinable vaccination status, 2 % were missing necessary covariables for the adjusted models and were also excluded from analyses. Finally, because data collection occurred at pharmacies situated in areas with higher social vulnerability, our sample may not represent the U.S. population in general.

This analysis demonstrates that receipt of 2023–2024 COVID-19 vaccination may reduce common symptoms associated with SARS-CoV-2 infection, which further emphasizes the benefits of receiving the recommended COVID-19 vaccination not only to prevent severe disease, but also to mitigate symptomatic illness [11].