Vaccine effectiveness against COVID‐19 among symptomatic persons aged ≥12 years with reported contact with COVID‐19 cases, February–September 2021

Abstract Background Individuals in contact with persons with COVID‐19 are at high risk of developing COVID‐19; protection offered by COVID‐19 vaccines in the context of known exposure is poorly understood. Methods Symptomatic outpatients aged ≥12 years reporting acute onset of COVID‐19‐like illness and tested for SARS‐CoV‐2 between February 1 and September 30, 2021 were enrolled. Participants were stratified by self‐report of having known contact with a COVID‐19 case in the 14 days prior to illness onset. Vaccine effectiveness was evaluated using the test‐negative study design and multivariable logistic regression. Results Among 2229 participants, 283/451 (63%) of those reporting contact and 331/1778 (19%) without known contact tested SARS‐CoV‐2‐positive. Adjusted vaccine effectiveness was 71% (95% confidence interval [CI], 49%–83%) among fully vaccinated participants reporting a known contact versus 80% (95% CI, 72%–86%) among those with no known contact (p‐value for interaction = 0.2). Conclusions This study contributes to growing evidence of the benefits of vaccinations in preventing COVID‐19 and support vaccination recommendations and the importance of efforts to increase vaccination coverage.


| INTRODUCTION
Individuals in contact with persons with COVID-19 disease are at high risk of SARS-CoV-2 infection and developing COVID-19 themselves.
The US Centers for Disease Control and Prevention (CDC) recommends vaccination as the best tool to prevent COVID-19 among persons aged ≥5 years in conjunction with non-pharmaceutical interventions (NPIs) such as hand washing, mask wearing, and physical distancing. Repeated, extended exposures in proximity to persons with SARS-CoV-2 can increase the risk of becoming infected. 1 Having close contact with a person with COVID-19, such as within a household, is a main source of new SARS-CoV-2 infections. Thus, CDC recommends persons who are not yet fully vaccinated to seek testing immediately after finding out they have had close contact, even if they do not have symptoms.
Data are limited regarding how COVID-19 vaccine effectiveness (VE) may vary by intensity of exposure. 2 One approach to assess impact of exposure would be to evaluate VE against symptomatic illness among individuals with known contact, compared with individuals unaware of close exposure. These data may contribute to efforts to increase COVID-19 vaccine uptake among persons who have not yet received vaccines and possibly inform NPI strategies as coverage increases [2]. In this report, we build upon prior studies of COVID-19 VE from the US Influenza Vaccine Effectiveness (Flu VE) Network to present VE against symptomatic laboratory-confirmed SARS-CoV-2 infection among persons aged ≥12 years with and without known contact with a person with SARS-CoV-2 infection from February to September 2021.

| METHODS
Methods used for estimating VE against laboratory-confirmed symptomatic SARS-CoV-2 infection or COVID-19 among persons seeking medical care/testing for SARS-CoV-2 in Flu VE Network study sites have been previously described. 3 Briefly, research staff screened persons who sought outpatient medical care (i.e., telehealth, primary care, urgent care, and/or emergency department) or clinical SARS-CoV-2 testing using a standard case-definition for COVID-like illness that included onset of fever/feverishness, cough, or loss of taste/ smell with symptom duration <10 days. 4 Research staff contacted potentially eligible outpatients in person, by telephone, or email to confirm eligibility and enroll participants who consented verbally or in writing. Standardized questionnaires collected demographic information, healthcare-related occupation, and COVID-19 vaccination. Participants were also asked "Did you have contact with a lab-confirmed COVID-19 case in the 14 days before your symptoms started?". Participants who answered "yes" were categorized as having "known contact," and participants who answered "no" were categorized as having "no known contact." Participants had SARS-CoV-2 molecular testing on respiratory specimens collected within 10 days of illness onset; results were used to classify SARS-CoV-2-positive cases and test-negative controls. participants were defined as those who received at least one dose of mRNA vaccine ≥14 days before illness onset but who were not fully vaccinated. Those who had no documentation of COVID-19 vaccination prior to illness onset were defined as unvaccinated. Participants whose first dose was received <14 days prior to illness onset (n = 141) were excluded from VE analyses.
We used the test-negative design to evaluate VE of currently available SARS-CoV-2 vaccines against symptomatic, laboratoryconfirmed outpatient COVID-19 6 among participants reporting contact with persons with confirmed COVID-19 and those reporting no known contact. Persons who did not complete the question regarding known contact were excluded from primary analyses. VE was calculated as 1-adjusted odds ratio of vaccination among symptomatic SARS-CoV-2-test-positive participants versus symptomatic testnegative participants (controls) using multivariable logistic regression.
An interaction term for known contact and vaccination status was assessed. Models were adjusted as previously described and included age, study site, enrollment period, and self-reported race/ethnicity. 3 We performed stratified analyses by (1) time of illness onset using February-May 2021 as a pre-Delta variant period and July-September 2021 as the Delta variant-predominant period and (2) by age group (as 12-49 years and >49 years due to sample size). 7 We performed several sensitivity analyses. We compared VE using plausible self-report of vaccination to VE using only documented vaccination status, where plausibility was determined by ability to report credible location of vaccination, as previously described. 3 We also compared findings when persons who identified as working in healthcare were excluded and also when persons with unknown status were classified as having had no known contact. Statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary,

| DISCUSSION
Vaccination against COVID-19 disease provided protection against laboratory-confirmed, symptomatic outpatient illness among individuals who reported known contact with a person with COVID-19.
Participants who reported known contact with a person with COVID-19 were more likely to test positive for SARS-CoV-2 compared with participants who reported no known contact. Those who reported a known contact were more likely to report living in a household with at least one child aged <12 years or to report work in a healthcare setting; our findings did not differ substantially when persons who work in a healthcare setting were excluded. In addition, we did not detect a statistically significant difference by known contact status when participants were further stratified by illness onset into pre-Delta variant versus Delta variant circulation periods.
Having contact with a known person with SARS-CoV-2 infection substantially increases the likelihood of testing positive for SARS-CoV-2. Contact tracing and transmission studies suggest that household settings have the highest secondary attack rates, with an estimated pooled secondary transmission rate of 21.1% (95% CI: 17. 4-24.8). 1 Although we were unable to categorize the setting of known exposure in our study, other studies have compared secondary transmission from a household contact compared with other forms of contact and highlighted the importance of household transmission compared with occupational, social, or transportation exposures. 8,9 The importance of household transmission is likely due to prolonged exposures in proximity with fewer protective measures in place. In one study, unvaccinated or partially vaccinated persons were more likely to transmit SARS-CoV-2 virus compared with fully vaccinated persons. 9 We show equivalent, high levels of protection of full vaccination against symptomatic, laboratory-confirmed COVID-19 regardless of known contact.
We build upon prior published findings from the Flu VE Network in several ways. This analysis includes four additional months of data compared with an earlier evaluation of COVID-19 VE between February and May 2021. 3 Despite predominance of the Delta variant in the latter study period, 7 our findings show protection against laboratory-confirmed symptomatic illness. A decline in VE point estimates in the latter period could be attributed to reduced protection against the Delta or a result of waning protection of the initial vaccination series. 10,11 However, this study was underpowered to evaluate and disentangle these factors. Similar to other published reports, we detected lower adjusted VE of Pfizer-BioNTech vaccine compared with Moderna vaccine. 12 We summarize VE of full vaccination against laboratory-confirmed symptomatic outpatient illness in the period of time prior to when third/booster doses became available and were recommended, as well as the period of time when vaccination was recommended for US children aged 5 to 12 years of age. 13,14 Booster doses of all COVID-19 vaccines are currently available for adults aged ≥18 years in the USA. 15 T A B L E 1 Characteristics of enrolled participants by self-reported known contact with a person with SARS-CoV-2 in the 14 days prior to illness onset, US Flu VE Network, February 1 to September 30, 2021 Abbreviation: VE, vaccine effectiveness. a P-value is for the chi-square test where p<0.05 was considered statistically significant. b Underlying condition (e.g., heart disease, lung disease, diabetes, cancer, liver or kidney disease, immune suppression, or high blood pressure) is selfreported; 38 participants (7 with known contact and 31 participants with no known contact) missing underlying condition status. c Work in healthcare setting is self-reported; 21 participants missing healthcare worker status; 163 participants <18 years old were not asked this question. d Prior SARS-CoV-2 infection is self-reported; 44 participants (6 with known contact and 44 with no known contact) missing prior infection status. e There were 112 participants who had indeterminate vaccination status (22 with known contact and 90 with no known contact).
F I G U R E 1 Estimates of vaccine effectiveness a against laboratory-confirmed symptomatic COVID-19 among participants with and without reported known contact with persons with COVID-19 during the 14 days before illness onset, US Flu VE Network, February 1 to September 30, 2021. CI, confidence interval. a Vaccine effectiveness (VE) of full vaccination by documented records versus unvaccinated. Model adjusted for study site, age in years (continuous), enrollment period (natural cubic spline with 3 percentile knots of interval between January 1, 2021 and illness onset date), and self-reported race/ethnicity This study contributes to growing evidence of COVID-19 VE against symptomatic illness, among members of the general population who have contact with persons with COVID-19. These findings support recommendations for COVID-19 vaccination for the prevention of symptomatic illness and highlight the importance of continued efforts to increase vaccination coverage.