key: cord-0265685-kyimssbe
authors: Chung, J.; Kim, S.; Belongia, E. A.; McLean, H. Q.; King, J. P.; Nowalk, M. P.; Zimmerman, R. K.; Moehling Geffel, K.; Martin, E. T.; Monto, A.; Lamerato, L. E.; Gaglani, M.; Hoffman, E.; Volz, M.; Jackson, M. L.; Jackson, L. A.; Patel, M. M.; Flannery, B.
title: Vaccine Effectiveness against COVID-19 among Symptomatic Persons Aged >=12 Years with Reported Contact with COVID-19 Cases, February - September 2021
date: 2022-01-01
journal: nan
DOI: 10.1101/2021.12.30.21267928
sha: a39c2e300435145c18d68ed48bcdd7faab9f8da0
doc_id: 265685
cord_uid: kyimssbe

Individuals in contact with persons with COVID-19 are at high risk of developing COVID-19, but protection offered by COVID-19 vaccines in the context of known exposure is unknown. Symptomatic outpatients reporting acute onset of COVID-19-like illness and tested for SARS-CoV-2 infection were enrolled. Among 2,229 participants, 283/451 (63%) of those reporting contact and 331/1778 (19%) without known contact tested SARS-CoV-2 positive. Using the test-negative design, adjusted vaccine effectiveness was 71% (95% confidence interval, 49%-83%) among fully vaccinated participants reporting contact versus 80% (95% CI, 72%-86%) among those without. This study supports COVID-19 vaccination and highlights the importance of efforts to increase vaccination coverage.

Individuals in contact with persons with COVID-19 disease are at high risk of SARS-CoV-2 infection and developing COVID-19 disease themselves [1] . The US Centers for Disease Control and Prevention (CDC) recommends vaccination as the best tool to prevent COVID-19 disease among persons aged ≥ 5 years in conjunction with non-pharmaceutical interventions (NPIs) such as hand washing, mask wearing, and physical distancing [2] . Repeated, extended exposures in close proximity to persons with SARS-CoV-2 infection can increase the risk of becoming infected [3] . Having close contact with a person with COVID-19 disease, such as within a household, is one of the main sources 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 [4] .

Data are limited regarding how COVID-19 vaccine effectiveness (VE) may vary by the intensity of the exposure [5] . One approach to assess the impact of exposure would be to evaluate VE against symptomatic illness among individuals with known contact, compared to 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 [5] . 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 This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 1, 2022. ; https://doi.org/10.1101/2021.12.30.21267928 doi: medRxiv preprint Methods used for estimating VE against laboratory-confirmed symptomatic COVID-19 disease among persons seeking medical care or testing for SARS-COV-2 infection in Flu VE Network study sites have been previously described [6] . 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 acute onset of fever/feverishness, cough, or loss of taste or smell, with symptom duration <10 days [7] . Research staff contacted potentially eligible outpatients either in person, by telephone, or email to confirm eligibility and enroll participants who consented verbally or in writing. Standardized questionnaires collected demographic information, selfreported contact ≤ 14 days before illness onset with a person with confirmed COVID-19 (i.e., "known contact"), healthcare-related occupation, and COVID-19 vaccination. 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.

For this analysis, we included participants aged This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 1, 2022. ; https://doi.org/10.1101/2021.12.30.21267928 doi: medRxiv preprint illness onset [8] . Partially vaccinated participants were defined as those who received at least one dose of an mRNA vaccine ≥ 14 days before illness onset but who were not fully vaccinated.

Those who had no documentation of any COVID-19 vaccination prior to illness onset were defined as unvaccinated. Participants whose first documented 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, laboratory-confirmed outpatient COVID-19 disease [9] among participants reporting contact with persons with confirmed COVID-19 disease 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 test-negative 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 [6] .

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) [10] .

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 [6] . 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, NC, USA).

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This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. disease were more likely than those with unknown contact to be healthcare workers, aged <65 years, household contacts of children aged <12 years, tested for SARS-CoV-2 less than four days since illness onset, and have no documented COVID-19 vaccination (Table 1) .

Among participants reporting known contact, 183 (43%) were fully vaccinated ≥ 14 days before illness onset versus 951 (56%) of those without known contact ( Table 1) This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 1, 2022. Table) . This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 1, 2022. ; https://doi.org/10.1101/2021.12.30.21267928 doi: medRxiv preprint Vaccination against COVID-19 disease provided protection against laboratoryconfirmed, symptomatic outpatient illness among individuals who reported known contact with a person with COVID-19 disease. Participants who reported known contact with a person with COVID-19 disease were more likely to test positive for SARS-CoV-2 infection compared to 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 were robust 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) [3] . 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 to other forms of contact and highlighted the importance of household transmission compared to occupational, social, or transportation exposures [11] [12] [13] . The importance of household transmission is likely due to prolonged exposures in close 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 to fully vaccinated persons [13] . We show equivalent, high levels of protection of full vaccination against symptomatic, laboratory-confirmed COVID-19 disease regardless of known contact.

for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. We build upon prior published findings from the Flu VE Network in several ways. This analysis includes four additional months of data compared to an earlier evaluation of COVID-19 VE between February and May 2021 [6] . Despite predominance of the Delta variant in the latter study period [10] , our findings show protection against laboratory-confirmed symptomatic illness. A decline in VE point estimates in the latter study period could be attributed to reduced protection against the Delta or a result of waning protection of the initial vaccination series [14, 15] . However, this study was underpowered to evaluate and disentangle these factors. Similar to other published reports, we detected a lower adjusted VE of Pfizer-BioNTech vaccine when compared to Moderna vaccine [16] . This analysis summarizes VE of full vaccination against laboratory-confirmed symptomatic outpatient illness in the period of time prior to when third (i.e., booster) doses became available and were recommended, as well as the period of time when vaccination was recommended for US children aged five to twelve years of age [17, 18] .

Booster doses of all COVID-19 vaccines are currently available for adults aged Our study was subject to at least five limitations. First, we did not assess the nature of reported contact and do not have information about whether the exposure was a household member, occupational, or other type of exposure. Second, we did not collect information about the timing of the reported known contact within the 14 days prior to illness onset. Participants could have been infected prior to the reported exposure. Third, some participants might have been aware of their SARS-CoV-2 test status when they completed the enrollment questionnaire, which could have influenced responses to the known contact question [11] . While the testnegative design reduces bias due to differences in healthcare-seeking behavior among vaccinated and unvaccinated persons [9] , vaccinated cases could have been more motivated to participate in for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 1, 2022. ; https://doi.org/10.1101/2021.12.30.21267928 doi: medRxiv preprint this study. Fourth, we did not ask about NPIs or duration of contact of the known exposure.

Differences in exposures and prevention measures among vaccinated and unvaccinated participants could have been associated with likelihood of testing positive for SARS-CoV-2 infection. Finally, our study was unable to account for differences in timing of vaccination.

This study contributes to growing evidence of COVID-19 VE against symptomatic illness, including sustained protection in the Delta-variant period, among members of the general population who have contact with persons with COVID-19 disease. 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.

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This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 1, 2022. ; This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 1, 2022. ; This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 1, 2022. ; Figure. Estimates of vaccine effectiveness a against laboratory-confirmed symptomatic COVID-19 among participants with and without reported known contact with persons with COVID-19 disease during 14 days before illness onset, US Flu VE Network, February 1-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.

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The copyright holder for this preprint this version posted January 1, 2022. 

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for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted January 1, 2022.