Background Households represent important settings for transmission of influenza and other respiratory viruses. Current influenza diagnosis and treatment relies upon patient visits to healthcare facilities, which may lead to under-diagnosis and treatment delays. This study aimed to assess the feasibility of an at-home approach to influenza diagnosis and treatment via home testing, telehealth care, and rapid antiviral home delivery.Methods We conducted a pilot interventional study of remote influenza diagnosis and treatment in Seattle-area households with children during the 2019-2020 influenza season using pre-positioned nasal swabs and home influenza tests. Home monitoring for respiratory symptoms occurred weekly; if symptoms were reported within 48 hours of onset, participants collected mid-nasal swabs and used a rapid home-based influenza immunoassay. An additional home-collected swab was returned to a laboratory for confirmatory influenza RT-PCR testing. Baloxavir antiviral treatment was prescribed and delivered to symptomatic and age-eligible participants, following a telehealth encounter.Results 124 households comprising 481 individuals self-monitored for respiratory symptoms, with 58 home tests administered. 12 home tests were positive for influenza, of which 8 were true positives confirmed by RT-PCR. The sensitivity and specificity of the home influenza test was 72.7% and 96.2%, respectively. There were 8 home deliveries of baloxavir, with 7 (87.5%) occurring within 3 hours of prescription, and all within 48 hours of symptom onset.Conclusions We demonstrate the feasibility of self-testing combined with rapid home delivery of influenza antiviral treatment. This approach may be an important control strategy for influenza epidemics and pandemics.Summary In this pilot study, 481 individuals self-monitored for respiratory symptoms. Of 58 home tests, 12 were influenza-positive. There were 8 baloxavir home deliveries within 48 hours of illness onset. A home-based approach to influenza diagnosis and treatment could be feasible.Competing Interest StatementH.Y.C. has received research support from GlaxoSmithKline, Novavax, and Sanofi Pasteur; J.A.E. has received research support from AstraZeneca, GlaxoSmithKine, Merck, and Pfizer and served as a consultant for Sanofi Pasteur and Meissa Vaccines. M.L.J. has received research support from Sanofi Pasteur. M.B. receives research support and serves as a consultant for Ansun Biopharma, Gilead Sciences, Janssen, and Vir Biotechnology; and serves as a consultant to GlaxoSmithKline, ReViral, ADMA, Pulmocdie and ModernaClinical TrialNCT04141930Funding StatementThe Seattle Flu Study is funded by Gates Ventures. The funder was not involved in the design of the study, does not have any ownership over the management and conduct of the study, the data, or the rights to publish.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:University of Washington Institutional Review Board (STUDY00008200)All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData and code used for analyses may be available upon request.

Evaluations of vaccine effectiveness (VE) are important to monitor as COVID-19 vaccines are introduced in the general population. Research staff enrolled symptomatic participants seeking outpatient medical care for COVID-19-like illness or SARS-CoV-2 testing from a multisite network. VE was evaluated using the test-negative design. Among 236 SARS-CoV-2 nucleic acid amplification test-positive and 576 test-negative participants aged ≥16 years, VE of mRNA vaccines against COVID-19 was 91% (95% CI: 83-95) for full vaccination and 75% (95% CI: 55-87) for partial vaccination. Vaccination was associated with prevention of most COVID-19 cases among people seeking outpatient medical care.Competing Interest StatementMPN reports grants from Merck & Co. outside the submitted work. RKZ reports grants from Sanofi Pasteur outside the submitted work. GKB reports grants from Merck & Co outside the submitted work and consulting fees from New World Medical, LLC. ETM reports grants from Merck & Co. outside the submitted work and consulting fees from Pfizer. ASM reports consulting fees from Sanofi Pasteur and Seqirus. LEL reports grants from Xcenda, Inc., eMAXHealth, AstraZeneca, Pfizer, Evidera outside the submitted work. MLJ reports grants from Sanofi Pasteur. All other authors report nothing to disclose.Funding StatementThis work was supported by the US Centers for Disease Control and Prevention through cooperative agreements U01IP001034-U01IP001039. At Pittsburgh, the project was also supported by the National Institutes of Health through grant ULTR001857.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Centers for Disease Control and Prevention IRB project determination numbers for included projects: 0900f3eb81c2e791, 0900f3eb81c52dc5; 0900f3eb81c52420, 0900f3eb81bc746b, 6238All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesDe-identified dataset can be made available upon request

Estimating prevalence of SARS-CoV-2 antibodies is important to determine disease burden. We tested residual samples from 763 Seattle-area adults for SARS-CoV-2 antibodies. Prevalence rose from 0% to 1.2% between October 2019–April 2020, suggesting a small percentage of this metropolitan-area cohort had been infected with SARS-CoV-2 at that time.Competing Interest StatementHelen Y. Chu receives research support from Cepheid and is a consultant for Merck, Pfizer, the Bill and Melinda Gates Foundation, and Ellume. Michael L. Jackson receives research funding from Sanofi Pasteur. Denise J. McCulloch, James P. Hughes, Sandra Lester, Lisa Mills, Brandi Freeman, Mohammad Ata Ut Rasheed, and Natalie J. Thornburg, declare no competing interests.Funding StatementThis work was supported by the University of Washington Department of Medicine Scholars Award to Helen Chu.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:University of Washington IRBAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data analyzed during the current study are available from the corresponding author on reasonable request.

We compared symptoms and characteristics of 4961 ambulatory patients with and without laboratory-confirmed SARS-CoV-2 infection. Findings indicate that clinical symptoms alone would be insufficient to distinguish between COVID-19 and other respiratory infections (e.g., influenza) and/or to evaluate the effects of preventive interventions (e.g., vaccinations).Competing Interest StatementAll authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: AM reports personal fees from Sanofi Pasteur and from Seqirus outside the submitted work; EB reports grants from CDC during the conduct of the study. EM reports grants from Centers for Disease Control and Prevention during the conduct of the study and personal fees from Pfizer outside the submitted work; LJ reports grants from CDC during the conduct of the study and grants from Novavax outside the submitted work; MG reports grants from Centers for Disease Control and Prevention during the conduct of the study and grants from Centers for Disease Control and Prevention - Abt Associates outside the submitted work; MJ reports grants from Centers for Disease Control during the conduct of the study and grants from Sanofi Pasteur outside the submitted work; MN reports grants from Centers for Disease Control and Prevention and National Institutes of Health during the conduct of the study and grants from Merck & Co outside the submitted work; RZ reports grants from Centers for Disease Control and Prevention and National Institutes of Health during the conduct of the study and grants from Sanofi Pasteur outside the submitted work. All other authors have nothing to disclose.Funding StatementThis work was supported through cooperative agreements funded by US Centers for Disease Control and Prevention and, at the University of Pittsburgh, by infrastructure funding by UL1 TR001857 from National Institutes of Health.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Approved or waived by the Centers for Disease Control and Prevention (CDC) IRB with reliance on: 1.University of Michigan IRB (Approved) a. CDC protocol 6238 b. University of Michigan protocol HUM00119183 2. University of Pittsburgh IRB (Approved) a. CDC protocol 6219 b. University of Pittsburgh protocol STUDY19070407 3. Baylor Scott and White Health IRB (Approved) a. CDC protocols 7125 and 7277 b. Baylor Scott and White protocols 160145 and 20-153 4. Kaiser Permanente Washington Research Institute (Waived) 5. Marshfield Clinic Research Institute (Approved) a. CDC protocol 6197 b. Marshfield Clinic Research Institute protocol BEL10511 All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData may be made available in accordance with CDC data availability policy.

Background. Studies have reported that prior-season influenza vaccination is associated with higher risk of clinical influenza infection among vaccinees in a given season. Understanding the underlying causes requires consideration of within-season waning and recent infection. Methods. Using the US Flu Vaccine Effectiveness (VE) Network data over 8 influenza seasons (2011-2012 to 2018-2019), we estimated the effect of prior-season vaccination on the odds of clinical infection in a given season, after accounting for waning vaccine protection using regression methods. We adjusted for potential confounding by recent clinical infection using inverse-probability weighting. We investigated theoretically whether unmeasured subclinical infection in the prior season, which is more likely in the non-repeat vaccinees, could explain the repeat vaccination effect. Results. Repeat vaccinees vaccinated earlier in a season by one week. After accounting for waning VE, repeat vaccinees were still more likely to test positive for influenza A(H3N2) (OR=1.11, 95% CI:1.02-1.21) but not for influenza B (OR=1.03, 95% CI:0.89-1.18) or A(H1N1) (OR=1.03, 95% CI:0.90-1.19) compared to those vaccinated in the given season only. Recent clinical infection with the homologous (sub)type protected against clinical infection with A(H3N2) or B. Individuals with clinical infection in one season had 1.11 (95% CI:1.03-1.19) times the odds of switching vaccination status in the following season. Adjusting for recent clinical infections did not strongly influence the estimated effect of prior-season vaccination. Adjusting for subclinical infection could theoretically attenuate this effect. Conclusion. Waning protection and recent clinical infection were insufficient to explain observed reduced VE in repeat vaccinees with a test-negative design. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.

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 SARSCoV-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. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

OBJECTIVE: To evaluate the risk of spontaneous abortion after quadrivalent human papillomavirus (4vHPV) vaccination before and during pregnancy across seven integrated health systems within the Vaccine Safety Datalink. METHODS: Within a retrospective observational cohort, we compared risks for spontaneous abortion after 4vHPV in three exposure windows: distal (16-22 weeks before the last menstrual period [LMP]), peripregnancy (within 6 weeks before the LMP), and during pregnancy (LMP through 19 weeks of gestation). Women 12-27 years of age with a pregnancy between 2008 and 2014, with continuous insurance enrollment 8 months before and through pregnancy end, and with a live birth, stillbirth, or spontaneous abortion were included. Pregnancies were identified through validated algorithms. Spontaneous abortions and stillbirths were verified by chart review with spontaneous abortions adjudicated by clinical experts. We excluded multiple gestations, spontaneous abortions before 6 weeks of gestation, and women using medications increasing risk of spontaneous abortion. Spontaneous abortion risk after 4vHPV during pregnancy was compared with distal vaccination using time-dependent covariate Cox models. Spontaneous abortion risk for peripregnancy compared with distal vaccination was evaluated with standard Cox models. RESULTS: We identified 2,800 pregnancies with 4vHPV exposure in specified risk windows: 919 (33%) distal, 986 (35%) peripregnancy, and 895 (32%) during pregnancy. Mean age was 22.4 years in distal and peripregnancy groups compared with 21.4 years among women vaccinated during pregnancy. Among women with distal 4vHPV exposure, 96 (10.4%) experienced a spontaneous abortion. For peripregnancy and during pregnancy exposures, spontaneous abortions occurred in 110 (11.2%) and 77 (8.6%), respectively. The risk of spontaneous abortion was not increased among women who received 4vHPV during pregnancy (adjusted hazard ratio 1.10, 95% CI 0.81-1.51) or peripregnancy 1.07 (0.81-1.41). CONCLUSION: Inadvertent 4vHPV exposure during or peripregnancy was not significantly associated with an increased risk of spontaneous abortion.

BACKGROUND AND OBJECTIVES: Infants and children are at increased risk of severe influenza virus infection and its complications. Influenza vaccine effectiveness (VE) varies by age, influenza season, and influenza virus type/subtype. This study's objective was to examine the effectiveness of inactivated influenza vaccine against outpatient influenza illness in the pediatric population over 9 influenza seasons after the 2009 A(H1N1) pandemic. METHODS: During the 2011-2012 through the 2019-2020 influenza seasons at outpatient clinics at 5 sites of the US Influenza Vaccine Effectiveness Network, children aged 6 months to 17 years with an acute respiratory illness were tested for influenza using real-time, reverse-transcriptase polymerase chain reaction. Vaccine effectiveness was estimated using a test-negative design. RESULTS: Among 24 148 enrolled children, 28% overall tested positive for influenza, 3017 tested positive for influenza A(H3N2), 1459 for influenza A(H1N1)pdm09, and 2178 for influenza B. Among all enrollees, 39% overall were vaccinated, with 29% of influenza cases and 43% of influenza-negative controls vaccinated. Across all influenza seasons, the pooled VE for any influenza was 46% (95% confidence interval, 43-50). Overall and by type/subtype, VE against influenza illness was highest among children in the 6- to 59-month age group compared with older pediatric age groups. VE was lowest for influenza A(H3N2) virus infection. CONCLUSIONS: Analysis of multiple seasons suggested substantial benefit against outpatient illness. Investigation of host-specific or virus-related mechanisms that may result in differences by age and virus type/subtype may help further efforts to promote increased vaccination coverage and other influenza-related preventative measures.

Persons with COVID-19-like illnesses are advised to stay home to reduce the spread of SARS-CoV-2. We assessed relationships between telework experience and COVID-19 illness with work attendance when ill. Adults experiencing fever, cough, or loss of taste or smell who sought healthcare or COVID-19 testing in the United States during March-November 2020 were enrolled. Adults with telework experience before illness were more likely to work at all (onsite or remotely) during illness (87.8%) than those with no telework experience (49.9%) (adjusted odds ratio 5.48, 95% CI 3.40-8.83). COVID-19 case-patients were less likely to work onsite (22.1%) than were persons with other acute respiratory illnesses (37.3%) (adjusted odds ratio 0.36, 95% CI 0.24-0.53). Among COVID-19 case-patients with telework experience, only 6.5% worked onsite during illness. Telework experience before illness gave mildly ill workers the option to work and improved compliance with public health recommendations to stay home during illness.

BACKGROUND: Epidemics of seasonal influenza vary in intensity annually, and influenza vaccine effectiveness (VE) fluctuates based in part on antigenic match to circulating viruses. We estimated the incidence of influenza and influenza cases averted by vaccination in four ambulatory care sites in the United States, during seasons when overall influenza VE ranged from 29% to 40%. METHODS: We conducted active surveillance for influenza at ambulatory care settings at four sites within the United States Influenza Vaccine Effectiveness Network. We extrapolated the total number of influenza cases in the source populations served by these organizations based on incidence of medically attended acute respiratory illness in the source population and influenza test results in those actively tested for influenza. We estimated the number of medically attended influenza cases averted based on incidence, vaccine coverage, and VE. RESULTS: From 2016/17 through 2018/19, incidence of ambulatory visits for laboratory-confirmed influenza ranged from 31 to 51 per 1,000 population. Incidence was highest in children aged 9-17years (range, 56 to 81 per 1,000) and lowest in adults aged 18-49years (range, 23-32 per 1,000). Medically attended cases averted by vaccination ranged from a high of 46.6 (95% CI, 12.1- 91.9) per 1,000 vaccinees in children aged 6months to 8years, to a low of 6.9 (95% CI, -5.1- 27.3) per 1,000 vaccinees in adults aged65years. DISCUSSION: Even in seasons with low vaccine effectiveness for a particular virus subtype, influenza vaccines can still lead to clinically meaningful reductions in ambulatory care visits for influenza.

OBJECTIVE: To assess the association between cumulative aluminum exposure from vaccines before age 24 months and persistent asthma at age 24 to 59 months. METHODS: A retrospective cohort study was conducted in the Vaccine Safety Datalink (VSD). Vaccination histories were used to calculate cumulative vaccine-associated aluminum in milligrams (mg). The persistent asthma definition required one inpatient or 2 outpatient asthma encounters, and 2 long-term asthma control medication dispenses. Cox proportional hazard models were used to evaluate the association between aluminum exposure and asthma incidence, stratified by eczema presence/absence. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) per 1 mg increase in aluminum exposure were calculated, adjusted for birth month/year, sex, race/ethnicity, VSD site, prematurity, medical complexity, food allergy, severe bronchiolitis, and health care utilization. RESULTS: The cohort comprised 326,991 children, among whom 14,337 (4.4%) had eczema. For children with and without eczema, the mean (standard deviation [SD]) vaccine-associated aluminumexposure was4.07mg (SD0.60) and 3.98mg (SD0.72), respectively. Among children with and without eczema, 6.0% and 2.1%, respectively, developed persistent asthma. Among children with eczema, vaccine-associated aluminum was positively associated with persistent asthma (aHR 1.26 per 1 mg increase in aluminum, 95% CI 1.07, 1.49); a positive association was also detected among children without eczema (aHR 1.19, 95% CI 1.14, 1.25). CONCLUSION: In a large observational study, a positive association was found between vaccine-related aluminum exposure and persistent asthma. While recognizing the small effect sizes identified and the potential for residual confounding, additional investigation of this hypothesis appears warranted.

Recombinant zoster vaccine (RZV) (Shingrix; GlaxoSmithKline, Brentford, United Kingdom) is an adjuvanted glycoprotein vaccine that was licensed in 2017 to prevent herpes zoster and its complications in older adults. In this prospective, post-licensure Vaccine Safety Datalink (VSD) study using electronic health records, we sequentially monitored a real-world population of adults aged 50 years and older who received care at multiple VSD health systems in the United States to identify potential increased risks of 10 pre-specified priority outcomes, including stroke, anaphylaxis, and Guillain-Barr Syndrome (GBS). Among 647,833 RZV doses administered from January 2018 through December 2019, we did not detect a sustained increased risk of any monitored outcome for RZV recipients relative either to historical (2013-2017) recipients of Zoster Vaccine Live (ZVL), a live-attenuated virus vaccine (Zostavax; Merck & Co., Inc., Kenilworth, New Jersey), or contemporary non-RZV vaccinated persons who had an annual well-visit during the 2018-2019 study period. We confirmed pre-licensure trial findings of increased risks of systemic and local reactions following RZV. Our study provides additional reassurance about the overall safety of RZV. Despite a large sample, uncertainty remains regarding potential associations with GBS due to the limited number of confirmed GBS cases that were observed.

Influenza vaccines can mitigate illness severity, including reduced risk of ICU admission and death, in people with breakthrough infection. Less is known about vaccine attenuation of mild/moderate influenza illness. We compared subjective severity scores in vaccinated and unvaccinated persons with medically attended illness and laboratory-confirmed influenza. Participants were prospectively recruited when presenting for care at five US sites over nine seasons. Participants aged ≥ 16 years completed the EQ-5D-5L visual analog scale (VAS) at enrollment. After controlling for potential confounders in a multivariable model, including age and general health status, VAS scores were significantly higher among 2,830 vaccinated participants compared with 3,459 unvaccinated participants, indicating vaccinated participants felt better at the time of presentation for care. No differences in VAS scores were observed by the type of vaccine received among persons aged ≥ 65 years. Our findings suggest vaccine-associated attenuation of milder influenza illness is possible.

OBJECTIVES: Having accurate influenza vaccination coverage estimates can guide public health activities. The objectives of this study were to (1) validate the accuracy of electronic health record (EHR)-based influenza vaccination data among pregnant women compared with survey self-report and (2) assess whether survey respondents differed from survey nonrespondents by demographic characteristics and EHR-based vaccination status. METHODS: This study was conducted in the Vaccine Safety Datalink, a network of 8 large medical care organizations in the United States. Using EHR data, we identified all women pregnant during the 2018-2019 or 2019-2020 influenza seasons. Surveys were conducted among samples of women who did and did not appear vaccinated for influenza according to EHR data. Separate surveys were conducted after each influenza season, and respondents reported their influenza vaccination status. Analyses accounted for the stratified design, sampling probability, and response probability. RESULTS: The survey response rate was 50.5% (630 of 1247) for 2018-2019 and 41.2% (721 of 1748) for 2019-2020. In multivariable analyses combining both survey years, non-Hispanic Black pregnant women had 3.80 (95% CI, 2.13-6.74) times the adjusted odds of survey nonresponse; odds of nonresponse were also higher for Hispanic pregnant women and women who had not received (per EHR data) influenza vaccine during current or prior influenza seasons. The sensitivity, specificity, and positive predictive value of EHR documentation of influenza vaccination compared with self-report were ≥92% for both survey years combined. The negative predictive value of EHR-based influenza vaccine status was 80.5% (95% CI, 76.7%-84.0%). CONCLUSIONS: EHR-based influenza vaccination data among pregnant women were generally concordant with self-report. New data sources and novel approaches to mitigating nonresponse bias may be needed to enhance influenza vaccination surveillance efforts.

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.

Residents and staff of emergency shelters for people experiencing homelessness (PEH) are at high risk of infection with SARS-CoV-2. The importance of shelter-related transmission of SARS-CoV-2 in this population remains unclear. It is also unknown whether there is significant spread of shelter-related viruses into surrounding communities. We analyzed genome sequence data for 28 SARS-CoV-2-positive specimens collected from 8 shelters in King County, Washington between March and October, 2020. We identified at least 12 separate SARS-CoV-2 introduction events into these 8 shelters and estimated that 57% (16 out of 28) of the examined cases of SARS-CoV-2 infection were the result of intra-shelter transmission. However, we identified just a few SARS-CoV-2 specimens from Washington that were possible descendants of shelter viruses. Our data suggest that SARS-CoV-2 spread in shelters is common, but we did not observe evidence of wide-spread transmission of shelter-related viruses into the general population.

BACKGROUND: The Vaccine Safety Datalink (VSD) uses vaccination data from electronic health records (EHR) at eight integrated health systems to monitor vaccine safety. Accurate capture of data from vaccines administered outside of the health system is critical for vaccine safety research, especially for COVID-19 vaccines, where many are administered in non-traditional settings. However, timely access and inclusion of data from Immunization Information Systems (IIS) into VSD safety assessments is not well understood. METHODS: We surveyed the eight data-contributing VSD sites to assess: 1) status of sending data to IIS; 2) status of receiving data from IIS; and 3) integration of IIS data into the site EHR. Sites reported separately for COVID-19 vaccination to capture any differences in capacity to receive and integrate data on COVID-19 vaccines versus other vaccines. RESULTS: All VSD sites send data to and receive data from their state IIS. All eight sites (100%) routinely integrate IIS data for COVID-19 vaccines into VSD research studies. Six sites (75%) also routinely integrate all other vaccination data; two sites integrate data from IIS following a reconciliation process, which can result in delays to integration into VSD datasets. CONCLUSIONS: COVID-19 vaccines are being administered in a variety of non-traditional settings, where IIS are commonly used as centralized reporting systems. All eight VSD sites receive and integrate COVID-19 vaccine data from IIS, which positions the VSD well for conducting quality assessments of vaccine safety. Efforts to improve the timely receipt of all vaccination data will improve capacity to conduct vaccine safety assessments within the VSD.

INTRODUCTION: Little is known about COVID-19 vaccination intent among people experiencing homelessness. This study assesses surveyed COVID-19 vaccination intent among adult homeless shelter residents and staff and identifies factors associated with vaccine deliberation (responded "undecided") and reluctance (responded "no"), including time trends. METHODS: From 11/1/2020-2/28/21, we conducted repeated cross-sectional surveys at nine shelters in King County, WA as part of ongoing community-based SARS-CoV-2 surveillance. We used a multinomial model to identify characteristics associated with vaccine deliberation and reluctance. RESULTS: A total of 969 unique staff (n = 297) and residents (n = 672) participated and provided 3966 survey responses. Among residents, 53.7% (n = 361) were vaccine accepting, 28.1% reluctant, 17.6% deliberative, and 0.6% already vaccinated, whereas among staff 56.2% were vaccine accepting, 14.1% were reluctant, 16.5% were deliberative, and 13.1% already vaccinated at their last survey. We observed higher odds of vaccine deliberation or reluctance among Black/African American individuals, those who did not receive a seasonal influenza vaccine, and those with lower educational attainment. There was no significant trend towards vaccine acceptance. CONCLUSIONS: Strong disparities in vaccine intent based on race, education, and prior vaccine history were observed. Increased vaccine intent over the study period was not detected. An intersectional, person-centered approach to addressing health inequities by public health authorities planning vaccination campaigns in shelters is recommended. Clinical Trial Registry Number: NCT04141917.

IMPORTANCE: The COVID-19 pandemic has affected routine vaccine delivery in the US and globally. The magnitude of these disruptions and their association with childhood vaccination coverage are unclear. OBJECTIVES: To compare trends in pediatric vaccination before and during the pandemic and to evaluate the proportion of children up to date (UTD) with vaccinations by age, race, and ethnicity. DESIGN, SETTING, AND PARTICIPANTS: This surveillance study used a prepandemic-postpandemic control design with data from 8 health systems in California, Oregon, Washington, Colorado, Minnesota, and Wisconsin in the Vaccine Safety Datalink. Children from age groups younger than 24 months and 4 to 6, 11 to 13, and 16 to 18 years were included if they had at least 1 week of health system enrollment from January 5, 2020, through October 3, 2020, over periods before the US COVID-19 pandemic (January 5, 2020, through March 14, 2020), during age-limited preventive care (March 15, 2020, through May 16, 2020), and during expanded primary care (May 17, 2020, through October 3, 2020). These individuals were compared with those enrolled during analogous weeks in 2019. EXPOSURES: This study evaluated UTD status among children reaching specific ages in February, May, and September 2020, compared with those reaching these ages in 2019. MAIN OUTCOMES AND MEASURES: Weekly vaccination rates for routine age-specific vaccines and the proportion of children UTD for all age-specific recommended vaccines. RESULTS: Of 1 399 708 children in 2019 and 1 402 227 in 2020, 1 371 718 were female (49.0%) and 1 429 979 were male (51.0%); 334 216 Asian individuals (11.9%), 900 226 were Hispanic individuals (32.1%), and 201 619 non-Hispanic Black individuals (7.2%). Compared with the prepandemic period and 2019, the age-limited preventive care period was associated with lower weekly vaccination rates, with ratios of rate ratios of 0.82 (95% CI, 0.80-0.85) among those younger than 24 months, 0.18 (95% CI, 0.16-0.20) among those aged 4 to 6 years, 0.16 (95% CI, 0.14-0.17) among those aged 11 to 13 years, and 0.10 (95% CI, 0.08-0.13) among those aged 16 to 18 years. Vaccination rates during expanded primary care remained lower for most ages (ratios of rate ratios: <24 months, 0.96 [95% CI, 0.93-0.98]; 11-13 years, 0.81 [95% CI, 0.76-0.86]; 16-18 years, 0.57 [95% CI, 0.51-0.63]). In September 2020, 74% (95% CI, 73%-76%) of infants aged 7 months and 57% (95% CI, 56%-58%) of infants aged 18 months were UTD vs 81% (95% CI, 80%-82%) and 61% (95% CI, 60%-62%), respectively, in September 2019. The proportion UTD was lowest in non-Hispanic Black children across most age groups, both during and prior to the COVID-19 pandemic (eg, in May 2019, 70% [95% CI, 64%-75%] of non-Hispanic Black infants aged 7 months were UTD vs 82% [95% CI, 81%-83%] in all infants aged 7 months combined). CONCLUSIONS AND RELEVANCE: As of September 2020, childhood vaccination rates and the proportion who were UTD remained lower than 2019 levels. Interventions are needed to promote catch-up vaccination, particularly in populations at risk for underimmunization.

Evaluations of vaccine effectiveness (VE) are important to monitor as COVID-19 vaccines are introduced in the general population. Research staff enrolled symptomatic participants seeking outpatient medical care for COVID-19-like illness or SARS-CoV-2 testing from a multisite network. VE was evaluated using the test-negative design. Among 236 SARS-CoV-2 nucleic acid amplification test-positive and 576 test-negative participants aged ≥16 years, VE of mRNA vaccines against COVID-19 was 91% (95% CI: 83-95) for full vaccination and 75% (95% CI: 55-87) for partial vaccination. Vaccination was associated with prevention of most COVID-19 cases among people seeking outpatient medical care.

Intra-season timing of influenza infection among persons of different ages could reflect relative contributions to propagation of seasonal epidemics and has not been examined among ambulatory patients. We calculated risk ratios derived from comparing weekly influenza cases pre-peak versus post-peak during the 2010-2011 through 2018-2019 influenza seasons using data from the US Influenza Vaccine Effectiveness network. We sought to determine age specific differences during the ascent versus the descent of a season by influenza virus types and subtypes. We estimated credible intervals around the risk ratios using Bayesian joint posterior sampling of weekly cases. Our population consisted of ambulatory patients with laboratory-confirmed influenza enrolled at five study sites during nine influenza seasons after the 2009 influenza A virus subtype H1N1 (H1N1) pandemic. We observed that young children aged <5 years tended to be more often infected with H1N1 during the pre-peak period while adults aged ≥65 years tended to be more often infected with H1N1 during the post-peak period. However, for influenza A virus subtype H3N2 children aged <5 years were more often infected during the post-peak period. These results may reflect a contribution of different age groups to seasonal spread, which may differ by influenza virus type and subtype.

Introduction: Monitoring the trends in undervaccination, including that because of parental vaccine refusal or delay, can inform public health responses directed at improving vaccine confidence and vaccination coverage. Methods: A retrospective cohort study was conducted in the Vaccine Safety Datalink. The cohort included all children born in 2004–2017 with ≥3 well-child visits between ages 2 and 23 months. Using electronic health record–based vaccination data, the average days undervaccinated was calculated for each child. Undervaccination patterns were assessed through age 23 months. Temporal trends were inspected for inflection points and were analyzed using linear regression. Nested within the cohort study, a survey was conducted to compare parent reports of vaccine refusal or delay with observed vaccination patterns. Data were analyzed in 2020. Results: The study cohort consisted of 808,170 children. The percentage of children with average days undervaccinated=0 (fully vaccinated, no delays) rose from a nadir of 47.1% for the birth year 2008 to 68.4% for the birth year 2017 (ptrend&lt;0.001). The percentage with no vaccines rose from 0.35% for the birth year 2004 to 1.28% for the birth year 2017 (ptrend&lt;0.001). Consistent vaccine limiting was observed in 2.04% for the birth year 2017. Omission of measles, mumps, and rubella vaccine peaked at 4.76% in the birth year 2007 and declined thereafter (ptrend&lt;0.001). On the parent survey (response rate 60.2%), a high proportion of parents of the most undervaccinated children reported refusing or delaying vaccines. Conclusions: In a 14-year cohort study, vaccination timeliness has improved. However, the small but increasing number of children who received no vaccines by age 23 months warrants additional attention. © 2021 American Journal of Preventive Medicine

INTRODUCTION: Mid-season influenza vaccine effectiveness (VE) estimates are a useful tool to help guide annual influenza vaccine strain selection, vaccine policy, and public health messaging. We propose using a sample size-driven approach with data-driven inputs for publication of mid-season influenza VE. METHODS: We used pooled inputs for VE by (sub)type and average vaccine coverage by age groups using data from eight seasons of the US Influenza VE Network to calculate sample sizes needed to estimate mid-season VE. RESULTS: We estimate that 135 influenza-positive cases would be needed to detect an overall VE of 40% with 55% vaccine coverage among test-negative controls. Larger sample sizes would be required to produce reliable estimates specifically against influenza A/H3N2 and for older age groups. CONCLUSION: Using an existing network, most of the recent influenza seasons in the US would facilitate valid mid-season VE estimates using the proposed sample sizes for broad age groupings.

BACKGROUND: The first US case of SARS-CoV-2 infection was detected on January 20, 2020. However, some serology studies suggest SARS-CoV-2 may have been present in the United States prior to that, as early as December 2019. The extent of domestic COVID-19 detection prior to 2020 has not been well-characterized. OBJECTIVES: To estimate the prevalence of SARS-CoV-2 antibody among healthcare users in the greater Seattle, Washington area from October 2019 through early April 2020. STUDY DESIGN: We tested residual samples from 766 Seattle-area adults for SARS-CoV-2 antibodies utilizing an ELISA against prefusion-stabilized Spike (S) protein. RESULTS: No antibody-positive samples were found between October 2, 2019 and March 13, 2020. Prevalence rose to 1.2% in late March and early April 2020. CONCLUSIONS: The absence of SARS-CoV-2 antibody-positive samples in October 2019 through mid-March, 2020, provides evidence against widespread circulation of COVID-19 among healthcare users in the Seattle area during that time. A small proportion of this metropolitan-area cohort had been infected with SARS-CoV-2 by spring of 2020.

BACKGROUND: Households represent important settings for transmission of influenza and other respiratory viruses. Current influenza diagnosis and treatment relies upon patient visits to healthcare facilities, which may lead to under-diagnosis and treatment delays. This study aimed to assess the feasibility of an at-home approach to influenza diagnosis and treatment via home testing, telehealth care, and rapid antiviral home delivery. METHODS: We conducted a pilot interventional study of remote influenza diagnosis and treatment in Seattle-area households with children during the 2019-2020 influenza season using pre-positioned nasal swabs and home influenza tests. Home monitoring for respiratory symptoms occurred weekly; if symptoms were reported within 48 hours of onset, participants collected mid-nasal swabs and used a rapid home-based influenza immunoassay. An additional home-collected swab was returned to a laboratory for confirmatory influenza RT-PCR testing. Baloxavir antiviral treatment was prescribed and delivered to symptomatic and age-eligible participants, following a telehealth encounter. RESULTS: 124 households comprising 481 individuals self-monitored for respiratory symptoms, with 58 home tests administered. 12 home tests were positive for influenza, of which eight were true positives confirmed by RT-PCR. The sensitivity and specificity of the home influenza test were 72.7% and 96.2%, respectively. There were eight home deliveries of baloxavir, with 7 (87.5%) occurring within 3 hours of prescription and all within 48 hours of symptom onset. CONCLUSIONS: We demonstrate the feasibility of self-testing combined with rapid home delivery of influenza antiviral treatment. This approach may be an important control strategy for influenza epidemics and pandemics.

BACKGROUND: Routine influenza vaccine effectiveness (VE) surveillance networks use frequentist methods to estimate VE. With data from more than a decade of VE surveillance from diverse global populations now available, using Bayesian methods to explicitly account for this knowledge may be beneficial. This study explores differences between Bayesian vs. frequentist inference in multiple seasons with varying VE. METHODS: We used data from the United States Influenza Vaccine Effectiveness (US Flu VE) Network. Ambulatory care patients with acute respiratory illness were enrolled during seasons of varying observed VE based on traditional frequentist methods. We estimated VE against A(H1N1)pdm in 2015/16, dominated by A(H1N1)pdm; against A(H3N2) in 2017/18, dominated by A(H3N2); and compared VE for live attenuated influenza vaccine (LAIV) vs. inactivated influenza vaccine (IIV) among children aged 2-17 years in 2013/14, also dominated by A(H1N1)pdm. VE was estimated using both frequentist and Bayesian methods using the test-negative design. For the Bayesian estimates, prior VE distributions were based on data from all published test-negative studies of the same influenza type/subtype available prior to the season of interest. RESULTS: Across the three seasons, 16,342 subjects were included in the analyses. For 2015/16, frequentist and Bayesian VE estimates were essentially identical (41% each). For 2017/18, frequentist and Bayesian estimates of VE against A(H3N2) viruses were also nearly identical (26% vs. 23%, respectively), even though the presence of apparent antigenic match could potentially have pulled Bayesian estimates upward. Precision of estimates was similar between methods in both seasons. Frequentist and Bayesian estimates diverged for children in 2013/14. Under the frequentist approach, LAIV effectiveness was 62 percentage points lower than IIV, while LAIV was only 27 percentage points lower than IIV under the Bayesian approach. CONCLUSION: Bayesian estimates of influenza VE can differ from frequentist estimates to a clinically meaningful degree when VE diverges substantially from previous seasons.

BACKGROUND: In the United States (U.S.), annual influenza vaccination has been recommended for all persons aged ≥6 months with the Healthy People 2020 coverage target of 70%. However, vaccination coverage has remained around 42-49% during the past eight influenza seasons. We sought to quantify influenza vaccination coverage and factors associated with vaccination in persons seeking outpatient medical care for an acute respiratory illness (ARI). METHODS: We enrolled outpatients aged ≥6 months with ARI from >50 U.S. clinics from 2011 to 2012 through 2018-2019 influenza seasons and tested for influenza with molecular assays. Vaccination status was based on documented receipt of the current season's influenza vaccine. We estimated vaccination coverage among influenza-negative study participants by study site, age, and season, and compared to state-level influenza coverage estimates in the general population based on annual immunization surveys. We used multivariable logistic regression to examine factors independently associated with receipt of influenza vaccines. RESULTS: We enrolled 45,424 study participants with ARI who tested negative for influenza during the study period. Annual vaccination coverage among influenza-negative ARI patients and the general population in the participating states averaged 55% (range: 47-62%), and 52% (range: 46-54%), respectively. Among enrollees, coverage was highest among adults aged ≥65 years (82%; range, 80-85%) and lowest among adolescents aged 13-17 years (38%; range, 35-41%). Factors significantly associated with non-vaccination included non-White race, no college degree, exposure to cigarette smoke, absence of high-risk conditions, and not receiving prior season influenza vaccine. CONCLUSIONS: Influenza vaccination coverage over eight seasons among outpatients with non-influenza respiratory illness was slightly higher than coverage in the general population but 15% lower than national targets. Increased efforts to promote vaccination especially in groups with lower coverage are warranted to attain optimal health benefits of influenza vaccine.

We compared symptoms and characteristics of 4961 ambulatory patients with and without laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection. Findings indicate that clinical symptoms alone would be insufficient to distinguish between coronavirus disease 2019 and other respiratory infections (eg, influenza) and/or to evaluate the effects of preventive interventions (eg, vaccinations).

BACKGROUND: At the start of the 2019-2020 influenza season, concern arose that circulating B/Victoria viruses of the globally emerging clade V1A.3 were antigenically drifted from the strain included in the vaccine. Intense B/Victoria activity was followed by circulation of genetically diverse A(H1N1)pdm09 viruses, that were also antigenically drifted. We measured vaccine effectiveness (VE) in the United States against illness from these emerging viruses. METHODS: We enrolled outpatients aged ≥6 months with acute respiratory illness at five sites. Respiratory specimens were tested for influenza by reverse-transcriptase polymerase chain reaction (RT-PCR). Using the test-negative design, we determined influenza VE by virus sub-type/lineage and genetic subclades by comparing odds of vaccination in influenza cases versus test-negative controls. RESULTS: Among 8,845 enrollees, 2,722 (31%) tested positive for influenza, including 1,209 (44%) for B/Victoria and 1,405 (51%) for A(H1N1)pdm09. Effectiveness against any influenza illness was 39% (95% confidence interval [CI]: 32-44), 45% (95%CI: 37-52) against B/Victoria and 30% (95%CI: 21-39) against A(H1N1)pdm09 associated illness. Vaccination offered no protection against A(H1N1)pdm09 viruses with antigenically drifted clade 6B.1A 183P-5A+156K HA genes (VE 7%; 95%CI: -14 to 23%) which predominated after January. CONCLUSIONS: Vaccination provided protection against influenza illness, mainly due to infections from B/Victoria viruses. Vaccine protection against illness from A(H1N1)pdm09 was lower than historically observed effectiveness of 40-60%, due to late-season vaccine mismatch following emergence of antigenically drifted viruses. The effect of drift on vaccine protection is not easy to predict and, even in drifted years, significant protection can be observed.

INTRODUCTION: Influenza is an important public health problem, but data on the impact of influenza among homeless shelter residents are limited. The primary aim of this study is to evaluate whether on-site testing and antiviral treatment of influenza in residents of homeless shelters reduces influenza spread in these settings. METHODS AND ANALYSIS: This study is a stepped-wedge cluster-randomized trial of on-site testing and antiviral treatment for influenza in nine homeless shelter sites within the Seattle metropolitan area. Participants with acute respiratory illness (ARI), defined as two or more respiratory symptoms or new or worsening cough with onset in the prior 7 days, are eligible to enroll. Approximately 3200 individuals are estimated to participate from October to May across two influenza seasons. All sites will start enrollment in the control arm at the beginning of each season, with routine surveillance for ARI. Sites will be randomized at different timepoints to enter the intervention arm, with implementation of a test-and-treat strategy for individuals with two or fewer days of symptoms. Eligible individuals will be tested on-site with a point-of-care influenza test. If the influenza test is positive and symptom onset is within 48 h, participants will be administered antiviral treatment with baloxavir or oseltamivir depending upon age and comorbidities. Participants will complete a questionnaire on demographics and symptom duration and severity. The primary endpoint is the incidence of influenza in the intervention period compared to the control period, after adjusting for time trends. TRIAL REGISTRATION: ClinicalTrials.gov NCT04141917 . Registered 28 October 2019. Trial sponsor: University of Washington.