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Importance: Although influenza vaccination has been found to be safe in pregnancy, few studies have assessed repeated influenza vaccination over successive pregnancies, including 2 vaccinations in a year, in terms of adverse perinatal outcomes., Objective: To examine the association of seasonal influenza vaccination across successive pregnancies with adverse perinatal outcomes and whether the association varies by interpregnancy interval (IPI) and vaccine type (quadrivalent or trivalent)., Design, Setting, and Participants: This retrospective cohort study included individuals with at least 2 successive singleton live-birth pregnancies between January 1, 2004, and December 31, 2018. Data were collected from the Vaccine Safety Datalink, a collaboration between the Centers for Disease Control and Prevention and integrated health care organizations. Data analysis was performed between January 8, 2021, and July 17, 2024., Exposures: Influenza vaccination was identified using vaccine administration codes. The vaccinated cohort consisted of people who received influenza vaccines during the influenza season (August 1 through April 30) in 2 successive pregnancies. The comparator cohort consisted of people identified as unvaccinated during both pregnancies., Main Outcomes and Measures: Main outcomes were risk of preeclampsia or eclampsia, placental abruption, fever, preterm birth, preterm premature rupture of membranes, chorioamnionitis, and small for gestational age among individuals with and without vaccination in both pregnancies. Adjusted relative risks (RRs) from Poisson regression were used to assess the magnitude of associations. The associations with adverse outcomes by IPI and vaccine type were evaluated., Results: Of 82 055 people with 2 singleton pregnancies between 2004 and 2018, 44 879 (54.7%) had influenza vaccination in successive pregnancies. Mean (SD) age at the start of the second pregnancy was 32.2 (4.6) years for vaccinated individuals and 31.2 (5.0) years for unvaccinated individuals. Compared with individuals not vaccinated in both pregnancies, vaccination in successive pregnancies was not associated with increased risk of preeclampsia or eclampsia (adjusted RR, 1.10; 95% CI, 0.99-1.21), placental abruption (adjusted RR, 1.01; 95% CI, 0.84-1.21), fever (adjusted RR, 0.87; 95% CI, 0.47-1.59), preterm birth (adjusted RR, 0.83; 95% CI, 0.78-0.89), preterm premature rupture of membranes (RR, 1.00; 95% CI, 0.94-1.06), chorioamnionitis (adjusted RR, 1.03; 95% CI, 0.90-1.18), or small for gestational age birth (adjusted RR, 0.99; 95% CI, 0.93-1.05). IPI and vaccine type did not modify the observed associations., Conclusions and Relevance: In this large cohort study of successive pregnancies, influenza vaccination was not associated with increased risk of adverse perinatal outcomes, irrespective of IPI and vaccine type. Findings support recommendations to vaccinate pregnant people or those who might be pregnant during the influenza season.

Households are a primary setting for transmission of SARS-CoV-2. We examined the role of prior SARS-CoV-2 immunity on the risk of infection in household close contacts. Households in the United States with an individual who tested positive for SARS-CoV-2 during September 2021-May 2023 were enrolled if the index case's illness began ≤6 days prior. Household members had daily self-collected nasal swabs tested by RT-PCR for SARS-CoV-2. The effects of prior SARS-CoV-2 immunity (vaccination, prior infection, or hybrid immunity) on SARS-CoV-2 infection risk among household contacts were assessed by robust, clustered multivariable Poisson regression. Of 1,532 contacts (905 households), 8% had immunity from prior infection alone, 51% from vaccination alone, 29% hybrid immunity, and 11% had no prior immunity. Sixty percent of contacts tested SARS-CoV-2-positive during follow-up. The adjusted risk of SARS-CoV-2 infection was lowest among contacts with vaccination and prior infection (aRR: 0.81, 95% CI: 0.70, 0.93, compared with contacts with no prior immunity) and was lowest when the last immunizing event occurred ≤6 months before COVID-19 affected the household (aRR: 0.69, 95% CI: 0.57, 0.83). In high-transmission settings like households, immunity from COVID-19 vaccination and prior infection was synergistic in protecting household contacts from SARS-CoV-2 infection., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2024.)

Background: Nirmatrelvir/ritonavir (N/R) reduces severe outcomes from coronavirus disease 2019 (COVID-19); however, rebound after treatment has been reported. We compared symptom and viral dynamics in individuals with COVID-19 who completed N/R treatment and similar untreated individuals., Methods: We identified symptomatic participants who tested severe acute respiratory syndrome coronavirus 2-positive and were N/R eligible from a COVID-19 household transmission study. Index cases from ambulatory settings and their households contacts were enrolled. We collected daily symptoms, medication use, and respiratory specimens for quantitative polymerase chain reaction for 10 days during March 2022-May 2023. Participants who completed N/R treatment (treated) were propensity score matched to untreated participants. We compared symptom rebound, viral load (VL) rebound, average daily symptoms, and average daily VL by treatment status measured after N/R treatment completion or 7 days after symptom onset if untreated., Results: Treated (n = 130) and untreated participants (n = 241) had similar baseline characteristics. After treatment completion, treated participants had greater occurrence of symptom rebound (32% vs 20%; P = .009) and VL rebound (27% vs 7%; P < .001). Average daily symptoms were lower among treated participants without symptom rebound (1.0 vs 1.6; P < .01) but not statistically lower with symptom rebound (3.0 vs 3.4; P = .5). Treated participants had lower average daily VLs without VL rebound (0.9 vs 2.6; P < .01) but not statistically lower with VL rebound (4.8 vs 5.1; P = .7)., Conclusions: Individuals who completed N/R treatment experienced fewer symptoms and lower VL but rebound occured more often compared with untreated individuals. Providers should prescribe N/R, when indicated, and communicate rebound risk to patients., Competing Interests: Potential conflicts of interest. S. R. reports grant support from BioFire. H. Q. M. reports grant/research support from CSL Sequiris and CSK. J. G. P. reports serving as a former consultant for CSL Seqirus and receipt of grants from the National Institutes of Health (NIH) and CSL Seqirus. E. A. reports serving as a former consultant for Hillevax and Moderna, presenting a Merck-supported lecture at the Latin American Vaccine Summit, and receipt of grant/research support from Pfizer for pneumococcal pneumonia studies. C. G. G. reports being a former advisor to Merck, participation on a data and safety monitoring board (DSMB) or advisory board for Merck, and receipt of grant/research support from AHRQ, CDC, US Food and Drug Administration, NIH, and Syneos Health. N. M.B. reports grant/contracts from NIH to the University of North Carolina School of Medicine, Doris Duke Charitable Foundation, and North Carolina Collaboratory; participation on a DSMB or advisory board for the Snowball Study Technical Interchange; a leadership or fiduciary role on the American Society of Tropical Medicine and Hygiene Scientific Committee; and other financial or nonfinancial interests with the COVID-19 Equity Evidence Academy (RADx-UP CDCC) Steering Committee and North Carolina Occupational Safety and Health Education Research Center. S. H. M. reports grants/contracts from NIH, the American Academy of Pediatrics, and the Doris Duke Charitable Foundation. E. A. B. reports research support to the Marshfield Clinic Research Institute from the CDC. E. S. reports grants or contracts to institution from Vanderbilt University Medical Center (originating at CDC #75D30121C11656). S. G. reports support for attending meetings and/or travel from the Infectious Diseases Society of America for Infectious Disease Week 2022 and 2023. K. G. M., L. M., S. B.-W., and V. O. report funding to Westat via the CDC (contract 75D30121C11571). M. S. S. reports a leadership role as Associate Director of the American Academy of Pediatrics’ Pediatric Research in Office Settings (PROS), paid to Trustees of Columbia University. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Objective: To assess the validity of electronic health record (EHR)-based influenza vaccination data among adults in a multistate network., Methods: Following the 2018-2019 and 2019-2020 influenza seasons, surveys were conducted among a random sample of adults who did or did not appear influenza-vaccinated (per EHR data) during the influenza season. Participants were asked to report their influenza vaccination status; self-report was treated as the criterion standard. Results were combined across survey years., Results: Survey response rate was 44.7% (777 of 1740) for the 2018-2019 influenza season and 40.5% (505 of 1246) for the 2019-2020 influenza season. The sensitivity of EHR-based influenza vaccination data was 75.0% (95% confidence interval [CI] 68.1, 81.1), specificity 98.4% (95% CI 92.9, 99.9), and negative predictive value 73.9% (95% CI 68.0, 79.3)., Conclusions: In a multistate research network across two recent influenza seasons, there was moderate concordance between EHR-based vaccination data and self-report., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We assessed serum neutralization of Omicron BA.5 in children following SARS-CoV-2 infection during the Delta or Omicron BA.1/BA.2 variant period. Convalescent BA.5 titers were higher following infections during the Omicron BA.1/BA.2 vs Delta variant period, and in vaccinated vs unvaccinated children. Titers against BA.5 did not differ by age group., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Human papillomavirus (HPV) vaccination can dramatically reduce the incidence of HPV-associated cancers. However, HPV vaccination coverage in rural areas is lower than in urban areas, and overall HPV vaccination coverage in the United States remains lower than other adolescent vaccines. We conducted 20 qualitative interviews with adolescent healthcare providers and clinic staff in urban and rural Minnesota and assessed their perspectives on HPV vaccination. Guiding interview topics included: strategies to persuade families to vaccinate their children, the impact of the patient-provider relationship and the clinical environment on vaccination uptake, and provider perceptions of parents' vaccine attitudes. In thematic analysis, all participants reported using common vaccination strategies, such as framing the HPV vaccine in terms of cancer prevention. The analysis also revealed three themes described as occurring uniquely or more intensely in rural communities than urban communities: the rural value of choice or independence, the spread of misinformation, and close-knit, multifaceted patient-provider relationships in clinical practice. Interventions aimed at increasing HPV vaccination should consider the distinctive circumstances of rural healthcare providers and patients.

Objective: Racial and ethnic disparities in influenza vaccination coverage among pregnant women in the United States have been documented. This study assessed the contribution of vaccine-related attitudes to coverage disparities., Methods: Surveys were conducted following the 2019-2020 and 2020-2021 influenza seasons in a US research network. Using electronic health record data to identify pregnant women, random samples were selected for surveying; non-Hispanic Black women and influenza-unvaccinated women were oversampled. Regression-based decomposition analyses were used to assess the contribution of vaccine-related attitudes to racial and ethnic differences in influenza vaccination. Data were combined across survey years, and analyses were weighted and accounted for survey design., Results: Survey response rate was 41.2% (721 of 1748) for 2019-2020 and 39.3% (706 of 1798) for 2020-2021. Self-reported influenza vaccination was higher among non-Hispanic White respondents (79.4% coverage, 95% CI 73.1%-85.7%) than Hispanic (66.2% coverage, 95% CI 52.5%-79.9%) and non-Hispanic Black (55.8% coverage, 95% CI 50.2%-61.4%) respondents. For all racial and ethnic groups, a high proportion (generally >80%) reported being seen for care, recommended for influenza vaccination, and offered vaccination. In decomposition analyses, vaccine-related attitudes (e.g., worry about vaccination causing influenza; concern about vaccine safety and effectiveness) explained a statistically significant portion of the observed racial and ethnic disparities in vaccination. Maternal age, education, and health status were not significant contributors after controlling for vaccine-related attitudes., Conclusions: In a setting with relatively high influenza vaccination coverage among pregnant women, racial and ethnic disparities in coverage were identified. Vaccine-related attitudes were associated with the disparities observed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Both SARS-CoV-2 and influenza virus can be transmitted by asymptomatic, presymptomatic, or symptomatic infected persons. We assessed effects on work attendance while ill before and during the COVID-19 pandemic in the United States by analyzing data collected prospectively from persons with acute respiratory illnesses enrolled in a multistate study during 2018-2022. Persons with previous hybrid work experience were significantly less likely to work onsite on the day before through the first 3 days of illness than those without that experience, an effect more pronounced during the COVID-19 pandemic than during prepandemic influenza seasons. Persons with influenza or COVID-19 were significantly less likely to work onsite than persons with other acute respiratory illnesses. Among persons with positive COVID-19 test results available by the second or third day of illness, few worked onsite. Hybrid and remote work policies might reduce workplace exposures and help reduce spread of respiratory viruses.

Purpose: This study assessed efficacy of one-time COVID-19 booster reminder/recall for booster eligible adolescents in a health-care system in Wisconsin., Methods: COVID-19 booster eligible patients aged 12-17 years were randomized 1:1 to receive one reminder/recall message from the health-care system using the parent's preferred communication method (intervention) or no reminder/recall (usual care) in May 2022., Results: Reminder/recall was sent to 2,146/4,296 (50%) adolescent patients. During the 90-day evaluation period following randomization, booster dose receipt was 2.0 percentage points (CI: 0.3%-3.7%) higher in the intervention (10.0%) versus usual care groups (8.0%). Among patients with ≥1 preventive visit during the evaluation period, uptake was 7.5 percentage points higher in the intervention (16.4%) versus usual care groups (8.9%)., Discussion: A single COVID-19 booster dose reminder/recall resulted in a small but statistically significant increase in booster dose receipt, though uptake overall was low. Additional strategies are needed to increase uptake., (Copyright © 2023 Society for Adolescent Health and Medicine. All rights reserved.)

Background: In the United States, influenza activity during the 2021-2022 season was modest and sufficient enough to estimate influenza vaccine effectiveness (VE) for the first time since the beginning of the coronavirus disease 2019 pandemic. We estimated influenza VE against laboratory-confirmed outpatient acute illness caused by predominant A(H3N2) viruses., Methods: Between October 2021 and April 2022, research staff across 7 sites enrolled patients aged ≥6 months seeking outpatient care for acute respiratory illness with cough. Using a test-negative design, we assessed VE against influenza A(H3N2). Due to strong correlation between influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, participants who tested positive for SARS-CoV-2 were excluded from VE estimations. Estimates were adjusted for site, age, month of illness, race/ethnicity, and general health status., Results: Among 6260 participants, 468 (7%) tested positive for influenza only, including 440 (94%) for A(H3N2). All 206 sequenced A(H3N2) viruses were characterized as belonging to genetic group 3C.2a1b subclade 2a.2, which has antigenic differences from the 2021-2022 season A(H3N2) vaccine component that belongs to clade 3C.2a1b subclade 2a.1. After excluding 1948 SARS-CoV-2-positive patients, 4312 patients were included in analyses of influenza VE; 2463 (57%) were vaccinated against influenza. Effectiveness against A(H3N2) for all ages was 36% (95% confidence interval, 20%-49%) overall., Conclusions: Influenza vaccination in 2021-2022 provided protection against influenza A(H3N2)-related outpatient visits among young persons., Competing Interests: Potential conflicts of interest. A. F. reports institutional grant support for research from Gilead, GlaxoSmithKline, Moderna, CDC, and Pfizer, unrelated to this work. C. G. G. reports consulting fees from Merck, Pfizer, and Sanofi Pasteur, and institutional grant support from the Agency for Healthcare Research and Quality, Campbell Alliance/Syneos Health, Food and Drug Administration, CDC, Sanofi, and National Institutes of Health. E. T. M. reports institutional grant support from Merck. A. S. M. reports personal fees from Sanofi and nonfinancial support from Seqirus. M. P. N. reports unrelated institutional grant support and personal fees from Merck Sharp & Dohme and institutional investigator-initiated grant support from Sanofi Pasteur. S. Y. T. reports institutional grant support from Pfizer and GlaxoSmithKline, unrelated to this work. M. G. reports CDC-BSWH US Flu VE Network HAIVEN grant studies, Synergy contract study, CDC-Abt HCP FluVax randomized controlled trial and RECOVER-PROTECT cohort studies, CDC-Vanderbilt IVY-3 and IVY-4 studies, and CDC-Westat VISION COVID/Flu VE Study, unrelated to this work., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

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., (Copyright © 2023 by the American Academy of Pediatrics.)

Background: US recommendations for COVID-19 vaccine boosters have expanded in terms of age groups covered and numbers of doses recommended, whereas evolution of Omicron sublineages raises questions about ongoing vaccine effectiveness., Methods: We estimated effectiveness of monovalent COVID-19 mRNA booster vaccination versus two-dose primary series during a period of Omicron variant virus circulation in a community cohort with active illness surveillance. Hazard ratios comparing SARS-CoV-2 infection between booster versus primary series vaccinated individuals were estimated using Cox proportional hazards models with time-varying booster status. Models were adjusted for age and prior SARS-CoV-2 infection. The effectiveness of a second booster among adults ≥50 years of age was similarly estimated., Results: The analysis included 883 participants ranging in age, from 5 to >90 years. Relative effectiveness was 51% (95% CI: 34%, 64%) favoring the booster compared with primary series vaccination and did not vary by prior infection status. Relative effectiveness was 74% (95% CI: 57%, 84%) at 15 to 90 days after booster receipt, but declined to 42% (95% CI: 16%, 61%) after 91 to 180 days, and to 36% (95% CI: 3%, 58%) after 180 days. The relative effectiveness of a second booster compared to a single booster was 24% (95% CI: -40% to 61%)., Conclusions: An mRNA vaccine booster dose added significant protection against SARS-CoV-2 infection, but protection decreased over time. A second booster did not add significant protection for adults ≥50 years of age. Uptake of recommended bivalent boosters should be encouraged to increase protection against Omicron BA.4/BA.5 sublineages., Competing Interests: HQM and DLM report research support from Seqirus outside the submitted work. JKM reports research support from Quidel and Seqirus outside the submitted work. All other authors report no potential conflicts., (© 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

In the United States, 2022-23 influenza activity began earlier than usual, increasing in October 2022, and has been associated with high rates of hospitalizations among children* (1). Influenza A(H3N2) represented most influenza viruses detected and subtyped during this period, but A(H1N1)pdm09 viruses cocirculated as well. Most viruses characterized were in the same genetic subclade as and antigenically similar to the viruses included in the 2022-23 Northern Hemisphere influenza vaccine (1,2). Effectiveness of influenza vaccine varies by season, influenza virus subtype, and antigenic match with circulating viruses. This interim report used data from two concurrent studies conducted at Marshfield Clinic Health System (MCHS) in Wisconsin during October 23, 2022-February 10, 2023, to estimate influenza vaccine effectiveness (VE). Overall, VE was 54% against medically attended outpatient acute respiratory illness (ARI) associated with laboratory-confirmed influenza A among patients aged 6 months-64 years. In a community cohort of children and adolescents aged <18 years, VE was 71% against symptomatic laboratory-confirmed influenza A virus infection. These interim analyses indicate that influenza vaccination substantially reduced the risk for medically attended influenza among persons aged <65 years and for symptomatic influenza in children and adolescents. Annual influenza vaccination is the best strategy for preventing influenza and its complications. CDC recommends that health care providers continue to administer annual influenza vaccine to persons aged ≥6 months as long as influenza viruses are circulating (2)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Huong Q. McLean, Joshua G. Petrie, Jennifer K. Meece, Edward A. Belongia, and Kayla E. Hanson report institutional support from CSL Seqirus. Gregg C. Sylvester is an employee of CSL Seqirus. Yoshihiro Kawaoka reports institutional funding from Fujifilm Toyama Chemical Company, LTD, Shionogi & Company, LTD, Daiichi Sankyo Pharmaceutical, Otsuka Pharmaceutical, KM Biologics, Kyoritsu Seiyaku, Fuji Rebio, Tauns Laboratories, Inc., and FluGen. Yoshihiro Kawaoka and Gabriele Neumann report status as a cofounder and stockholder of FluGen. No other potential conflicts of interest were disclosed.

Importance: Influenza virus infections declined globally during the COVID-19 pandemic. Loss of natural immunity from lower rates of influenza infection and documented antigenic changes in circulating viruses may have resulted in increased susceptibility to influenza virus infection during the 2021-2022 influenza season., Objective: To compare the risk of influenza virus infection among household contacts of patients with influenza during the 2021-2022 influenza season with risk of influenza virus infection among household contacts during influenza seasons before the COVID-19 pandemic in the US., Design, Setting, and Participants: This prospective study of influenza transmission enrolled households in 2 states before the COVID-19 pandemic (2017-2020) and in 4 US states during the 2021-2022 influenza season. Primary cases were individuals with the earliest laboratory-confirmed influenza A(H3N2) virus infection in a household. Household contacts were people living with the primary cases who self-collected nasal swabs daily for influenza molecular testing and completed symptom diaries daily for 5 to 10 days after enrollment., Exposures: Household contacts living with a primary case., Main Outcomes and Measures: Relative risk of laboratory-confirmed influenza A(H3N2) virus infection in household contacts during the 2021-2022 season compared with prepandemic seasons. Risk estimates were adjusted for age, vaccination status, frequency of interaction with the primary case, and household density. Subgroup analyses by age, vaccination status, and frequency of interaction with the primary case were also conducted., Results: During the prepandemic seasons, 152 primary cases (median age, 13 years; 3.9% Black; 52.0% female) and 353 household contacts (median age, 33 years; 2.8% Black; 54.1% female) were included and during the 2021-2022 influenza season, 84 primary cases (median age, 10 years; 13.1% Black; 52.4% female) and 186 household contacts (median age, 28.5 years; 14.0% Black; 63.4% female) were included in the analysis. During the prepandemic influenza seasons, 20.1% (71/353) of household contacts were infected with influenza A(H3N2) viruses compared with 50.0% (93/186) of household contacts in 2021-2022. The adjusted relative risk of A(H3N2) virus infection in 2021-2022 was 2.31 (95% CI, 1.86-2.86) compared with prepandemic seasons., Conclusions and Relevance: Among cohorts in 5 US states, there was a significantly increased risk of household transmission of influenza A(H3N2) in 2021-2022 compared with prepandemic seasons. Additional research is needed to understand reasons for this association.

Background: Measles, mumps, and rubella vaccine (MMR) is routinely administered to children; however, adolescents and adults may receive MMR for various reasons. Safety studies in adolescents and adults are limited. We report on safety of MMR in this age group in the Vaccine Safety Datalink., Methods: We included adolescents (aged 9-17 years) and adults (aged ≥ 18 years) who received ≥ 1 dose of MMR from January 1, 2010-December 31, 2018. Pre-specified outcomes were identified by diagnosis codes. Clinically serious outcomes included anaphylaxis, encephalitis/myelitis, Guillain-Barré syndrome, immune thrombocytopenia, meningitis, and seizure. Non-serious outcomes were allergic reaction, arthropathy, fever, injection site reaction, lymphadenopathy, non-specific reaction, parotitis, rash, and syncope. All serious outcomes underwent medical record review. Outcome-specific incidence was calculated in pre-defined post-vaccination windows. A self-controlled risk interval design was used to determine the relative risk of each outcome in a risk window after vaccination compared to a more distal control window., Results: During the study period, 276,327 MMR doses were administered to adolescents and adults. Mean age of vaccinees was 34.8 years; 65.8 % were female; 53.2 % of doses were administered simultaneously with ≥ 1 other vaccine. Serious outcomes were rare, with incidence ≤ 6 per 100,000 doses for each outcome assessed, and none had a significant elevation in incidence during the risk window compared to the control window. Incidence of non-serious outcomes per 100,000 doses ranged from 3.4 for parotitis to 263.0 for arthropathy. Other common outcomes included injection site reaction and rash (157.0 and 112.9 per 100,000 doses, respectively). Significantly more outcomes were observed during the risk window compared to the control window for all non-serious outcomes except parotitis. Some variability was observed by sex and age group., Conclusion: Serious outcomes after MMR are rare in adolescents and adults, but vaccinees should be counseled regarding anticipated local and systemic non-serious adverse events., (© 2023 The Author(s).)

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 9-17 years (range, 56 to 81 per 1,000) and lowest in adults aged 18-49 years (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 6 months to 8 years, to a low of 6.9 (95 % CI, -5.1- 27.3) per 1,000 vaccinees in adults aged ≥ 65 years., 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

We used daily real-time reverse-transcription polymerase chain reaction (RT-PCR) results from 67 cases of SARS-CoV-2 infection in a household transmission study, conducted April 2020-May 2021, to examine the trajectory of cycle threshold (Ct) values, an inverse correlate of viral RNA concentration. Ct values varied across RT-PCR platforms and by participant age. Specimens collected from children and adolescents had higher Ct values and adults aged ≥50 years showed lower Ct values than adults aged 18-49 years. Ct values were lower on days when participants reported experiencing symptoms, with the lowest Ct value occurring 2-6 days after symptom onset., Competing Interests: Potential conflicts of interest. C. G. G. reports grants from Campbell Alliance/Syneos, the National Institutes of Health, the Food and Drug Administration, the Agency for Health Care Research and Quality, and Sanofi-Pasteur; and consultation fees from Pfizer, Merck, and Sanofi-Pasteur. N. B. H. reports grant support from Sanofi-Pasteur and Quidel. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Background: We estimated SARS-CoV-2 Delta- and Omicron-specific effectiveness of two and three mRNA COVID-19 vaccine doses in adults against symptomatic illness in US outpatient settings., Methods: Between October 1, 2021, and February 12, 2022, research staff consented and enrolled eligible participants who had fever, cough, or loss of taste or smell and sought outpatient medical care or clinical SARS-CoV-2 testing within 10 days of illness onset. Using the test-negative design, we compared the odds of receiving two or three mRNA COVID-19 vaccine doses among SARS-CoV-2 cases versus controls using logistic regression. Regression models were adjusted for study site, age, onset week, and prior SARS-CoV-2 infection. Vaccine effectiveness (VE) was calculated as (1 - adjusted odds ratio) × 100%., Results: Among 3847 participants included for analysis, 574 (32%) of 1775 tested positive for SARS-CoV-2 during the Delta predominant period and 1006 (56%) of 1794 participants tested positive during the Omicron predominant period. When Delta predominated, VE against symptomatic illness in outpatient settings was 63% (95% CI: 51% to 72%) among mRNA two-dose recipients and 96% (95% CI: 93% to 98%) for three-dose recipients. When Omicron predominated, VE was 21% (95% CI: -6% to 41%) among two-dose recipients and 62% (95% CI: 48% to 72%) among three-dose recipients., Conclusions: In this adult population, three mRNA COVID-19 vaccine doses provided substantial protection against symptomatic illness in outpatient settings when the Omicron variant became the predominant cause of COVID-19 in the United States. These findings support the recommendation for a third mRNA COVID-19 vaccine dose., Competing Interests: Ana Florea reports unrelated institutional grant support for research from Gilead, GlaxoSmithKline, Moderna, and Pfizer. Carlos G. Grijalva reports consulting fees from Merck, Pfizer, and Sanofi Pasteur, and institutional grant support from the Agency for Health Care Research and Quality, Campbell Alliance/Syneos Health, the Food and Drug Administration, and the National Institutes of Health. Emily T. Martin reports institutional grant support from Merck. Arnold S. Monto reports personal fees from Sanofi and non‐financial support from Seqirus. Mary Patricia Nowalk reports unrelated institutional grant support and personal fees from Merck Sharp & Dohme and institutional investigator‐initiated grant support from Sanofi Pasteur. Sara Y. Tartof reports unrelated institutional grant support from Pfizer and GlaxoSmithKline. No other potential conflicts of interest were disclosed., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Mutations occurring during egg-based influenza vaccine production may affect vaccine effectiveness. The mammalian cell-based quadrivalent inactivated influenza vaccine (IIV4c) demonstrated improved protection relative to egg-based vaccines in prior seasons. This study estimated the relative vaccine effectiveness (rVE) of IIV4c versus standard-dose egg-based quadrivalent inactivated influenza vaccine (IIV4e) in preventing influenza-related medical encounters (IRMEs) in the 2019-2020 US influenza season., Methods: This retrospective cohort study was conducted using a dataset linking electronic medical records with medical and pharmacy claims data among individuals ≥18 years vaccinated with IIV4c or IIV4e during 2019-2020. A doubly robust inverse probability of treatment weighting model was used to obtain odds ratios (ORs) adjusted for age, sex, race, ethnicity, region, vaccination week, health status, frailty, and baseline healthcare resource utilization. rVE was calculated by (1 - OR) × 100. An exploratory analysis evaluated IRMEs in inpatient and outpatient settings separately., Results: The final study cohort included 1 499 215 IIV4c and 4 126 263 IIV4e recipients ≥18 years of age. Fewer IRMEs were reported in individuals with recorded IIV4c versus IIV4e. The rVE for IIV4c versus IIIV4e for any IRME was 9.5% (95% confidence interval [CI], 7.9%-11.1%). Inpatient and outpatient rVEs were 5.7% (95% CI, 2.1%-9.2%) and 11.4% (95% CI, 9.5%-13.3%), respectively. In age subgroup analyses, rVEs favored IIV4c except in adults aged ≥65 years., Conclusions: Adults vaccinated with IIV4c had a lower risk of IRMEs versus IIV4e recipients in the 2019-2020 US influenza season. These results support IIV4c as a potentially more effective public health measure against influenza than egg-based vaccines., Competing Interests: Potential conflicts of interest. M. I. and C. B. are employees of Seqirus Inc. J. A. M. was an employee of Seqirus during study conduct. J. R. O. reports receiving grants to his institution from the National Institutes of Health for influenza vaccine research; grants to his institution from GSK, Pfizer, and PATH for vaccine (noninfluenza) research; and honoraria from Seqirus to serve on the Real World Evidence Scientific Advisory Board and from Pfizer to serve on the Immunization for All Ages Advisory Board. All other authors report no potential conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Egg-based influenza vaccine production can lead to the accumulation of mutations that affect antigenicity. The mammalian cell-based inactivated quadrivalent influenza vaccine (IIV4c) may improve effectiveness compared with egg-based vaccines. This study estimated the relative vaccine effectiveness (rVE) of IIV4c versus egg-based inactivated quadrivalent influenza vaccine (IIV4e) in preventing influenza-related medical encounters (IRME) among children and adolescents during the 2019-2020 US influenza season., Methods: This retrospective cohort study used a dataset linking primary and specialty care electronic medical records with medical and pharmacy claims data from US residents 4 through 17 years of age vaccinated with IIV4c or IIV4e during the 2019-2020 influenza season. Odds ratios (ORs) were derived from a doubly robust inverse probability of treatment-weighted approach adjusting for age, sex, race, ethnicity, region, index week, health status and two proxy variables for healthcare accessibility and use. Adjusted rVE was estimated by (1-OR adjusted )*100, and an exploratory analysis evaluated IRMEs separately for outpatient and inpatient settings., Results: The final study cohort included 60,480 (IIV4c) and 1,240,990 (IIV4e) vaccine recipients. Fewer IRMEs were reported in subjects vaccinated with IIV4c than IIV4e. The rVE for IIV4c versus IIV4e was 12.2% [95% confidence interval (CI): 7.5-16.6] for any IRME and 14.3% (9.3-19.0) for outpatient IRMEs. Inpatient IRMEs were much less frequent, and effectiveness estimates were around the null., Conclusions: Fewer IRMEs occurred in pediatric subjects vaccinated with IIV4c versus IIV4e. These results support the greater effectiveness of IIV4c over IIV4e in this population during the 2019-2020 US influenza season., Competing Interests: M.I., C.B. are employees of Seqirus Inc. J.A.M. was an employee of Seqirus during study conduct. J.R.O. reports receiving grants to his institution from NIH for influenza vaccine research, grants to his institution from GSK, Pfizer, and PATH for vaccine (non-influenza) research, honoraria from Seqirus to serve on Real World Evidence Scientific Advisory Board and from Pfizer to serve on the Immunization for All Ages Advisory Board. The other authors have no conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Dr. Gaglani reports grants from CDC outside the submitted work. Dr. McLean reports grants from Seqirus outside the submitted work. Dr. Nowalk reports grants from Merck & Co outside the submitted work. Dr. Zimmerman reports grants from Sanofi Pasteur outside the submitted work. Dr. L. Jackson reports grants from Novavax outside the submitted work. Dr. Martin reports personal fees from Pfizer outside the submitted work. All other authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.’, (Published by Elsevier Ltd.)

Background: The human papillomavirus (HPV) vaccine is recommended for all adolescents age 11-12 years. HPV vaccine coverage remains suboptimal in the United States though, particularly in rural areas. We surveyed adolescent immunization providers in two Midwestern states to assess rural vs. urban differences in HPV vaccine resources, practices, and attitudes., Methods: A cross-sectional survey was sent to all licensed adolescent care providers in a subset of urban and rural counties in Minnesota and Wisconsin during 2019. Multivariable regression was used to identify attitudes and practices that differentiated rural vs. urban providers., Results: There were 437 survey respondents (31% rural). Significantly fewer rural providers had evening/weekend adolescent vaccination appointments available (adjusted odds ratio (aOR) = 0.21 [95% confidence interval (CI): 0.12, 0.36]), had prior experience with adolescent vaccine quality improvement projects (aOR = 0.52 [95% CI: 0.28, 0.98]), and routinely recommended HPV vaccine during urgent/acute care visits (aOR = 0.37 [95% CI: 0.18, 0.79]). Significantly more rural providers had standing orders to administer all recommended adolescent vaccines (aOR = 2.81 [95% CI: 1.61, 4.91]) and reported giving HPV vaccine information to their patients/families before it is due (aOR = 3.10 [95% CI: 1.68, 5.71])., Conclusions: Rural vs. urban differences in provider practices were mixed in that rural providers do not implement some practices that may promote HPV vaccination, but do implement other practices that promote HPV vaccination. It remains unclear how the observed differences would affect HPV vaccine attitudes or adolescent vaccination decisions for parents in rural areas., (© 2022. The Author(s).)

Reduced COVID-19 vaccine effectiveness (VE) has been observed with increasing predominance of SARS-CoV-2 Delta (B.1.617.2) variant. Two-dose VE against laboratory-confirmed SARS-CoV-2 infection (symptomatic and asymptomatic) was estimated using Cox proportional hazards models with time-varying vaccination status in a prospective rural community cohort of 1266 participants aged ≥12 years. Between November 3, 2020 and December 7, 2021, VE was 56% for mRNA COVID-19 vaccines overall, 65% for Moderna, and 50% for Pfizer-BioNTech. VE when Delta predominated (June to December 2021) was 54% for mRNA COVID-19 vaccines overall, 59% for Moderna, and 52% for Pfizer-BioNTech., (© 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

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., (© Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Studies have shown that adolescent vaccination rates with human papillomavirus (HPV) and quadrivalent meningococcal conjugate (MenACWY) vaccines are lower in rural areas of the U.S. than in urban areas. We sought to determine factors associated with vaccine acceptance in these two settings., Methods: We conducted a cross-sectional survey of 536 parents or guardians of teens age 13 through 15 years in select rural and urban counties of Minnesota and Wisconsin. We collected information on demographic variables, receipt of adolescent vaccines, and attitudes toward HPV vaccine in particular. Multivariable logistic regression models were used to assess associations between covariates and outcomes of interest (HPV vaccine receipt and MenACWY receipt)., Results: Of the 536 respondents, 267 (50%) resided in a rural county. Most respondents were female (78%) and non-Hispanic White (88%). About half (52%) of teens of the surveyed parents received the three vaccines recommended specifically for adolescents: 90% received tetanus-diphtheria-acellular pertussis (Tdap), 84% received MenACWY, and 60% received one or more doses of HPV vaccine. Rural and urban parents surveyed differed on several covariates relating to teen's health services, parent's demographics, and household characteristics. Parent's perception of the importance that their healthcare providers placed on vaccination with HPV and MenACWY were independently associated with receipt of each of those vaccines (odds ratio [OR] 6.37, 95% confidence interval [CI] 2.90-13.96 and OR 2.15, 95% CI 1.07-4.31, respectively). Parents of vaccinated teens were less likely to report concerns about potential harm from the HPV vaccine or having heard stories about health problems caused by the HPV vaccine., Conclusion: Teen receipt of HPV vaccine and MenACWY appears to be influenced by parents' perception of vaccine importance, provider recommendations, and concerns regarding potential harm from the HPV vaccine. Continued education of providers and parents of the importance of adolescent vaccinations is warranted., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

In the United States, annual vaccination against seasonal influenza is recommended for all persons aged ≥6 months except when contraindicated (1). Currently available influenza vaccines are designed to protect against four influenza viruses: A(H1N1)pdm09 (the 2009 pandemic virus), A(H3N2), B/Victoria lineage, and B/Yamagata lineage. Most influenza viruses detected this season have been A(H3N2) (2). With the exception of the 2020-21 season, when data were insufficient to generate an estimate, CDC has estimated the effectiveness of seasonal influenza vaccine at preventing laboratory-confirmed, mild/moderate (outpatient) medically attended acute respiratory infection (ARI) each season since 2004-05. This interim report uses data from 3,636 children and adults with ARI enrolled in the U.S. Influenza Vaccine Effectiveness Network during October 4, 2021-February 12, 2022. Overall, vaccine effectiveness (VE) against medically attended outpatient ARI associated with influenza A(H3N2) virus was 16% (95% CI = -16% to 39%), which is considered not statistically significant. This analysis indicates that influenza vaccination did not reduce the risk for outpatient medically attended illness with influenza A(H3N2) viruses that predominated so far this season. Enrollment was insufficient to generate reliable VE estimates by age group or by type of influenza vaccine product (1). CDC recommends influenza antiviral medications as an adjunct to vaccination; the potential public health benefit of antiviral medications is magnified in the context of reduced influenza VE. CDC routinely recommends that health care providers continue to administer influenza vaccine to persons aged ≥6 months as long as influenza viruses are circulating, even when VE against one virus is reduced, because vaccine can prevent serious outcomes (e.g., hospitalization, intensive care unit (ICU) admission, or death) that are associated with influenza A(H3N2) virus infection and might protect against other influenza viruses that could circulate later in the season., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Ana Florea reports unrelated institutional grant support for research from Gilead, GlaxoSmithKline, Moderna, and Pfizer. Carlos G. Grijalva reports consulting fees from Merck, Pfizer, and Sanofi Pasteur, and institutional grant support from the Agency for Health Care Research and Quality, Campbell Alliance/Syneos Health, the Food and Drug Administration, and the National Institutes of Health. Emily T. Martin reports institutional grant support from Merck. Arnold S. Monto reports personal fees from Sanofi and nonfinancial support from Seqirus. Mary Patricia Nowalk reports unrelated institutional grant support and personal fees from Merck Sharp & Dohme and institutional investigator-initiated grant support from Sanofi Pasteur. Sara Y. Tartof reports unrelated institutional grant support from Pfizer and GlaxoSmithKline. David E. Wentworth reports institutional grant support from Seqirus for a cooperative research and development agreement on isolation and propagation of influenza viruses in qualified manufacturing cell lines and patents 10,030,231 (influenza reassortment) and 10,272,149 (modified bat influenza viruses and their uses). No other potential conflicts of interest were disclosed.

Objectives: Examine age differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission risk from primary cases and infection risk among household contacts and symptoms among those with SARS-CoV-2 infection., Methods: People with SARS-CoV-2 infection in Nashville, Tennessee and central and western Wisconsin and their household contacts were followed daily for 14 days to ascertain symptoms and secondary transmission events. Households were enrolled between April 2020 and April 2021. Secondary infection risks (SIR) by age of the primary case and contacts were estimated using generalized estimating equations., Results: The 226 primary cases were followed by 198 (49%) secondary SARS-CoV-2 infections among 404 household contacts. Age group-specific SIR among contacts ranged from 36% to 53%, with no differences by age. SIR was lower in primary cases age 12 to 17 years than from primary cases 18 to 49 years (risk ratio [RR] 0.42; 95% confidence interval [CI] 0.19-0.91). SIR was 55% and 45%, respectively, among primary case-contact pairs in the same versus different age group (RR 1.47; 95% CI 0.98-2.22). SIR was highest among primary case-contact pairs age ≥65 years (76%) and 5 to 11 years (69%). Among secondary SARS-CoV-2 infections, 19% were asymptomatic; there was no difference in the frequency of asymptomatic infections by age group., Conclusions: Both children and adults can transmit and are susceptible to SARS-CoV-2 infection. SIR did not vary by age, but further research is needed to understand age-related differences in probability of transmission from primary cases by age., Competing Interests: CONFLICT OF INTEREST DISCLOSURES: Dr Halasa reports grants from Sanofi and Quidel. Dr Grijalva reports grants from Campbell Alliance/Syneos, the National Institutes of Health, the Food and Drug Administration, the Agency for Health Care Research and Quality and Sanofi-Pasteur, and consultation fees from Pfizer, Merck, and Sanofi-Pasteur. Other authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2022 by the American Academy of Pediatrics.)

Intraseason 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. Using data from the US Influenza Vaccine Effectiveness Network, we calculated risk ratios derived from comparing weekly numbers of influenza cases prepeak with those postpeak during the 2010-2011 through 2018-2019 influenza seasons. We sought to determine age-specific differences during the ascent versus descent of an influenza season by influenza virus type and subtype. We estimated 95% credible intervals around the risk ratios using Bayesian joint posterior sampling of weekly cases. Our population consisted of ambulatory patients with laboratory-confirmed influenza who enrolled in an influenza vaccine effectiveness study at 5 US sites during 9 influenza seasons after the 2009 influenza A virus subtype H1N1 (H1N1) pandemic. We observed that young children aged <5 years tended to more often be infected with H1N1 during the prepeak period, while adults aged ≥65 years tended to more often be infected with H1N1 during the postpeak period. However, for influenza A virus subtype H3N2, children aged <5 years were more often infected during the postpeak period. These results may reflect a contribution of different age groups to seasonal spread, which may differ by influenza virus type and subtype., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

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 5 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 subtype/lineage and genetic subclades by comparing odds of vaccination in influenza cases versus test-negative controls., Results: Among 8845 enrollees, 2722 (31%) tested positive for influenza, including 1209 (44%) for B/Victoria and 1405 (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., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Background: The effects of sequential vaccination with enhanced influenza vaccines are poorly understood. We conducted an exploratory open-label study to assess serologic response to sequential vaccination in older adults., Methods: 160 adults aged 65 through 74 years were randomized (1:1:1) to receive trivalent inactivated standard dose (SD), high-dose (HD), or MF59-adjuvanted (AD) vaccine in 2016/17. In 2017/18, HD and AD recipients received the same vaccine; SD recipients were re-randomized to HD or AD. Hemagglutination inhibition assays were performed using turkey erythrocytes against A/California/7/2009(H1N1)-like and B/Brisbane/60/2008(B/Victoria)-like in both seasons, and A/Michigan/45/2015(H1N1)-like in season 2. Microneutralization assays were performed against cell-propagated A/Hong Kong/4801/2014(H3N2)-like using MDCK-SIAT1 cells. Postvaccination geometric mean titer (GMT), percent with titer ≥ 40, and mean fold rise (MFR, ratio of postvaccination versus prevaccination titer) in season 2 were compared across groups, and ratio of MFR in season 2 versus season 1 was assessed for each strain., Results: Analysis included 152 participants (55 HD → HD, 58 AD → AD, 19 SD → HD, and 20 SD → AD). Season 2 postvaccination GMTs and percent with titer ≥ 40 did not differ between HD → HD and AD → AD recipients for vaccine strains examined. However, a higher percent of HD → HD and AD → AD recipients had postvaccination titer ≥ 40 than SD → AD recipients for A/H1N1 (86%-89% versus 60%) and SD → AD and SD → HD recipients for A/H3N2 (83%-87% versus 40%-53%). GMTs were higher in AD → AD versus SD → AD recipients for A/H1N1 (p = .01) and A/H3N2 (p = .002). MFRs in season 2 were low in all groups for A/H3N2 (1.5-2.2) and B/Victoria (1.7-2.3). MFR was lower in season 2 versus 1 for HD → HD and AD → AD recipients for all vaccine strains (1.6-3.7 versus 2.6-6.2)., Conclusions: Sequential vaccination with enhanced vaccines did not reduce immunogenicity in adults aged 65 through 74 years. Serologic response to cell-propagated A/H3N2 was suboptimal for all vaccines. ClinicalTrials.gov identifier. NCT02872311., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention and funding agency. HQM receives research funding from Seqirus unrelated to the present work. All other authors have no conflicts to report., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Evaluations of vaccine effectiveness (VE) are important to monitor as coronavirus disease 2019 (COVID-19) vaccines are introduced in the general population. Research staff enrolled symptomatic participants seeking outpatient medical care for COVID-19-like illness or severe acute respiratory syndrome coronavirus 2 (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, the VE of messenger RNA vaccines against COVID-19 was 91% (95% confidence interval, 83%-95%) for full vaccination and 75% (55%-87%) for partial vaccination. Vaccination was associated with prevention of most COVID-19 cases among people seeking outpatient medical care., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

The association of influenza vaccine and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was assessed by test-negative design using data collected for a study of outpatient COVID-19-like illness with onset dates from June to September 2020. Multivariable logistic regression models examined the association between receipt of 2019-2020 influenza vaccine and PCR-confirmed SARS-CoV-2 with adjustment for potential confounders. Receipt of influenza vaccine during the 2019-2020 influenza season was not associated with increased odds of SARS-CoV-2 infection in adults (aOR 0.83, 95% CI 0.63 to 1.10) or children (aOR 0.92, 95% CI 0.47 to 1.80)., (© 2021 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Background: A third measles-mumps-rubella vaccine (MMR) dose (MMR3) is recommended in the United States for persons at increased risk for mumps during outbreaks. MMR3 is also likely given to persons who might have received 2 doses of MMR but lack documentation. Since MMR3 safety data are limited, we describe adverse events in persons receiving MMR3 in a nonoutbreak setting., Methods: Young adults with 2 documented MMR doses were administered MMR3. From 2 weeks before until 4 weeks after MMR3 receipt, participants reported daily on 11 solicited, common symptoms potentially associated with MMR. Weekly rate differences in post- vs prevaccination (baseline) were evaluated by Poisson regression. Baseline rates were subtracted from postvaccination rates of significantly different symptoms to estimate the number and percentage of participants with excess risk for symptoms post-MMR3. Descriptive analyses were performed for 3 postvaccination injection-site symptoms., Results: The 662 participants were aged 18-28 years (median = 20 years); 56% were women. Headache, joint problems, diarrhea, and lymphadenopathy rates were significantly higher postvaccination vs baseline. We estimate that 119 participants (18%) reported more symptoms after MMR3 than prevaccination. By symptom, 13%, 10%, 8%, and 6% experienced increased symptoms of headache, joint problems, diarrhea, and lymphadenopathy, respectively, after MMR3. The median onset was Days 3-6 postvaccination; the median duration was 1-2 days. One healthcare visit for a potential vaccination-related symptom (urticaria) was reported. Injection-site symptoms were reported by 163 participants (25%); the median duration was 1-2 days., Conclusions: Reported systemic and local events were mild and transient. MMR3 is safe and tolerable among young adults., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Background: We compared effects of prior vaccination and added or lost protection from current season vaccination among those previously vaccinated., Methods: Our analysis included data from the US Flu Vaccine Effectiveness Network among participants ≥9 years old with acute respiratory illness from 2012-2013 through 2017-2018. Vaccine protection was estimated using multivariate logistic regression with an interaction term for effect of prior season vaccination on current season vaccine effectiveness. Models were adjusted for age, calendar time, high-risk status, site, and season for combined estimates. We estimated protection by combinations of current and prior vaccination compared to unvaccinated in both seasons or current vaccination among prior vaccinated., Results: A total of 31 819 participants were included. Vaccine protection against any influenza averaged 42% (95% confidence interval [CI], 38%-47%) among those vaccinated only the current season, 37% (95% CI, 33-40) among those vaccinated both seasons, and 26% (95% CI, 18%-32%) among those vaccinated only the prior season, compared with participants vaccinated neither season. Current season vaccination reduced the odds of any influenza among patients unvaccinated the prior season by 42% (95% CI, 37%-46%), including 57%, 27%, and 55% against A(H1N1), A(H3N2), and influenza B, respectively. Among participants vaccinated the prior season, current season vaccination further reduced the odds of any influenza by 15% (95% CI, 7%-23%), including 29% against A(H1N1) and 26% against B viruses, but not against A(H3N2)., Conclusions: Our findings support Advisory Committee on Immunization Practices recommendations for annual influenza vaccination. Benefits of current season vaccination varied among participants with and without prior season vaccination, by virus type/subtype and season., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Background: Demonstration of influenza vaccine effectiveness (VE) against hospitalized illness in addition to milder outpatient illness may strengthen vaccination messaging. Our objective was to compare patient characteristics and VE between United States (US) inpatient and outpatient VE networks., Methods: We tested adults with acute respiratory illness (ARI) for influenza within 1 outpatient-based and 1 hospital-based VE network from 2015 through 2018. We compared age, sex, and high-risk conditions. The test-negative design was used to compare vaccination odds in influenza-positive cases vs influenza-negative controls. We estimated VE using logistic regression adjusting for site, age, sex, race/ethnicity, peak influenza activity, time to testing from, season (overall VE), and underlying conditions. VE differences (ΔVE) were assessed with 95% confidence intervals (CIs) determined through bootstrapping with significance defined as excluding the null., Results: The networks enrolled 14 573 (4144 influenza-positive) outpatients and 6769 (1452 influenza-positive) inpatients. Inpatients were older (median, 62 years vs 49 years) and had more high-risk conditions (median, 4 vs 1). Overall VE across seasons was 31% (95% CI, 26%-37%) among outpatients and 36% (95% CI, 27%-44%) among inpatients. Strain-specific VE (95% CI) among outpatients vs inpatients was 37% (25%-47%) vs 53% (37%-64%) against H1N1pdm09; 19% (9%-27%) vs 23% (8%-35%) against H3N2; and 46% (38%-53%) vs 46% (31%-58%) against B viruses. ΔVE was not significant for any comparison across all sites., Conclusions: Inpatients and outpatients with ARI represent distinct populations. Despite comparatively poor health among inpatients, influenza vaccination was effective in preventing influenza-associated hospitalizations., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Background: Preexisting antibodies to influenza, shaped by early infection and subsequent exposures, may impact responses to influenza vaccination., Methods: We enrolled 72 children (aged 7-17 years) in 2015-2016; all received inactivated influenza vaccines. Forty-one were also vaccinated in 2014-2015, with 12 becoming infected with A(H3N2) in 2014-2015. Thirty-one children did not have documented influenza exposures in the prior 5 seasons. Sera were collected pre- and postvaccination in both seasons. We constructed antibody landscapes using hemagglutination inhibition antibody titers against 16 A(H3N2) viruses representative of major antigenic clusters that circulated between 1968 and 2015., Results: The breadth of the antibody landscapes increased with age. Vaccine-induced antibody responses correlated with boosting of titers to previously encountered antigens. Postvaccination titers were the highest against vaccine antigens rather than the historic A(H3N2) viruses previously encountered. Prevaccination titers to the vaccine were the strongest predictors of postvaccination titers. Responses to vaccine antigens did not differ by likely priming virus. Influenza A(H3N2)-infected children in 2014-2015 had narrower antibody landscapes than those uninfected, but prior season infection status had little effect on antibody landscapes following 2015-2016 vaccination., Conclusions: A(H3N2) antibody landscapes in children were largely determined by age-related immune priming, rather than recent vaccination or infection., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

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 (p trend <0.001). The percentage with no vaccines rose from 0.35% for the birth year 2004 to 1.28% for the birth year 2017 (p trend <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 (p trend <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., (Copyright © 2021 American Journal of Preventive Medicine. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Methods for assessing influenza vaccine efficacy and effectiveness have evolved over six decades. Randomized trials remain the gold standard for licensure, but observational studies are needed for annual assessment of vaccine effectiveness (VE). The test-negative design (TND) has become the de facto standard for these field studies. Patients who seek medical care with acute respiratory illness are tested for influenza, and VE is estimated from the odds of vaccination among influenza cases versus test-negative controls. VE varies across seasons, populations, age groups, and products, but VE estimates are consistently higher for A(H1N1)pdm09 and type B compared with A(H3N2). VE studies are increasingly used in combination with molecular epidemiology to understand the viral and immune system factors that drive clinical efficacy and effectiveness. The emerging field of immunoepidemiology offers the potential to understand complex host-virus interactions that affect vaccine protection, and this knowledge will contribute to universal vaccine development., (Copyright © 2021 Cold Spring Harbor Laboratory Press; all rights reserved.)

Background: Since 2013, quadrivalent influenza vaccines containing 2 B viruses gradually replaced trivalent vaccines in the United States. We compared the vaccine effectiveness of quadrivalent to trivalent inactivated vaccines (IIV4 to IIV3, respectively) against illness due to influenza B during the transition, when IIV4 use increased rapidly., Methods: The US Influenza Vaccine Effectiveness (Flu VE) Network analyzed 25 019 of 42 600 outpatients aged ≥6 months who enrolled within 7 days of illness onset during 6 seasons from 2011-2012. Upper respiratory specimens were tested for the influenza virus type and B lineage. Using logistic regression, we estimated IIV4 or IIV3 effectiveness by comparing the odds of an influenza B infection overall and the odds of B lineage among vaccinated versus unvaccinated participants. Over 4 seasons from 2013-2014, we compared the relative odds of an influenza B infection among IIV4 versus IIV3 recipients., Results: Trivalent vaccines included the predominantly circulating B lineage in 4 of 6 seasons. During 4 influenza seasons when both IIV4 and IIV3 were widely used, the overall effectiveness against any influenza B was 53% (95% confidence interval [CI], 45-59) for IIV4 versus 45% (95% CI, 34-54) for IIV3. IIV4 was more effective than IIV3 against the B lineage not included in IIV3, but comparative effectiveness against illnesses related to any influenza B favored neither vaccine valency., Conclusions: The uptake of quadrivalent inactivated influenza vaccines was not associated with increased protection against any influenza B illness, despite the higher effectiveness of quadrivalent vaccines against the added B virus lineage. Public health impact and cost-benefit analyses are needed globally., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

To prevent further transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), CDC currently recommends that persons who have been in close contact with someone with SARS-CoV-2 infection should quarantine (stay away from other persons) for 14 days after the last known contact.* However, quarantine might be difficult to maintain for a prolonged period. A shorter quarantine might improve compliance, and CDC recommends two options to reduce the duration of quarantine for close contacts without symptoms, based on local circumstances and availability of testing: 1) quarantine can end on day 10 without a test or 2) quarantine can end on day 7 after receiving a negative test result. † However, shorter quarantine might permit ongoing disease transmission from persons who develop symptoms or become infectious near the end of the recommended 14-day period. Interim data from an ongoing study of household transmission of SARS-CoV-2 were analyzed to understand the proportion of household contacts that had detectable virus after a shortened quarantine period. Persons who were household contacts of index patients completed a daily symptom diary and self-collected respiratory specimens for 14 days. Specimens were tested for SARS-CoV-2 using reverse transcription-polymerase chain reaction (RT-PCR). Among 185 household contacts enrolled, 109 (59%) had detectable SARS-CoV-2 at any time; 76% (83/109) of test results were positive within 7 days, and 86% (94 of 109) were positive within 10 days after the index patient's illness onset date. Among household contacts who received negative SARS-CoV-2 test results and were asymptomatic through day 7, there was an 81% chance (95% confidence interval [CI] = 67%-90%) of remaining asymptomatic and receiving negative RT-PCR test results through day 14; this increased to 93% (95% CI = 78%-98%) for household members who were asymptomatic with negative RT-PCR test results through day 10. Although SARS-CoV-2 quarantine periods shorter than 14 days might be easier to adhere to, there is a potential for onward transmission from household contacts released before day 14., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal potential conflicts of interest were disclosed. Carlos G. Grijalva reports personal consulting fees from Sanofi, Merck, and Pfizer; grants from Sanofi, Campbell Alliance, the National Institutes of Health, and the Agency for HealthCare Research and Quality; and a contract from the Food and Drug Administration, outside the submitted work. Natasha B. Halasa reports grants from Sanofi and Quidel, and personal fees from Genetech, outside the submitted work. No other potential conflicts of interest were disclosed.

Background: Improving appropriate antibiotic use is crucial for combating antibiotic resistance and unnecessary adverse drug reactions. Acute respiratory illness (ARI) commonly causes outpatient visits and accounts for ~41% of antibiotics used in the United States. We examined the influence of influenza vaccination on reducing antibiotic prescriptions among outpatients with ARI., Methods: We enrolled outpatients aged ≥6 months with ARI from 50-60 US clinics during 5 winters (2013-2018) and tested for influenza with RT-PCR; results were unavailable for clinical decision making and clinical influenza testing was infrequent. We collected antibiotic prescriptions and diagnosis codes for ARI syndromes. We calculated vaccine effectiveness (VE) by comparing vaccination odds among influenza-positive cases with test-negative controls. We estimated ARI visits and antibiotic prescriptions averted by influenza vaccination using estimates of VE, coverage, and prevalence of antibiotic prescriptions and influenza., Results: Among 37 487 ARI outpatients, 9659 (26%) were influenza positive. Overall, 36% of ARI and 26% of influenza-positive patients were prescribed antibiotics. The top 3 prevalent ARI syndromes included: viral upper respiratory tract infection (47%), pharyngitis (18%), and allergy or asthma (11%). Among patients testing positive for influenza, 77% did not receive an ICD-CM diagnostic code for influenza. Overall, VE against influenza-associated ARI was 35% (95% CI, 32-39%). Vaccination prevented 5.6% of all ARI syndromes, ranging from 2.8% (sinusitis) to 11% (clinical influenza). Influenza vaccination averted 1 in 25 (3.8%; 95% CI, 3.6-4.1%) antibiotic prescriptions among ARI outpatients during influenza seasons., Conclusions: Vaccination and accurate influenza diagnosis may curb unnecessary antibiotic use and reduce the global threat of antibiotic resistance., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Improved understanding of transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), within households could aid control measures. However, few studies have systematically characterized the transmission of SARS-CoV-2 in U.S. households (1). Previously reported transmission rates vary widely, and data on transmission rates from children are limited. To assess household transmission, a case-ascertained study was conducted in Nashville, Tennessee, and Marshfield, Wisconsin, commencing in April 2020. In this study, index patients were defined as the first household members with COVID-19-compatible symptoms who received a positive SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) test result, and who lived with at least one other household member. After enrollment, index patients and household members were trained remotely by study staff members to complete symptom diaries and obtain self-collected specimens, nasal swabs only or nasal swabs and saliva samples, daily for 14 days. For this analysis, specimens from the first 7 days were tested for SARS-CoV-2 using CDC RT-PCR protocols. † A total of 191 enrolled household contacts of 101 index patients reported having no symptoms on the day of the associated index patient's illness onset, and among these 191 contacts, 102 had SARS-CoV-2 detected in either nasal or saliva specimens during follow-up, for a secondary infection rate of 53% (95% confidence interval [CI] = 46%-60%). Among fourteen households in which the index patient was aged <18 years, the secondary infection rate from index patients aged <12 years was 53% (95% CI = 31%-74%) and from index patients aged 12-17 years was 38% (95% CI = 23%-56%). Approximately 75% of secondary infections were identified within 5 days of the index patient's illness onset, and substantial transmission occurred whether the index patient was an adult or a child. Because household transmission of SARS-CoV-2 is common and can occur rapidly after the index patient's illness onset, persons should self-isolate immediately at the onset of COVID-like symptoms, at the time of testing as a result of a high risk exposure, or at the time of a positive test result, whichever comes first. Concurrent to isolation, all members of the household should wear a mask when in shared spaces in the household. § ., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Carlos G. Grijalva reports personal consulting fees from Sanofi, Merck, and Pfizer; grants from Sanofi, Campbell Alliance, the National Institutes of Health, the Agency for HealthCare Research and Quality, and a contract from the Food and Drug Administration, outside the submitted work. Natasha B. Halasa reports grants from Sanofi and Quidel and personal fees from Genetech, outside the submitted work. No other potential conflicts of interest were disclosed.

Background: New influenza vaccine formulations are designed to improve vaccine effectiveness and protect those most vulnerable to infection. High dose trivalent inactivated influenza vaccine (HD-IIV3), licensed for ages ≥65 years, produces greater antibody responses and efficacy in clinical trials, but post-licensure vaccine effectiveness (VE) compared to standard dose (SD-IIV3/4) vaccine remains an open question., Methods: Using a test-negative, case control design and propensity analyses to adjust for confounding, US Influenza VE Network data from the 2015-2016 through 2018-2019 seasons were analyzed to determine relative VE (rVE) between HD-IIV3 and SD-IIV3/4 among outpatients ≥65 years old presenting with acute respiratory illness. Influenza vaccination status was derived from electronic medical records and immunization registries., Results: Among 3861 enrollees, 2993 (78%) were vaccinated; 1573 (53%) received HD-IIV3 and 1420 (47%) received SD-IIV3/4. HD-IIV3 recipients differed from SD-IIV3/4 recipients by race, previous vaccination, number of outpatient visits in the previous year and timing of vaccination, and were balanced in the propensity model except the timing of vaccination. Compared with no vaccination, significant protection against any influenza A was observed from both HD-IIV3 (VE = 29%; 95%CI = 10%, 44%) and SD-IIV3/4 (VE = 24%; 95%CI = 5%, 39%); rVE = 18% (95%CI = 0%, 33%, SD as referent). When stratified by virus type, against A/H1N1, HD-IIV3 VE was 30% (95%CI = -7%, 54%), SD-IIV3/4 VE was 40% (95%CI = 10%, 61%), and rVE = -32%; (95%CI = -94%, 11%); Against A/H3N2, HD-IIV3 VE was 31% (95%CI = 9%, 47%), SD-IIV3/4 VE was 19% (95%CI = -5%, 37%), and rVE = 27%; (95% CI = 9%, 42%)., Conclusions: Among adults ≥65 years of age, recipients of standard and high dose influenza vaccines differed significantly in their characteristics. After adjusting for these differences, high dose vaccine offered more protection against A/H3N2 and borderline significant protection against all influenza A requiring outpatient care during the 2015-2018 influenza seasons., Competing Interests: Declaration of Competing Interest RKZ has/had a research grant from Sanofi Pasteur, Inc. RKZ and MPN have/had research grant funding from Merck & Co, Inc. MLG has received institutional research grant from AstraZeneca-MedImmune. MLJ reports research funding from Sanofi Pasteur, unrelated to the present work. ASM reports consulting fees from Sanofi, Seqirus and Roche. ETM reports consulting fees from Pfizer. HQM reports research funding from Seqirus unrelated to the present work. The other authors have no conflicts to report., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Many enteric pathogens disproportionately infect children. Hospital discharge data can provide information on severe infections, including cost. However, the diagnosis must be recorded on the discharge record and coded accurately. We estimated the rate of underascertainment in hospital discharge data among children with culture-confirmed Campylobacter , Salmonella , and Escherichia coli O157 infections using linked laboratory and hospital discharge data from an integrated health care organization. We reviewed the International Classification of Diseases, 9th and 10th Revisions, Clinical Modification (ICD-9/10-CM) diagnosis codes on each patient's discharge record. We determined the percentage of patients who had a pathogen-specific diagnosis code (for Campylobacter , Salmonella , or E. coli O157) or nonspecific gastroenteritis code. We included the first admission or positive test and calculated the number of days between specimen submission (outpatient ≤7 days before admission or inpatient) and hospital discharge. Of 65 hospitalized children with culture-confirmed Campylobacter ( n  = 30), Salmonella ( n  = 24), or E. coli O157 ( n  = 11) infections, 55% had that pathogen-specific diagnosis code listed on the discharge record (79% Salmonella , 54% E. coli O157, 37% Campylobacter ). The discharge records of the 35 children with a specimen submitted for culture ≥3 days before discharge were 16 times more likely to have a pathogen-specific diagnosis than the records of the 30 children with a specimen submitted <3 days before discharge (83% vs. 23%; odds ratio 15.9, 95% confidence interval: 4.7-53.8). Overall, 34% of records of children with culture-confirmed infection had ≥1 nonspecific gastroenteritis code ( Campylobacter 43%, Salmonella 29%, E. coli O157 18%), including 59% of those for children without a pathogen-specific diagnosis ( Campylobacter 63%; Salmonella 60%; E. coli O157 40%). This study showed that hospital discharge data under-ascertain enteric illnesses in children even when the infections are culture confirmed, especially for infections that usually have a short length of stay.

Seasonal variation in the age distribution of influenza A cases suggests that factors other than age shape susceptibility to medically attended infection. We ask whether these differences can be partly explained by protection conferred by childhood influenza infection, which has lasting impacts on immune responses to influenza and protection against new influenza A subtypes (phenomena known as original antigenic sin and immune imprinting). Fitting a statistical model to data from studies of influenza vaccine effectiveness (VE), we find that primary infection appears to reduce the risk of medically attended infection with that subtype throughout life. This effect is stronger for H1N1 compared to H3N2. Additionally, we find evidence that VE varies with both age and birth year, suggesting that VE is sensitive to early exposures. Our findings may improve estimates of age-specific risk and VE in similarly vaccinated populations and thus improve forecasting and vaccination strategies to combat seasonal influenza., Competing Interests: PA, EB, SC No competing interests declared, HM has received funding from Seqirus, unrelated to this work. The author has no other competing interests to declare, (© 2020, Arevalo et al.)

Importance: The burden of influenza among young children is high, and influenza vaccination is the primary strategy to prevent the virus and its complications. Less is known about differences in clinical protection following 1 vs 2 doses of initial influenza vaccination., Objectives: To describe patterns of influenza vaccination among young children who receive outpatient care for acute respiratory tract illness in the US and compare vaccine effectiveness (VE) against medically attended laboratory-confirmed influenza by number of influenza vaccine doses received., Design: This test-negative case-control study was conducted in outpatient clinics, including emergency departments, at 5 sites of the US Influenza Vaccine Effectiveness Network during the 2014-2015 through 2017-2018 influenza seasons. The present study was performed from November 5, 2014, to April 12, 2018, during periods of local influenza circulation. Children aged 6 months to 8 years with an acute respiratory tract illness with cough who presented for outpatient care within 7 days of illness onset were included. All children were tested using real-time, reverse-transcriptase polymerase chain reaction for influenza for research purposes., Exposures: Vaccination in the enrollment season with either 1 or 2 doses of inactivated influenza vaccine as documented from electronic medical records, including state immunization information systems., Main Outcomes and Measures: Medically attended acute respiratory tract infection with real-time, reverse-transcriptase polymerase chain reaction testing for influenza., Results: Of 7533 children, 3480 children (46%) were girls, 4687 children (62%) were non-Hispanic white, and 4871 children (65%) were younger than 5 years. A total of 3912 children (52%) were unvaccinated in the enrollment season, 2924 children (39%) were fully vaccinated, and 697 children (9%) were partially vaccinated. Adjusted VE against any influenza was 51% (95% CI, 44%-57%) among fully vaccinated children and 41% (95% CI, 25%-54%) among partially vaccinated children. Among 1519 vaccine-naive children aged 6 months to 2 years, the VE of 2 doses in the enrollment season was 53% (95% CI, 28%-70%), and the VE of 1 dose was 23% (95% CI, -11% to 47%); those who received 2 doses were less likely to test positive for influenza compared with children who received only 1 dose (adjusted odds ratio, 0.57; 95% CI, 0.35-0.93)., Conclusions and Relevance: Consistent with US influenza vaccine policy, receipt of the recommended number of doses resulted in higher VE than partial vaccination in 4 influenza seasons. Efforts to improve 2-dose coverage for previously unvaccinated children may reduce the burden of influenza in this population.

Background: The effects of repeated influenza vaccination in children are not well understood. In this study, we evaluated previous vaccination effects on antibody response after vaccination with trivalent inactivated influenza vaccine (IIV) or quadrivalent live-attenuated influenza vaccine (LAIV) among school-aged children (5-17 years) across 3 seasons., Methods: Children were enrolled in the fall of 2013, 2014, and 2015. The participants received IIV or LAIV according to parent preference (2013-2014) or our randomization scheme (2014-2015). All study children received IIV in 2015-2016. Hemagglutination-inhibition assays measured antibody response to egg-grown vaccine strains from prevaccination and postvaccination serum samples. Geometric mean titers (GMTs) and increases in GMTs from before to after vaccination (geometric mean fold rise [GMFR]) were estimated from repeated-measures linear mixed models., Results: We enrolled 161 children in 2013-2014, 128 in 2014-2015, and 126 in 2015-2016. Among the IIV recipients, responses to the influenza A(H1N1)pdm09 and B vaccine strains were lowest among children who had received a previous-season IIV. The GMFRs for strains A(H1N1)pdm09 and B were 1.5 to 2.3 for previous-season IIV and 4.3 to 12.9 for previous-season LAIV or no previous vaccine. GMFRs were lower for strain A(H3N2), and differences according to previous-season vaccination history were smaller and not significant in most seasons. Most children had a post-IIV vaccination titer of ≥40 for vaccine strains in all seasons, regardless of previous-season vaccination history. Little to no increase in antibody levels was observed after vaccination with LAIV., Conclusions: Serologic response to vaccination was greatest for IIV, but previous-season vaccination modified IIV response to A(H1N1)pdm09 and B. Influenza A(H3N2) responses were low in all groups, and LAIV generated minimal serologic response against all strains., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)