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Table 1.  Descriptive Characteristics of Children Aged 6 Months to 8 Years by Vaccination History
Descriptive Characteristics of Children Aged 6 Months to 8 Years by Vaccination History
Table 2.  Vaccine Effectiveness of Inactivated Influenza Vaccine Against Any Medically Attended, Laboratory-Confirmed Influenza Among Fully and Partially Vaccinated Children Aged 8 Years or Youngera
Vaccine Effectiveness of Inactivated Influenza Vaccine Against Any Medically Attended, Laboratory-Confirmed Influenza Among Fully and Partially Vaccinated Children Aged 8 Years or Youngera
Table 3.  Vaccine Effectiveness of Inactivated Influenza Vaccine Among Children Aged ≤2 Years Who Were Unvaccinated Prior to Current Season
Vaccine Effectiveness of Inactivated Influenza Vaccine Among Children Aged ≤2 Years Who Were Unvaccinated Prior to Current Season
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Centers for Disease Control and Prevention. Past seasons estimated influenza disease burden: 2018. Updated January 9, 2020. Accessed July 3, 2019. https://www.cdc.gov/flu/about/burden/past-seasons.html
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Grohskopf  LA, Sokolow  LZ, Broder  KR, Walter  EB, Fry  AM, Jernigan  DB.  Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2018-19 influenza season.   MMWR Recomm Rep. 2018;67(3):1-20. doi:10.15585/mmwr.rr6703a1 PubMedGoogle ScholarCrossref
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Neuzil  KM, Jackson  LA, Nelson  J,  et al.  Immunogenicity and reactogenicity of 1 versus 2 doses of trivalent inactivated influenza vaccine in vaccine-naive 5-8-year-old children.   J Infect Dis. 2006;194(8):1032-1039. doi:10.1086/507309 PubMedGoogle ScholarCrossref
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Englund  JA, Walter  EB, Gbadebo  A, Monto  AS, Zhu  Y, Neuzil  KM.  Immunization with trivalent inactivated influenza vaccine in partially immunized toddlers.   Pediatrics. 2006;118(3):e579-e585. doi:10.1542/peds.2006-0201 PubMedGoogle ScholarCrossref
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Walter  EB, Neuzil  KM, Zhu  Y,  et al.  Influenza vaccine immunogenicity in 6- to 23-month-old children: are identical antigens necessary for priming?   Pediatrics. 2006;118(3):e570-e578. doi:10.1542/peds.2006-0198 PubMedGoogle ScholarCrossref
6.
Bodewes  R, de Mutsert  G, van der Klis  FR,  et al.  Prevalence of antibodies against seasonal influenza A and B viruses in children in Netherlands.   Clin Vaccine Immunol. 2011;18(3):469-476. doi:10.1128/CVI.00396-10 PubMedGoogle ScholarCrossref
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Grohskopf  LA, Sokolow  LZ, Broder  KR,  et al.  Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2016-17 influenza season.   MMWR Morb Mortal Wkly Rep. 2016;65(5):1-54. doi:10.15585/mmwr.rr6505a1Google Scholar
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Grohskopf  LA, Sokolow  LZ, Broder  KR,  et al.  Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2017-18 influenza season.   MMWR Recomm Rep. 2017;66(2):1-20. doi:10.15585/mmwr.rr6602a1 PubMedGoogle ScholarCrossref
9.
Grohskopf  LA, Sokolow  LZ, Olsen  SJ, Bresee  JS, Broder  KR, Karron  RA.  Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2015-16 influenza season.   MMWR Morb Mortal Wkly Rep. 2015;64(30):818-825. doi:10.15585/mmwr.mm6430a3 PubMedGoogle ScholarCrossref
10.
Thompson  MG, Clippard  J, Petrie  JG,  et al.  Influenza vaccine effectiveness for fully and partially vaccinated children 6 months to 8 years old during 2011-2012 and 2012-2013: the importance of two priming doses.   Pediatr Infect Dis J. 2016;35(3):299-308. doi:10.1097/INF.0000000000001006 PubMedGoogle ScholarCrossref
11.
Jackson  ML, Chung  JR, Jackson  LA,  et al.  Influenza vaccine effectiveness in the United States during the 2015-2016 season.   N Engl J Med. 2017;377(6):534-543. doi:10.1056/NEJMoa1700153 PubMedGoogle ScholarCrossref
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Centers for Disease Control and Prevention. Information on rapid molecular assays, RT-PCR, and other molecular assays for diagnosis of influenza virus infection. Updated October 21, 2019. Accessed March 28, 2020. https://www.cdc.gov/flu/professionals/diagnosis/molecular-assays.htm
13.
Murthy  N, Rodgers  L, Pabst  L, Fiebelkorn  AP, Ng  T.  Progress in childhood vaccination data in immunization information systems—United States, 2013-2016.   MMWR Morb Mortal Wkly Rep. 2017;66(43):1178-1181. doi:10.15585/mmwr.mm6643a4 PubMedGoogle ScholarCrossref
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Wisconsin Department of Health Services. Evaluation of the Wisconsin Immunization Registry. Published September 12, 2014. Accessed March 16, 2020. https://www.dhs.wisconsin.gov/publications/p00862.pdf
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Washington State Department of Health. Information for healthcare providers about the ImmunizationIinformation System. Accessed August 28, 2019. https://www.doh.wa.gov/ForPublicHealthandHealthcareProviders/HealthcareProfessionsandFacilities/DataReportingandRetrieval/ImmunizationInformationSystem/ForProviders
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Pennsylvania Department of Health. IID-18: Percent of children who participate in immunization registries, under age 6. Accessed August 28, 2019. https://www.health.pa.gov/topics/HealthStatistics/HealthyPeople/Documents/current/state/iid-18-percent-of-children-who-participate-in-immunization-registries-under-age-6.aspx
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Michigan Care Improvement Registry. About MCIR. Accessed August 28, 2019. https://www.mcir.org/
18.
Texas Department of State Health Services. Requesting immunization records for a child or adult. Updated April 2, 2017. Accessed August 28, 2019. https://www.dshs.state.tx.us/immunize/immunization-records.aspx
19.
Flannery  B, Zimmerman  RK, Gubareva  LV,  et al.  Enhanced genetic characterization of influenza A(H3N2) viruses and vaccine effectiveness by genetic group, 2014-2015.   J Infect Dis. 2016;214(7):1010-1019. doi:10.1093/infdis/jiw181 PubMedGoogle ScholarCrossref
20.
Eisenberg  KW, Szilagyi  PG, Fairbrother  G,  et al; New Vaccine Surveillance Network.  Vaccine effectiveness against laboratory-confirmed influenza in children 6 to 59 months of age during the 2003-2004 and 2004-2005 influenza seasons.   Pediatrics. 2008;122(5):911-919. doi:10.1542/peds.2007-3304 PubMedGoogle ScholarCrossref
21.
Allison  MA, Daley  MF, Crane  LA,  et al.  Influenza vaccine effectiveness in healthy 6- to 21-month-old children during the 2003-2004 season.   J Pediatr. 2006;149(6):755-762. doi:10.1016/j.jpeds.2006.06.036 PubMedGoogle ScholarCrossref
22.
Ferdinands  JM, Olsho  LE, Agan  AA,  et al; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network.  Effectiveness of influenza vaccine against life-threatening RT-PCR–confirmed influenza illness in US children, 2010-2012.   J Infect Dis. 2014;210(5):674-683. doi:10.1093/infdis/jiu185 PubMedGoogle ScholarCrossref
23.
Ritzwoller  DP, Bridges  CB, Shetterly  S, Yamasaki  K, Kolczak  M, France  EK.  Effectiveness of the 2003-2004 influenza vaccine among children 6 months to 8 years of age, with 1 vs 2 doses.   Pediatrics. 2005;116(1):153-159. doi:10.1542/peds.2005-0049 PubMedGoogle ScholarCrossref
24.
Segaloff  HE, Leventer-Roberts  M, Riesel  D,  et al.  Influenza vaccine effectiveness against hospitalization in fully and partially vaccinated children in Israel: 2015-2016, 2016-2017, and 2017-2018.   Clin Infect Dis. 2019;69(12):2153-2161. doi:10.1093/cid/ciz125 PubMedGoogle Scholar
25.
Chua  H, Chiu  SS, Chan  ELY,  et al.  Effectiveness of partial and full influenza vaccination in children aged <9 years in Hong Kong, 2011-2019.   J Infect Dis. 2019;220(10):1568-1576. doi:10.1093/infdis/jiz361 PubMedGoogle ScholarCrossref
26.
Szilagyi  PG, Fairbrother  G, Griffin  MR,  et al; New Vaccine Surveillance Network.  Influenza vaccine effectiveness among children 6 to 59 months of age during 2 influenza seasons: a case-cohort study.   Arch Pediatr Adolesc Med. 2008;162(10):943-951. doi:10.1001/archpedi.162.10.943 PubMedGoogle ScholarCrossref
27.
Treanor  JJ, Talbot  HK, Ohmit  SE,  et al; US Flu-VE Network.  Effectiveness of seasonal influenza vaccines in the United States during a season with circulation of all three vaccine strains.   Clin Infect Dis. 2012;55(7):951-959. doi:10.1093/cid/cis574 PubMedGoogle ScholarCrossref
28.
Neuzil  KM, Mellen  BG, Wright  PF, Mitchel  EF  Jr, Griffin  MR.  The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children.   N Engl J Med. 2000;342(4):225-231. doi:10.1056/NEJM200001273420401 PubMedGoogle ScholarCrossref
29.
Iwane  MK, Edwards  KM, Szilagyi  PG,  et al; New Vaccine Surveillance Network.  Population-based surveillance for hospitalizations associated with respiratory syncytial virus, influenza virus, and parainfluenza viruses among young children.   Pediatrics. 2004;113(6):1758-1764. doi:10.1542/peds.113.6.1758 PubMedGoogle ScholarCrossref
30.
Hughes  MM, Reed  C, Flannery  B,  et al.  Projected population benefit of increased effectiveness and coverage of influenza vaccination on influenza burden—United States [ published online July 25, 2019].  Clin Infect Dis. doi:10.1093/cid/ciz676 PubMedGoogle Scholar
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Centers for Disease Control and Prevention. Full and partial flu vaccination coverage in young children, six immunization information system sentinel sites, 2013-14 through 2017-18. Updated November 8, 2018. Accessed July 3, 2019. https://www.cdc.gov/flu/fluvaxview/full-partial-vaccination-children-2018.htm
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Ampofo  K, Gesteland  PH, Bender  J,  et al.  Epidemiology, complications, and cost of hospitalization in children with laboratory-confirmed influenza infection.   Pediatrics. 2006;118(6):2409-2417. doi:10.1542/peds.2006-1475 PubMedGoogle ScholarCrossref
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White  T, Lavoie  S, Nettleman  MD.  Potential cost savings attributable to influenza vaccination of school-aged children.   Pediatrics. 1999;103(6):e73. doi:10.1542/peds.103.6.e73 PubMedGoogle Scholar
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Cohen  GM, Nettleman  MD.  Economic impact of influenza vaccination in preschool children.   Pediatrics. 2000;106(5):973-976. doi:10.1542/peds.106.5.973 PubMedGoogle ScholarCrossref
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Government of Canada. Canadian immunization guide chapter on influenza and statement on seasonal influenza vaccine for 2018-2019. Accessed May 1, 2018. https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2018-2019.html
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National Health Service. Flu vaccine overview. Updated May 1, 2018. Accessed July 3, 2019. https://www.nhs.uk/conditions/vaccinations/flu-influenza-vaccine/#
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European Centre for Disease Prevention and Control. Vaccine scheduler: Influenza: recommended vaccinations. Accessed July 3, 2019. https://vaccine-schedule.ecdc.europa.eu/Scheduler/ByDisease?SelectedDiseaseId=15&SelectedCountryIdByDisease=-1
38.
Grohskopf  LA, Olsen  SJ, Sokolow  LZ,  et al; Centers for Disease Control and Prevention.  Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2014-15 influenza season.   MMWR Morb Mortal Wkly Rep. 2014;63(32):691-697.PubMedGoogle Scholar
39.
Skowronski  DM, Hottes  TS, Chong  M,  et al.  Randomized controlled trial of dose response to influenza vaccine in children aged 6 to 23 months.   Pediatrics. 2011;128(2):e276-e289. doi:10.1542/peds.2010-2777 PubMedGoogle ScholarCrossref
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    Original Investigation
    May 4, 2020

    Patterns of Influenza Vaccination and Vaccine Effectiveness Among Young US Children Who Receive Outpatient Care for Acute Respiratory Tract Illness

    Author Affiliations
    • 1Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia
    • 2Texas A&M University Health Science Center College of Medicine, Temple
    • 3Baylor Scott & White Health Research Institute, Temple, Texas
    • 4Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
    • 5Department of Pediatric Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
    • 6Kaiser Permanente Washington Health Research Institute, Seattle, Washington
    • 7Center for Clinical Epidemiology & Population Health, Marshfield Clinic Research Institute, Marshfield, Wisconsin
    • 8Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor
    JAMA Pediatr. 2020;174(7):705-713. doi:10.1001/jamapediatrics.2020.0372
    Key Points

    Question  What vaccination sequence is associated with the best protection against influenza for children?

    Findings  In this case-control study including 7533 children, vaccine effectiveness against medically attended, laboratory-confirmed influenza was higher among children who received the recommended number of doses compared with children who did not receive the recommended number of doses. Vaccine-naive children aged 2 years or younger who received 2 doses of influenza vaccine in their first vaccination season were less likely to test positive for influenza than those who received 1 dose.

    Meaning  Results of this study suggest that the burden of influenza among young children in the US might be reduced by improving adherence to an initial 2-dose series of influenza vaccination in previously unvaccinated children.

    Abstract

    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.

    Introduction

    Influenza disease burden is high among young children, and annual vaccination is recommended in the US beginning at age 6 months.1,2 For influenza and other pathogens, the immune system’s prime (ie, first) exposure to vaccination establishes a baseline for immune response to subsequent exposures through vaccination or infection. In young children, a 2-dose (ie, full) influenza vaccination series has been shown to generate higher antibody titers than single (ie, partial) vaccination, but less is known about differences in clinical protection following 1 vs 2 doses on initial influenza vaccination.3-5 The US Advisory Committee on Immunization Practices (ACIP) presently recommends 2 doses of influenza vaccine for children aged 6 months to 8 years who have received fewer than 2 previous doses in their lifetime.2,6-9 For older children, adolescents, and all other persons aged 9 years or older who are more likely than younger children to be immunologically primed, the ACIP recommends 1 annual dose for all other persons.

    Current ACIP recommendations for vaccinating children recognize the need for a priming dose and a booster dose but also allow flexibility for vaccinations to be received across influenza seasons. A child is not recommended to receive 1 annual dose until they have received at least 2 previous doses or reach the age of 9 years. Previous doses do not need to be administered in the same or consecutive seasons to count toward the total. Children previously vaccinated with fewer than 2 doses who receive only 1 dose in the current season are considered to be partially vaccinated. Limited data exist to describe and compare the various sequences currently used by parents and clinicians. A previous study examined vaccine effectiveness (VE) among children primed with different sequences in 2 influenza seasons and found that receipt of 2 doses within a season might provide more protection than other strategies.10 The present study extends the previous study using data from the US Influenza Vaccine Effectiveness (Flu VE) Network over 4 more contemporary seasons to (1) describe influenza vaccination sequences currently received by US children who presented for outpatient medical care for acute respiratory tract infection, (2) compare VE among fully and partially vaccinated children, and (3) determine whether the number of doses administered in the first season of vaccination affected VE among children aged 6 months to 2 years.

    Methods

    Methods used in the Flu VE Network have been described previously.11 Briefly, patients who presented with a cough of less than 8 days’ duration were enrolled at outpatient facilities, including emergency departments, at 5 study sites in Michigan, Pennsylvania, Texas, Washington, and Wisconsin during periods of influenza circulation from 2014-2015 through 2017-2018 (enrollment dates available in eTable 1 in the Supplement). The present study was performed from November 5, 2014, to April 12, 2018, during periods of local influenza circulation. Eligible patients were aged 6 months or older on September 1 of the enrollment season; we included only those aged 8 years or younger at enrollment. Study staff collected combined nasal and oropharyngeal swab specimens (nasal swabs only for children aged <2 years) that were tested for influenza viruses at site laboratories using real-time, reverse-transcriptase polymerase chain reaction (rRT-PCR) using Centers for Disease Control and Prevention primers, probes, and testing protocol.12 After providing written or oral informed consent, parents or guardians completed an enrollment interview including questions regarding the child’s demographics and general health status. Study procedures, forms, and consent documents were approved by each site’s institutional review boards. Participants received financial compensation.

    Influenza vaccination histories, including doses received in the enrollment season, were determined using documentation from electronic medical records and immunization information systems, including state registries. We assumed that few children would have received doses outside the state of enrollment and that state immunization information systems would capture most vaccinations.13-18 We excluded participants if they were younger than 6 months at receipt of their first dose (eTable 2 in the Supplement). We also excluded children who were vaccinated 0 to 13 days before illness onset, those who received 2 doses of influenza vaccine less than 4 weeks apart in the enrollment season, and those who received live attenuated influenza vaccine in the enrollment season.

    Statistical Analysis

    We assessed VE through a test-negative design during each of the 2014-2015 through 2017-2018 influenza seasons. Influenza VE compares the odds of testing positive for influenza between vaccinated and unvaccinated participants. We calculated the VE of inactivated influenza vaccine in the enrollment season as (1 − odds ratio) × 100% separately against any influenza, influenza A(H3N2), influenza A(H1N1)pdm09, and influenza B. For all analyses, test-negative controls were rRT-PCR negative for all influenza viruses. We considered the enrollment season as the current influenza season. Adjusted odds ratios (aORs) and 95% CIs were determined from logistic regression models that included study site, influenza season, age in months at enrollment, calendar time of enrollment relative to the peak of influenza activity (as prepeak, peak, or postpeak periods), and presence of 1 or more high-risk medical conditions (eg, asthma) documented in the electronic medical record in the preceding year.2,11 These covariate data were complete for cases and controls. Other variables (eg, age at first dose of influenza vaccine, sex, race/Hispanic ethnicity, days from illness onset to enrollment, general reported health status, and household exposure to cigarette smoke) were assessed as potential confounders but were not retained in the final model because they did not modify the aOR by greater than 5%. We used Firth corrected logistic regression when the number of influenza-positive cases was less than 50. Estimates were not calculated when the number of influenza-positive cases was less than 10. Analyses were conducted using SAS statistical software, version 9.4 (SAS Institute Inc).

    We assessed whether current-season VE differed among children who were fully vs partially vaccinated according to current ACIP recommendations.2 Fully vaccinated children were those who received 1 dose or none before the current season and 2 doses of influenza vaccine in the current season at least 4 weeks apart or children who received 2 or more doses before the current season and 1 or more dose in the current season. All other vaccinated children were considered to be partially vaccinated. We also stratified VE for fully and partially vaccinated children by the number of doses received in the first vaccination season. To further examine the associations of different vaccination histories on influenza risk, we compared the odds of influenza among vaccinated groups.

    To test the hypothesis that 2 doses of influenza vaccine provided better protection than 1 dose against medically attended laboratory-confirmed influenza, we examined the VE of 1 inactivated influenza vaccine dose vs 2 doses in the current season among previously unvaccinated children aged 2 years or younger. We restricted this analysis to this age group because most (>80%) children received the first vaccine dose when they were younger than 2 years. We also compared the odds of influenza among previously unvaccinated children aged 2 years or younger who received 2 current-season doses with those who received 1 dose. A 95% CI that excluded the null value of 1.0 was considered statistically significant.

    In sample size calculations, we estimated that 1104 children including 138 influenza-positive cases would be needed to detect a 40% reduction in influenza (VE) at 80% power (α = .05), with 55% of children receiving 2 doses.

    We conducted 2 sensitivity analyses. In the first, we excluded children enrolled in the 2014-2015 influenza season when antigenically distinct influenza A(H3N2) viruses circulated in the US, for which the vaccine was poorly matched.19 In the second analysis, in a conservative attempt to ensure that all influenza immunizations were included in our data, we excluded children for whom electronic medical records at the enrolling health system did not extend back to the child’s year of birth.

    Results

    From 2014-2015 through 2017-2018, 8339 children aged 6 months to 8 years were enrolled; of these, 806 children were excluded from analyses. The most common reason for exclusion was documented receipt of live attenuated influenza vaccine in the current season (435 [54%]) (eTable 2 in the Supplement). Thus, the number of children included in the analysis was 7533; of these, 3480 children were girls (46%), 4687 children were non-Hispanic white (62%), and 4871 children (65%) were younger than 5 years.

    Most of the 7533 included children (5093 [68%]) were first vaccinated before the current season, 902 children (12%) were vaccinated for the first time in the current season, and 1538 children (20%) were never vaccinated (Table 1). Most children (5355/5995 [89%]) who had been vaccinated in their lifetime either during and/or before the current season received their first influenza vaccine dose documented when they were younger than 2 years. In 5642 vaccinated children (94%), inactivated influenza vaccine was the first influenza vaccine type received.

    Overall, 3579 of 5995 vaccinated children (60%) received 2 documented doses during their first vaccination season. Children who first received 2 doses within their initial vaccination season were younger when they were first vaccinated (median, 8 months; interquartile range, 6-11) compared with children who received only 1 dose during their first vaccination season (median, 11 months; interquartile range, 6-18) (Table 1). Children who received 2 doses within their first vaccination season were also more likely to be non-Hispanic white (2423/3579 [68%]) and have private health insurance (454/1141 [40%]). The proportion of children who received 2 doses within their first vaccination season was higher among those initially vaccinated before age 2 years (3485/5355[65%]) compared with children first vaccinated at age 2 to 4 years (85/528 [16%]) or 5 to 8 years (9/112 [8%]). Children who were never vaccinated were younger at enrollment (median, 39 months; interquartile range, 19-67); less likely to have a high-risk medical condition, such as asthma or reactive airways disease (295/1538 [19%]); and more likely to report excellent general health (941/1536 [61%]) compared with vaccinated children.

    Only 2924 of all 7533 children (39%) received the recommended number of doses in the current season and were considered fully vaccinated. Most fully vaccinated children (2437/2924 [83%]) received 1 dose in the current season; few (487/2924 [17%]) received 2 doses. In all, 3912 of 7533 children (52%) were unvaccinated in the current season, and a smaller proportion of all children (697/7533 [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 (Table 2). Full vaccination was associated with having lower odds of influenza compared with partially vaccinated children (aOR, 0.78; 95% CI, 0.61-1.01).

    Among children recommended to receive 2 doses in the current season, adjusted VE was 58% (95% CI, 40%-70%) among fully vaccinated children compared with 46% (95% CI, 31%-58%) among partially vaccinated children; the odds of influenza were lower among children who received 2 doses compared with children who received only 1 dose (aOR, 0.61; 95% CI, 0.40-0.94). Only 51 children who received 1 previous dose received 2 doses in the current season despite recommendations. Adjusted VE was 50% (95% CI, 22%-67%) among 231 partially vaccinated children with 1 prior dose and 1 current-season dose.

    Among 2140 children who were unvaccinated before the current season, 902 children (42%) were vaccinated in the current season, including 466 children (52%) who received 1 dose and 436 children (48%) who received 2 doses. Most of the children whose first vaccination occurred in the current season (794/902 [88%]) were aged 2 years or younger. Adjusted VE against any influenza virus among children aged 2 years or younger who were first vaccinated during the current season was 38% (95% CI, 15%-55%) (Table 3). Vaccine effectiveness was 53% (95% CI, 28%-70%) among vaccine-naive children aged 6 months to 2 years who received 2 doses and 23% (95% CI, −11% to 47%) for children who received 1 dose. The odds of influenza were lower among children who received 2 doses compared with those who received 1 dose (aOR = 0.57; 95% CI, 0.35-0.93). Vaccine effectiveness against influenza A(H3N2) was 49% (95% CI, 10%-71%) among children who received 2 doses and 20% (95% CI, −26% to 49%) in those who received 1 dose. Sample sizes were small and 95% CIs were wide for influenza A(H1N1)pdm09 and influenza B.

    The results of our sensitivity analyses were similar to our overall findings. However, in general, estimates were less precise owing to smaller sample sizes (eTable 3 in the Supplement).

    Discussion

    Combining 4 seasons of data from the US Flu VE Network, we evaluated the current ACIP influenza vaccination recommendations for children and identified several lines of evidence that appear to support the current recommendations. First, we detected higher VE against medically attended influenza in fully vaccinated children compared with partially vaccinated children. Among children recommended to receive 2 doses in the current season, the odds of influenza among fully vaccinated children were lower compared with the odds in partially vaccinated children. Second, VE was comparable between the various vaccine patterns constituting the fully vaccinated groups. Third, vaccination reduced the risk of medically attended influenza illness by 38% among children who were vaccinated for the first time. The risk of influenza was lower and VE was higher for young, previously unvaccinated children who received 2 doses in the current season (53%) vs 1 dose (23%).

    The higher risk of infection resulting from underdeveloped immune and respiratory tract systems provides a reason to identify vaccination strategies focusing on this vulnerable population of younger children. Our study suggests a benefit of receiving 2 doses of inactivated influenza in the first season of vaccination as well as full vaccination as recommended by the ACIP. This finding is consistent with antibody immune response and limited observational studies of both outpatients and inpatients in the US and elsewhere.20-25 Among partially vaccinated children overall, we detected statistically significant VE, which has been reported in fewer studies.10,26,27 However, 1 dose of vaccine in the current season did not provide statistically significant protection against laboratory-confirmed influenza among the small proportion of previously unvaccinated children aged 2 years or younger. Compared with older children, young children, even if healthy, are at an elevated risk of influenza infection and influenza-associated complications, such as hospitalization.28,29 One recent simulation study reported that even small improvements in either vaccine coverage or VE, and ideally both, may avert substantial amounts of influenza-associated illnesses, medical visits, and hospitalizations.30

    Approximately half (48%) of children were documented as being vaccinated in the current season. This level of coverage is consistent with national estimates since the 2013-2014 influenza season of 40% to 60%.31 Coverage in the US, including the proportion considered partially vaccinated, has remained stable in recent seasons. About half of the children received 2 documented doses in their first season, and most were primed with at least 1 dose of influenza vaccine before age 2 years. However, our results suggest that older children (aged 5-8 years) who are receiving influenza vaccine for the first time are less likely to receive the recommended 2 doses compared with younger children. Improving overall coverage, and particularly 2-dose influenza vaccination adherence, in this vulnerable age group may improve child health with commensurate savings in hospital and indirect costs.32-34

    It was uncommon for children with 1 documented previous dose to receive 2 doses in the current season; most children with 1 documented previous dose received only 1 dose of inactivated influenza vaccine in the current season. Reasons why partially vaccinated children did not receive 2 doses within a season as recommended are unclear. Nevertheless, we observed statistically significant VE in this partially vaccinated group that was comparable with other fully vaccinated groups, which has not been consistently observed in all observational studies. Outside the US and during some US influenza seasons (eg, 2014-2015, when the vaccine composition was identical in the previous season), these children might be considered fully vaccinated.35-38 Some studies have reported significant vaccine protection only among fully vaccinated children.20-24 Differences in criteria for fully and partially vaccinated children might somewhat explain the variation in VE by these policy definitions reported from observational studies. Age is likely an important factor; in our study, vaccination with 1 dose in the current season was not protective among previously unvaccinated children aged 2 years or younger. Additional reasons may include differences in the comparison or control group across studies and potential effect modification by prior vaccination history.

    Limitations

    This study has limitations. It is possible that some influenza vaccine doses were missing from records that we included, which would lead to an underestimate of the number of fully vaccinated children. However, the results were similar in a sensitivity analysis restricted to children with records in the enrolling medical system back to their year of birth. Until the 2018-2019 influenza season, the only licensed influenza vaccine in the US for children aged 3 years or younger was a half-dose product. Vaccine effectiveness may differ in children first vaccinated with 1 full-dose vaccine, which we were unable to examine.39 Likewise, we were unable to stratify by type of first vaccine because few children initially received live attenuated influenza vaccine.

    While we compared VE across 4 seasons, sample sizes were relatively small, and we were underpowered to detect moderate VE in subtype-specific analyses. Our data on any influenza virus were largely driven by influenza A(H3N2) circulation during the study years, with some influenza B and little influenza A(H1N1)pdm09. We lacked information on previous influenza infections. However, since most vaccinated children in our study were first vaccinated before age 2 years, it is plausible that many children were vaccinated before exposure to influenza virus.6 It is unknown how initial exposure to natural infection differs from priming with influenza vaccine. In addition, we cannot rule out the potential for unmeasured or residual confounding since children who received the recommended number of doses may have different care-seeking behavior compared with children who did not. Children who receive medical care for acute respiratory tract virus infection may have different vaccination histories than children in the general population. Observational studies may be limited in their ability to examine VE among persons with varied immunization histories, but we controlled for age as a proxy for number of vaccinations received.

    Conclusions

    Consistent with current US influenza vaccine recommendations, our findings suggest protection against influenza for fully vaccinated children who received inactivated influenza vaccine, with higher effectiveness for 2 doses among previously unvaccinated children aged 2 years or younger. Promoting efforts to improve influenza vaccine coverage—particularly with 2 doses in the first vaccination season—may reduce the burden of influenza illness among young children, who are particularly vulnerable to complications and death from influenza infection.

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    Article Information

    Accepted for Publication: January 4, 2020.

    Corresponding Author: Jessie R. Chung, MPH, Influenza Division, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Mailstop A-32, Atlanta, GA 30333 (jchung@cdc.gov).

    Published Online: May 4, 2020. doi:10.1001/jamapediatrics.2020.0372

    Author Contributions: Ms Chung had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Chung, Flannery, Patel.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Chung, Flannery.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Chung.

    Obtained funding: Gaglani, Patel.

    Administrative, technical, or material support: Reis, M. L. Jackson, Belongia, McLean, Martin, Segaloff.

    Supervision: Flannery, Patel.

    Conflict of Interest Disclosures: Dr Gaglani reported receiving grants from the Centers for Disease Control and Prevention (CDC) during the conduct of the study; grants from the CDC and from Abt Associates outside the submitted work; and institutional contracts with MedImmune/AstraZeneca and Janssen (Johnson & Johnson) outside the submitted work. Dr M. L. Jackson reported receiving grants from the CDC during the conduct of the study and grants from Sanofi Pasteur outside the submitted work. Dr L. A. Jackson reported receiving grants from the CDC during the conduct of the study and grants from Pfizer outside the submitted work. Dr Belongia reported receiving grants from the CDC during the conduct of the study. Dr McLean reported receiving grants from the CDC during the conduct of the study and grants from Seqirus outside the submitted work. Dr Martin reported receiving grants from the CDC during the conduct of the study and personal fees from Pfizer outside the submitted work. Dr Segaloff reported receiving grants from the CDC during the conduct of the study. No other disclosures were reported.

    Funding/Support: The US Influenza Vaccine Effectiveness Network was supported by the CDC through cooperative agreements with the University of Michigan (U01 IP000474), Kaiser Permanente Washington Health Research Institute (U01 IP000466), Marshfield Clinic Research Institute (U01 IP000471), University of Pittsburgh (U01 IP000467), and Baylor Scott and White Healthcare (U01 IP000473). At the University of Pittsburgh, the project was also supported by the National Institutes of Health through grants UL1 RR024153 and UL1 TR000005.

    Role of the Funder/Sponsor: CDC Health designed and conducted the study; collected, managed, analyzed, and interpreted the data; prepared, reviewed, and approved the manuscript; and had a role in the decision to submit the manuscript for publication. The National Institutes of Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.

    Additional Contributions: We appreciate and thank the children and parents who participated in this study.

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