BACKGROUND:

Influenza A(H1N1)pdm09 viruses initially predominated during the US 2018–2019 season, with antigenically drifted influenza A(H3N2) viruses peaking later. We estimated vaccine effectiveness (VE) against laboratory-confirmed influenza-associated hospitalizations and emergency department (ED) visits among children in the New Vaccine Surveillance Network.

METHODS:

We tested children 6 months to 17 years with acute respiratory illness for influenza using molecular assays at 7 pediatric hospitals (ED patients <5 years at 3 sites). Vaccination status sources were parental report, state immunization information systems and/or provider records for inpatients, and parental report alone for ED patients. We estimated VE using a test-negative design, comparing odds of vaccination among children testing positive versus negative for influenza using multivariable logistic regression.

RESULTS:

Of 1792 inpatients, 226 (13%) were influenza-positive: 47% for influenza A(H3N2), 36% for A(H1N1)pdm09, 9% for A (not subtyped), and 7% for B viruses. Among 1944 ED children, 420 (22%) were influenza-positive: 48% for A(H3N2), 35% for A(H1N1)pdm09, 11% for A (not subtyped), and 5% for B viruses. VE was 41% (95% confidence interval [CI], 20% to 56%) against any influenza-related hospitalizations, 41% (95% CI, 11% to 61%) for A(H3N2), and 47% (95% CI, 16% to 67%) for A(H1N1)pdm09. VE was 51% (95% CI, 38% to 62%) against any influenza-related ED visits, 39% (95% CI, 15% to 56%) against A(H3N2), and 61% (95% CI, 44% to 73%) against A(H1N1)pdm09.

CONCLUSIONS:

The 2018–2019 influenza vaccine reduced pediatric influenza A-associated hospitalizations and ED visits by 40% to 60%, despite circulation of a drifted A(H3N2) clade.

What’s Known on This Subject:

Annual influenza vaccination is 40% to 60% effective against influenza-associated illnesses among children in the ambulatory care setting. Fewer recent national data are available regarding effectiveness specifically against pediatric influenza-associated hospitalizations and emergency department visits.

What This Study Adds:

During the 2018–2019 US influenza season, influenza vaccine effectiveness was 41% against influenza-related hospitalizations and 51% against influenza-related emergency department visits among children. Vaccination provided protection against both influenza A(H1N1)pdm09 and A(H3N2), despite circulation of antigenically drifted A(H3N2) viruses.

Seasonal influenza causes substantial morbidity in children. Annual influenza vaccination is the best protection against influenza and is recommended in the United States for all people ≥6 months.1  Although the overall burden of influenza disease in children varies by season, influenza is estimated to be associated with 12 000 to 46 000 hospitalizations among children each season.2  Influenza-related hospitalizations and emergency department (ED) visits reflect substantial moderate to severe childhood morbidity and economic burden caused by influenza in children.37 

Multiple studies conducted by the US Flu Vaccine Effectiveness (VE) Network have demonstrated that vaccination generally provides 40% to 60% overall protection against influenza-associated ambulatory care office visits among children.816  However, reports of VE against severe influenza illness requiring hospitalization in children are scarce. Likewise, although annual US estimates of influenza VE are generated for combined ambulatory care settings, which include mainly primary care offices and few EDs,9,10,1215  estimated VE against influenza-associated ED visits, specifically, is not generally reported. Our ongoing surveillance data from the New Vaccine Surveillance Network (NVSN) provide timely estimation of VE against severe influenza illness in children evaluated in EDs and/or hospitalized. NVSN studies estimating VE against influenza illness at the severe end of the spectrum in children use the same methodologic approach to estimating VE as ambulatory networks and thus complement published estimates of VE for ambulatory office visits.

In the 2018–2019 US influenza season, influenza A(H1N1)pdm09 viruses initially predominated, with a secondary peak of influenza A(H3N2) viruses, of which 74% belonged to clade 3C.3a, which was antigenically distinct from the A(H3N2) component of the 2018–2019 northern hemisphere influenza vaccines.17  We estimated VE among children 6 months to 17 years who were treated in pediatric hospitals and EDs making up the NVSN during the 2018–2019 influenza season. Our primary objective was to assess VE against laboratory-confirmed influenza hospitalizations, and our secondary objective was to assess VE against laboratory-confirmed influenza ED visits. We evaluated VE against both outcomes for any influenza virus and for influenza A subtypes.

We evaluated VE among study participants in the NVSN, a network of pediatric hospitals in 7 cities (Kansas City, MO; Rochester, NY; Cincinnati, OH; Pittsburgh, PA; Nashville, TN; Houston, TX; and Seattle, WA) that performed prospective surveillance for acute respiratory illness among children who were hospitalized or who sought care in and were discharged from the ED. One main objective of the NVSN was to evaluate protection conferred by vaccination against severe influenza-associated illnesses (hospitalization) among children. All sites enrolled hospitalized children <18 years. Among ED visits, 4 sites enrolled children <18 years (Rochester, Cincinnati, Nashville, and Houston), and 3 sites enrolled children only <5 years of age (Kansas City, Pittsburgh, and Seattle). Although the NVSN enrolled children year-round, for this analysis, we included participants enrolled during each site-specific influenza season, defined as the date of the first through the last influenza-positive case in enrolled subjects at each site.

Children were eligible for NVSN enrollment if they had at least one of the following symptoms or events with a duration <14 days: fever, cough, otalgia, nasal congestion, rhinorrhea, pharyngitis, myalgias, posttussive vomiting, wheezing, dyspnea or rapid or shallow breathing, apnea, and brief resolved unexplained event. Children were excluded from enrollment if they had fever and neutropenia (absolute neutrophil count of <500 neutrophils per μL) with malignancy, were a newborn who had never been discharged from the hospital, had been hospitalized for >48 hours or transferred from another hospital after an admission of >48 hours, were discharged from a hospital in the previous 4 days, had been previously enrolled within 14 days before their current hospitalization or ED visit, or had a known nonrespiratory condition as the reason for their hospitalization or ED visit.

Study staff obtained demographic information, illness characteristics, and medical history, including underlying medical conditions, for each enrolled child through parent or guardian interviews and standardized medical chart review. The data were considered preliminary at the time of analysis. The study protocol was approved by the Centers for Disease Control and Prevention (CDC) and participating institutional review boards. Written informed consent was obtained by the parent or legal guardian of the child, and assent from the child was obtained as required.

At enrollment, we collected a midturbinate nasal swab and throat swab to be combined in viral transport medium. An alternative to swabs collected by research staff was a comparable respiratory specimen (eg, tracheal aspirate, nasal wash, nasopharyngeal swab, or midturbinate nasal swab) collected for clinically indicated testing independent of this study.

Research testing was performed for influenza viruses by using molecular assays, which varied by site: Luminex NxTAG Respiratory Pathogen Panel18  (Kansas City and Cincinnati sites), BioFire FilmArray Respiratory Panel (Seattle site),19  Applied Biosystems TaqMan Array microfluidic card (Rochester site),20,21  and in-house real-time reverse transcription-polymerase chain reaction assays with primers, probes, and the testing protocol developed by the CDC (Pittsburgh, Nashville, and Houston sites).22,23  Subsequent reverse transcription-polymerase chain reaction assays were performed as needed to identify influenza A subtypes and B lineage on research and salvage specimens. For some patients with only a hospital clinical standard-of-care result, there were insufficient samples to determine influenza A subtypes or B lineage. Annual CDC proficiency panels were successfully completed by all participating laboratories.

We collected information from the medical record regarding clinical molecular test results for influenza obtained as part of standard patient care. In situations with discordant results between research and clinical testing, we classified a positive result by either research or clinical molecular influenza testing as influenza-positive. We excluded clinical testing by rapid antigen detection tests from this analysis.

For all children, we asked the parent or guardian about their child’s receipt of the 2018–2019 influenza vaccine during the enrollment interview to determine if a vaccine had been received for the current season (since July 1, 2018). For hospitalized children, current-season vaccination status was confirmed from documentation in state immunization information systems, from the electronic medical record, and/or via phone call or fax from providers.24  When using documented vaccination status, we classified a child as vaccinated if they received a current-season vaccine at least 2 weeks before symptom onset. Because complete data regarding influenza vaccination status for past seasons were not yet available, we defined children as vaccinated or unvaccinated and did not evaluate full and partial vaccination status. For hospitalized children missing documentation, we supplemented vaccination status with that obtained by parent or guardian report. When using parental report, a child was considered vaccinated for the current season if they were said to have received a current-season vaccine before the hospitalization or ED visit.

The primary analysis was evaluation of VE against influenza-associated hospitalizations for any influenza virus and for influenza A subtypes. As a secondary analysis, we evaluated VE against influenza-associated ED visits. We excluded participants <6 months of age who were not eligible to receive the influenza vaccine, those with inconclusive laboratory test results or those who were influenza-positive only by a rapid antigen detection test, those enrolled >10 days after symptom onset, children with documented vaccination <2 weeks before symptom onset, and children missing data for relevant covariates to be considered in the multivariable model (Figs 1 and 2). We compared characteristics among influenza-positive case patients and influenza-negative control patients using descriptive statistics (χ2 or Wilcoxon rank tests).

FIGURE 1

NVSN study enrollment and influenza case status for children hospitalized for acute respiratory illness during influenza season, 2018–2019.

FIGURE 1

NVSN study enrollment and influenza case status for children hospitalized for acute respiratory illness during influenza season, 2018–2019.

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FIGURE 2

NVSN study enrollment and influenza case status for children with ED visits for acute respiratory illness during influenza season, 2018–2019.

FIGURE 2

NVSN study enrollment and influenza case status for children with ED visits for acute respiratory illness during influenza season, 2018–2019.

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We estimated influenza VE using a test-negative study design, comparing the odds of vaccination among case patients who tested positive for influenza compared with control patients who tested negative for influenza, using multivariable logistic regression models with Firth penalization.25  The test-negative design is widely used nationally and internationally for observational studies of influenza VE, including in previous NVSN and other US VE publications, and among ambulatory and hospitalized adults and children.8,10,12,13,24,2634  This methodology is considered to reduce bias associated with confounding by health care–seeking behavior, to lower rates of misclassification of influenza status, and to be better at identifying control patients who arise from the same source population as case patients, which is particularly important for studies of severe influenza outcomes, such as hospitalization.3034  VE was calculated as (1 − the adjusted odds ratio) × 100%.

A priori, we included study site, age, and calendar time (month of enrollment) in logistic regression models.13  The Akaike information criterion values were similar when age was included as a continuous or categorical variable; therefore, we added age as a continuous variable to conserve model parameters. Additional potential covariates to be evaluated included sex, race and/or ethnicity, insurance status, reported number of hospitalizations in the past year, days from illness onset to enrollment, and underlying medical conditions. Models were built by using a manual forward stepwise procedure. Covariates were retained if they were considered to be a priori confounders, if they remained significant at a P value <.05, or if they influenced the VE estimate by >5%. For all analyses, we conducted a subgroup analysis to estimate VE by age (<5 years and 5–17 years) and evaluated P values from an interaction term to determine if estimates between age groups were statistically significantly different. All analyses were completed in SAS version 9.4 (SAS Institute, Inc, Cary, NC).

During the 7 site-specific dates for the influenza season (encompassing November 7, 2018, to June 21, 2019), we enrolled 2748 hospitalized children and 2676 children with ED visits that did not result in hospitalization (Figs 1 and 2).

Hospitalized Children

After exclusions (mostly for children <6 months), 1792 (65%) hospitalized children were eligible for the primary VE analysis. Among the hospitalized group, 226 (13%) children were positive for influenza virus infection; 211 (93%) had influenza A viruses, and 15 (7%) had influenza B viruses. Of the influenza A viruses, 107 (51%) were A(H3N2), 82 (39%) were A(H1N1)pdm09, 1 was a dual infection with both viruses, and 21 (10%) were not subtyped (Fig 1). Among the 1792 hospitalized children in the VE analysis, 1611 (90%) had confirmed documentation of vaccination status available and 181 (10%) had vaccination status by parental report alone. Only 1 participant was documented to have received a live-attenuated influenza vaccine. Of those who received an inactivated influenza vaccine, >98% received a quadrivalent vaccine. Overall, in the hospitalized VE analysis group, 88 (5%) participants received mechanical ventilation and 7 (<1%) died.

Approximately half of influenza-positive case patients (109 of 226) and 1146 (73%) of 1566 influenza-negative control patients were 6 months to <5 years old (Table 1). Influenza-positive case patients differed from control patients by race and/or ethnicity and study site but were similar with respect to other characteristics. Influenza-vaccinated children differed from unvaccinated children by race and/or ethnicity, number of hospitalizations in the past year, and insurance status.

TABLE 1

Characteristics of Children Hospitalized With Acute Respiratory Illness Overall and by Influenza Positivity and Influenza Vaccination Status (Documentation Supplemented by Parental Report), NVSN, 2018–2019

CharacteristicNo. Enrolled, n (%)Influenza-Positive, n (%)Influenza-Negative, n (%)PVaccinated (≥1 Dose), n (%)Not Vaccinated, n (%)P
Overall 1792 226 1566  1070 722  
Sex    .98   .69 
 Male 998 (56) 126 (56) 872 (56)  600 (56) 398 (55)  
 Female 794 (44) 100 (44) 694 (44)  470 (44) 324 (45)  
Age category    <.001   <.001 
 6 mo to <5 y 1255 (70) 109 (48) 1146 (73)  784 (73) 471 (65)  
 5–17 y 537 (30) 117 (52) 420 (27)  286 (27) 251 (35)  
Race and/or ethnicity    .004   <.001 
 White, non-Hispanic 696 (39) 104 (46) 592 (38)  429 (40) 267 (37)  
 Black, non-Hispanic 423 (24) 61 (27) 362 (23)  200 (19) 223 (31)  
 Other, non-Hispanic 177 (10) 20 (9) 157 (10)  103 (10) 74 (10)  
 Hispanic 496 (28) 41 (18) 455 (29)  338 (32) 158 (22)  
Underlying medical conditionsa    .32   .01 
 ≥1 1031 (58) 137 (61) 894 (57)  642 (60) 389 (54)  
 None 761 (42) 89 (39) 672 (43)  428 (40) 333 (46)  
Hospitalization in past year    .27   <.001 
 0 1093 (61) 144 (64) 949 (61)  609 (57) 484 (67)  
 ≥1 685 (38) 82 (36) 603 (39)  451 (42) 234 (32)  
 Unknown 14 (1) 0 (0) 14 (1)  10 (1) 4 (1)  
Surveillance site    <.001   <.001 
 Cincinnati 133 (7) 22 (10) 111 (7)  65 (6) 68 (9)  
 Houston 471 (26) 45 (20) 426 (27)  341 (32) 130 (18)  
 Kansas City 137 (8) 7 (3) 130 (8)  59 (6) 78 (11)  
 Nashville 275 (15) 24 (11) 251 (16)  136 (13) 139 (19)  
 Pittsburgh 448 (25) 84 (37) 364 (23)  247 (23) 201 (28)  
 Rochester 113 (6) 14 (6) 99 (6)  69 (6) 44 (6)  
 Seattle 215 (12) 30 (13) 185 (12)  153 (14) 62 (9)  
Insurance status    .45   <.001 
 Public (or none or self-pay) 1169 (65) 148 (65) 1021 (65)  660 (62) 509 (70)  
 Private or both 605 (34) 74 (33) 531 (34)  403 (38) 202 (28)  
 Unknown 18 (1) 4 (2) 14 (1)  7 (1) 11 (2)  
Days of symptoms since illness onset    .73   .07 
 0–2 717 (40) 96 (42) 621 (40)  430 (40) 287 (40)  
 3–4 561 (31) 64 (28) 497 (32)  353 (33) 208 (29)  
 5–7 384 (21) 48 (21) 336 (21)  220 (21) 164 (23)  
 8–10 130 (7) 18 (8) 112 (7)  67 (6) 63 (9)  
Received mechanical ventilation 88 (5) 12 (5) 76 (5) .94 51 (5) 37 (5) .62 
Death 7 (<1) 1 (<1) 6 (<1)  5 (<1) 2 (<1)  
CharacteristicNo. Enrolled, n (%)Influenza-Positive, n (%)Influenza-Negative, n (%)PVaccinated (≥1 Dose), n (%)Not Vaccinated, n (%)P
Overall 1792 226 1566  1070 722  
Sex    .98   .69 
 Male 998 (56) 126 (56) 872 (56)  600 (56) 398 (55)  
 Female 794 (44) 100 (44) 694 (44)  470 (44) 324 (45)  
Age category    <.001   <.001 
 6 mo to <5 y 1255 (70) 109 (48) 1146 (73)  784 (73) 471 (65)  
 5–17 y 537 (30) 117 (52) 420 (27)  286 (27) 251 (35)  
Race and/or ethnicity    .004   <.001 
 White, non-Hispanic 696 (39) 104 (46) 592 (38)  429 (40) 267 (37)  
 Black, non-Hispanic 423 (24) 61 (27) 362 (23)  200 (19) 223 (31)  
 Other, non-Hispanic 177 (10) 20 (9) 157 (10)  103 (10) 74 (10)  
 Hispanic 496 (28) 41 (18) 455 (29)  338 (32) 158 (22)  
Underlying medical conditionsa    .32   .01 
 ≥1 1031 (58) 137 (61) 894 (57)  642 (60) 389 (54)  
 None 761 (42) 89 (39) 672 (43)  428 (40) 333 (46)  
Hospitalization in past year    .27   <.001 
 0 1093 (61) 144 (64) 949 (61)  609 (57) 484 (67)  
 ≥1 685 (38) 82 (36) 603 (39)  451 (42) 234 (32)  
 Unknown 14 (1) 0 (0) 14 (1)  10 (1) 4 (1)  
Surveillance site    <.001   <.001 
 Cincinnati 133 (7) 22 (10) 111 (7)  65 (6) 68 (9)  
 Houston 471 (26) 45 (20) 426 (27)  341 (32) 130 (18)  
 Kansas City 137 (8) 7 (3) 130 (8)  59 (6) 78 (11)  
 Nashville 275 (15) 24 (11) 251 (16)  136 (13) 139 (19)  
 Pittsburgh 448 (25) 84 (37) 364 (23)  247 (23) 201 (28)  
 Rochester 113 (6) 14 (6) 99 (6)  69 (6) 44 (6)  
 Seattle 215 (12) 30 (13) 185 (12)  153 (14) 62 (9)  
Insurance status    .45   <.001 
 Public (or none or self-pay) 1169 (65) 148 (65) 1021 (65)  660 (62) 509 (70)  
 Private or both 605 (34) 74 (33) 531 (34)  403 (38) 202 (28)  
 Unknown 18 (1) 4 (2) 14 (1)  7 (1) 11 (2)  
Days of symptoms since illness onset    .73   .07 
 0–2 717 (40) 96 (42) 621 (40)  430 (40) 287 (40)  
 3–4 561 (31) 64 (28) 497 (32)  353 (33) 208 (29)  
 5–7 384 (21) 48 (21) 336 (21)  220 (21) 164 (23)  
 8–10 130 (7) 18 (8) 112 (7)  67 (6) 63 (9)  
Received mechanical ventilation 88 (5) 12 (5) 76 (5) .94 51 (5) 37 (5) .62 
Death 7 (<1) 1 (<1) 6 (<1)  5 (<1) 2 (<1)  
a

Comorbid conditions obtained from medical chart review included chronic pulmonary and/or airway, cardiac, gastrointestinal, kidney, endocrine, neurologic and/or neuromuscular, developmental, hematologic and oncologic, genetic and/or metabolic, and immunocompromised conditions; pregnancy; and prematurity.

ED

Among ED patients, 1944 (73%) of 2676 were eligible after exclusions. Of 1944 ED patients, 420 (22%) were positive for influenza virus infection, with 398 (95%) positive for influenza A viruses and 22 (5%) positive for influenza B viruses. Among influenza A virus infections, 203 (51%) were A(H3N2), 146 (35%) were A(H1N1)pdm09, 1 was a dual infection, and 48 (12%) were not subtyped (Fig 2). Both A(H1N1)pdm09 and A(H3N2) detections overlapped throughout the season (Fig 3).

FIGURE 3

Epidemiological curve of influenza virus infections in NVSN enrollees, including hospitalized children and children presenting to the ED for acute respiratory illness during influenza season, 2018–2019.

FIGURE 3

Epidemiological curve of influenza virus infections in NVSN enrollees, including hospitalized children and children presenting to the ED for acute respiratory illness during influenza season, 2018–2019.

Close modal

Among 1944 enrolled children with ED visits, 290 (69%) of 420 influenza-positive case patients and 1268 (83%) of 1524 influenza-negative control patients were 6 months to <5 years old (Table 2). Influenza-positive case patients differed from control patients by race and/or ethnicity, number of hospitalizations in the past year, insurance status, and time since symptom onset. Influenza-vaccinated ED children differed from unvaccinated children by race and/or ethnicity, presence of underlying medical conditions, number of hospitalizations in the past year, and insurance status.

TABLE 2

Characteristics of Children in the ED With Acute Respiratory Illness Overall and by Influenza Positivity and Influenza Parent-Reported Vaccination Status, NVSN, 2018–2019

CharacteristicNo. Enrolled, n (%)Influenza-Positive, n (%)Influenza-Negative, n (%)PVaccinated (≥1 Dose), n (%)Not Vaccinated, n (%)P
Overall 1944 420 1524  1048 896  
Sex    .23   .12 
 Male 1055 (54) 217 (52) 838 (55)  586 (56) 469 (52)  
 Female 889 (46) 203 (48) 686 (45)  462 (44) 427 (48)  
Age category    <.001   .004 
 6 mo to <5 y 1558 (80) 290 (69) 1268 (83)  865 (83) 693 (77)  
 5–17 y 386 (20) 130 (31) 256 (17)  183 (17) 203 (23)  
Race and/or ethnicity    <.001   <.001 
 White, non-Hispanic 410 (21) 58 (14) 352 (23)  268 (26) 142 (16)  
 Black, non-Hispanic 799 (41) 199 (47) 600 (39)  323 (31) 476 (53)  
 Other, non-Hispanic 158 (8) 34 (8) 124 (8)  100 (10) 58 (6)  
 Hispanic 577 (30) 129 (31) 448 (29)  357 (34) 220 (25)  
Underlying medical conditionsa    .20   .01 
 ≥1 548 (28) 108 (26) 440 (29)  321 (31) 227 (25)  
 None 1396 (72) 312 (74) 1084 (71)  727 (69) 669 (75)  
Hospitalization in past year    .04   <.001 
 0 1667 (86) 376 (90) 1291 (85)  858 (82) 809 (90)  
 ≥1 269 (14) 42 (10) 227 (15)  185 (18) 84 (9)  
 Unknown 8 (0) 2 (0) 6 (0)  5 (0) 3 (0)  
Surveillance site    .03   <.001 
 Cincinnati 129 (7) 41 (10) 88 (6)  49 (5) 80 (9)  
 Houston 234 (12) 48 (11) 186 (12)  129 (12) 105 (12)  
 Kansas City 272 (14) 45 (11) 227 (15)  91 (9) 181 (20)  
 Nashville 615 (32) 132 (31) 483 (32)  353 (34) 262 (29)  
 Pittsburgh 286 (15) 60 (14) 226 (15)  147 (14) 139 (16)  
 Rochester 107 (6) 29 (7) 78 (5)  61 (6) 46 (5)  
 Seattle 301 (15) 65 (15) 236 (15)  218 (21) 83 (9)  
Insurance status    .01   <.001 
 Public (or none or self-pay) 1570 (81) 356 (85) 1214 (80)  805 (77) 765 (85)  
 Private or both 352 (18) 57 (14) 295 (19)  232 (22) 120 (13)  
 Unknown 22 (1) 7 (2) 15 (1)  11 (1) 11 (1)  
Days of symptoms since illness onset    .01   .16 
 0–2 1093 (56) 265 (63) 828 (54)  585 (56) 508 (57)  
 3–4 491 (25) 91 (22) 400 (26)  283 (27) 208 (23)  
 5–7 295 (15) 55 (13) 240 (16)  146 (14) 149 (17)  
 8–10 65 (3) 9 (2) 56 (4)  34 (3) 31 (3)  
CharacteristicNo. Enrolled, n (%)Influenza-Positive, n (%)Influenza-Negative, n (%)PVaccinated (≥1 Dose), n (%)Not Vaccinated, n (%)P
Overall 1944 420 1524  1048 896  
Sex    .23   .12 
 Male 1055 (54) 217 (52) 838 (55)  586 (56) 469 (52)  
 Female 889 (46) 203 (48) 686 (45)  462 (44) 427 (48)  
Age category    <.001   .004 
 6 mo to <5 y 1558 (80) 290 (69) 1268 (83)  865 (83) 693 (77)  
 5–17 y 386 (20) 130 (31) 256 (17)  183 (17) 203 (23)  
Race and/or ethnicity    <.001   <.001 
 White, non-Hispanic 410 (21) 58 (14) 352 (23)  268 (26) 142 (16)  
 Black, non-Hispanic 799 (41) 199 (47) 600 (39)  323 (31) 476 (53)  
 Other, non-Hispanic 158 (8) 34 (8) 124 (8)  100 (10) 58 (6)  
 Hispanic 577 (30) 129 (31) 448 (29)  357 (34) 220 (25)  
Underlying medical conditionsa    .20   .01 
 ≥1 548 (28) 108 (26) 440 (29)  321 (31) 227 (25)  
 None 1396 (72) 312 (74) 1084 (71)  727 (69) 669 (75)  
Hospitalization in past year    .04   <.001 
 0 1667 (86) 376 (90) 1291 (85)  858 (82) 809 (90)  
 ≥1 269 (14) 42 (10) 227 (15)  185 (18) 84 (9)  
 Unknown 8 (0) 2 (0) 6 (0)  5 (0) 3 (0)  
Surveillance site    .03   <.001 
 Cincinnati 129 (7) 41 (10) 88 (6)  49 (5) 80 (9)  
 Houston 234 (12) 48 (11) 186 (12)  129 (12) 105 (12)  
 Kansas City 272 (14) 45 (11) 227 (15)  91 (9) 181 (20)  
 Nashville 615 (32) 132 (31) 483 (32)  353 (34) 262 (29)  
 Pittsburgh 286 (15) 60 (14) 226 (15)  147 (14) 139 (16)  
 Rochester 107 (6) 29 (7) 78 (5)  61 (6) 46 (5)  
 Seattle 301 (15) 65 (15) 236 (15)  218 (21) 83 (9)  
Insurance status    .01   <.001 
 Public (or none or self-pay) 1570 (81) 356 (85) 1214 (80)  805 (77) 765 (85)  
 Private or both 352 (18) 57 (14) 295 (19)  232 (22) 120 (13)  
 Unknown 22 (1) 7 (2) 15 (1)  11 (1) 11 (1)  
Days of symptoms since illness onset    .01   .16 
 0–2 1093 (56) 265 (63) 828 (54)  585 (56) 508 (57)  
 3–4 491 (25) 91 (22) 400 (26)  283 (27) 208 (23)  
 5–7 295 (15) 55 (13) 240 (16)  146 (14) 149 (17)  
 8–10 65 (3) 9 (2) 56 (4)  34 (3) 31 (3)  
a

Comorbid conditions obtained from medical chart review included chronic pulmonary and/or airway, cardiac, gastrointestinal, kidney, endocrine, neurologic and/or neuromuscular, developmental, hematologic and oncologic, genetic and/or metabolic, and immunocompromised conditions; pregnancy; and prematurity.

Influenza-positive case patients were less likely to be vaccinated than influenza-negative control patients among both hospitalized (47% vs 62%) and ED patients (40% vs 58%). Overall, adjusted VE against any influenza-associated hospitalization in children was 41% (95% confidence interval [CI], 20% to 56%) (Table 3). When stratified by virus subtype, VE was 41% (95% CI, 11% to 61%) against A(H3N2) viruses and 47% (95% CI, 16% to 67%) against A(H1N1)pdm09 viruses. VE for influenza B viruses was not estimated because of insufficient influenza cases (n = 15). By age group for hospitalized patients for all influenza viruses, VE was 46% (95% CI, 19% to 64%) among children 6 months to <5 years and 23% (95% CI, −23% to 51%) among children 5 to 17 years (P value for differences between age groups = .37). When estimating VE for influenza-associated hospitalizations using vaccination status by parental report alone for hospitalized children in the data set, VE estimates were similar: 41% (95% CI, 20% to 56%) for all influenza viruses, 35% (95% CI, 2% to 57%) against A(H3N2) viruses, and 50% (95% CI, 20% to 69%) against A(H1N1)pdm09 viruses.

TABLE 3

Influenza VE for Prevention of Influenza A and B–Associated Hospitalizations Among Children by Using Documented Influenza Vaccination Status Supplemented by Parental Report, NVSN, 2018–2019


Influenza-Positive (Case Patients)Influenza-Negative (Control Patients)VE
No. Vaccinated/Total%No. Vaccinated/Total%VE, % (95% CI)Adjusteda VE, % (95% CI)
All influenza viruses       
 All ages 106/226 47 964/1566 62 45 (27 to 58) 41 (20 to 56) 
  6 mo to <5 y 54/109 50 730/1146 64 44 (17 to 62) 46 (19 to 64) 
  5–17 y 52/117 44 234/420 56 36 (4 to 58) 23 (−23 to 51) 
A(H3N2) viruses 50/108 46 964/1566 62 46 (20 to 63) 41 (11 to 61) 
A(H1N1)pdm09 viruses 36/83 43 964/1566 62 52 (25 to 69) 47 (16 to 67) 

Influenza-Positive (Case Patients)Influenza-Negative (Control Patients)VE
No. Vaccinated/Total%No. Vaccinated/Total%VE, % (95% CI)Adjusteda VE, % (95% CI)
All influenza viruses       
 All ages 106/226 47 964/1566 62 45 (27 to 58) 41 (20 to 56) 
  6 mo to <5 y 54/109 50 730/1146 64 44 (17 to 62) 46 (19 to 64) 
  5–17 y 52/117 44 234/420 56 36 (4 to 58) 23 (−23 to 51) 
A(H3N2) viruses 50/108 46 964/1566 62 46 (20 to 63) 41 (11 to 61) 
A(H1N1)pdm09 viruses 36/83 43 964/1566 62 52 (25 to 69) 47 (16 to 67) 
a

Adjusted for study site, age as a continuous variable, and calendar time (monthly intervals).

Among ED patients, adjusted VE was 51% (95% CI, 38% to 62%) against any influenza virus infection (Table 4). When stratified for virus subtype, VE was 39% (95% CI, 15% to 56%) against A(H3N2) viruses and 61% (95% CI, 44% to 73%) for A(H1N1)pdm09 viruses. VE for influenza B viruses was not estimated because of insufficient influenza cases (n = 22). VE for all viruses was 55% (95% CI, 39% to 67%) among children 6 months to <5 years and 35% (95% CI, −6% to 60%) among those 5 to 17 years (P value for differences between age groups = .19).

TABLE 4

Influenza VE for Prevention of Influenza A and B–Associated ED Visits Among Children by Using Influenza Vaccination Status Obtained by Parental Report, NVSN, 2018–2019

Influenza-Positive (Case Patients)Influenza-Negative (Non–Case Patients)VE
No. Vaccinated/Total%No. Vaccinated/Total%VE, % (95% CI)Adjusteda VE, % (95% CI)
All influenza viruses       
 All ages 170/420 40 878/1524 58 50 (38 to 60) 51 (38 to 62) 
  6 mo to <5 y 116/290 40 749/1268 59 54 (40 to 64) 55 (39 to 67) 
  5–17 yb 54/130 42 129/256 50 30 (−7 to 54) 35 (−6 to 60) 
A(H3N2) viruses 96/204 47 878/1524 58 35 (12 to 51) 39 (15 to 56) 
A(H1N1)pdm09 viruses 54/147 37 878/1524 58 57 (39 to 70) 61 (44 to 73) 
Influenza-Positive (Case Patients)Influenza-Negative (Non–Case Patients)VE
No. Vaccinated/Total%No. Vaccinated/Total%VE, % (95% CI)Adjusteda VE, % (95% CI)
All influenza viruses       
 All ages 170/420 40 878/1524 58 50 (38 to 60) 51 (38 to 62) 
  6 mo to <5 y 116/290 40 749/1268 59 54 (40 to 64) 55 (39 to 67) 
  5–17 yb 54/130 42 129/256 50 30 (−7 to 54) 35 (−6 to 60) 
A(H3N2) viruses 96/204 47 878/1524 58 35 (12 to 51) 39 (15 to 56) 
A(H1N1)pdm09 viruses 54/147 37 878/1524 58 57 (39 to 70) 61 (44 to 73) 
a

Adjusted for study site, age as a continuous variable, race and/or ethnicity, and calendar time (monthly intervals).

b

Children <18 y were enrolled in 4 of 7 NVSN sites: Cincinnati, Houston, Nashville, and Rochester; children <5 y only were enrolled in Kansas City, Pittsburgh, and Seattle.

Circulating influenza viruses are constantly evolving,35  and during the 2018–2019 US influenza season, influenza A viruses predominated, with cocirculating A(H1N1)pdm09 and A(H3N2). This study reveals that influenza vaccination significantly reduced laboratory-confirmed influenza hospitalization among children enrolled in the NVSN by 41%. We estimated a significant reduction in hospitalizations associated with both A(H3N2) and A(H1N1)pdm09 viruses (point estimates of 41% and 47%, respectively), despite circulating A(H3N2) viruses that were antigenically different from the A(H3N2) influenza vaccine component.17  We also found that influenza vaccination reduced laboratory-confirmed influenza ED visits by half. This study reveals that in this season, influenza vaccines prevented moderate to severe illness in children even when one of the vaccine components was not well matched. VE estimates for both outcomes were similar against all influenza viruses including against both A(H3N2) and A(H1N1)pdm09 viruses, specifically.

Studies from other countries for the 2018–2019 influenza season have demonstrated significant protection against influenza-associated ambulatory care visits and hospitalizations among children infected with A(H1N1)pdm09 viruses. However, protection against A(H3N2) viruses in children has varied: 24% in the United States (outpatients 0–8 years), 17% and 31% in England (outpatients and hospitalized patients 2–17 years, respectively), 46% in Europe (outpatients 0–14 years), and 48% in Canada (outpatients 1–19 years).3640  In the United States, genetic characterization of US Flu VE Network influenza A(H3N2)-positive specimens revealed that the majority of specimens belonged to clade 3C.3a viruses, which differed from the A(H3N2) subclade 3C.2a1 component of the vaccine.17,36  Thus, it could be expected that vaccination with a 3C.2a1 virus may not result in significant protection against illnesses caused by the predominantly circulating clade 3C.3a viruses. In fact, some research groups have explored VE against A(H3N2) viruses by clade and age and have demonstrated that a pronounced lower VE was estimated for clade 3C.3a viruses among certain adult age groups compared with children.37,40  Authors of these studies have hypothesized that the observed differences in VE suggests a differential immune effect of vaccination by age related to childhood imprinting.37,40  Our VE data are consistent with the protective effect of vaccination against influenza illness associated with H3N2 viruses in children during the 2018–2019 season.

Reasons for variation in vaccine protection are multifactorial and can include virus-, host-, and environment-related factors. We do not have sequence data for our A(H3N2) specimens, but A(H1N1)pdm09 and A(H3N2) viruses composed mostly of clade 3C.2a viruses (matched to vaccine viruses) were more common in the United States until February 2019; subsequently, there was varying geographic distribution.36  Only 14% of A(H3N2) viruses from our hospitalized subjects and 21% of A(H3N2) viruses from our ED participants were collected from the start of the season to February 2, 2019, when we would have expected the vaccine to be well matched. Thus, other factors, such as regional variation in circulating viruses, and host factors, such as age (and thus, birth cohort), imprinting, and previous vaccination, are likely related to our finding of vaccine protection against both A(H1N1)pdm09 and A(H3N2) viruses.

We observed similar VE estimates against influenza-associated ED visits and hospitalizations. One notable difference between the two populations is that hospitalized children likely represent more medically complex patients, with 58% having underlying medical conditions and 38% reporting at least one hospitalization in the past year, compared with 28% and 14%, respectively, among ED participants.

Strengths of our study include prospective multisite enrollment across clinical settings in geographically diverse locations, with systematic testing using sensitive molecular influenza assays. This study uniquely included pediatric hospitalizations and ED care, for which previous data were sparse. Our analysis also has limitations as a single-season study with a limited sample size, especially for age group–specific estimates. We controlled for enrollment month, but this may not have been sufficient to account for potential effects of calendar time on VE. We did not evaluate full and partial vaccination status. In addition, we lacked documented vaccination data for many ED patients. Verification of vaccination status for the current season and past seasons using documentation of vaccine receipt is ongoing for hospitalized children but is not routinely performed, per the NVSN protocol, for ED enrollees. Therefore, we chose to use parent- or guardian-reported vaccination status for the ED analysis, which may be subject to recall bias and exposure misclassification. However, self- or parent-reported influenza vaccination has been reported to be generally accurate for current-season vaccination,4143  and the estimates we present for hospitalized patients, using mostly (90%) documented vaccination status, were similar to the estimates using parent-reported vaccination status alone. Finally, ours is an observational study; we may not have controlled for all confounders, and there are limits to test-negative designs, such as the risk of selection bias.44,45  Although we believe the test-negative design is optimal for our study of hospitalized and ED children, our results should not be interpreted as VE against influenza-associated ambulatory care visits or infections that are not medically attended.

In this study, we provide timely evidence of the overall benefit of vaccination in reducing pediatric hospitalizations and ED visits associated with influenza infections. Unlike studies that are focused on ambulatory care office visits, our data provide important VE estimates against severe influenza in children. Strikingly, the vaccine was ∼40% effective against A(H3N2)-related hospitalizations and ED visits, even in a season when antigenically drifted clade 3C.3a influenza viruses were the predominant circulating A(H3N2) viruses. These data provide important evidence supporting the annual recommendation that all children ≥6 months should receive influenza vaccination.

We acknowledge Elizabeth Schlaudecker (Cincinnati, OH); Pedro A Piedra, Vasanthi Avadhanula, and Flor M. Munoz (Houston, TX); Samar Musa, Noreen Jeffrey, and Monika Johnson (Pittsburgh, PA); Christina Albertin, Wende Fregoe, Lynne Shelley, Miranda Marchand, Theodore Pristash, and Joshua Aldred (Rochester, NY); Kirsten Lacombe, Bonnie Strelitz, Ashley Akramoff, Jennifer Baxter, Rachel Buchmeier, Kaitlin Cappetto, Jennifer Jensen, Sarah Korkowski, Katarina Ost, Hannah Schlaack, Hannah Smith, Sarah Steele, Ariundari Tsogoo, and Emily Walter (Seattle, WA); Jessie Chung, Jill Ferdinands, Yingtao Zhou, Iddrisu Sulemana, Roberto Mejia, LaShondra Berman, and John Barnes (Atlanta, GA); and all the members of the NVSN.

We thank the children and parents who participated in this study.

Dr Campbell conceptualized and designed the study, designed data collection instruments, supervised data collection nationally, provided substantial contributions to analysis and interpretation of the data, drafted the initial manuscript, and critically reviewed and revised the manuscript; Dr Patel conceptualized and designed the study, supervised data collection nationally, supervised data analyses and interpretation, and critically reviewed and revised the manuscript; Ms Ogokeh provided substantial contributions to supervision of data collection nationally and interpretation of data, performed analyses of the data, and critically reviewed and revised the manuscript; Ms Lively provided substantial contributions to supervision of data collection nationally and critically reviewed and revised the manuscript; Drs Staat, Selvarangan, Harrison, Halasa, Englund, Klein, Boom, Sahni, Szilagyi, and Weinberg provided substantial contributions to the design of data collection instruments, supervised data collection locally, provided substantial contributions to interpretation of the data, and critically reviewed and revised the manuscript for important intellectual content; Ms McNeal and Drs Stewart, Williams, Michaels, Hickey, Pahud, Schuster, and Weddle provided substantial contributions to supervision of local data collection and interpretation of data and critically reviewed and revised the manuscript for important intellectual content; Dr Rha provided substantial contributions to the conception and design of the study and the design of data collection instruments and critically reviewed and revised the manuscript; Dr Fry provided substantial contributions to the conception and design of the study and the interpretation of the data and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: Supported by the US Centers for Disease Control and Prevention (cooperative agreement CDC-RFA-IP16–004). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

     
  • CDC

    Centers for Disease Control and Prevention

  •  
  • CI

    confidence interval

  •  
  • ED

    emergency department

  •  
  • NVSN

    New Vaccine Surveillance Network

  •  
  • VE

    vaccine effectiveness

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(
12
):
2686
2697

Competing Interests

POTENTIAL CONFLICT OF INTEREST: Other than those provided under “Financial Disclosure,” the authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Dr Halasa receives grant support from Sanofi and Quidel and was a consultant for Moderna and Karius. Dr Williams serves on a scientific advisory board for Quidel, a scientific advisory board for Infectious Disease Connect, and an independent data monitoring committee for GlaxoSmithKline. Children’s Mercy Hospital-Kansas City receives grant funding from GlaxoSmithKline, Merck, and Pfizer for pneumococcal, meningococcal, and rotavirus vaccine studies, on which Drs Harrison and Pahud are investigators, and from Merck for Dr Schuster. Dr Pahud was a consultant for Merck, Pfizer, GlaxoSmithKline, and Sanofi. Dr Englund receives grant support from GlaxoSmithKline, AstraZeneca, Merck, and Novavax and is a consultant for Sanofi Pasteur and Meissa Vaccines, Inc; the other authors have indicated they have no financial relationships relevant to this article to disclose.