Immunogenicity and Reactogenicity of High-dose or Standard-dose Influenza Vaccine in a Second Consecutive Influenza Season.

BACKGROUND: Pediatric hematopoietic cell transplant (HCT) recipients are at high-risk for morbidity from influenza virus infection. We demonstrated in a primary phase II randomized controlled trial that two post-HCT doses of high-dose trivalent influenza vaccine (HD-TIV) given four weeks apart were more immunogenic than two doses of standard-dose quadrivalent influenza vaccine (SD-QIV). Herein, we present immunogenicity and safety of influenza vaccination in a consecutive season post-HCT using the same dosing regimen. METHODS: A subcohort of study participants re-enrolled and had hemagglutinin inhibition (HAI) titers measured at baseline and four weeks after each vaccine dose in year two. We estimated geometric mean fold rise (GMFR) in HAI titer from baseline for each group and used linear mixed effects models to estimate adjusted geometric mean ratios (aGMR, comparing HD-TIV to SD-QIV) for each antigen at each time point. We described systemic and injection-site reactions. RESULTS: A total of 65 subcohort patients participated (33 SD-QIV, 32 HD-TIV). Post-vaccine GMFR and aGMR estimates were higher for both groups following a single influenza vaccine dose in year two compared to two doses of the same formulation in year one. Both groups had similar frequencies of injection-site and systemic reactions. CONCLUSIONS: A single dose of HD-TIV or SD-QIV was more immunogenic in year two than two doses of the same formulation in year one. Reactogenicity was comparable between groups. One dose of influenza vaccine may be sufficient after a two-dose schedule in the prior year post-HCT.

The Durability of Antibody Responses of Two Doses of High-Dose Relative to Two Doses of Standard-Dose Inactivated Influenza Vaccine in Pediatric Hematopoietic Cell Transplant Recipients: A Multi-Center Randomized Controlled Trial.

BACKGROUND: Our previous study established a 2-dose regimen of high-dose trivalent influenza vaccine (HD-TIV) to be immunogenically superior compared to a 2-dose regimen of standard-dose quadrivalent influenza vaccine (SD-QIV) in pediatric allogeneic hematopoietic cell transplant (HCT) recipients. However, the durability of immunogenicity and the role of time post-HCT at immunization as an effect modifier are unknown. METHODS: This phase II, multi-center, double-blinded, randomized controlled trial compared HD-TIV to SD-QIV in children 3-17 years old who were 3-35 months post-allogeneic HCT, with each formulation administered twice, 28-42 days apart. Hemagglutination inhibition (HAI) titers were measured at baseline, 28-42 days following each dose, and 138-222 days after the second dose. Using linear mixed effects models, we estimated adjusted geometric mean HAI titer ratios (aGMR: HD-TIV/SD-QIV) to influenza antigens. Early and late periods were defined as 3-5 and 6-35 months post-HCT, respectively. RESULTS: During 3 influenza seasons (2016-2019), 170 participants were randomized to receive HD-TIV (n = 85) or SD-QIV (n = 85). HAI titers maintained significant elevations above baseline for both vaccine formulations, although the relative immunogenic benefit of HD-TIV to SD-QIV waned during the study. A 2-dose series of HD-TIV administered late post-HCT was associated with higher GMTs compared to the early post-HCT period (late group: A/H1N1 aGMR = 2.16, 95% confidence interval [CI] = [1.14-4.08]; A/H3N2 aGMR = 3.20, 95% CI = [1.60-6.39]; B/Victoria aGMR = 1.91, 95% CI = [1.01-3.60]; early group: A/H1N1 aGMR = 1.03, 95% CI = [0.59-1.80]; A/H3N2 aGMR = 1.23, 95% CI = [0.68-2.25]; B/Victoria aGMR = 1.06, 95% CI = [0.56-2.03]). CONCLUSIONS: Two doses of HD-TIV were more immunogenic than SD-QIV, especially when administered ≥6 months post-HCT. Both groups maintained higher titers compared to baseline throughout the season. CLINICAL TRIALS REGISTRATION: NCT02860039.

Seasonality, Clinical Characteristics, and Outcomes of Respiratory Syncytial Virus Disease by Subtype Among Children Aged <5 Years: New Vaccine Surveillance Network, United States, 2016-2020.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory illnesses in children. RSV can be broadly categorized into 2 major subtypes: A and B. RSV subtypes have been known to cocirculate with variability in different regions of the world. Clinical associations with viral subtype have been studied among children with conflicting findings such that no conclusive relationships between RSV subtype and severity have been established. METHODS: During 2016-2020, children aged <5 years were enrolled in prospective surveillance in the emergency department or inpatient settings at 7 US pediatric medical centers. Surveillance data collection included parent/guardian interviews, chart reviews, and collection of midturbinate nasal plus/minus throat swabs for RSV (RSV-A, RSV-B, and untyped) using reverse transcription polymerase chain reaction. RESULTS: Among 6398 RSV-positive children aged <5 years, 3424 (54%) had subtype RSV-A infections, 2602 (41%) had subtype RSV-B infections, and 272 (5%) were not typed, inconclusive, or mixed infections. In both adjusted and unadjusted analyses, RSV-A-positive children were more likely to be hospitalized, as well as when restricted to <1 year. By season, RSV-A and RSV-B cocirculated in varying levels, with 1 subtype dominating proportionally. CONCLUSIONS: Findings indicate that RSV-A and RSV-B may only be marginally clinically distinguishable, but both subtypes are associated with medically attended illness in children aged <5 years. Furthermore, circulation of RSV subtypes varies substantially each year, seasonally and geographically. With introduction of new RSV prevention products, this highlights the importance of continued monitoring of RSV-A and RSV-B subtypes.

Medical Costs of Respiratory Syncytial Virus-Associated Hospitalizations and Emergency Department Visits in Children Aged Younger Than 5 Years: Observational Findings from the New Vaccine Surveillance Network, 2016-2019.

OBJECTIVE: To assess medical costs of hospitalizations and emergency department (ED) care associated with respiratory syncytial virus (RSV) disease in children enrolled in the New Vaccine Surveillance Network. STUDY DESIGN: We used accounting and prospective surveillance data from 6 pediatric health systems to assess direct medical costs from laboratory-confirmed RSV-associated hospitalizations (n = 2007) and ED visits (n = 1267) from 2016 through 2019 among children aged <5 years. We grouped costs into categories relevant to clinical care and administrative billing practices. We examined RSV-associated medical costs by care setting using descriptive and bivariate analyses. We assessed associations between known RSV risk factors and hospitalization costs and length of stay using χ2 tests of association. RESULTS: The median cost was $7100 (IQR $4006-$13 355) per hospitalized child and $503 (IQR $387-$930) per ED visit. Eighty percent (n = 2628) of our final sample were children aged younger than 2 years. Fewer weeks' gestational age was associated with greater median costs in hospitalized children (P < .001, ≥37 weeks of gestational age: $6840 [$3905-$12 450]; 29-36 weeks of gestational age: $7721 [$4362-$15 274]; <29 weeks of gestational age: $9131 [$4518-$19 924]). Infants born full term accounted for 70% of the total expenditures in our sample. Almost three quarters of the health care dollars spent originated in children younger than 12 months of age, the primary age group targeted by recommended RSV prophylactics. CONCLUSIONS: Reducing the cost burden for RSV-associated medical care in young children will require prevention of RSV in all young children, not just high-risk infants. Newly available maternal vaccine and immunoprophylaxis products could substantially reduce RSV-associated medical costs.

Early Estimate of Nirsevimab Effectiveness for Prevention of Respiratory Syncytial Virus-Associated Hospitalization Among Infants Entering Their First Respiratory Syncytial Virus Season - New Vaccine Surveillance Network, October 2023-February 2024.

Respiratory syncytial virus (RSV) is the leading cause of hospitalization among infants in the United States. In August 2023, CDC's Advisory Committee on Immunization Practices recommended nirsevimab, a long-acting monoclonal antibody, for infants aged <8 months to protect against RSV-associated lower respiratory tract infection during their first RSV season and for children aged 8-19 months at increased risk for severe RSV disease. In phase 3 clinical trials, nirsevimab efficacy against RSV-associated lower respiratory tract infection with hospitalization was 81% (95% CI = 62%-90%) through 150 days after receipt; post-introduction effectiveness has not been assessed in the United States. In this analysis, the New Vaccine Surveillance Network evaluated nirsevimab effectiveness against RSV-associated hospitalization among infants in their first RSV season during October 1, 2023-February 29, 2024. Among 699 infants hospitalized with acute respiratory illness, 59 (8%) received nirsevimab ≥7 days before symptom onset. Nirsevimab effectiveness was 90% (95% CI = 75%-96%) against RSV-associated hospitalization with a median time from receipt to symptom onset of 45 days (IQR = 19-76 days). The number of infants who received nirsevimab was too low to stratify by duration from receipt; however, nirsevimab effectiveness is expected to decrease with increasing time after receipt because of antibody decay. Although nirsevimab uptake and the interval from receipt of nirsevimab were limited in this analysis, this early estimate supports the current nirsevimab recommendation for the prevention of severe RSV disease in infants. Infants should be protected by maternal RSV vaccination or infant receipt of nirsevimab.

Comparison of Two High-Dose Versus Two Standard-Dose Influenza Vaccines in Adult Allogeneic Hematopoietic Cell Transplant Recipients.

BACKGROUND: Adult hematopoietic cell transplant (HCT) recipients are at high risk for influenza-related morbidity and mortality and have suboptimal influenza vaccine immune responses compared to healthy adults, particularly within 2 years of transplant. METHODS: This phase II, double-blind, multicenter randomized controlled trial compared 2 doses of high-dose trivalent (HD-TIV) to 2 doses of standard-dose quadrivalent (SD-QIV) influenza vaccine administered 1 month apart in adults 3-23 months post-allogeneic HCT. Hemagglutinin antibody inhibition (HAI) titers were measured at baseline, 4 weeks following each vaccine dose, and approximately 7 months post-second vaccination. Injection-site and systemic reactions were assessed for 7 days post-vaccination. The primary immunogenicity comparison was geometric mean HAI titer (GMT) at visit 3 (4 weeks after the second dose); we used linear mixed models to estimate adjusted GMT ratios (aGMRs) comparing HD-TIV/SD-QIV for each antigen. RESULTS: We randomized 124 adults; 64 received SD-QIV and 60 received HD-TIV. Following the second vaccination, HD-TIV was associated with higher GMTs compared to SD-QIV for A/H3N2 (aGMR = 2.09; 95% confidence interval [CI]: [1.19, 3.68]) and B/Victoria (aGMR = 1.61; 95% CI: [1.00, 2.58]). The increase was not statistically significant for A/H1N1 (aGMR = 1.16; 95% CI: [0.67, 2.02]). There was a trend to more injection-site reactions for HD-TIV after the second vaccination compared to SD-QIV (50% vs 33%; adjusted odds ratio [aOR] = 4.53; 95% CI: [0.71, 28.9]), whereas systemic reactions were similar between groups with both injections. CONCLUSIONS: Adult allogeneic HCT recipients who received 2 doses of HD-TIV produced higher HAI antibody responses for A/H3N2 and B/Victoria compared with 2 doses of SD-QIV, with comparable injection-site or systemic reactions.

Sustained Within-season Vaccine Effectiveness Against Influenza-associated Hospitalization in Children: Evidence From the New Vaccine Surveillance Network, 2015-2016 Through 2019-2020.

BACKGROUND: Adult studies have demonstrated within-season declines in influenza vaccine effectiveness (VE); data in children are limited. METHODS: We conducted a prospective, test-negative study of children 6 months through 17 years hospitalized with acute respiratory illness at 7 pediatric medical centers during the 2015-2016 through 2019-2020 influenza seasons. Case-patients were children with an influenza-positive molecular test matched by illness onset to influenza-negative control-patients. We estimated VE [100% × (1 - odds ratio)] by comparing the odds of receipt of ≥1 dose of influenza vaccine ≥14 days before illness onset among influenza-positive children to influenza-negative children. Changes in VE over time between vaccination date and illness onset date were estimated using multivariable logistic regression. RESULTS: Of 8430 children, 4653 (55%) received ≥1 dose of influenza vaccine. On average, 48% were vaccinated through October and 85% through December each season. Influenza vaccine receipt was lower in case-patients than control-patients (39% vs 57%, P < .001); overall VE against hospitalization was 53% (95% confidence interval [CI]: 46, 60%). Pooling data across 5 seasons, the odds of influenza-associated hospitalization increased 4.2% (-3.2%, 12.2%) per month since vaccination, with an average VE decrease of 1.9% per month (n = 4000, P = .275). Odds of hospitalization increased 2.9% (95% CI: -5.4%, 11.8%) and 9.6% (95% CI: -7.0%, 29.1%) per month in children ≤8 years (n = 3084) and 9-17 years (n = 916), respectively. These findings were not statistically significant. CONCLUSIONS: We observed minimal, not statistically significant within-season declines in VE. Vaccination following current Advisory Committee on Immunization Practices (ACIP) guidelines for timing of vaccine receipt remains the best strategy for preventing influenza-associated hospitalizations in children.

SARS-CoV-2 Epidemiology and COVID-19 mRNA Vaccine Effectiveness Among Infants and Children Aged 6 Months-4 Years - New Vaccine Surveillance Network, United States, July 2022-September 2023.

SARS-CoV-2 infection in young children is often mild or asymptomatic; however, some children are at risk for severe disease. Data describing the protective effectiveness of COVID-19 mRNA vaccines against COVID-19-associated emergency department (ED) visits and hospitalization in this population are limited. Data from the New Vaccine Surveillance Network, a prospective population-based surveillance system, were used to estimate vaccine effectiveness using a test-negative, case-control design and describe the epidemiology of SARS-CoV-2 in infants and children aged 6 months-4 years during July 1, 2022-September 30, 2023. Among 7,434 children included, 5% received a positive SARS-CoV-2 test result, and 95% received a negative test result; 86% were unvaccinated, 4% had received 1 dose of any vaccine product, and 10% had received ≥2 doses. When compared with receipt of no vaccines among children, receipt of ≥2 COVID-19 mRNA vaccine doses was 40% effective (95% CI = 8%-60%) in preventing ED visits and hospitalization. These findings support existing recommendations for COVID-19 vaccination of young children to reduce COVID-19-associated ED visits and hospitalization.

Clinical characteristics and outcomes of children with single or co-detected rhinovirus-associated acute respiratory infection in Middle Tennessee.

BACKGROUND: Rhinovirus (RV) is one of the most common etiologic agents of acute respiratory infection (ARI), which is a leading cause of morbidity and mortality in young children. The clinical significance of RV co-detection with other respiratory viruses, including respiratory syncytial virus (RSV), remains unclear. We aimed to compare the clinical characteristics and outcomes of children with ARI-associated RV-only detection and those with RV co-detection-with an emphasis on RV/RSV co-detection. METHODS: We conducted a prospective viral surveillance study (11/2015-7/2016) in Nashville, Tennessee. Children < 18 years old who presented to the emergency department (ED) or were hospitalized with fever and/or respiratory symptoms of < 14 days duration were eligible if they resided in one of nine counties in Middle Tennessee. Demographics and clinical characteristics were collected by parental interviews and medical chart abstractions. Nasal and/or throat specimens were collected and tested for RV, RSV, metapneumovirus, adenovirus, parainfluenza 1-4, and influenza A-C using reverse transcription quantitative polymerase chain reaction assays. We compared the clinical characteristics and outcomes of children with RV-only detection and those with RV co-detection using Pearson's χ2 test for categorical variables and the two-sample t-test with unequal variances for continuous variables. RESULTS: Of 1250 children, 904 (72.3%) were virus-positive. RV was the most common virus (n = 406; 44.9%), followed by RSV (n = 207; 19.3%). Of 406 children with RV, 289 (71.2%) had RV-only detection, and 117 (28.8%) had RV co-detection. The most common virus co-detected with RV was RSV (n = 43; 36.8%). Children with RV co-detection were less likely than those with RV-only detection to be diagnosed with asthma or reactive airway disease both in the ED and in-hospital. We did not identify differences in hospitalization, intensive care unit admission, supplemental oxygen use, or length of stay between children with RV-only detection and those with RV co-detection. CONCLUSION: We found no evidence that RV co-detection was associated with poorer outcomes. However, the clinical significance of RV co-detection is heterogeneous and varies by virus pair and age group. Future studies of RV co-detection should incorporate analyses of RV/non-RV pairs and include age as a key covariate of RV contribution to clinical manifestations and infection outcomes.

Vaccine Effectiveness Against Influenza Hospitalization and Emergency Department Visits in 2 A(H3N2) Dominant Influenza Seasons Among Children <18 Years Old-New Vaccine Surveillance Network 2016-2017 and 2017-2018.

Studies have shown egg-adaptive mutations in influenza vaccine strains that might have impaired protection against circulating A(H3N2) influenza viruses during the 2016-2017 and 2017-2018 seasons. We used the test-negative design and multivariable models to assess vaccine effectiveness against influenza-associated hospitalization and emergency department visits among children (<18 years old) during the 2016-2017 and 2017-2018 seasons. Effectiveness was 71% (95% confidence interval, 59%-79%), 46% (35%-55%), and 45% (33%-55%) against A(H1N1)pdm09, A(H3N2), and B viruses respectively, across both seasons. During high-severity seasons with concerns for vaccine mismatch, vaccination offered substantial protection against severe influenza outcomes requiring hospitalization or emergency department visits among children.

Vaccine Effectiveness Against Life-Threatening Influenza Illness in US Children.

BACKGROUND: Predominance of 2 antigenically drifted influenza viruses during the 2019-2020 season offered an opportunity to assess vaccine effectiveness against life-threatening pediatric influenza disease from vaccine-mismatched viruses in the United States. METHODS: We enrolled children aged <18 years admitted to the intensive care unit with acute respiratory infection across 17 hospitals. Respiratory specimens were tested using reverse-transcription polymerase chain reaction for influenza viruses and sequenced. Using a test-negative design, we estimated vaccine effectiveness comparing odds of vaccination in test-positive case patients vs test-negative controls, stratifying by age, virus type, and severity. Life-threating influenza included death or invasive mechanical ventilation, vasopressors, cardiopulmonary resuscitation, dialysis, or extracorporeal membrane oxygenation. RESULTS: We enrolled 159 critically ill influenza case-patients (70% ≤8 years; 51% A/H1N1pdm09 and 25% B-Victoria viruses) and 132 controls (69% were aged ≤8 years). Among 56 sequenced A/H1N1pdm09 viruses, 29 (52%) were vaccine-mismatched (A/H1N1pdm09/5A+156K) and 23 (41%) were vaccine-matched (A/H1N1pdm09/5A+187A,189E). Among sequenced B-lineage viruses, majority (30 of 31) were vaccine-mismatched. Effectiveness against critical influenza was 63% (95% confidence interval [CI], 38% to 78%) and similar by age. Effectiveness was 75% (95% CI, 49% to 88%) against life-threatening influenza vs 57% (95% CI, 24% to 76%) against non-life-threating influenza. Effectiveness was 78% (95% CI, 41% to 92%) against matched A(H1N1)pdm09 viruses, 47% (95% CI, -21% to 77%) against mismatched A(H1N1)pdm09 viruses, and 75% (95% CI, 37% to 90%) against mismatched B-Victoria viruses. CONCLUSIONS: During a season when vaccine-mismatched influenza viruses predominated, vaccination was associated with a reduced risk of critical and life-threatening influenza illness in children.

Understanding Variation in Rotavirus Vaccine Effectiveness Estimates in the United States: The Role of Rotavirus Activity and Diagnostic Misclassification.

BACKGROUND: Estimates of rotavirus vaccine effectiveness (VE) in the United States appear higher in years with more rotavirus activity. We hypothesized rotavirus VE is constant over time but appears to vary as a function of temporal variation in local rotavirus cases and/or misclassified diagnoses. METHODS: We analyzed 6 years of data from eight US surveillance sites on 8- to 59-month olds with acute gastroenteritis symptoms. Children's stool samples were tested via enzyme immunoassay (EIA); rotavirus-positive results were confirmed with molecular testing at the US Centers for Disease Control and Prevention. We defined rotavirus gastroenteritis cases by either positive on-site EIA results alone or positive EIA with Centers for Disease Control and Prevention confirmation. For each case definition, we estimated VE against any rotavirus gastroenteritis, moderate-to-severe disease, and hospitalization using two mixed-effect regression models: the first including year plus a year-vaccination interaction, and the second including the annual percent of rotavirus-positive tests plus a percent positive-vaccination interaction. We used multiple overimputation to bias-adjust for misclassification of cases defined by positive EIA alone. RESULTS: Estimates of annual rotavirus VE against all outcomes fluctuated temporally, particularly when we defined cases by on-site EIA alone and used a year-vaccination interaction. Use of confirmatory testing to define cases reduced, but did not eliminate, fluctuations. Temporal fluctuations in VE estimates further attenuated when we used a percent positive-vaccination interaction. Fluctuations persisted until bias-adjustment for diagnostic misclassification. CONCLUSIONS: Both controlling for time-varying rotavirus activity and bias-adjusting for diagnostic misclassification are critical for estimating the most valid annual rotavirus VE.

Respiratory Virus Surveillance Among Children with Acute Respiratory Illnesses - New Vaccine Surveillance Network, United States, 2016-2021.

The New Vaccine Surveillance Network (NVSN) is a prospective, active, population-based surveillance platform that enrolls children with acute respiratory illnesses (ARIs) at seven pediatric medical centers. ARIs are caused by respiratory viruses including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human parainfluenza viruses (HPIVs), and most recently SARS-CoV-2 (the virus that causes COVID-19), which result in morbidity among infants and young children (1-6). NVSN estimates the incidence of pathogen-specific pediatric ARIs and collects clinical data (e.g., underlying medical conditions and vaccination status) to assess risk factors for severe disease and calculate influenza and COVID-19 vaccine effectiveness. Current NVSN inpatient (i.e., hospital) surveillance began in 2015, expanded to emergency departments (EDs) in 2016, and to outpatient clinics in 2018. This report describes demographic characteristics of enrolled children who received care in these settings, and yearly circulation of influenza, RSV, HMPV, HPIV1-3, adenovirus, human rhinovirus and enterovirus (RV/EV),* and SARS-CoV-2 during December 2016-August 2021. Among 90,085 eligible infants, children, and adolescents (children) aged <18 years† with ARI, 51,441 (57%) were enrolled, nearly 75% of whom were aged <5 years; 43% were hospitalized. Infants aged <1 year accounted for the largest proportion (38%) of those hospitalized. The most common pathogens detected were RV/EV and RSV. Before the emergence of SARS-CoV-2, detected respiratory viruses followed previously described seasonal trends, with annual peaks of influenza and RSV in late fall and winter (7,8). After the emergence of SARS-CoV-2 and implementation of associated pandemic nonpharmaceutical interventions and community mitigation measures, many respiratory viruses circulated at lower-than-expected levels during April 2020-May 2021. Beginning in summer 2021, NVSN detected higher than anticipated enrollment of hospitalized children as well as atypical interseasonal circulation of RSV. Further analyses of NVSN data and continued surveillance are vital in highlighting risk factors for severe disease and health disparities, measuring the effectiveness of vaccines and monoclonal antibody-based prophylactics, and guiding policies to protect young children from pathogens such as SARS-CoV-2, influenza, and RSV.

Respiratory Syncytial Virus Disease Severity in Young Children.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute respiratory infections (ARIs) in hospitalized children. Although prematurity and underlying medical conditions are known risk factors, most of these children are healthy, and factors including RSV load and subgroups may contribute to severity. Therefore, we aimed to evaluate the role of RSV in ARI severity and determine factors associated with increased RSV-ARI severity in young children. METHODS: Children aged <5 years with fever and/or ARI symptoms were recruited from the emergency department (ED) or inpatient settings at Vanderbilt Children's Hospital. Nasal and/or throat swabs were tested using quantitative reverse-transcription polymerase chain reaction for common respiratory viruses, including RSV. A severity score was calculated for RSV-positive children. RESULTS: From November 2015 through July 2016, 898 participants were enrolled, and 681 (76%) had at least 1 virus detected, with 191 (28%) testing positive for RSV. RSV-positive children were more likely to be hospitalized, require intensive care unit admission, and receive oxygen compared with children positive for other viruses. Higher viral load, White race, younger age, and higher severity score were independently associated with hospitalization in RSV-positive children. No differences in disease severity were noted between RSV A and RSV B. CONCLUSIONS: RSV was associated with increased ARI severity in young children enrolled from the ED and inpatient settings, but no differences in disease severity were noted between RSV A and RSV B. These findings emphasize the need for antiviral therapy and/or preventive measures such as vaccines against RSV in young children.

Effect of Vaccination on Preventing Influenza-Associated Hospitalizations Among Children During a Severe Season Associated With B/Victoria Viruses, 2019-2020.

BACKGROUND: The 2019-2020 influenza season was characterized by early onset with B/Victoria followed by A(H1N1)pdm09 viruses. Emergence of new B/Victoria viruses raised concerns about possible vaccine mismatch. We estimated vaccine effectiveness (VE) against influenza-associated hospitalizations and emergency department (ED) visits among children in the United States. METHODS: We assessed VE among children aged 6 months-17 years with acute respiratory illness and ≤10 days of symptoms enrolled at 7 pediatric medical centers in the New Vaccine Surveillance Network. Combined midturbinate/throat swabs were tested for influenza virus using molecular assays. Vaccination history was collected from parental report, state immunization information systems, and/or provider records. We estimated VE from a test-negative design using logistic regression to compare odds of vaccination among children testing positive vs negative for influenza. RESULTS: Among 2029 inpatients, 335 (17%) were influenza positive: 37% with influenza B/Victoria alone and 44% with influenza A(H1N1)pdm09 alone. VE was 62% (95% confidence interval [CI], 52%-71%) for influenza-related hospitalizations, 54% (95% CI, 33%-69%) for B/Victoria viruses, and 64% (95% CI, 49%-75%) for A(H1N1)pdm09. Among 2102 ED patients, 671 (32%) were influenza positive: 47% with influenza B/Victoria alone and 42% with influenza A(H1N1)pdm09 alone. VE was 56% (95% CI, 46%-65%) for an influenza-related ED visit, 55% (95% CI, 40%-66%) for B/Victoria viruses, and 53% (95% CI, 37%-65%) for A(H1N1)pdm09. CONCLUSIONS: Influenza vaccination provided significant protection against laboratory-confirmed influenza-associated hospitalizations and ED visits associated with the 2 predominantly circulating influenza viruses among children, including against the emerging B/Victoria virus subclade.

The Changing Landscape of Pediatric Viral Enteropathogens in the Post-Rotavirus Vaccine Era.

BACKGROUND: Acute gastroenteritis (AGE) is a common reason for children to receive medical care. However, the viral etiology of AGE illness is not well described in the post-rotavirus vaccine era, particularly in the outpatient (OP) setting. METHODS: Between 2012 and 2015, children 15 days through 17 years old presenting to Vanderbilt Children's Hospital, Nashville, Tennessee, with AGE were enrolled prospectively from the inpatient, emergency department, and OP settings, and stool specimens were collected. Healthy controls (HCs) were enrolled and frequency matched for period, age group, race, and ethnicity. Stool specimens were tested by means of reverse-transcription real-time quantitative polymerase chain reaction for norovirus, sapovirus, and astrovirus RNA and by Rotaclone enzyme immunoassay for rotavirus antigen, followed by polymerase chain reaction verification of antigen detection. RESULTS: A total of 3705 AGE case patients and 1563 HCs were enrolled, among whom 2885 case patients (78%) and 1110 HCs (71%) provided stool specimens that were tested. All 4 viruses were more frequently detected in AGE case patients than in HCs (norovirus, 22% vs 8%, respectively; rotavirus, 10% vs 1%; sapovirus, 10% vs 5%; and astrovirus, 5% vs 2%; P < .001 for each virus). In the OP setting, rates of AGE due to norovirus were higher than rate for the other 3 viruses. Children <5 years old had higher OP AGE rates than older children for all viruses. CONCLUSIONS: Norovirus remains the most common virus detected in all settings, occurring nearly twice as frequently as the next most common pathogens, sapovirus and rotavirus. Combined, norovirus, sapovirus, rotavirus, and astrovirus were associated with almost half of all AGE visits and therefore are an important reason for children to receive medical care.

Characteristics of GII.4 Norovirus Versus Other Genotypes in Sporadic Pediatric Infections in Davidson County, Tennessee, USA.

BACKGROUND: Norovirus is a leading cause of epidemic acute gastroenteritis (AGE), with most outbreaks occurring during winter. The majority of outbreaks are caused by GII.4 noroviruses; however, data to support whether this is true for sporadic medically attended AGE are limited. Therefore, we sought to compare the clinical characteristics and seasonality of GII.4 vs non-GII.4 viruses. METHODS: Children aged 15 days -17 years with AGE symptoms were recruited from the outpatient, emergency department, and inpatient settings at Vanderbilt Children's Hospital, Davidson County, Nashville, Tennessee, from December 2012 -November 2015. Stool specimens were tested using qRT-PCR for GI and GII noroviruses and subsequently genotyped by sequencing a partial region of the capsid gene. RESULTS: A total of 3705 patients were enrolled, and stool specimens were collected and tested from 2885 (78%) enrollees. Overall, 636 (22%) samples were norovirus-positive, of which 567 (89%) were GII. Of the 460 (81%) genotyped GII-positive samples, 233 (51%) were typed as GII.4 and 227 (49%) as non-GII.4. Compared with children with non-GII.4 infections, children with GII.4 infections were younger, more likely to have diarrhea, and more likely to receive oral rehydration fluids. Norovirus was detected year-round and peaked during winter. CONCLUSIONS: Approximately 40% of sporadic pediatric norovirus AGE cases were caused by GII.4 norovirus. Children infected with GII.4 had more severe symptoms that required more medical care. Seasonal variations were noticed among different genotypes. These data highlight the importance of continuous norovirus surveillance and provide important information on which strains pediatric norovirus vaccines should protect against.

Low In-School COVID-19 Transmission and Asymptomatic Infection Despite High Community Prevalence.

There is concern that in-person schooling during the coronavirus disease 2019 (COVID-19) pandemic will facilitate disease transmission. Through asymptomatic surveillance and contact tracing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we found low rates of asymptomatic SARS-CoV-2 infection and little in-school transmission of COVID-19 when physical distancing and masking strategies were enforced despite a high community prevalence of COVID-19.

Enterovirus D68-Associated Acute Respiratory Illness ─ New Vaccine Surveillance Network, United States, July-November 2018-2020.

Enterovirus D68 (EV-D68) is associated with a broad spectrum of illnesses, including mild to severe acute respiratory illness (ARI) and acute flaccid myelitis (AFM). Enteroviruses, including EV-D68, are typically detected in the United States during late summer through fall, with year-to-year fluctuations. Before 2014, EV-D68 was infrequently reported to CDC (1). However, numbers of EV-D68 detection have increased in recent years, with a biennial pattern observed during 2014-2018 in the United States, after the expansion of surveillance and wider availability of molecular testing. In 2014, a national outbreak of EV-D68 was detected (2). EV-D68 was also reported in 2016 via local (3) and passive national (4) surveillance. EV-D68 detections were limited in 2017, but substantial circulation was observed in 2018 (5). To assess recent levels of circulation, EV-D68 detections in respiratory specimens collected from patients aged <18 years* with ARI evaluated in emergency departments (EDs) or admitted to one of seven U.S. medical centers† within the New Vaccine Surveillance Network (NVSN) were summarized. This report provides a provisional description of EV-D68 detections during July-November in 2018, 2019 and 2020, and describes the demographic and clinical characteristics of these patients. In 2018, a total of 382 EV-D68 detections in respiratory specimens obtained from patients aged <18 years with ARI were reported by NVSN; the number decreased to six detections in 2019 and 30 in 2020. Among patients aged <18 years with EV-D68 in 2020, 22 (73%) were non-Hispanic Black (Black) persons. EV-D68 detections in 2020 were lower than anticipated based on the biennial circulation pattern observed since 2014. The circulation of EV-D68 in 2020 might have been limited by widespread COVID-19 mitigation measures; how these changes in behavior might influence the timing and levels of circulation in future years is unknown. Ongoing monitoring of EV-D68 detections is warranted for preparedness for EV-D68-associated ARI and AFM.