Substantial Burden of Nonmedically Attended RSV Infection in Healthy-Term Infants: An International Prospective Birth Cohort Study.

BACKGROUND: During the first year of life, 1 in 4 infants develops a symptomatic respiratory syncytial virus (RSV) infection, yet only half seek medical attention. The current focus on medically attended RSV therefore underrepresents the true societal burden of RSV. We assessed the burden of nonmedically attended RSV infections and compared with medically attended RSV. METHODS: We performed active RSV surveillance until the age of 1 year in a cohort (n = 993) nested within the Respiratory Syncytial Virus Consortium in EUrope (RESCEU) prospective birth cohort study enrolling healthy term-born infants in 5 European countries. Symptoms, medication use, wheezing, and impact on family life were analyzed. RESULTS: For 97 of 120 (80.1%) nonmedically attended RSV episodes, sufficient data were available for analysis. In 50.5% (49/97), symptoms lasted ≥15 days. Parents reported impairment in usual daily activities in 59.8% (58/97) of episodes; worries, 75.3% (73/97); anxiety, 34.0% (33/97); and work absenteeism, 10.8% (10/93). Compared with medically attended RSV (n = 102, 9 hospital admissions), Respiratory Syncytial Virus NETwork (ReSViNET) severity scores were lower (3.5 vs 4.6, P < .001), whereas duration of respiratory symptoms and was comparable. CONCLUSIONS: Even when medical attendance is not required, RSV infection poses a substantial burden to infants, families, and society. These findings are important for policy makers when considering the implementation of RSV immunization. Clinical Trials Registration. ClinicalTrials.gov (NCT03627572).

Year-Round Respiratory Syncytial Virus Transmission in The Netherlands Following the COVID-19 Pandemic: A Prospective Nationwide Observational and Modeling Study.

We initiated a nationwide prospective study to monitor respiratory syncytial virus (RSV)-related pediatric hospitalizations in 46 hospitals throughout the Netherlands between May 2021 and August 2022. We showed year-round RSV transmission in the Netherlands after an initial 2021 summer outbreak. The pattern was unprecedented and distinct from neighboring countries. We extended a dynamic simulation model to evaluate the impact of waning immunity on pediatric RSV hospitalizations in the Netherlands using 4 different scenarios. Our results suggest that the observed continuous RSV transmission pattern could be associated with waning immunity due to the period of very low RSV circulation during the COVID-19 pandemic.

Economic burden and health-related quality-of-life among infants with respiratory syncytial virus infection: A multi-country prospective cohort study in Europe.

BACKGROUND: Respiratory syncytial virus (RSV) causes a considerable disease burden in young children globally, but reliable estimates of RSV-related costs and health-related quality-of-life (HRQoL) are scarce. This study aimed to evaluate the RSV-associated costs and HRQoL effects in infants and their caregivers in four European countries. METHODS: Healthy term-born infants were recruited at birth and actively followed up in four European countries. Symptomatic infants were systematically tested for RSV. Caregivers recorded the daily HRQoL of their child and themselves, measured by a modified EQ-5D with Visual Analogue Scale, for 14 consecutive days or until symptoms resolved. At the end of each RSV episode, caregivers reported healthcare resource use and work absenteeism. Direct medical costs per RSV episode were estimated from a healthcare payer's perspective and indirect costs were estimated from a societal perspective. Means and 95% confidence intervals (CI) of direct medical costs, total costs (direct costs + productivity loss) and quality-adjusted life-day (QALD) loss per RSV episode were estimated per RSV episode, as well as per subgroup (medical attendance, country). RESULTS: Our cohort of 1041 infants experienced 265 RSV episodes with a mean symptom duration of 12.5 days. The mean (95% CI) cost per RSV episode was €399.5 (242.3, 584.2) and €494.3 (317.7, 696.1) from the healthcare payer's and societal perspective, respectively. The mean QALD loss per RSV episode of 1.9 (1.7, 2.1) was independent of medical attendance (in contrast to costs, which also differed by country). Caregiver and infant HRQoL evolved similarly. CONCLUSION: This study fills essential gaps for future economic evaluations by prospectively estimating direct and indirect costs and HRQoL effects on healthy term infants and caregivers separately, for both medically attended (MA) and non-MA laboratory-confirmed RSV episodes. We generally observed greater HRQoL losses than in previous studies which used non-community and/or non-prospective designs.

The burden of respiratory syncytial virus in healthy term-born infants in Europe: a prospective birth cohort study.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of hospitalisation in infants. The burden of RSV infection in healthy term infants has not yet been established. Accurate health-care burden data in healthy infants are necessary to determine RSV immunisation policy when RSV immunisation becomes available. METHODS: We performed a multicentre, prospective, observational birth cohort study in healthy term-born infants (≥37 weeks of gestation) in five sites located in different European countries to determine the health-care burden of RSV. The incidence of RSV-associated hospitalisations in the first year of life was determined by parental questionnaires and hospital chart reviews. We performed active RSV surveillance in a nested cohort to determine the incidence of medically attended RSV infections. The study is registered with ClinicalTrials.gov, NCT03627572. FINDINGS: In total, 9154 infants born between July 1, 2017, and April 1, 2020, were followed up during the first year of life and 993 participated in the nested active surveillance cohort. The incidence of RSV-associated hospitalisations in the total cohort was 1·8% (95% CI 1·6-2·1). There were eight paediatric intensive care unit admissions, corresponding to 5·5% of 145 RSV-associated hospitalisations and 0·09% of the total cohort. Incidence of RSV infection in the active surveillance cohort confirmed by any diagnostic assay was 26·2% (24·0-28·6) and that of medically attended RSV infection was 14·1% (12·3-16·0). INTERPRETATION: RSV-associated acute respiratory infection causes substantial morbidity, leading to the hospitalisation of one in every 56 healthy term-born infants in high-income settings. Immunisation of pregnant women or healthy term-born infants during their first winter season could have a major effect on the health-care burden caused by RSV infections. FUNDING: Innovative Medicines Initiative 2 Joint Undertaking, with support from the EU's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations.

International changes in respiratory syncytial virus (RSV) epidemiology during the COVID-19 pandemic: Association with school closures.

BACKGROUND: Little RSV activity was observed during the first expected RSV season since the COVID-19 pandemic. Multiple countries later experienced out-of-season RSV resurgences, yet their association with non-pharmaceutical interventions (NPIs) is unclear. This study aimed to describe the changes in RSV epidemiology during the COVID-19 pandemic and to estimate the association between individual NPIs and the RSV resurgences. METHODS: RSV activity from Week (W)12-2020 to W44-2021 was compared with three pre-pandemic seasons using RSV surveillance data from Brazil, Canada, Chile, France, Israel, Japan, South Africa, South Korea, Taiwan, the Netherlands and the United States. Changes in nine NPIs within 10 weeks before RSV resurgences were described. Associations between NPIs and RSV activity were assessed with linear mixed models. Adherence to NPIs was not taken into account. RESULTS: Average delay of the first RSV season during the COVID-19 pandemic was 39 weeks (range: 13-88 weeks). Although the delay was <40 weeks in six countries, a missed RSV season was observed in Brazil, Chile, Japan, Canada and South Korea. School closures, workplace closures, and stay-at-home requirements were most commonly downgraded before an RSV resurgence. Reopening schools and lifting stay-at-home requirements were associated with increases of 1.31% (p = 0.04) and 2.27% (p = 0.06) in the deviation from expected RSV activity. CONCLUSION: The first RSV season during the COVID-19 pandemic was delayed in the 11 countries included. Reopening of schools was consistently associated with increased RSV activity. As NPIs were often changed concomitantly, the association between RSV activity and school closures may be partly attributed to other NPIs.

Year-to-year variation in attack rates could result in underpowered respiratory syncytial virus vaccine efficacy trials.

OBJECTIVES: Year-to-year variation in respiratory viruses may result in lower attack rates than expected. We aimed to illustrate the impact of year-to-year variation in attack rates on the likelihood of demonstrating vaccine efficacy (VE). STUDY DESIGN AND SETTING: We considered an individually randomized maternal vaccine trial against respiratory syncytial virus (RSV)-associated hospitalizations. For 10 RSV-associated hospitalizations per 1,000 infants, sample size to have 80% power for true VE of 50% and 70% was 9,846 and 4,424 participants. We reported power to show VE for varying attack rates, selected to reflect realistic year-to-year variation using observational studies. Eight scenarios including varying number of countries and seasons were developed to assess the influence of these trial parameters. RESULTS: Including up to three seasons decreased the width of the interquartile range for power. Including more seasons concentrated statistical power closer to 80%. Least powered trials had higher statistical power with more seasons. In all scenarios, at least half of the trials had <80% power. For three-season trials, increasing the sample size by 10% reduced the percentage of underpowered trials to less than one-quarter of trials. CONCLUSION: Year-to-year variation in RSV attack rates should be accounted for during trial design. Mitigation strategies include recruiting over more seasons, or adaptive trial designs.

Impact of COVID-19 social distancing on viral infection in France: A delayed outbreak of RSV.

INTRODUCTION: COVID-19 pandemic and associated lockdown measures have deeply modified the natural course of seasonal viral infections, such as respiratory syncytial virus (RSV). METHODS: We analyzed French national data from three networks: emergency departments (ED) of French hospitals, general practitioners (GP), and hospital laboratories. We compared the number of ED or GP visits for bronchiolitis in children <2 years of age, and the percentage of RSV positive tests in the 2020 to 2021 season with those of the two previous seasons (2018-2019 and 2019-2020). We used time series of the previous 5 years to calculate epidemic thresholds. RESULTS: During the 2020-2021 season, the epidemic begun in February (Week 05) in the Ile de France (Paris and suburbs) region, 12 weeks later compared with the previous seasons and progressively spread across all the French metropolitan regions. The highest number of bronchiolitis cases in 2021 (Week 12) occurred 10-12 weeks after the previous seasonal peaks of previous seasons, but the number of cases remained lower than in the previous seasonal peaks. CONCLUSION: We identified a delayed RSV epidemic in the period that usually corresponds at the end of the epidemic season, raising concerns for the burden of RSV in the already strained healthcare systems during the COVID-19 pandemic.

Effectiveness of palivizumab immunoprophylaxis to prevent respiratory syncytial virus hospitalizations in healthy full-term <6-month-old infants from the circumpolar region of Nunavik, Quebec, Canada.

In Quebec, Canada, eligibility for palivizumab (PVZ) immunoprophylaxis was expanded in fall 2016 to include healthy-full-term (HFT) infants residing in the circumpolar region of Nunavik and aged <3 months at the start of the RSV season or born during the season. This study assessed the effectiveness of PVZ to prevent RSV hospitalizations in these infants during the 3 seasons following its implementation. Medical and laboratory records of <1-year-old infants (375 average annual birth cohort) admitted to regional and tertiary hospitals with respiratory infection during 6 years were reviewed. Individual pharmacy data and birth registries were used to estimate adherence to PVZ and direct PVZ effectiveness in 0-5-month-old HFT infants by comparing the incidence of RSV hospitalizations 1) in protected and unprotected infants, and 2) during PVZ-protected and unprotected days. Over six seasons, the RSV hospitalization rate was 50.2/1000 (72.6/1000 adjusted for underdetection) in <1-year-old infants. PVZ was administered to 73% (469) of eligible HFT infants; 37% (237) received all recommended doses. Overall for the three RSV seasons the incidence of RSV hospitalization in PVZ-protected infants was similar to PVZ-unprotected infants, resulting in PVZ direct effectiveness of -6.7% (95% CI -174.8%, 85.6%). The incidence of RSV hospitalization during PVZ-protected and during PVZ-unprotected days was also similar, resulting in PVZ direct effectiveness of -3.8% (CI -167.6%, 64.9%). Over three RSV seasons, there was no evidence that PVZ reduced RSV hospitalizations in HFT Nunavik infants. In addition, the sub-optimal adherence to the recommended PVZ administration schedule suggests feasibility and acceptability issues.

Effect of age at vaccination on the measles vaccine effectiveness and immunogenicity: systematic review and meta-analysis.

BACKGROUND: The objectives of this review were to evaluate the effect of age at administration of the first dose of a measles-containing vaccine (MCV1) on protection against measles and on antibody response after one- and two-dose measles vaccinations. METHODS: We conducted a systematic review of the PubMed/MEDLINE, Embase, Web of Science and Cochrane databases (1964-2017) to identify observational studies estimating vaccine effectiveness and/or measles attack rates by age at first vaccination as well as experimental studies comparing seroconversion by age at first vaccination. Random effect models were used to pool measles risk ratios (RR), measles odds ratios (OR) and seroconversion RR of MCV1 administered at < 9, 9-11 or ≥ 15 months compared with 12 or 12-14 months of age. RESULTS: We included 41 and 67 studies in the measles protection and immunogenicity analyses. Older age at MCV1, from 6 to ≥15 months, improved antibody response and measles protection among one-dose recipients. Pooled measles RR ranged from 3.56 (95%CI: 1.28, 9.88) for MCV1 at < 9 months to 0.48 (95%CI: 0.36, 0.63) for MCV1 at ≥15 months, both compared to 12-14 months. Pooled seroconversion RR ranged from 0.93 (95%CI: 0.90, 0.96) for MCV1 at 9-11 months to 1.03 (95%CI: 1.00, 1.06) for MCV1 at ≥15 months, both compared to 12 months. After a second dose, serological studies reported high seropositivity regardless of age at administration of MCV1 while epidemiological data based on few studies suggested lower protection with earlier age at MCV1. CONCLUSIONS: Earlier age at MCV1 decreases measles protection and immunogenicity after one dose and might still have an impact on vaccine failures after two doses of measles vaccine. While two-dose vaccination coverage is most critical to interrupt measles transmission, older age at first vaccination may be necessary to keep the high level of population immunity needed to maintain it.

Nephrotic syndrome following four-component meningococcal B vaccination: Epidemiologic investigation of a surveillance signal.

BACKGROUND: In May 2014, a mass vaccination campaign with four-component meningococcal serogroup B (4CMenB) vaccine was launched in a localized region of Quebec, Canada experiencing high invasive meningococcal B disease endemicity. Active post-marketing surveillance identified several cases of nephrotic syndrome (NS) among ∼49,000 vaccinated individuals aged 2 months to 20 years. We report the epidemiologic investigation of this potential vaccine safety signal. METHODS: Active vaccine safety surveillance was conducted electronically, with participants completing an online questionnaire prompted at 7 days after each dose and 6 months following the last dose. Additional NS cases were sought from provincial hospitalization and emergency room databases. RESULTS: In the year following the first dose of 4CMenB vaccination, four confirmed NS cases (three hospitalized) were identified among vaccinated children 2-5-years-old with onset several months post-vaccination. None had renal biopsy but given their age, and positive response to steroids, idiopathic NS was presumptively diagnosed. Among vaccinated children 1-9-years-old, the NS incidence in the year post-vaccination was 17.7 per 100,000 (1 per 5650 vaccinees) with an NS hospitalization rate (i.e. excluding the outpatient case) that was 3.6-fold higher (95%CI = 0.7-11.8; p = 0.12) than the rest of the province for the same period, and 8.3-fold greater (95%CI = 1.1-62.0; p = 0.039) than during the eight years preceding the immunization campaign in the affected region. CONCLUSION: Active safety surveillance identified an unexpected increase in NS incidence following 4CMenB vaccination. Further epidemiological investigation identified four vaccinated cases in total over a 12 month period of follow up. The greater risk in vaccinees had wide confidence intervals with he lower limit including or just above the nul value, an observation with no or marginal statistical significance. The temporal association with vaccination may be explained by other causes and/or chance clustering of a rare event unrelated to vaccination. To confirm or refute a potential link to vaccination, surveillance in other jurisdictions administering 4CMenB to children 1-9-years-old is needed.

Short-term safety of 4CMenB vaccine during a mass meningococcal B vaccination campaign in Quebec, Canada.

BACKGROUND: To address a high incidence of serogroup B invasive meningococcal disease (IMD-B) in the Saguenay-Lac-Saint-Jean region, Quebec, Canada, a mass vaccination campaign targeting nearly 60,000 individuals ≤20 years old was launched in May 2014. Because of the limited clinical experience with the four-component meningococcal B vaccine (4CMenB), active surveillance for adverse events following immunization (AEFI) was conducted. This paper reports 4CMenB AEFI surveillance findings. METHODS: Active surveillance assessed AEFIs with acute onset within 7-days post-immunization, AEFI-associated absenteeism and medical consultations, impact of antipyretic prophylaxis and coadministration of other vaccines. RESULTS: By July 17, 2015, 83% and 77% of the 59,098 individuals targeted by the campaign had received a first and a second dose of 4CMenB. The incidence of fever on days1-2 was highest in children <2 years old but only 0.6% reported a temperature ≥40◦C. Among children <10 years old, ≥2doses of acetaminophen prophylaxis significantly reduced fever incidence on days1-2 after dose1&2. Absenteeism or a medical consultation during the 7 days following vaccination was reported by 6.2% of vaccinees post-dose1 and 9.2% post-dose2 and was most often reported in association with fever/malaise (4.2%) or injection site reactions (3.6%). CONCLUSION: Large-scale population-based surveillance identified a 7-day reactogenicity profile consistent with earlier clinical trials with the 4CMenB vaccine but indicating frequent AEFI-associated absenteeism and medical consultations affecting the societal cost of this vaccine. We conclude acceptable vaccine safety and risk-benefit profile overall on the short term, particularly as an intervention to address a high regional incidence of IMD-B.

Investigation of an increase in large local reactions following vaccine schedule change to include DTaP-HB-IPV-Hib (Infanrix-hexa®) and MMRV (ProQuad®) at 18 months of age.

CONTEXT: In 2015 in Quebec, Canada, the passive vaccine adverse event reporting system detected an increase in large local reactions associated with vaccines recommended at the 18-month visit. This followed changes to the pediatric vaccine schedule to include hexavalent diphtheria-tetanus-acellular-pertusis-inactivated polio-Haemophilus influenzae type b-hepatitis B vaccine (DTaP-IPV-Hib-HB, Infanrix-hexa®, GSK) and quadrivalent measles-mumps-rubella-varicella vaccine (MMRV, ProQuad®, Merck) as 18-month booster doses. OBJECTIVES: To determine if the excess of large local reactions was caused by a specific vaccine or their co-administration in the same limb or during the same visit. METHODS: A case-control study was conducted among cases born between January 2012 and April 2015 with a large local reaction following MMR ±â€¯V or DTaP-IPV-Hib ±â€¯HB vaccines administered between 16 and 23 months of age. Controls were randomly selected from the provincial medicare database among children born during the same period. RESULTS: Our analysis included 96 cases and 494 controls vaccinated with MMRV or DTaP-IPV-Hib ±â€¯HB vaccines. Among the 96 cases, 46% had a cellulitis and 54% had an injection site reaction extending beyond the nearest joint and/or lasting ≥ 4 days. Among the 39 cases who were immunized in different limbs, 77% of the large local reactions were located at the Infanrix-hexa® site, 5% at the DTaP-IPV-Hib site and 18% at the ProQuad® site. Large local reactions were significantly more frequent with Infanrix-hexa® than with DTaP-IPV-Hib vaccine (OR 5.9 95% CI: 1.4-25.7). Administration of ProQuad® and Infanrix-hexa® in the same limb did not increase the risk of large local reactions. CONCLUSION: This investigation suggested that most large local reactions were causally associated with the Infanrix-hexa® vaccine and that the risk was not greater when ProQuad® and Infanrix-hexa® were administered in the same limb. Given the improved vaccine coverage for hepatitis B, benefit-risk analysis likely still favours ongoing use of Infanrix-hexa® with informed parental consent.

Prevalence of risk factors for acquiring measles during the 2011 outbreak in Quebec and impact of the province-wide school-based vaccination campaign on population immunity.

BACKGROUND: A large measles outbreak occurred in Quebec, Canada, in 2011. Although nearly two-thirds of the cases occurred in only two health districts, a mass vaccination campaign targeting all Quebec elementary and high school students without valid two-dose history was undertaken to prevent future outbreaks. We compared rates of non-vaccination and age at first measles vaccine dose among students in the two most-affected districts and the rest of the province and estimated the improvement in overall student measles immunity due to the mass school-based vaccination campaign. METHODS: Data were extracted from the provincial vaccination registry for students in kindergarten to grade 11 during the 2011/2012 school year. A telephone survey was conducted in three sub-groups: students whose first measles vaccine dose recorded in the vaccination registry was received during the 2011 school vaccination campaign; students with no dose recorded in the registry whose parents refused receipt during the school campaign; and students with no dose recorded in the registry and no information about parental consent/refusal during the school campaign. RESULTS: Neither the prevalence of being non-vaccinated nor a younger age at first pediatric dose were higher in the two most-affected districts versus the rest of the province. The school campaign vaccinated nearly 8% of all students including 7% who previously received at least one dose. Before the outbreak, 3% of students were not vaccinated and one-third of these (1%/3%) were vaccinated during the campaign. The campaign likely increased the absolute school population immunity by just 1.7%. CONCLUSION: The concentration of measles cases in the two most-affected health districts during the large Quebec outbreak is not explained by more students who were unvaccinated or who had received their first vaccine dose at a younger age. The vaccination campaign reached one-third of unvaccinated students and only marginally improved population immunity.

Immunizing Patients With Adverse Events After Immunization and Potential Contraindications to Immunization: A Report From the Special Immunization Clinics Network.

BACKGROUND: For patients who have experienced adverse events following immunization (AEFI) or who have specific medical conditions, there is limited evidence regarding the best approach to immunization. The Special Immunization Clinics (SICs) Network was established to standardize patient management and assess outcomes after reimmunization. The study objective was to describe the first 2 years of the network's implementation. METHODS: Twelve SICs were established across Canada by infectious diseases specialists and allergists. Inclusion criteria were as follows: local reaction ≥ 10 cm, allergic symptoms < 24 hours postimmunization, neurologic symptoms and other AEFI or medical conditions of concern. Eligible patients underwent a standardized evaluation, causality assessment was performed, immunization recommendations were made by expert physicians and patients were followed up to capture AEFI. After individual consent, data were transferred to a central database for analysis. RESULTS: From June 2013 to May 2015, 151 patients were enrolled. Most were referred for prior AEFI (132/151, 87%): 42 (32%) for allergic-like reactions, 31 (23%) for injection-site reactions, 20 (15%) for neurologic symptoms and 39 (30%) for other systemic symptoms. Nineteen patients (13%) were seen for underlying conditions that complicated immunization. Reimmunization was recommended for 109 patients, 60 of whom (55%) were immunized and followed up. Eleven patients (18%) experienced recurrence of their AEFI; none were serious (eg, resulting in hospitalization, permanent disability or death). CONCLUSIONS: The most frequent reasons for referral to a SIC were allergic-like events and injection site reactions. Reimmunization was safe in most patients. Larger studies are needed to determine outcomes for specific types of AEFI.