Effectiveness of Immunization Products Against Medically Attended Respiratory Syncytial Virus Infection: Generic Protocol for a Test-Negative Case-Control Study.

Monitoring the real-life effectiveness of respiratory syncytial virus (RSV) products is of major public health importance. This generic protocol for a test-negative design study aims to address currently envisioned approaches for RSV prevention (monoclonal antibodies and vaccines) to study effectiveness of these products among target groups: children, older adults, and pregnant women. The generic protocol approach was chosen to allow for flexibility in adapting the protocol to a specific setting. This protocol includes severe acute respiratory infection (SARI) and acute respiratory infection (ARI), both due to RSV, as end points. These end points can be applied to studies in hospitals, primarily targeting patients with more severe disease, but also to studies in general practitioner clinics targeting ARI.

Inference of age-dependent case-fatality ratios for seasonal influenza virus subtypes A(H3N2) and A(H1N1)pdm09 and B lineages using data from the Netherlands.

Background: Despite the known relatively high disease burden of influenza, data are lacking regarding a critical epidemiological indicator, the case-fatality ratio. Our objective was to infer age-group and influenza (sub)type specific values by combining modelled estimates of symptomatic incidence and influenza-attributable mortality. Methods: The setting was the Netherlands, 2011/2012 through 2019/2020 seasons. Sentinel surveillance data from general practitioners and laboratory testing were synthesised to supply age-group specific estimates of incidence of symptomatic infection, and ecological additive modelling was used to estimate influenza-attributable deaths. These were combined in an Bayesian inferential framework to estimate case-fatality ratios for influenza A(H3N2), A(H1N1)pdm09 and influenza B, per 5-year age-group. Results: Case-fatality estimates were highest for influenza A(H3N2) followed by influenza B and then A(H1N1)pdm09 and were highest for the 85+ years age-group, at 4.76% (95% credible interval [CrI]: 4.52-5.01%) for A(H3N2), followed by influenza B at 4.08% (95% CrI: 3.77-4.39%) and A(H1N1)pdm09 at 2.51% (95% CrI: 2.09-2.94%). For 55-59 through 85+ years, the case-fatality risk was estimated to double with every 3.7 years of age. Conclusions: These estimated case-fatality ratios, per influenza sub(type) and per age-group, constitute valuable information for public health decision-making, for assessing the retrospective and prospective value of preventative interventions such as vaccination and for health economic evaluations.

Burden of Respiratory Syncytial Virus in the European Union: estimation of RSV-associated hospitalizations in children under 5 years.

BACKGROUND: No overall estimate of respiratory syncytial virus (RSV)-associated hospitalizations in children aged under 5 years has been published for the European Union (EU). We aimed to estimate the RSV hospitalization burden in children aged under 5 years in EU countries and Norway, by age group. METHODS: We collated national RSV-associated hospitalization estimates calculated using linear regression models via the RESCEU project for Denmark, England, Finland, Norway, the Netherlands, and Scotland, 2006-2018. Additional estimates were obtained from a systematic review. Using multiple imputation and nearest neighbor matching methods, we estimated overall RSV-associated hospitalizations and rates in the EU. RESULTS: Additional estimates for 2 countries (France and Spain) were found in the literature. In the EU, an average of 245 244 (95% confidence interval [CI], 224 688-265 799) yearly hospital admissions with a respiratory infection per year were associated with RSV in children aged under 5 years, with most cases occurring among children aged under 1 year (75%). Infants aged under 2 months represented the most affected group (71.6 per 1000 children; 95% CI, 66.6-76.6). CONCLUSIONS: Our findings will help support decisions regarding prevention efforts and represent an important benchmark to understand changes in the RSV burden following the introduction of RSV immunization programs in Europe.

A Systematic Review of European Clinical Practice Guidelines for Respiratory Syncytial Virus Prophylaxis.

BACKGROUND: Since the widespread adoption of palivizumab prophylaxis in Europe, there have been a number of clinical practice guidelines (CPGs) published for the prevention of respiratory syncytial virus (RSV) infection in children. The aim of this systematic review was to identify CPGs for the prevention of RSV infection across Europe. METHODS: We performed a systematic literature search and contacted European influenza and respiratory virus networks and public health institutions, to identify national CPGs for the prevention of RSV infection. The Reporting Items for practice Guidelines in Healthcare (RIGHT) Statement checklist was applied to extract data and review the quality of reporting. RESULTS: A total of 20 national CPGs were identified, all published between 2000 and 2018. The greatest discrepancy between guidelines was the recommendations for palivizumab prophylaxis for premature infants, with recommendations varying by gestational age. All guidelines recommended or considered the use of palivizumab in infants with bronchopulmonary dysplasia, 85% (n = 17) in children with congenital heart disease (CHD), and 60% (n = 12) in children with severe combined immunodeficiency. CONCLUSIONS: We recommend that agencies publishing RSV prevention guidelines adopt the RIGHT reporting requirements when updating these guidelines to improve the presentation of the evidence-base for decisions.

Sex differences in COVID-19 mortality in the Netherlands.

INTRODUCTION: Since the first reports of COVID-19 cases, sex-discrepancies have been reported in COVID-19 mortality. We provide a detailed description of these sex differences in relation to age and comorbidities among notified cases as well as in relation to age and sex-specific mortality in the general Dutch population. METHODS: Data on COVID-19 cases and mortality until May 31st 2020 was extracted from the national surveillance database with exclusion of healthcare workers. Association between sex and case fatality was analyzed with multivariable logistic regression. Subsequently, male-female ratio in standardized mortality ratios and population mortality rates relative to all-cause and infectious disease-specific mortality were computed stratified by age. RESULTS: Male-female odds ratio for case fatality was 1.33 [95% CI 1.26-1.41] and among hospitalized cases 1.27 [95% CI 1.16-1.40]. This remained significant after adjustment for age and comorbidities. The male-female ratio of the standardized mortality ratio was 1.70 [95%CI 1.62-1.78]. The population mortality rate for COVID-19 was 35.1 per 100.000, with a male-female rate ratio of 1.25 (95% CI 1.18-1.31) which was higher than in all-cause population mortality and infectious disease mortality. CONCLUSION: Our study confirms male sex is a predisposing factor for severe outcomes of COVID-19, independent of age and comorbidities. In addition to general male-female-differences, COVID-19 specific mechanisms likely contribute to this mortality discrepancy.

Respiratory Syncytial Virus-Associated Hospital Admissions and Bed Days in Children <5 Years of Age in 7 European Countries.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infections (RTIs) in young children. High-quality country-specific estimates of bed days and length of stay (LOS) show the population burden of RSV-RTI on secondary care services and the burden among patients, and can be used to inform RSV immunization implementation decisions. METHODS: We estimated the hospital burden of RSV-associated RTI (RSV-RTI) in children under 5 years in 7 European countries (Finland, Denmark, Norway, Scotland, England, the Netherlands, and Italy) using routinely collected hospital databases during 2001-2018. We described RSV-RTI admission rates during the first year of life by birth month and assessed their correlation with RSV seasonality in 5 of the countries (except for England and Italy). We estimated average annual numbers and rates of bed days for RSV-RTI and other-pathogen RTI, as well as the hospital LOS. RESULTS: We found that infants born 2 months before the peak month of RSV epidemics more frequently had the highest RSV-RTI hospital admission rate. RSV-RTI hospital episodes accounted for 9.9-21.2 bed days per 1000 children aged <5 years annually, with the median (interquartile range) LOS ranging from 2 days (0.5-4 days) to 4 days (2-6 days) between countries. Between 70% and 89% of these bed days were in infants aged <1 year, representing 40.3 (95% confidence interval [CI], 40.1-40.4) to 91.2 (95% CI, 90.6-91.8) bed days per 1000 infants annually. The number of bed days for RSV-RTI was higher than that for RTIs associated with other pathogens in infants aged <1 year, especially in those <6 months. CONCLUSIONS: RSV disease prevention therapies (monoclonal antibodies and maternal vaccines) for infants could help prevent a substantial number of bed days due to RSV-RTI. "High-risk" birth months should be considered when developing RSV immunization schedules. Variation in LOS between countries might reflect differences in hospital care practices.

Increasing burden of viral bronchiolitis in the pediatric intensive care unit; an observational study.

PURPOSE: Viral bronchiolitis is a major cause of pediatric intensive care unit (PICU) admission. Insight in the trends of bronchiolitis-associated PICU admissions is limited, but imperative for future PICU resource and capacity planning. MATERIALS AND METHODS: We retrospectively studied trends in PICU admissions for bronchiolitis in six European sites, including three full national registries, between 2000 and 2019 and calculated population-based estimates per 100,000 children where appropriate. Information concerning risk factors for severe disease and use of invasive mechanical ventilation was also collected when available. RESULTS: In total, there were 15,606 PICU admissions for bronchiolitis. We observed an increase in the annual number, rate and estimates per 100,000 children of PICU admissions for bronchiolitis at all sites over the last two decades, while the proportion of patients at high risk for severe disease remained relatively stable. CONCLUSIONS: The international increased burden of bronchiolitis for the PICU is concerning, and warrants further international attention and investigation.

Low levels of respiratory syncytial virus activity in Europe during the 2020/21 season: what can we expect in the coming summer and autumn/winter?

Since the introduction of non-pharmacological interventions to control COVID-19, respiratory syncytial virus (RSV) activity in Europe has been limited. Surveillance data for 17 countries showed delayed RSV epidemics in France (≥ 12 w) and Iceland (≥ 4 w) during the 2020/21 season. RSV cases (predominantly small children) in France and Iceland were older compared with previous seasons. We hypothesise that future RSV epidemic(s) could start outside the usual autumn/winter season and be larger than expected. Year-round surveillance of RSV is of critical importance.

Recommendations for respiratory syncytial virus surveillance at the national level.

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infections and hospitalisations among young children and is globally responsible for many deaths in young children, especially in infants aged <6 months. Furthermore, RSV is a common cause of severe respiratory disease and hospitalisation among older adults. The development of new candidate vaccines and monoclonal antibodies highlights the need for reliable surveillance of RSV. In the European Union (EU), no up-to-date general recommendations on RSV surveillance are currently available. Based on outcomes of a workshop with 29 European experts in the field of RSV virology, epidemiology and public health, we provide recommendations for developing a feasible and sustainable national surveillance strategy for RSV that will enable harmonisation and data comparison at the European level. We discuss three surveillance components: active sentinel community surveillance, active sentinel hospital surveillance and passive laboratory surveillance, using the EU acute respiratory infection and World Health Organization (WHO) extended severe acute respiratory infection case definitions. Furthermore, we recommend the use of quantitative reverse transcriptase PCR-based assays as the standard detection method for RSV and virus genetic characterisation, if possible, to monitor genetic evolution. These guidelines provide a basis for good quality, feasible and affordable surveillance of RSV. Harmonisation of surveillance standards at the European and global level will contribute to the wider availability of national level RSV surveillance data for regional and global analysis, and for estimation of RSV burden and the impact of future immunisation programmes.

Excess Deaths during Influenza and Coronavirus Disease and Infection-Fatality Rate for Severe Acute Respiratory Syndrome Coronavirus 2, the Netherlands.

Since the 2009 influenza pandemic, the Netherlands has used a weekly death monitoring system to estimate deaths in excess of expectations. We present estimates of excess deaths during the ongoing coronavirus disease (COVID-19) epidemic and 10 previous influenza epidemics. Excess deaths per influenza epidemic averaged 4,000. The estimated 9,554 excess deaths (41% in excess) during the COVID-19 epidemic weeks 12-19 of 2020 appeared comparable to the 9,373 excess deaths (18%) during the severe influenza epidemic of 2017-18. However, these deaths occurred in a shorter time, had a higher peak, and were mitigated by nonpharmaceutical control measures. Excess deaths were 1.8-fold higher than reported laboratory-confirmed COVID-19 deaths (5,449). Based on excess deaths and preliminary results from seroepidemiologic studies, we estimated the infection-fatality rate to be 1%. Monitoring of excess deaths is crucial for timely estimates of disease burden for influenza and COVID-19. Our data complement laboratory-confirmed COVID-19 death reports and enable comparisons between epidemics.

Estimating Transmission Parameters for Respiratory Syncytial Virus and Predicting the Impact of Maternal and Pediatric Vaccination.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of respiratory tract illness in young children and a major cause of hospital admissions globally. METHODS: Here we fit age-structured transmission models with immunity propagation to data from the Netherlands (2012-2017). Data included nationwide hospitalizations with confirmed RSV, general practitioner (GP) data on attendance for care from acute respiratory infection, and virological testing of acute respiratory infections at the GP. The transmission models, equipped with key parameter estimates, were used to predict the impact of maternal and pediatric vaccination. RESULTS: Estimates of the basic reproduction number were generally high (R0 > 10 in scenarios with high statistical support), while susceptibility was estimated to be low in nonelderly adults (<10% in persons 20-64 years) and was higher in older adults (≥65 years). Scenario analyses predicted that maternal vaccination reduces the incidence of infection in vulnerable infants (<1 year) and shifts the age of first infection from infants to young children. CONCLUSIONS: Pediatric vaccination is expected to reduce the incidence of infection in infants and young children (0-5 years), slightly increase incidence in 5 to 9-year-old children, and have minor indirect benefits.

Respiratory Syncytial Virus-Associated Hospital Admissions in Children Younger Than 5 Years in 7 European Countries Using Routinely Collected Datasets.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infection (RTI) in young children. Registries provide opportunities to explore RSV epidemiology and burden. METHODS: We explored routinely collected hospital data on RSV in children aged < 5 years in 7 European countries. We compare RSV-associated admission rates, age, seasonality, and time trends between countries. RESULTS: We found similar age distributions of RSV-associated hospital admissions in each country, with the highest burden in children < 1 years old and peak at age 1 month. Average annual rates of RTI admission were 41.3-112.0 per 1000 children aged < 1 year and 8.6-22.3 per 1000 children aged < 1 year. In children aged < 5 years, 57%-72% of RTI admissions with specified causal pathogen were coded as RSV, with 62%-87% of pathogen-coded admissions in children < 1 year coded as RSV. CONCLUSIONS: Our results demonstrate the benefits and limitations of using linked routinely collected data to explore epidemiology and burden of RSV. Our future work will use these data to generate estimates of RSV burden using time-series modelling methodology, to inform policymaking and regulatory decisions regarding RSV immunization strategy and monitor the impact of future vaccines.

Current practices for respiratory syncytial virus surveillance across the EU/EEA Member States, 2017.

BackgroundRespiratory syncytial virus (RSV) is a major contributor to lower respiratory tract infections worldwide and several vaccine candidates are currently in development. Following vaccine introduction, reliable RSV surveillance should enable monitoring of vaccination impact. Data on the RSV disease burden in the European Union and European Economic Area (EU/EEA) are sparse.AimThe aim of this study was to gather knowledge on current practices of national RSV surveillance in the EU/EEA.MethodsNational Coordinators and National Focal Points for Influenza (epidemiologists and virologists) from the EU/EEA countries (n = 31) were invited to participate in an online survey in August and September 2017. The questionnaire covered questions on epidemiological and laboratory aspects of RSV surveillance.ResultsAll EU/EEA countries except Liechtenstein replied to the survey. Eighteen countries reported to have a sentinel surveillance system, 26 countries a non-sentinel surveillance system and three countries to have neither. RSV data collection was mostly done within the context of influenza surveillance. A wide range of diagnostic and characterisation assays was used for the detection of RSV.DiscussionThe majority of EU/EEA countries have some surveillance for RSV in place. The prevailing integration of RSV surveillance into the existing influenza sentinel surveillance system may lead to under-reporting of RSV. The documented variations in existing RSV surveillance systems and their outputs indicate that there is scope for developing guidelines on establishing comparable methods and outcomes for RSV surveillance across the EU/EEA, to ensure the availability of a consistent evidence base for assessing future vaccination programmes.

Use of the moving epidemic method (MEM) to assess national surveillance data for respiratory syncytial virus (RSV) in the Netherlands, 2005 to 2017.

BackgroundTo control respiratory syncytial virus (RSV), which causes acute respiratory infections, data and methods to assess its epidemiology are important.AimWe sought to describe RSV seasonality, affected age groups and RSV-type distribution over 12 consecutive seasons in the Netherlands, as well as to validate the moving epidemic method (MEM) for monitoring RSV epidemics.MethodsWe used 2005-17 laboratory surveillance data and sentinel data. For RSV seasonality evaluation, epidemic thresholds (i) at 1.2% of the cumulative number of RSV-positive patients per season and (ii) at 20 detections per week (for laboratory data) were employed. We also assessed MEM thresholds.ResultsIn laboratory data RSV was reported 25,491 times (no denominator). In sentinel data 5.6% (767/13,577) of specimens tested RSV positive. Over 12 seasons, sentinel data showed percentage increases of RSV positive samples. The average epidemic length was 18.0 weeks (95% confidence intervals (CI): 16.3-19.7) and 16.5 weeks (95% CI: 14.0-18.0) for laboratory and sentinel data, respectively. Epidemics started on average in week 46 (95% CI: 45-48) and 47 (95% CI: 46-49), respectively. The peak was on average in the first week of January in both datasets. MEM showed similar results to the other methods. RSV incidence was highest in youngest (0-1 and >1-2 years) and oldest (>65-75 and > 75 years) age groups, with age distribution remaining stable over time. RSV-type dominance alternated every one or two seasons.ConclusionsOur findings provide baseline information for immunisation advisory groups. The possibility of employing MEM to monitor RSV epidemics allows prospective, nearly real-time use of surveillance data.

Excess all-cause and influenza-attributable mortality in Europe, December 2016 to February 2017.

Since December 2016, excess all-cause mortality was observed in many European countries, especially among people aged ≥ 65 years. We estimated all-cause and influenza-attributable mortality in 19 European countries/regions. Excess mortality was primarily explained by circulation of influenza virus A(H3N2). Cold weather snaps contributed in some countries. The pattern was similar to the last major influenza A(H3N2) season in 2014/15 in Europe, although starting earlier in line with the early influenza season start.

Plasmodium falciparum Infection of Human Volunteers Activates Monocytes and CD16+ Dendritic Cells and Induces Upregulation of CD16 and CD1c Expression.

Antigen-presenting cells (APCs) are key players in the induction and regulation of immune responses. In Plasmodium falciparum malaria, determination of which cells and pathways are activated in the network of APCs remains elusive. We therefore investigated the effects of a controlled human malaria infection in healthy, malaria-naive volunteers on the subset composition and activation status of dendritic cells (DCs) and monocytes. While subsets of monocytes increased in frequency during blood-stage infection, DC frequencies remained largely stable. Activation markers classically associated with peptide presentation to and priming of αßT cells, HLA-DR and CD86, were upregulated in monocytes and inflammatory CD16 myeloid DCs (mDCs) but not in the classical CD1c, BDCA2, or BDCA3 DC subsets. In addition, these activated APC subsets showed increased expression of CD1c, which is involved in glycolipid antigen presentation, and of the immune complex binding Fcγ receptor III (CD16). Our data show that P. falciparum asexual parasites do not activate classical DC subsets but instead activate mainly monocytes and inflammatory CD16 mDCs and appear to prime alternative activation pathways via induction of CD16 and/or CD1c. Changes in expression of these surface molecules might increase antigen capture and enhance glycolipid antigen presentation in addition to the classical major histocompatibility complex class II (MHC-II) peptide presentation and thereby contribute to the initiation of T-cell responses in malaria. (This study has been registered at Clinicaltrials.gov under registration no. NCT01086917.).

Memory B-cell and antibody responses induced by Plasmodium falciparum sporozoite immunization.

BACKGROUND: Immunization of healthy volunteers during receipt of chemoprophylaxis with Plasmodium falciparum sporozoites (CPS-immunization) induces sterile protection from malaria. Antibody responses have long been known to contribute to naturally acquired immunity against malaria, but their association with sterile protection after whole sporozoite immunization is not well established. We therefore studied the induction and kinetics of malaria parasite antigen-specific antibodies and memory B-cells (MBCs) during CPS-immunization and their correlation with protection from challenge infection. METHODS: We assessed humoral reactivity to 9 antigens representing different stages of the life cycle of P. falciparum by performing standardized MBC enzyme-linked immunospot and enzyme-linked immunosorbent assays on peripheral blood mononuclear cells and plasma samples from 38 Dutch volunteers enrolled in 2 randomized controlled clinical trials. RESULTS: MBCs and antibodies recognizing pre-erythrocytic and cross-stage antigens were gradually acquired during CPS-immunization. The magnitude of these humoral responses did not correlate with protection but directly reflected parasite exposure in CPS-immunization and challenge. CONCLUSIONS: Humoral responses to the malarial antigens circumsporozoite protein, liver-stage antigen-1, apical membrane antigen-1, and merozoite surface protein-1 do not to predict protection from challenge infection but can be used as sensitive marker of recent parasite exposure. CLINICAL TRIALS REGISTRATION: NCT01236612 and NCT01218893.

Cytotoxic markers associate with protection against malaria in human volunteers immunized with Plasmodium falciparum sporozoites.

BACKGROUND: Immunization of healthy volunteers by bites from Plasmodium falciparum-infected mosquitoes during chloroquine chemoprophylaxis (hereafter, chemoprophylaxis and sporozoites [CPS] immunization) induces sterile protection against malaria. CPS-induced protection is mediated by immunity against pre-erythrocytic stages, presumably at least partially by cytotoxic cellular responses. We therefore aimed to investigate the association of CPS-induced cytotoxic T-cell markers with protection. METHODS: In a double-blind randomized controlled trial, we performed dose titration of CPS immunization followed by homologous challenge infection in 29 subjects. Immune responses were assessed by in vitro restimulation of peripheral blood mononuclear cells and flow cytometry. RESULTS: Dose-dependent complete protection was obtained in 4 of 5 volunteers after immunization with bites from 45 P. falciparum-infected mosquitoes, in 8 of 9 volunteers with bites from 30, and in 5 of 10 volunteers with bites from 15 (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.5-17). Completely protected subjects had significantly higher proportions of CD4 T cells expressing the degranulation marker CD107a (OR, 8.4; 95% CI, 1.5-123; P = .011) and CD8 cells producing granzyme B (OR, 11; 95% CI, 1.9-212; P = .004) after P. falciparum restimulation. CONCLUSIONS: These data underline the efficiency of CPS immunization to induce sterile protection and support a possible role for cytotoxic CD4 and CD8 T-cell responses in pre-erythrocytic immunity. CLINICAL TRIALS REGISTRATION: NCT01218893.