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IntroductionStudying antibody dynamics following re-exposure to infection and/or vaccination is crucial for a better understanding of fundamental immunological processes, vaccine development, and health policy research. MethodsWe adopted a nonlinear mixed modeling approach based on ordinary differential equations (ODE) to characterize varicella-zoster virus specific antibody dynamics during and after clinical herpes zoster. Our ODEs models convert underlying immunological processes into mathematical formulations, allowing for testable data analysis. In order to cope with inter- and intra-individual variability, mixed models include population-averaged parameters (fixed effects) and individual-specific parameters (random effects). We explored the use of various ODE-based nonlinear mixed models to describe longitudinally collected markers of immunological response in 61 herpes zoster patients. ResultsStarting from a general formulation of such models, we study different plausible processes underlying observed antibody titer concentrations over time, including various individual-specific parameters. Among the converged models, the best fitting and most parsimonious model implies that once Varicella-zoster virus (VZV) reactivation is clinically apparent (i.e., Herpes-zoster (HZ) can be diagnosed), short-living and long-living antibody secreting cells (SASC and LASC, respectively) will not expand anymore. Additionally, we investigated the relationship between age and viral load on SASC using a covariate model to gain a deeper understanding of the population's characteristics. ConclusionThe results of this study provide crucial and unique insights that can aid in improving our understanding of VZV antibody dynamics and in making more accurate projections regarding the potential impact of vaccines. Funding BO acknowledges funding received from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement 851752-CELLULOEPI) and Research Foundation Flanders (FWO) (grant agreement 1861219N). NH and IGF acknowledge support from the EBOVAC3 project which has received funding from the IMI2 Joint Undertaking under grant agreement No 800176 (IMI-EU). Acknowledgments We thank Nina Keersmaekers for her contribution in the early stages of this work. Also, we acknowledge that the resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by the Research Foundation - Flanders (FWO) and the Flemish Government.

Background In older adults, the burden of respiratory syncytial virus (RSV) resembles that of influenza and may even be considered worse due to the lack of preventive interventions. This study was performed to identify the available literature on RSV infection in older adults, and to provide updated exploratory results of the cost-effectiveness of a hypothetical RSV vaccine in the Netherlands and the United Kingdom. Methods A literature search was performed in Medline and EMBASE on 11 November 2019, which served as input for a static decision-tree model that was used to estimate the EJP, for an RSV vaccine applying different willingness-to-pay (WTP) thresholds. WTP thresholds applied were €20 000 and €50 000 per quality-adjusted life-year for the Netherlands, and £20 000 and £30 000 per quality-adjusted life-year for the United Kingdom. Analyses were—in line with country-specific guidelines—conducted from a societal perspective for the Netherlands and a third-party payer perspective for the United Kingdom. The robustness of the cost-effectiveness results was tested in sensitivity analysis. Results After screening the literature, 3 studies for the Netherlands and 6 for the United Kingdom remained to populate the country-specific models. In the base case analysis for the Netherlands (mean RSV incidence, 3.32%), justifiable vaccine prices of €16.38 and €50.03 were found, based on applying the lower and higher WTP thresholds, respectively. Similarly, for the United Kingdom (mean incidence, 7.13%), vaccine prices of £72.29 and £109.74 were found, respectively. Conclusion RSV vaccination may well be cost-effective in both the Netherlands and the United Kingdom, depending on the exact RSV incidence, vaccine effectiveness and price. However, sensitivity analysis showed that the results were robust based on varying the different parameter estimates and assumptions. With RSV vaccines reaching the final stages of development, a strong need exists for cost-effectiveness studies to understand economically justifiable pricing of the vaccine.

Wereldwijd vertrouwen regeringen op de ontwikkeling van een COVID-19-vaccin als middel om een einde te maken aan de pandemie en de daaruit voortvloeiende crisis. Hoewel de wetenschappelijke vooruitgang in de ontwikkeling van een vaccin veelbelovend is, worden beleidsmakers geconfronteerd met een extra hindernis, nu mensen lijken te aarzelen om zo'n vaccin te nemen. Deze studie wil de vaccinatiebereidheid verklaren door ze te koppelen aan het vertrouwen in de overheid en experts. Het vertrouwen in het vermogen van de overheid om de coronacrisis aan te pakken en het vertrouwen in het advies van experts geeft legitimiteit aan het handelen van beleidsmakers en zal daarom naar verwachting een centrale rol spelen in de vaccinatiebeslissing. Het verband tussen vertrouwen in de overheid en/of experts en de vaccinatiebereidheid werd onderzocht aan de hand van de Grote Coronastudie, die wekelijks (en later tweewekelijks) in België werd uitgevoerd. We stellen vast dat vertrouwen in de overheid een positief maar vrij klein effect heeft op de vaccinatiebereidheid. Het vertrouwen in experts heeft een meer uitgesproken invloed op de vaccinatiebereidheid. Aangezien de aanvaarding van vaccinatie cruciaal zal zijn voor het succes van geplande vaccinatiecampagnes ter bestrijding van COVID-19, hopen we dat deze resultaten zullen leiden tot een beter begrip van deze dynamieken.

Wereldwijd vertrouwen regeringen op de ontwikkeling van een COVID-19-vaccin als middel om een einde te maken aan de pandemie en de daaruit voortvloeiende crisis. Hoewel de wetenschappelijke vooruitgang in de ontwikkeling van een vaccin veelbelovend is, worden beleidsmakers geconfronteerd met een extra hindernis, nu mensen lijken te aarzelen om zo'n vaccin te nemen. Deze studie wil de vaccinatiebereidheid verklaren door ze te koppelen aan het vertrouwen in de overheid en experts. Het vertrouwen in het vermogen van de overheid om de coronacrisis aan te pakken en het vertrouwen in het advies van experts geeft legitimiteit aan het handelen van beleidsmakers en zal daarom naar verwachting een centrale rol spelen in de vaccinatiebeslissing. Het verband tussen vertrouwen in de overheid en/of experts en de vaccinatiebereidheid werd onderzocht aan de hand van de Grote Coronastudie, die wekelijks (en later tweewekelijks) in België werd uitgevoerd. We stellen vast dat vertrouwen in de overheid een positief maar vrij klein effect heeft op de vaccinatiebereidheid. Het vertrouwen in experts heeft een meer uitgesproken invloed op de vaccinatiebereidheid. Aangezien de aanvaarding van vaccinatie cruciaal zal zijn voor het succes van geplande vaccinatiecampagnes ter bestrijding van COVID-19, hopen we dat deze resultaten zullen leiden tot een beter begrip van deze dynamieken.

How will the coronavirus disease 2019 (COVID-19) pandemic develop in the coming months and years? Based on an expert survey, we examine key aspects that are likely to influence the COVID-19 pandemic in Europe. The challenges and developments will strongly depend on the progress of national and global vaccination programs, the emergence and spread of variants of concern (VOCs), and public responses to non-pharmaceutical interventions (NPIs). In the short term, many people remain unvaccinated, VOCs continue to emerge and spread, and mobility and population mixing are expected to increase. Therefore, lifting restrictions too much and too early risk another damaging wave. This challenge remains despite the reduced opportunities for transmission given vaccination progress and reduced indoor mixing in summer 2021. In autumn 2021, increased indoor activity might accelerate the spread again, whilst a necessary reintroduction of NPIs might be too slow. The incidence may strongly rise again, possibly filling intensive care units, if vaccination levels are not high enough. A moderate, adaptive level of NPIs will thus remain necessary. These epidemiological aspects combined with economic, social, and health-related consequences provide a more holistic perspective on the future of the COVID-19 pandemic.

Influenza vaccine effectiveness (IVE) assessment is increasingly stratified by vaccine type or brand, such as done by the European network of DRIVE. In 2019/2020, eleven influenza vaccines were licensed in Europe. If more than one vaccine type is recommended or if more than one vaccine brand is available for a specific risk group, it is not clear which factors affect the choice of a specific vaccine (type or brand) by a health practitioner for individual patients. This is important for IVE assessment. A survey tailored to the 2019/20 local vaccine recommendations was conducted among GPs in four European countries (Austria, Italy, Spain, UK) to understand how influenza vaccine is offered to recommended risk groups and, if GPs have a choice between 2 or more vaccines, what factors influence their vaccine choice for patients. Overall, 360 GPs participated. In Austria, Italy and Spain GPs indicated that influenza vaccines are commonly offered when patients present for consultation, whereas in the UK all GPs indicated that all relevant patients are contacted by letter. In Austria and Italy, roughly 80% of GPs had only one vaccine type available for patients 65y in Austria (45%), Italy (70%) and Spain (79%). In this group, patient characteristics played a role in choice of vaccine, notably older age and presence of (multiple) comorbidities. Knowing that a non-patient related factor usually determines the vaccine type a patient receives in settings where more than one vaccine type is recommended for risk groups 65y.

BackgroundRespiratory syncytial virus (RSV) infection in older adults is recognised as an important health issue. We aimed to assess the community burden of RSV in Europe in older adults aged ≥60 years.MethodsThis international, prospective, observational cohort study is part of work by the REspiratory Syncytial virus Consortium in EUrope (RESCEU). Participants were recruited through general practitioners' (GPs) offices before two independent RSV seasons. Participants reported weekly about symptoms of acute respiratory tract infection (ARTI) during one RSV season. ARTI patients were tested for RSV during home visits and completed a daily symptom diary. RSV illness included PCR-confirmed ARTI and those showing seroconversion over the season. RSV ARTI was based on PCR alone (ClinicalTrials.gov,NCT03621930).ResultsWe recruited 1040 participants (527 in season 2017–2018 and 513 in season 2018–2019) with a median age of 75 years (range 60–100 years). Of these, 1023 (99%) lived independently at home at baseline. RSV illness incidence was 22 out of 527 (4.2%) and 37 out of 513 (7.2%) in the respective seasons. RSV illness did not affect frailty or cardiopulmonary status during the course of the study. No patients were hospitalised or died from RSV illness. In the 36 patients with PCR confirmed RSV ARTI, symptom duration averaged 19 days, while a doctor's visit took place in 11 out of 36 cases (31%). RSV ARTI could not be differentiated clinically from all other ARTIs based on symptoms.ConclusionThis European study showed that RSV is prevalent in community-dwelling older adults and rarely causes severe disease. This suggests that watchful waiting, using a continuity of care approach to identify those who do need more intensive care, is often justified when RSV is suspected in family practice.

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017–2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups., Respiratory syncytial virus (RSV) is a common infection in children and older adults but little is known about within-host viral population diversity. Here, the authors perform deep sequencing and find that RSV subgroup B exhibited more diversity than subgroup A, with implications for development of therapeutics and vaccines.

Little is known about the possible impact of an influenza pandemic on a nation's economy. We applied the UK macroeconomic model 'COMPACT' to epidemiological data on previous UK influenza pandemics, and extrapolated a sensitivity analysis to cover more extreme disease scenarios. Analysis suggests that the economic impact of a repeat of the 1957 or 1968 pandemics, allowing for school closures, would be short lived, constituting a loss of 3.35% and 0.58% of GDP in the first pandemic quarter and year respectively. A more severe scenario (with more than 1% of the population dying) could yield impacts of 21% and 4.5% respectively. The economic shockwave would be gravest when absenteeism (through school closures) increases beyond a few weeks, creating policy repercussions for influenza pandemic planning as the most severe economic impact is due to policies to contain the pandemic rather than the pandemic itself. Accounting for changes in consumption patterns made in an attempt to avoid infection worsens the potential impact. Our mild disease scenario then shows first quarter/first year reductions in GDP of 9.5%/2.5%, compared to our severe scenario reductions of 29.5%. These results clearly indicate the significance of behavioural change over disease parameters.

Background Despite the universal use of the two-dose trivalent measles-mumps-rubella (MMR) vaccine in the past two decades, outbreaks of these diseases still occur in countries with high vaccine uptake, giving rise to concerns about primary and secondary failure of MMR vaccine components. We aimed to provide seroconversion and waning rate estimates for the measles, mumps, and rubella components of MMR vaccines.Methods In this systematic review and meta-analysis we searched PubMed (including MEDLINE), Web of Science, and Embase for randomised controlled trials, cohort studies, or longitudinal studies reporting the immunogenicity and persistence of MMR vaccines, published in English from database inception to Dec 31, 2019. Studies were included if they investigated vaccine-induced immunity in healthy individuals who received a trivalent MMR vaccine, including different dosages and timepoints of vaccine administration. Studies featuring coadministration of MMR with other vaccines, maternal immunity to the MMR vaccine, or non-trivalent formulations of the vaccine were excluded. Pooled seroconversion and waning rates were estimated by random-effects meta-analyses. This study is registered with PROSPERO, CRD42019116705.Findings We identified 3615 unique studies, 62 (1.7%) of which were eligible for analysis. Estimated overall seroconversion rates were 96.0% (95% CI 94.5-97.4; I-2=91.1%) for measles, 93.3% (91.1-95.2; I-2=94.9%) for mumps when excluding the Rubini strain, 91.1% (87.4-94.1; I-2=96.6%) for mumps when including the Rubini strain, and 98.3% (97.3-99.2; I-2=93.0%) for rubella. Estimated overall annual waning rates were 0.009 (95% CI 0.005-0.016; I-2=85.2%) for measles, 0.024 (0.016-0.039; I-2=94.7%) for mumps, and 0.012 (0.010-0.014; I-2=93.3%) for rubella.Interpretation Our meta-analysis provides estimates of primary and secondary vaccine failure, which are essential to improve the accuracy of mathematical and statistical modelling to understand and predict the occurrence of future measles, mumps, and rubella outbreaks in countries with high vaccine uptake. Funding European Research Council. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Objective To assess between-hospital variations in standardized in-hospital mortality ratios of community-acquired pneumonia (CAP), and identify possible leads for quality improvement. Design We used an administrative database to estimate standardized in-hospital mortality ratios for 111 Belgian hospitals, by carrying out a set of hierarchical logistic regression models, intended to disentangle therapeutic attitudes and biases. To facilitate the detection of false-negative/positive results, we added an inconclusive zone to the funnel plots, derived from the results of the study. Data quality was validated by comparison with (i) alternative data from the largest Belgian Sickness Fund, (ii) published German hospital data and (iii) the results of an on-site audit. Setting All Belgian hospital discharge records from 2004 to 2007. Study participants A total of 111 776 adult patients were admitted for CAP. Main outcome measure Risk-adjusted standardized in-hospital mortality ratios. Results Out of the 111 hospitals, we identified five and six outlying hospitals, with standardized mortality ratios of CAP consistently on the extremes of the distribution, as providing possibly better or worse care, respectively, and 18 other hospitals as having possible quality weaknesses/strengths. At the individuals' level of the analysis, adjusted odds ratios showed the paramount importance of old age, comorbidity and mechanical ventilation. The data compared well with the different validation sources. Conclusions Despite the limitations inherent to administrative data, it seemed possible to establish inter-hospital differences in standardized in-hospital mortality ratios of CAP and to identify leads for quality improvement. Monitoring is needed to assess progress in quality. A.B.'s participation is funded by the University of Antwerp (UA)'s concerted research action number 23405 (BOF-GOA). N.H. holds the UA Scientific Chair in Evidence Based Vaccinology, financed in 2011-2014 by a gift from Pfizer. G.M., P.B., N.H. and A.B. acknowledge support from a Methusalem research grant from the Flemish government. G.M. and N.H. received funding from IAP research Network P7/06 of the Belgian Government (Belgian Science Policy).

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Objectives: Health economic evaluations (HEEs) of vaccines are commonly considered during immunization introduction decision-making processes in most industrialized countries. Despite the availability of guidelines advocating more standardization for such HEEs, there are still several infection/immunization-specific particularities that are debated in the scientific community. An international expert-workshop was convened to identify good practices for (i) how to conduct HEEs of vaccines and (ii) how to consider results of HEE in vaccine introduction decision-making. Methods: A systematic literature search was conducted to identify prevailing opinions and remaining issues of HEE in vaccination. Twentytwo experts in the field of health economics and immunization decision-making were invited to a workshop and were asked to answer a survey-questionnaire based on the systematic literature search beforehand to inform the preparation of group work sessions (GWS). In GWS, issues focusing on 'mathematical modeling', 'health economics', and 'decision-making' were discussed and summarized. Results: The GWS (based on systematic literature search) included topics such as cost-components, quality of life (QoL), discounting, and perspectives leading to suggestions such as including caregiver QoL impact and applying decreasing time-related discount rates. Since vaccination often causes indirect effects, the use of dynamic models is required and exceptions should be justified. In order to facilitate transparent decision-making, the results of HEE should present parameter and methodological uncertainty as well as cumulative and time-specific figures. The majority of countries in Europe use results from HEEs in an informal judgment-process without willingness to pay (WTP) threshold. The expert-group emphasized that transparency should be maximized in decisionmaking process. Conclusions: The deliberations led to suggestions on several HEE issues. However, vaccines not always need to be considered differently in HEE since other interventions might share similar characteristics. Transparency in the conduct and presentation of HEE, and subsequent decision-making is essential, especially in the absence of explicit WTP thresholds.

In order to restrict the damage caused by an epidemic, intervention strategies are needed to reduce the transmission of infected-specific antigens. To this purpose, the estimation of age-dependent transmission rates is required. In the past, different mixing patterns were imposed to the so-called Who-Acquires-Infection-From-Whom matrix (WAIFW) to make them estimable from seroprevalence data (Anderson and May, 1991). These mixing assumptions, however are rather artificial and result in large differences on the estimation of the basic reproduction number R0, a basic quantity in infectious disease epidemiology. More recently, an alternative approach has come up, originating from assuming transmission rates for directly transmitted airborne infections are proportional to rates of conversational contact making (Wallinga et al., 2006). In this paper, we shown how transmission parameters can be estimated using serological data on varicella zoster virus (VZV) and social contact data from Belgium. We elaborate on the methodology as presented by Walling et al. (2006), by explicitly accounting for the different sources of variability, using a continuous rather than discrete modeling approach and by testing the proportionality assumption. A cross-sectional survey on social contacts was conducted in Belgium from March to June 2006. Contacted persons had to record their contacts during one day including characteristics as age, gender, location and duration of the contact. Moreover, a distinction between two types of contact was made: non-close contacts, defined as a two-way conversation of at least three words in each others proximity, and close contacts that involve any sort of physical skin-to-skin touching. The 'social contact matrix' is estimated using a bivariate smoothing approach based on thin plate regression splines. Using the mass action principle, these estimated contact rates are contrasted to seroprevalence data to obtain transmission parameters. A first analysis focuses on the constant proportionality assumption: transmission rates are proportional to contact rates up to a constant q. Five contact types which are likely to be responsible for VZV transmission are considered. According to the AIC-criterion, close contacts lasting longer than 15 minutes are most capable of explaining the observed serological profile. A non-parametric bootstrap approach is applied to assess sampling variability and to account for age uncertainty. Secondly, we explore whether the proportionality factor q depends on the age of the susceptible person, the age of the infected person or both. This consideration makes logical sense, since transmission dynamics might also be influenced by age differences in susceptibility, infectivity, hygiene, etc. Age dependence is modeled using discrete structures as well as loglinear regression models. For VZV in Belgium, extending the model to age-dependent proportionality entails an improvement in fit. Concepts of model selection uncertainty are illustrated for the set of candidate models and a model averaged estimate is calculated for the set of candidate models and a model averaged estimate is calculated for the basic reproduction number R0.

In cost-effectiveness analysis, the valuing of costs and health effects over time remains a controversial issue. The debate mostly focuses on whether the discount rates for health and money should be equal and which discounting model and time preferences are most appropriate. In this paper we add to the debate by arguing that the assessment of effectiveness of a preventive intervention may influence the choice of the discounting procedure for health. Health effects in cost-effectiveness analysis are commonly expressed in life-years gained, QALYs gained or lives saved. These denominators are only indirect and partial measures of the effects of a preventive intervention. The actual effect of the intervention is a reduction of the risk of mortality and morbidity in a given period of time. This risk reduction will not always coincide with the moment at which the impact on (quality-adjusted) life-years gained is made (i.e. at risk exposure), for example when preventing chronic disease with an asymptomatic stage. In this paper we show that truly acknowledging the origin of health benefits could have implications for the discounting procedure. We present a discounting model that adequately focuses on the reduction of risk. This model recognises the potential interpretation of risk reduction for infection as an economic good to be acquired with associated mortality reductions as later indirect effects. This implies that our suggested discounting model focuses on the moment(s) of risk reduction. A numerical example illustrates our approach. We discuss the associated potential implications for public health policy and discuss how the effects of the intervention can be,additionally corrected for societal preferences.

Background and Objective Influenza-like illness (ILI) leads to a substantial disease burden every winter in Europe; however, oseltamivir is not frequently prescribed to ILI patients in the primary-care setting. An open-label, multi-country, multi-season, randomised controlled trial investigated the effectiveness of oseltamivir for treating ILI in 15 European countries. We aimed to evaluate whether patients presenting with ILI in primary care and being managed with the addition of oseltamivir to usual care had lower average direct and indirect costs compared to patients with usual care alone. Methods Resource use data were extracted from participants' daily diaries. Itemised country-specific unit costs were collected through official tariffs, pharmacies or literature. Costs were converted to 2018 values. The null hypothesis was tested based on one-sided credible intervals (CrIs) obtained by bootstrapping. Base-case analysis estimated direct cost and productivity losses using itemised costed resource use and the human capital approach. Scenario analyses with self-reported spending rather than itemised costing were also performed. Results Patients receiving oseltamivir (N = 1306) reported fewer healthcare visits, medication uses, hospital attendances and paid-work hours lost than the other patients (N = 1298). Excluding the oseltamivir cost, the average direct costs were lower in patients treated with oseltamivir from all perspectives, but these differences were not statistically significant (perspective of patient: euro17 [0-95% Crl: 16-19] vs. euro24 [5-100% Crl: 18-29]; healthcare provider: euro37 [28-67] vs. euro44 [25-55]; healthcare payers: euro54 [45-85] vs. euro68 [45-81]; and society: euro423 [399-478] vs. euro451 [390-478]). Scenario and age-group analyses confirmed these findings, but with some between-country differences. Conclusion The average direct and indirect costs were consistently lower in patients treated with oseltamivir than in patients without from four perspectives (excluding the oseltamivir cost). However, these differences were not statistically significant. The ALIC4E trial and the contributions of AWV, EB, SC, NF, PS, NJH, PaB, AGS, DG, KK, RMP, RRJ, BS, NT, RA, CCB and PB were funded by the European Commission’s Seventh Framework Programme: Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) (grant HEALTH-F3-2013-602525). PB, XL, JB and RB acknowledge partial Methusalem funding from the VAXIDEA and ASCID Centres of Excellence in vaccination and infectious diseases at the University of Antwerp. JB and RB were funded by their personal postdoctoral grants from the Research Foundation—Flanders (FWO). PS acknowledges that The Healthcare Committee, Region Västra Götaland, Sweden, partially funded the Swedish part of the study.

ObjectiveEstablishing a social contact data sharing initiative and an interactive tool to assess mitigation strategies for COVID-19.ResultsWe organized data sharing of published social contact surveys via online repositories and formatting guidelines. We analyzed this social contact data in terms of weighted social contact matrices, next generation matrices, relative incidence and R$$_{0}$$0. We incorporated location-specific physical distancing measures (e.g. school closure or at work) and capture their effect on transmission dynamics. All methods have been implemented in an online application based on R Shiny and applied to COVID-19 with age-specific susceptibility and infectiousness. Using our online tool with the available social contact data, we illustrate that physical distancing could have a considerable impact on reducing transmission for COVID-19. The effect itself depends on assumptions made about disease-specific characteristics and the choice of intervention(s).

Objectives: To identify key determinants explaining countryyear variations in antibiotic use and resistance. Methods: Ambulatory antibiotic use data [in defined daily doses per 1000 inhabitants per day (DIDs)] for 19 European countries from 1999 to 2007 were collected, along with 181 variables describing countries in terms of their agriculture, culture, demography, disease burden, education, healthcare organization and socioeconomics. After assessing data availability, overlap and relevance, multiple imputation generalized estimating equations were applied with a stepwise selection procedure to select significant determinants of global antibiotic use (expressed in DIDs), relative use of subgroups (amoxicillin and co-amoxiclav) and resistance of Escherichia coli and Streptococcus pneumoniae. Results: Relative humidity, healthcare expenditure proportional to grossdomestic product, feelings of distrust, proportion of population aged .65 years and availability of treatment guidelines were associated with higher total antibiotic use expressed in DIDs. Restrictions on marketing activities towards prescribers, population density, number of antibiotics, educational attainment and degree of atheism were associated with a lower number of total DIDs used. Relative prescribing of amoxicillin and co-amoxiclav was mainly determined by healthcare system choices [e.g. general practitioner (GP) registration and restricted marketing]. Specific antibiotic use was found to be a significant determinant of resistance for some but not all drug/organism combinations. Incentives to stimulate GP gatekeeping were associated with lower levels of resistance, and life expectancy at age 65+ and atheism were associated with more resistance. Conclusions: Myriad factors influence antibiotic use and resistance at the country level and an important part of these can be modified by policy choices.

This paper shows how to model seroprevalence data using change-point fractional polynomials (FPs). The inclusion of a change point in the FP framework allows to detect distortions arising from common (often untestable) assumptions made in the estimation of the age-specific prevalence and force of infection from cross-sectional data. The method is motivated using seroprevalence data on the parvovirus B19 and the varicella zoster virus in Belgium. We gratefully acknowledge two referees and an associate editor for provoking thoughts that have led to an improved version of the manuscript. This work was based on a serum sample collected for the European Commission's ESEN2-project. We are grateful to the Institute of Public Health, Brussels (Dr Robert Vranckx, Dr Veronik Hutse) for assistance with PVB19 testing. This work is part of the research project MSM 0021620839 that has been funded by 'SIMID', a strategic basic research project funded by the institute for the Promotion of Innovation by Science and Technology in Flanders, project number 060081, by the Fund of Scientific Research (Research Grant G039304) in Flanders, Belgium, by the IAP research network number P6/03 of the Belgian Government (Belgian Science Policy) and by the Grant Agency of Charles University, project number 252387/2007. This work benefited from discussions held in POLYMOD, a European Commission project funded within the Sixth Framework Programme, contract number: SSP22-CT-2004-502084.

The force of infection, describing the rate at which a susceptible person acquires an infection, is a key parameter in models estimating the infectious disease burden, and the effectiveness and cost-effectiveness of infectious disease prevention. Since Muench formulated the first catalytic model to estimate the force of infection from current status data in 1934, exactly 75 years ago, several authors addressed the estimation of this parameter by more advanced statistical methods, while applying these to seroprevalence and reported incidence/case notification data. In this paper we present an historical overview, discussing the relevance of Muench's work, and we explain the wide array of newer methods with illustrations on pre-vaccination serological survey data of two airborne infections: rubella and parvovirus B19. We also provide guidance on deciding which method(s) to apply to estimate the force of infection, given a particular set of data. We thank the editor and both referees for their valuable suggestions that have led to an improved version of the manuscript. This work was supported by research project (MSM 0021620839), funded by 'SIMID', a strategic basic research project funded by the institute for the Promotion of Innovation by Science and Technology in Flanders (IWT) (project number 06008); by the Fund of Scientific Research (FWO, Research Grant G039304) in Flanders, Belgium; and by the TAP research network (no. P6/03) of the Belgian Government (Belgian Science Policy). The R-code used to analyse the datasets in this manuscript is available from the authors.