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Objectives: The ALIC4E trial has shown that oseltamivir reduces recovery time while increasing the risk of nausea. This secondary analysis of the ALIC4E trial aimed to determine the gain in quality-adjusted life-years (QALYs) associated with adding oseltamivir to usual primary care in patients presenting with influenza-like illness (ILI). Methods: Patients with ILI were recruited during the influenza season (2015-2018) in 15 European countries. Patients were assigned to usual care with or without oseltamivir through stratified randomization (age, severity, comorbidities, and symptom onset). Patients' health status was valued with the EQ-5D and visual analog scale (VAS) for up to 28 days. Average EQ-5D and VAS scores over time were estimated for both treatment groups using one-inflated beta regression in children (-13 years old). QALY gain was calculated as the difference between the groups. Sensitivity analysis considered the value set to convert EQ-5D answers to summary scores and the follow-up period. Results: In adults, oseltamivir gained 0.0006 (95% confidence interval 0.0002-0.0010) QALYs, whereas no statistically significant gain was found in children (14-day follow-up, EQ-5D). QALY gains were statistically significant in patients aged >-65 years, patients without relevant comorbidities, or patients experiencing symptoms for

Background SARS-CoV-2 dynamics are driven by human behaviour. Social contact data are of utmost importance in the context of transmission models of close-contact infections. Methods Using online representative panels of adults reporting on their own behaviour as well as parents reporting on the behaviour of one of their children, we collect contact mixing (CoMix) behaviour in various phases of the COVID-19 pandemic in over 20 European countries. We provide these timely, repeated observations using an online platform: SOCRATES-CoMix. In addition to providing cleaned datasets to researchers, the platform allows users to extract contact matrices that can be stratified by age, type of day, intensity of the contact and gender. These observations provide insights on the relative impact of recommended or imposed social distance measures on contacts and can inform mathematical models on epidemic spread. Conclusion These data provide essential information for policymakers to balance non-pharmaceutical interventions, economic activity, mental health and wellbeing, during vaccine rollout.

Purpose Health-related quality of life outcomes are increasingly used to monitor population health and health inequalities and to assess the (cost-) effectiveness of health interventions. The EQ-5D-5L has been included in the Belgian Health Interview Survey, providing a new source of population-based self-perceived health status information. This study aims to estimate Belgian population norms for the EQ-5D-5L by sex, age, and region and to analyze its association with educational attainment. Methods The BHIS 2018 provided EQ-5D-5L data for a nationally representative sample of the Belgian population. The dimension scores and index values were analyzed using logistic and linear regressions, respectively, accounting for the survey design. Results More than half of respondents reported problems of pain/discomfort, while over a quarter reported problems of anxiety/depression. The average index value was 0.84. Women reported more problems on all dimensions, but particularly on anxiety/depression and pain/discomfort, resulting in significantly lower index values. Problems with mobility, self-care, and usual activities showed a sharp increase after the age of 80 years. Consequently, index values decreased significantly by age. Lower education was associated with a higher prevalence of problems for all dimensions except anxiety/depression and with a significantly lower index value. Conclusion This paper presents the first nationally representative Belgian population norms using the EQ-5D-5L. Inclusion of the EQ-5D in future surveys will allow monitoring over time of self-reported health, disease burden, and health inequalities.

Antigen recognition through the T cell receptor (TCR) alpha beta heterodimer is one of the primary determinants of the adaptive immune response. Vaccines activate naive T cells with high specificity to expand and differentiate into memory T cells. However, antigen-specific memory CD4 T cells exist in unexposed antigen-naive hosts. In this study, we use high-throughput sequencing of memory CD4 TCR beta repertoire and machine learning to show that individuals with preexisting vaccine-reactive memory CD4 T cell clonotypes elicited earlier and higher antibody titers and mounted a more robust CD4 T cell response to hepatitis B vaccine. In addition, integration of TCR beta sequence patterns into a hepatitis B epitope-specific annotation model can predict which individuals will have an early and more vigorous vaccine-elicited immunity. Thus, the presence of preexisting memory T cell clonotypes has a significant impact on immunity and can be used to predict immune responses to vaccination. eLife digest Immune cells called CD4 T cells help the body build immunity to infections caused by bacteria and viruses, or after vaccination. Receptor proteins on the outside of the cells recognize pathogens, foreign molecules called antigens, or vaccine antigens. Vaccine antigens are usually inactivated bacteria or viruses, or fragments of these pathogens. After recognizing an antigen, CD4 T cells develop into memory CD4 T cells ready to defend against future infections with the pathogen. People who have never been exposed to a pathogen, or have never been vaccinated against it, may nevertheless have preexisting memory cells ready to defend against it. This happens because CD4 T cells can recognize multiple targets, which enables the immune system to be ready to defend against both new and familiar pathogens. Elias, Meysman, Bartholomeus et al. wanted to find out whether having preexisting memory CD4 T cells confers an advantage for vaccine-induced immunity. Thirty-four people who were never exposed to hepatitis B or vaccinated against it participated in the study. These individuals provided blood samples before vaccination, with 2 doses of the hepatitis B vaccine, and at 3 time points afterward. Using next generation immune sequencing and machine learning techniques, Elias et al. analyzed the individuals' memory CD4 T cells before and after vaccination. The experiments showed that preexisting memory CD4 T cells may determine vaccination outcomes, and people with more preexisting memory cells develop quicker and stronger immunity after vaccination against hepatitis B. This information may help scientists to better understand how people develop immunity to pathogens. It may guide them develop better vaccines or predict who will develop immunity after vaccination.

Background The empirical basis for a quantitative assessment of the disease burden imposed by long-COVID is currently scant. We aimed to inform the disease burden caused by long-COVID in Japan. Methods We conducted a cross sectional self-report questionnaire survey. The questionnaire was mailed to 526 eligible patients, who were recovered from acute COVID-19 in April 2021. Answers were classified into two groups; participants who have no symptom and those who have any ongoing prolonged symptoms that lasted longer than four weeks at the time of the survey. We estimated the average treatment effect (ATE) of ongoing prolonged symptoms on EQ-VAS and EQ-5D-3L questionnaire using inverse probability weighting. In addition to symptom prolongation, we investigated whether other factors (including demography, lifestyle, and acute severity) were associated with low EQ-VAS and EQ-5D-3L values, by multivariable linear regression. Results 349 participants reported no symptoms and 108 reported any symptoms at the time of the survey. The participants who reported any symptoms showed a lower average value on the EQ-VAS (69.9 vs 82.8, respectively) and on the EQ-5D-3L (0.85 vs 0.96, respectively) than those reporting no symptoms considering the ATE of ongoing prolonged symptoms. The ATE of ongoing prolonged symptoms on EQ-VAS was − 12.9 [95% CI − 15.9 to − 9.8], and on the EQ-5D-3L it was − 0.11 [95% CI − 0.13 to − 0.09], implying prolonged symptoms have a negative impact on patients’ EQ-VAS and EQ-5D-3L score. In multivariable linear regression, only having prolonged symptoms was associated with lower scores (− 11.7 [95% CI − 15.0 to − 8.5] for EQ-VAS and − 0.10 [95% CI − 0.13 to − 0.08] for EQ-5D-3L). Conclusions Due to their long duration, long-COVID symptoms represent a substantial disease burden expressed in impact on health-related quality of life.

Fear of a reduced exogenous boosting effect of varicella vaccination and its impact on population health and wellbeing seems to be the main reason why many countries have hesitated to implement thi...

Highlights • First study examining potential impact of a maternal RSV vaccine across LMICs. • Results from independent models to inform Gavi’s 2018 Vaccine Investment Strategy. • Experts and stakeholders advised on methods, assumptions, and key model inputs. • Substantial potential to reduce infant morbidity and mortality in Gavi countries., Background Interventions to protect young infants against respiratory syncytial virus (RSV) are in advanced phases of development and are expected to be available in the foreseeable future. Gavi, the Vaccine Alliance, included maternal vaccines and infant monoclonal antibodies for RSV as part of the 2018 vaccine investment strategy (VIS) and decided to support these products subject to licensure, World Health Organization prequalification, Strategic Advisory Group of Experts recommendation, and meeting the financial assumptions used as the basis of the investment case. Impact estimates reported in this manuscript were used to inform the Gavi VIS. Methods We compared two independent vaccine impact models to evaluate a potential maternal RSV vaccine’s impact on infant health in 73 Gavi-supported countries. Key inputs were harmonized across both models. We analyzed various scenarios to evaluate the effect of uncertain model parameters such as vaccine efficacy, duration of infant protection, and infant disease burden. Estimates of averted cases, severe cases, hospitalizations, deaths, and disability-adjusted life years (DALYs) were calculated over the 2023–2035 horizon. Findings A maternal RSV vaccine with 60% efficacy offering 5 months of infant protection implemented across 73 low- and middle-income countries could avert 10.1–12.5 million cases, 2.8–4.0 million hospitalizations, 123.7–177.7 thousand deaths, and 8.5–11.9 million DALYs among infants under 6 months of age for the duration of analysis (2023–2035). Maternal RSV vaccination was projected to avert up to 42% of estimated RSV deaths among infants under 6 months in year 2035. Alternative scenario analyses with higher disease burden assumptions showed that a maternal vaccine could avert as many as 325–355 thousand deaths among infants under 6 months. Interpretation RSV maternal immunization is projected to substantially reduce mortality and morbidity among young infants if introduced across Gavi-supported countries. Funding This work was supported by Bill & Melinda Gates Foundation, Seattle, WA, and Respiratory Syncytial Virus Consortium in Europe. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation or of the Respiratory Syncytial Virus Consortium. LW is supported by Research Foundation–Flanders (1234620 N).

To increase vaccination coverage, it is essential to understand the vaccine decision-making process. High population coverage is required to obtain herd immunity and to protect vulnerable groups in terms of age (e.g. the very young) or health (e.g. immunodeficiency). Vaccine confidence and coverage in South Africa are relatively low, opening the window for sustained outbreaks of vaccine-preventable diseases in a country facing one of the most severe HIV epidemics in the world. To capture the vaccine-related decision-making process in South Africa, we performed a discrete choice experiment with 1200 participants in December 2017. We asked for their preferences with respect to (1) vaccine effectiveness, (2) vaccine-preventable burden of disease, (3) accessibility of the vaccine in terms of co-payment and prescription requirements, (4) frequency of mild vaccine-related side-effects, (5) population vaccination coverage and (6) local vaccination coverage. We distinguished between decision-making for vaccines administered to the participant, and for vaccines administered to their youngest child. We analyzed the data for each of these groups using a panel mixed logit model and found similar results for decisions to vaccinate oneself or one's child. Vaccine effectiveness was the most important attribute followed by population coverage and burden of disease. Local coverage and accessibility were also important determinants of vaccination behavior, but to a lesser extent. Regarding population and local coverage, we observed a positive effect on vaccine utility indicating the potential of peer influence. As such, social normative influence could be exploited to increase vaccination confidence and coverage. With respect to vaccine-preventable burden of the disease, the marginal utilities showed disease severity to be more important than frequency of disease. Policymakers and health care workers should stress the effectiveness of vaccines together with the severity of vaccine-preventable diseases. Copyright (c) 2019 Elsevier Ltd. All rights reserved.

Background:Streptococcus pneumoniae (Sp) is a major cause of acute otitis media (AOM). Pneumococcal conjugate vaccine (PCV) programs have altered pneumococcal serotype epidemiology in disease and carriage. In this study, we used samples collected during a cross-sectional study to examine if the clinical picture of acute otitis media (AOM) in young children exposed to the PCV program in Belgium was related to the carried pneumococcal strains, and if their carriage profile differed from healthy children attending daycare centers.Material/Methods: In three collection periods from February 2016 to May 2018, nasopharyngeal swabs and background characteristics were collected from children aged 6–30 months either presenting at their physician with AOM (AOM-group) or healthy and attending day care (DCC-group). Clinical signs of AOM episodes and treatment schedule were registered by the physicians. Sp was detected, quantified, and characterized using both conventional culture analysis and real-time PCR analysis.Results: Among 3,264 collected samples, overall pneumococcal carriage and density were found at similar rates in both AOM and DCC. As expected non-vaccine serotypes were most frequent: 23B (AOM: 12.3%; DCC: 17.4%), 11A (AOM: 7.5%; DCC: 7.4%) and 15B (AOM: 7.5%; DCC: 7.1%). Serotypes 3, 6C, 7B, 9N, 12F, 17F, and 29 were more often found in AOM than in DCC (p-value < 0.05), whereas 23A and 23B were less often present in AOM (p-value < 0.05). Antibiotic non-susceptibility of Sp strains was similar in both groups. No predictors of AOM severity were identified.Conclusion: In the present study, overall carriage prevalence and density of S. pneumoniae were found similar in young children with AOM and in healthy children attending day-care centers in Belgium. Certain serotypes not currently included in the PCV vaccines were found to be carried more often in children with AOM than in DCC, a finding that might suggest a relationship between these serotypes and AOM.

SummaryBackgroundDue to a limited initial supply of COVID-19 vaccines, the prioritisation of individuals for vaccination is of utmost importance for public health. Here, we provide the optimal allocation strategy for COVID-19 vaccines according to age in Japan and South Korea.MethodsCombining national case reports, age-specific contact matrices, and observed periods between each stages of infection (Susceptible-Exposed-Infectious-Quarantined), we constructed a compartmental model. We estimated the age-stratified probability of transmission given contact (qi) using Bayesian inference method and simulated different vaccination scenarios to reduce either case numbers or death toll. We also performed sensitivity analyses on the proportion of asymptomatic cases and vaccine efficacy.FindingsThe model inferred age-stratified probability of transmission given contact (qi) showed similar age-dependent increase in Japan and South Korea. Assuming the reported COVID-19 vaccine efficacy, our results indicate that Japan and South Korea need to prioritise individuals aged 20–35 years and individuals aged over 60 years, respectively, to minimise case numbers. To minimise the death toll, both countries need to prioritise individuals aged over 75 years. These trends were not changed by proportions of asymptomatic cases and varying vaccine efficacy on individuals under 20 years.InterpretationWe presented the optimal vaccination strategy for Japan and South Korea. Comparing the results of these countries demonstrates that not only the effective contact rates containing qi but also the age-demographics of current epidemic in Japan (dominance in 20s) and South Korea (dominant cases over 50s) affect vaccine allocation strategy.

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.

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.

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.

The COVID-19 pandemic has shown how a newly emergent communicable disease can lay considerable burden on public health. To avoid system collapse, governments have resorted to several social distancing measures. In Belgium, this included a lockdown and a following period of phased re-opening. A representative sample of Belgian adults was asked about their contact behaviour from mid-April to the beginning of August, during different stages of the intervention measures in Belgium. Use of personal protection equipment (face masks) and compliance to hygienic measures was also reported. We estimated the expected reproduction number computing the ratio of $$\hbox {R}_{0}$$ R 0 with respect to pre-pandemic data. During the first two waves (the first month) of the survey, the reduction in the average number of contacts was around 80% and was quite consistent across all age-classes. The average number of contacts increased over time, particularly for the younger age classes, still remaining significantly lower than pre-pandemic values. From the end of May to the end of July , the estimated reproduction number has a median value larger than one, although with a wide dispersion. Estimated $$\hbox {R}_{0}$$ R 0 fell below one again at the beginning of August. We have shown how a rapidly deployed survey can measure compliance to social distancing and assess its impact on COVID-19 spread. Monitoring the effectiveness of social distancing recommendations is of paramount importance to avoid further waves of COVID-19.

BACKGROUND: Changes in serotype distribution have been described after the switch from the 13-valent pneumococcal conjugate vaccine (PCV13) to the 10-valent pneumococcal conjugate vaccine (PCV10) in Belgium. AIM: To describe serotype's invasive disease potential and the detailed evolution of serotype distribution and antimicrobial susceptibility of pneumococcal isolates (carriage and IPD) in children up to 30 months of age over a period during and after the vaccine switch (2015-2018). METHODS: S. pneumoniae strains isolated from the nasopharynx of healthy children attending day-care centres (DCCs) and strains from normally sterile sites of children with IPD were serotyped (Quellung-reaction) and antimicrobial susceptibility testing was performed. Invasive disease potential was defined as the serotype-specific odds ratio (OR). RESULTS: The highly invasive (OR > 1) serotypes 12F, 1, 3, 24A/B/F, 33F, 19A, and 9N were not frequently carried (

Background To optimize the focus of future public information campaigns in The Netherlands promoting the uptake of vaccines among adults and children, we quantified the contribution of several attributes to the vaccination decision. Method We performed a discrete choice experiment (DCE) among Dutch adults including six attributes, i.e. vaccine effectiveness, vaccine-preventable burden of disease (specified in severity and frequency), accessibility of vaccination in terms of co-payment and prescription requirements, frequency of mild side-effects, population-level vaccination coverage and local vaccination coverage among family and friends. Participants answered the DCE from their own perspective (‘oneself’ group) or with regard to a vaccine decision for their youngest child (‘child’ group). The data was analysed by means of panel mixed logit models. Results We included 1547 adult participants (825 ‘oneself’ and 722 ‘child’). Vaccine effectiveness was the most important attribute in the ‘oneself’ group, followed by burden of disease (relative importance (RI) 78%) and accessibility (RI 76%). In the ‘child’ group, burden of disease was most important, but tied closely with vaccine effectiveness (RI 97%). Of less importance was the risk of mild vaccine-related side-effects and both population and local vaccination coverage. Interestingly, participants were more willing to vaccinate when uptake among the population or family and friends was high, indicating that social influence and social norms plays a role. Conclusions Vaccine effectiveness and disease severity are key attributes in vaccination decision-making for adults making a decision for themselves and for parents who decide for their children. Hence, public information campaigns for both adult and child vaccination should primarily focus on these two attributes. In addition, reinforcing social norms may be considered.

European healthcare systems face extreme pressure from coronavirus disease (COVID-19). We relate country-specific accumulated COVID-19 deaths (intensity approach) and active COVID-19 cases (magnitude approach) to measures of healthcare system capacity: hospital beds, healthcare workers and healthcare expenditure. Modelled by the intensity approach with a composite measure for healthcare capacity, the countries experiencing the highest pressure on 25 March 2020 - relative to Italy on 11 March - were Italy, Spain, the Netherlands and France (www.covid-hcpressure.org). This work is funded by the Epipose project from the European Union's SC1- PHE-CORONAVIRUS-2020 programme, project number 101003688.0 Verelst, F (reprint author), Univ Antwerp, Vaccine & Infect Dis Inst VAXINFECTIO, CHERMID, Antwerp, Belgium. frederik.verelst@uantwerp.be

Summary Pathogen exposure, including but not limited to herpesviruses, moulds the shape of the immune system, both at a basal state and in response to immune challenge. However, little is known about the impact of high exposure to other viruses on baseline immune signatures and how the immune system copes with repetitive exposures to maintain a balanced functionality. Here we investigated baseline immune signatures, including detailed T cell phenotyping, antigen-specific CD4+ and CD8+ T cell responses and cytokine profile in paediatric (PED) nurses, who have high occupational exposure to viral pathogens including varicella zoster virus (VZV) and respiratory viruses, and in neonatal intensive care unit (NICU) nurses, as a control group with infrequent occupational exposure. Our results show a lower CD4+ T cell response to two VZV proteins (IE62 and gE) and to tetanus toxoid (TT) in PED nurses who are cytomegalovirus (CMV)-seronegative, compared to CMV-seronegative NICU nurses, and that the decline might be more pronounced the more sustained the exposure. This decline might be due to an attrition of VZV- and TT-specific T cells as a result of the continuous pressure on the CD4+ T cell compartment. Moreover, our data suggest that the distinct T cell phenotypes known to be associated with CMV-seropositivity might be less prominent in PED nurses compared to NICU nurses, implying a plausible attenuating effect of occupational exposure on CMV-associated immunosenescence. Overall, this pilot study reveals an impact of occupational exposure to viral pathogens on CD4+ T cell immunity and supports further investigation in a larger cohort.

It is essential for public health to understand what drives people's hesitance towards vaccination. Theoretical models of vaccination decisions are ubiquitous, often incorporating herd immunity, perceptions of vaccine-related side-effects (VRSE) and of vaccine-preventable burden of disease, but with little to no empirical exploration. Herd immunity is a (usually) positive externality where vaccinated individuals influence others' risks by their reduced capability to transmit an infectious disease to them. It is often assumed that (rational) individuals incorporate this externality in their strategic vaccination decision, from which free-riding behavior arises. We performed a Bayesian D-efficient discrete choice experiment in February-March 2017 to study vaccination behavior in 1919 Belgian respondents. Choice sets with vaccine profiles were constructed using six attributes: vaccine effectiveness, VRSE, accessibility (in terms of convenience and reimbursement), vaccine-preventable burden of disease, local (respondents' network of contacts) vaccination coverage, and population (the population at large) vaccination coverage. VRSE and accessibility are the most influential attributes, followed by vaccine effectiveness and burden of disease. Both population and local coverage are less important than the other attributes, but show a significant direct linear relationship with vaccine utility. This supports the existence of peer influence (more incentivized as more and more vaccinate), rather than free-riding on herd immunity. These findings were independent of whether respondents made vaccine choices for themselves or for their child. Around 40% of the respondents indicated accepting vaccination with little or no questioning. These 'acceptors' were less sensitive to changes in the vaccine-preventable burden of disease for their child's vaccination choices (but not for themselves). Public health institutions are critical in stimulating vaccine uptake by making vaccines conveniently available at an affordable price and by communicating pro-actively on perceived VRSEs. The free-riding assumption as a driver of individual vaccine decisions, seems inappropriate, but this observation needs confirming in other populations. Copyright (c) 2018 Elsevier Ltd. All rights reserved.

Background. New health technologies are more likely adopted when they have lower incremental cost-effectiveness ratios (ICERs) and/or when their ICER is presented with more certainty. Industry-funded (IF) health economic evaluations use often more favorable base-case values, leading to more favorable conclusions. Purpose. To study whether IF health economic evaluations of varicella-zoster virus vaccination in the elderly use more favorable base-case values and account for less uncertainty than non–industry-funded (NIF) evaluations. Methods. Data source: PubMed. Data extracted: funding source; incremental cost per quality-adjusted life year (QALY) gained; vaccine price; study quality score; base-case values, uncertainty ranges, and data sources for influential parameters: duration of vaccine protection, utility loss due to herpes zoster (HZ) disease, percentage of HZ patients developing postherpetic neuralgia (PHN), and duration of PHN. Data synthesis: qualitative comparisons; Fisher exact test for differences in study quality score and 1-sided Mann-Whitney U tests for differences in base-case values and uncertainty ranges. Results. Despite using the same data sources, IF studies ( n = 10) assume a longer duration of vaccine protection ( U = 56, P = 0.03), have a higher percentage of HZ patients developing PHN ( U = 22/33, P = 0.02/0.03 for ages 60–64/65–69), and tend to use higher HZ utility loss than NIF studies ( n = 11) for their baseline. IF studies show lower ICERs given similar or even higher vaccine prices than NIF studies, consider less uncertainty around the duration of vaccine protection ( U = 8, P < 0.001), and tend to use less uncertainty around the duration of PHN. Yet their quality has been rated equally well, using current standard quality rating tools. Conclusion. Researchers and decision makers should be aware of potential sponsorship bias in health economic evaluations, especially in the way source data are used to specify base-case values and uncertainty ranges.

While the impact of the timeliness of vaccine administration has been well-studied for childhood vaccinations, there has been little detailed quantitative analysis on the potential impact of the timeliness of vaccinations in older adults. The aim of this study was to explore the impact of implementing more realistic observed uptake distributions, taking into the account reduced vaccine efficacy but higher pneumococcal, disease burden with increasing age beyond 65 years. A multi-cohort Markov model was constructed to evaluate the cost-effectiveness of a pneumococcal (PCV13) immunisation program in Australia, assuming two different uptake modelling approaches. The approach using an estimate of observed uptake was compared with a scenario in which the total cumulative uptake was delivered at the recommended age of vaccination. We found these two approaches produced different results both in terms of cases prevented and cost-effectiveness. The impact of the non-timely uptake in adult programs may sometimes have positive and other times negative effects, depending on several factors including the age-specific disease rates and the duration of vaccine protection. Our study highlights the importance of using realistic assumptions around uptake (including non-timely vaccination) when estimating the impact of vaccination in adults. (C) 2018 Elsevier Ltd. All rights reserved.

From 2014 to 2017, the World Health Organization convened a working group to evaluate influenza disease burden and vaccine efficacy to inform estimates of maternal influenza immunization program impact. The group evaluated existing systematic reviews and relevant primary studies, and conducted four new systematic reviews. There was strong evidence that maternal influenza immunization prevented influenza illness in pregnant women and their infants, although data on severe illness prevention were lacking. The limited number of studies reporting influenza incidence in pregnant women and infants under six months had highly variable estimates and underrepresented low- and middle-income countries. The evidence that maternal influenza immunization reduces the risk of adverse birth outcomes was conflicting, and many observational studies were subject to substantial bias. The lack of scientific clarity regarding disease burden or magnitude of vaccine efficacy against severe illness poses challenges for robust estimation of the potential impact of maternal influenza immunization programs.KeywordsInfluenzaImmunizationPregnancyInfants

To identify determinants of health-related quality-of-life in the Belgian population and to provide age-specific population norms of health-related quality-of-life. Between September 2010 and February 2011, a representative sample of 1774 persons (age 0-99) was surveyed using the standard Euroqol questionnaire (EQ-5D-3L) with a Visual Analogue Scale (VAS). Significant determinants were identified using multivariate beta (VAS) and one-inflated beta (EQ-5D) regression, the latter modelling the probability to be in perfect health separately from the average EQ-5D score if not in perfect health. Health-related quality-of-life depends largely on age and experience with severe disease. The probability to be in perfect health is highest for children. For 0-2 years children who are not in perfect health, proxies report EQ-5D and VAS scores as low as that of the elderly. Also smoking behaviour, educational attainment, pet ownership, working or having worked in health care, and potentially household size and 60+ living on their own (yes/no) are associated with health-related quality-of-life, whereas no association was found with gender, living in a single-parent home, educational attainment of mothers, alcohol consumption of 60+, having (grand-) children and the frequency of seeing them. The same determinants are significant for VAS and the probability to be in perfect health, but not for the average EQ-5D score if not in perfect health. The population norms provided can be used directly as input in health economic evaluations. Estimating health-related quality-of-life in children and developing statistical tools capturing the particular features of health-related quality-of-life measures are important areas for future research. JB is supported by a postdoctoral grant from the Research Foundation-Flanders (FWO). Support from the IAP Research Network P7/06 of the Belgian State (Belgian Science Policy) is gratefully acknowledged. This study was supported by the Research Foundation Flanders project G0D5917N. NH gratefully acknowledges support from the University of Antwerp scientific chair in Evidence-Based Vaccinology, financed in 2009-2015 by a gift from Pfizer. The authors acknowledge support of the Antwerp Study Centre for Infectious Diseases (ASCID) at the University of Antwerp. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Background Case management is one of the principal strategies for malaria control. This study aimed to estimate the economic costs of uncomplicated malaria case management and explore the influence of health-seeking behaviours on those costs. Methods A knowledge, attitudes and practices (KAP) survey was applied to 680 households of fifteen communities in Mazan-Loreto in March 2017, then a socio-economic survey was conducted in September 2017 among 161 individuals with confirmed uncomplicated malaria in the past 3 months. Total costs per episode were estimated from both provider (Ministry of Health, MoH) and patient perspectives. Direct costs were estimated using a standard costing estimation procedure, while the indirect costs considered the loss of incomes among patients, substitute labourers and companions due to illness in terms of the monthly minimum wage. Sensitivity analysis evaluated the uncertainty of the average cost per episode. Results The KAP survey showed that most individuals (79.3%) that had malaria went to a health facility for a diagnosis and treatment, 2.7% received those services from community health workers, and 8% went to a drugstore or were self-treated at home. The average total cost per episode in the Mazan district was US$ 161. The cost from the provider’s perspective was US$ 30.85 per episode while from the patient’s perspective the estimated cost was US$ 131 per episode. The average costs per Plasmodium falciparum episode (US$ 180) were higher than those per Plasmodium vivax episode (US$ 156) due to longer time lost from work by patients with P. falciparum infections (22.2 days) than by patients with P. vivax infections (17.0 days). The delayed malaria diagnosis (after 48 h of the onset of symptoms) was associated with the time lost from work due to illness (adjusted mean ratio 1.8; 95% CI 1.3, 2.6). The average cost per malaria episode was most sensitive to the uncertainty around the lost productivity cost due to malaria. Conclusions Despite the provision of free malaria case management by MoH, there is delay in seeking care and the costs of uncomplicated malaria are mainly borne by the families. These costs are not well perceived by the society and the substantial financial impact of the disease can be frequently undervalued in public policy planning.

Starting from historic reflections, the current SARS-CoV-2 induced COVID-19 pandemic is examined from various perspectives, in terms of what it implies for the implementation of non-pharmaceutical interventions, the modeling and monitoring of the epidemic, the development of early-warning systems, the study of mortality, prevalence estimation, diagnostic and serological testing, vaccine development, and ultimately clinical trials. Emphasis is placed on how the pandemic had led to unprecedented speed in methodological and clinical development, the pitfalls thereof, but also the opportunities that it engenders for national and international collaboration, and how it has simplified and sped up procedures. We also study the impact of the pandemic on clinical trials in other indications. We note that it has placed biostatistics, epidemiology, virology, infectiology, and vaccinology, and related fields in the spotlight in an unprecedented way, implying great opportunities, but also the need to communicate effectively, often amidst controversy. Buyse, M (corresponding author), Hasselt Univ, Interuniv Inst Biostat & Stat Bioinformat, Data Sci Inst, Martelarenlaan 42, Hasselt, Belgium. marc.buyse@iddi.com

Thanks to the recommendation of a combined Measles/Mumps/Rubella (MMR) vaccine, like Priorix®, these childhood diseases are less common now. This is beneficial to limit the spread of these diseases and work towards their elimination. However, the measles, mumps and rubella antibody titers show a large variability in short- and long-term immunity. The recent outbreaks worldwide of measles and mumps and previous studies, which mostly focused on only one of the three virus responses, illustrate that there is a clear need for better understanding the immune responses after vaccination. Our healthy cohort was already primed with the MMR antigens in their childhood. In this study, the adult volunteers received one Priorix® vaccine dose at day 0. First, we defined 4 different groups of responders, based on their antibody titers’ evolution over 4 time points (Day 0, 21, 150 and 365). This showed a high variability within and between individuals. Second, we determined transcriptome profiles using 3′mRNA sequencing at day 0, 3 and 7. Using two analytical approaches, “one response group per time point” and “a time comparison per response group”, we correlated the short-term gene expression profiles to the different response groups. In general, the list of differentially expressed genes is limited, however, most of them are clearly immune-related and upregulated at day 3 and 7, compared to the baseline day 0. Depending on the specific response group there are overlapping signatures for two of the three viruses. Antibody titers and transcriptomics data showed that an additional Priorix vaccination does not facilitate an equal immune response against the 3 viruses or among different vaccine recipients.

When estimating important measures such as the herd immunity threshold, and the corresponding efforts required to eliminate measles, it is often assumed that susceptible individuals are uniformly distributed throughout populations. However, unvaccinated individuals may be clustered in a variety of ways, including by geographic location, by age, in schools, or in households. Here, we investigate to which extent different levels of within-household clustering of susceptible individuals may impact the risk and persistence of measles outbreaks. To this end, we apply an individual-based model, Stride, to a population of 600,000 individuals, using data from Flanders, Belgium. We construct a metric to estimate the level of within-household susceptibility clustering in the population. Furthermore, we compare realistic scenarios regarding the distribution of susceptible individuals within households in terms of their impact on epidemiological measures for outbreak risk and persistence. We find that higher levels of within-household clustering of susceptible individuals increase the risk, size and persistence of measles outbreaks. Ignoring within-household clustering thus leads to underestimations of required measles elimination and outbreak mitigation efforts. EK, LW and PB acknowledge support of the Antwerp Study Centre for Infectious Diseases (ASCID) at the University of Antwerp, and the Research Foundation Flanders (FWO) (research project G043815N and a postdoctoral fellowship 1234620N (LW)). NH acknowledges funding received from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement 682540-TransMID). Acknowledgements EK, LW and PB acknowledge support of the Antwerp Study Centre for Infectious Diseases (ASCID) at the University of Antwerp, and the Research Foundation Flanders (FWO) (research project G043815N and a postdoctoral fellowship 1234620N (LW)). NH acknowledges funding received from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement 682540-TransMID). Kuylen, E (corresponding author), Univ Antwerp, Ctr Hlth Econ Res & Modelling Infect Dis CHERMID, Vaccine & Infect Dis Inst, Antwerp, Belgium ; Hasselt Univ, Data Sci Inst DSI, Hasselt, Belgium. elise.kuylen@uantwerpen.be

Objectives: To better target new vaccines and treatments being developed for respiratory syncytial virus (RSV) and influenza virus (influenza), we studied the association of age with prevalence, diagnostic features and course of illness of these infections in primary care patients. Methods: Secondary analysis of observational data on the aetiology, diagnosis and prognosis in adults presenting to primary care with acute cough in 12 European countries (2007-2010) using regression analyses corrected for clustering of patients within countries. Age groups were 18-59 years, 60-74 years, and 75 years and older (75+). Results: Nasopharyngeal swabs for 144 (4.6%), 169 (5.4%) and 104 (3.4%) out of 3104 patients were polymerase chain reaction (PCR) positive for RSV, influenza A and influenza B, respectively. RSV prevalence in patients 75+ (8.5%) was twice the prevalence in those under 60 years (4.2%). Influenza prevalence was not associated with age. Diagnostic features for these viruses were not associated with age. Symptom duration was associated with age for RSV and influenza B, but not for influenza A. The odds of unresolved symptoms after 28 days were associated with age for RSV only. Illness deterioration was associated with age for RSV, with patients 75+ at increased risk, but not for influenza. Conclusion: In adults presenting to primary care with acute cough, the diagnostic features of RSV or influenza infection are not associated with age. For RSV both the prevalence and illness course are significantly worse at higher age, for influenza only the illness course is. (C) 2020 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. RB is funded as a postdoctoral researcher by the Research Foundation -Flanders (FWO). SC, CB, NH, PB and HG are members of the Respiratory Syncytial Virus Consortium in Europe (RESCUE). RESCUE has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 116019. NH acknowledges support from the University of Antwerp scientific chair in Evidence-Based Vaccinology, financed in 2009-2020 by a gift from Pfizer and in 2016-2019 from GSK. The GRACE project was funded by the European Community's Sixth Framework Programme (grant agreement 518226). Work in the UK was also supported by the National Institute for Health Research. Work in Barcelona was also supported by 2009 SGR 911 Ciber de Enfermedades Respiratorias (Ciberes CB06/06/0028). Work in Belgium was also supported by the Methusalem financing programme of the Flemish Government and by FWO (G.0274.08N). This work was also supported through the European Science Foundation (ESF), in the framework of the Research Networking Programme TRACE (www.esf.org/trace). Bruyndonckx, R (corresponding author), Hasselt Univ, DSI, Martelarenlaan 42, B-3500 Hasselt, Belgium. robin.bruyndonckx@uhasselt.be

BackgroundIdentifying determinants of health and understanding their role in health production constitutes an important research theme. We aimed to document the state of recent multi-country research on this theme in the literature.MethodsWe followed the PRISMA-ScR guidelines to systematically identify, triage and review literature (January 2013-July 2019). We searched for studies that performed cross-national statistical analyses aiming to evaluate the impact of one or more aggregate level determinants on one or more general population health outcomes in high-income countries. To assess in which combinations and to what extent individual (or thematically linked) determinants had been studied together, we performed multidimensional scaling and cluster analysis.ResultsSixty studies were selected, out of an original yield of 3686. Life-expectancy and overall mortality were the most widely used population health indicators, while determinants came from the areas of healthcare, culture, politics, socio-economics, environment, labor, fertility, demographics, life-style, and psychology. The family of regression models was the predominant statistical approach. Results from our multidimensional scaling showed that a relatively tight core of determinants have received much attention, as main covariates of interest or controls, whereas the majority of other determinants were studied in very limited contexts. We consider findings from these studies regarding the importance of any given health determinant inconclusive at present. Across a multitude of model specifications, different country samples, and varying time periods, effects fluctuated between statistically significant and not significant, and between beneficial and detrimental to health.ConclusionsWe conclude that efforts to understand the underlying mechanisms of population health are far from settled, and the present state of research on the topic leaves much to be desired. It is essential that future research considers multiple factors simultaneously and takes advantage of more sophisticated methodology with regards to quantifying health as well as analyzing determinants' influence.

Background Universal vaccination against rotavirus was included in the funded Australian National Immunisation Program in July 2007. Predictive cost-effectiveness models assessed the program before introduction. Methods We conducted a retrospective economic evaluation of the Australian rotavirus program using national level post-implementation data on vaccine uptake, before-after measures of program impact and published estimates of excess intussusception cases. These data were used as inputs into a multi-cohort compartmental model which assigned cost and quality of life estimates to relevant health states, adopting a healthcare payer perspective. The primary outcome was discounted cost per quality adjusted life year gained, including or excluding unspecified acute gastroenteritis (AGE) hospitalisations. Results Relative to the baseline period (19972006), over the 6 years (20072012) after implementation of the rotavirus program, we estimated that ∼77,000 hospitalisations (17,000 coded rotavirus and 60,000 unspecified AGE) and ∼3 deaths were prevented, compared with an estimated excess of 78 cases of intussusception. Approximately 90% of hospitalisations prevented were in children

To assess the cost-effectiveness of the tuberculosis screening activities currently funded by the Flemish government in Flanders, Belgium.After estimating the expenses for 2013-2014 of each of nine screening components - which include high-risk groups, contacts and people who are seeking tuberculosis consultation at a centre for respiratory health care - and the associated costs per active case of tuberculosis identified between 2007 and 2014, we compared the cost-effectiveness of each component. The applied perspective was that of the Flemish government.The three most cost-effective activities appeared to be the follow-up of asylum seekers who were found to have abnormal X-rays in initial screening at the Immigration Office, systematic screening in prisons and contact investigation. The mean costs of these activities were 5564 (95% uncertainty interval, UI: 3791-8160), 11 603 (95% UI: 9010-14 909) and 13 941 (95% UI: 10 723-18 201) euros (€) per detected active case, respectively. The periodic or supplementary initial screening of asylum seekers and the screening of new immigrants from high-incidence countries - which had corresponding costs of €51 813 (95% UI: 34 855-76 847), €126 236 (95% UI: 41 984-347 822) and €418 359 (95% UI: 74 975-1 686 588) - appeared much less cost-effective. Between 2007 and 2014, no active tuberculosis cases were detected during screening in the juvenile detention centres.In Flanders, tuberculosis screening in juvenile detention centres and among new immigrants and the periodic or supplementary initial screening of asylum seekers appear to be relatively expensive ways of detecting people with active tuberculosis.Évaluer la rentabilité des activités de dépistage de la tuberculose actuellement financées par le gouvernement flamand en Flandre, en Belgique.Après avoir estimé les dépenses pour 2013–2014 au titre de chacun des neuf composants du dépistage – notamment les groupes à haut risque, les contacts et les personnes venant en consultation pour la tuberculose dans un centre de traitement des problèmes respiratoires – ainsi que les coûts associés par cas de tuberculose active identifié entre 2007 et 2014, nous avons comparé la rentabilité de chaque composant. La perspective appliquée était celle du gouvernement flamand.Il est apparu que les trois activités les plus rentables étaient le suivi des demandeurs d'asile dont les radiographies réalisées lors du dépistage initial à l'Office des étrangers étaient anormales, le dépistage systématique dans les prisons et la recherche des contacts. Le coût moyen de ces activités était respectivement de 5564 (intervalle d'incertitude de 95%, II: 3791–8160), 11 603 (II 95%: 9010–14 909) et 13 941 (II 95%: 10 723–18 201) euros (€) par cas actif détecté. Le dépistage initial périodique ou complémentaire des demandeurs d'asile et le dépistage des nouveaux immigrants originaires de pays à forte incidence – dont le coût était respectivement de 51 813 € (II 95%: 34 855–76 847), 126 236 € (II 95%: 41 984–347 822) et 418 359 € (II 95%: 74 975–1 686 588) – se sont révélés beaucoup moins rentables. Entre 2007 et 2014, aucun cas de tuberculose active n'a été détecté lors du dépistage dans les centres de détention pour mineurs.En Flandre, le dépistage de la tuberculose dans les centres de détention pour mineurs et chez les nouveaux immigrants ainsi que le dépistage initial, périodique ou complémentaire, des demandeurs d'asile, est un moyen relativement coûteux de détecter les cas de tuberculose active.Evaluar la rentabilidad de las actividades de detección de tuberculosis actualmente financiadas por el gobierno flamenco en Flandes, Bélgica.Tras calcular los gastos de 2013–2014 de cada uno de los nueve componentes de los exámenes de detección (que incluyen grupos de alto riesgo, contactos y personas que buscan consulta para la tuberculosis en un centro de atención respiratoria) y los costes asociados por caso activo de tuberculosis identificados entre 2007 y 2014, se comparó la rentabilidad de cada componente. Se aplicó la perspectiva del gobierno flamenco.Parece que las tres actividades más rentables fueron el seguimiento de los buscadores de asilo con unas radiografías poco habituales en el examen de detección inicial en la Oficina de Inmigración, los exámenes de detección sistemáticos en prisiones y la investigación de contactos. Los costes medios de estas actividades fueron de 5 564 (intervalo de incertidumbre, II, del 95%: 3 791–8 160), 11 603 (II del 95%: 9 010–14 909) y 13 941 (II del 95%: 10 723–18 201) euros (€) por caso activo detectado respectivamente. Los exámenes de detección inicial periódicos o complementarios de los buscadores de asilo y los exámenes de detección de los nuevos inmigrantes de países con una alta incidencia (con costes correspondientes de 51 813 (II del 95%: 34 855–76 847), 126 236 (II del 95%: 41 984–347 822) y 418 359 (II del 95%: 74 975–1 686 588) euros) parecieron ser mucho menos rentables. Entre 2007 y 2014 no se detectaron casos de tuberculosis activa durante los exámenes de detección en centros penitenciarios juveniles.En Flandes, los exámenes de detección de tuberculosis en centros penitenciarios juveniles y aquellos realizados entre nuevos inmigrantes, así como los exámenes de detección inicial periódicos o complementarios de los buscadores de asilo, parecen ser formas relativamente caras de detectar a personas con tuberculosis activa.تقييم فعالية تكلفة أنشطة فحص السل المُمولة حاليًا من قبل الحكومة الفلمنكية في فلاندرز ببلجيكا.بعد تقدير نفقات عامي 2013 و2014 لكلٍ من عناصر الفحص التسعة – والتي تشمل المجموعات المعرضة للخطر، والاتصالات، والأشخاص الذين يسعون لمشورة تتعلق بالسل في أحد مراكز الرعاية الصحية للجهاز التنفسي – والتكاليف المرتبطة لكل حالة نشطة من السل تم تحديدها بين عامي 2007 و2014، فقد قارنا فعالية التكلفة لكل مكون. وكان المنظور المطبق هو منظور الحكومة الفلمنكية.اتضح أن الأنشطة الثلاثة الأكثر فعالية من حيث التكلفة هي متابعة طالبي اللجوء الذين خرجت صور الأشعة السينية التي تم إجراؤها لهم بنتائج غير طبيعية في الفحص الأولي في مكتب الهجرة، والفحص المنهجي في السجون، والتحري من خلال الاتصالات. وبلغ متوسط التكاليف لهذه الأنشطة 5564 (بهامش الشك بنسبة 95‏‏%، ويتراوح ما بين 3791-8160)، و11603 (بهامش الشك بنسبة 95‏%، ويتراوح ما بين 9010-149090) و13,941 (بهامش شك بنسبة 95‏‏%، ويتراوح ما بين 10723-18201) يورو للكشف عن كل حالة نشطة، على التوالي. بدا كلاً من الفحص الدوري أو الإضافي الأولي لطالبي اللجوء وفحص المهاجرين الجدد من الدول ذات نسب إصابة العالية - الذي ترتب عنه تكاليف تساوي 51813 يورو (بهامش شك بنسبة ‏95٪، يتراوح ما بين 34855–76847)، و126236 (بهامش الشك بنسبة 95‏%، ويتراوح ما بين 41984-347822)، و418359 (بهامش شك بنسبة 95‏%، يتراوح ما بين 74975 – 1686588) – أقل من حيث فعالية التكلفة. وبين عامي 2007 و2014، لم يتم الكشف عن أي حالات سل نشطة أثناء الفحص في مراكز احتجاز الأحداث.يبدو أن فحص السل في مراكز احتجاز الأحداث وبين المهاجرين الجدد والفحص الأولي الدوري أو التكميلي لطالبي اللجوء في فلاندرز يمثل طريقة مكلفة نسبيًا للكشف عن المصابين بحالات من مرض السل النشط.旨在评估当前由比利时弗兰德斯佛兰德政府赞助的肺结核筛查活动的成本效益。.我们评估了 2013–2014 年 9 个筛查项目中每个项目的费用，这 9 个项目包括高危人群、接触人群及在呼吸科医疗保健中心寻求肺结核疾病咨询的人员。同时评估了 2007 到 2014 年之间确认的每例活动性肺结核病例的相关成本，随后，我们对各个组成部分的成本效益进行了比较。 应用前景与佛兰德政府相关。.三个成本效益最高的活动是对寻求庇护者的随访，这些寻求庇护者在移民局、监狱系统筛查和联系调查的初步筛查中表现出 X 射线异常的情况。 这些活动的均值成本为每个检测到的活动性病例 5564 欧元（95% 不确定区间，UI： 3791–8160），11 603 (95% UI: 9010–14 909) 和 13 941 (95% UI: 10 723–18 201)。 对寻求庇护者的定期或补充初步筛查以及对来自高发病国家的新移民筛查——相应的成本为 51 813 欧元 (95% UI: 34 855–76 847)，126 236 欧元 (95% UI: 41 984–347 822) 以及 418 359 欧元 (95% UI: 74 975–1 686 588) – 成本效益更低。 2007 到 2014 年间，在青少年拘留中心的筛查中，未发现活动性肺结核病例。.在弗兰德斯，青少年拘留中心和在新移民中筛查肺结核病例以及对寻求庇护者进行定期或补充初步筛查是一种相对昂贵的活动性肺结核人群筛查方式。.Дать оценку экономической эффективности мероприятий скринингового обследования на туберкулез, финансируемых в настоящее время фламандским правительством во Фландрии, Бельгия.После подсчета расходов за период с 2013 по 2014 год каждого из девяти компонентов скринингового обследования, к которым относятся группы высокого риска, контакты и люди, стремящиеся получить консультацию по туберкулезу в центре лечения респираторных заболеваний, и связанных затрат для каждого случая активного туберкулеза, идентифицированного в период с 2007 по 2014 год, авторы сравнили экономическую эффективность каждого компонента. Оценка была проведена с позиций фламандского правительства.В тройку наиболее экономически эффективных мероприятий вошли последующее врачебное наблюдение просителей убежища, у которых были обнаружены патологии в ходе рентгеновского обследования при первичном скрининговом обследовании в Иммиграционном бюро, систематическое скрининговое обследование в тюрьмах и отслеживание контактов. Средняя стоимость этих мероприятий составила 5564 евро (95%-й интервал неопределенности, ИН: 3791–8160), 11 603 евро (95%-й ИН: 9010–14 909) и 13 941 евро (95%-й ИН: 10 723–18 201) за каждый случай диагностированного активного заболевания соответственно. Периодическое или дополнительное первичное скрининговое обследование просителей убежища и скрининговое обследование новых иммигрантов из стран с высокой заболеваемостью, стоимость которых составляла соответственно 51 813 евро (95%-й ИН: 34 855–76 847), 126 236 евро (95%-й ИН: 41 984–347 822) и 418 359 евро (95%-й ИН: 74 975–1 686 588), оказались гораздо менее экономически эффективными. В период между 2007 и 2014 годами случаи активного туберкулеза во время скринингового обследования в изоляторах временного содержания несовершеннолетних правонарушителей обнаружены не были.Во Фландрии скрининговое обследование на туберкулез в изоляторах временного содержания несовершеннолетних правонарушителей и периодическое или дополнительное первичное скрининговое обследование просителей убежища являются сравнительно дорогими способами выявления людей с активным туберкулезом.

High-income countries are undergoing demographic transitions towards populations with substantial larger proportions of older adults. Due to the increased susceptibility of older adults to infectious diseases and their consequences, vaccination programmes are an important health intervention to help maintain healthy ageing. While much of the existing literature suggests that current vaccination programmes targeted at older adults and the elderly are likely to be cost effective in high-income countries, we argue that it is important to more fully consider some important issues and challenges. Since the majority of vaccines have been developed for children, economic evaluations of vaccination programmes have consequentially tended to focus on this age group and on how to incorporate herd-immunity effects. While programmes targeted at older adults and the elderly may also induce some herd effects, there are other important challenges to consider in these economic evaluations. For example, age and time effects in relation to vaccine efficacy and duration of immunity, as well as heterogeneity between targeted individuals in terms of risk of infection, severity of disease and response to vaccination. For some pathogens, there is also the potential for interactions with childhood programmes in the form of herd-immunity effects.

Acute gastroenteritis (AGE) remains a common condition in both low- and high-income countries. In Belgium, however, there is currently a lack of information on the societal health and economic impact of AGE. We conducted a retrospective study using mortality and cause-of-death data, hospital data, primary care data, health interview survey data and other published data. We estimated the burden of illness during a 5-year period (2010-2014) in Belgium in terms of deaths, patients admitted to hospitals, patients consulting their general practitioner (GP) and cases occurring in the community. We further quantified the health impact in terms of disability-adjusted life years (DALYs) and the economic impact in terms of cost-of-illness estimates. We estimated 343 deaths, 27 707 hospitalised patients, 464 222 GP consultations and 10 058 741 episodes occurring in the community (0.91 cases/person) on average per year. AGE was associated with 11 855 DALYs per year (107 DALY per 100 000 persons). The economic burden was estimated to represent direct costs of €112 million, indirect costs of €927 million (90% of the total costs) and an average total cost of €103 per case and €94 per person. AGE results in a substantial health and economic impact in Belgium, justifying continued mitigation efforts. ispartof: EPIDEMIOLOGY AND INFECTION vol:147 ispartof: location:England status: published

Cytomegalovirus (CMV) infection is endemic worldwide but its seroprevalence varies widely. The goal of this study was to estimate the age-specific seroprevalence of CMV infection in Belgium based on two cross-sectional serological datasets from 2002 and 2006. The seroprevalence was estimated relying on diagnostic test results based on cut-off values pre-specified by the manufacturers of the tests as well as relying on mixture models applied to continuous pathogen-specific immunoglobulin G antibody titre concentrations. The age-specific seroprevalence of hepatitis A virus (HAV), based on three Belgian cross-sectional serological datasets from 1993, 2002 and 2006, was used as a comparator since individuals acquire lifelong immunity upon recovery, implying an increasing seroprevalence with age. The age group weighted overall CMV seroprevalence derived from the mixture model was 32% (95% confidence interval (CI) 31–34%) in 2002 and 31% (95% CI 30–32%) in 2006. We demonstrated that CMV epidemiology differs from the immunizing infection HAV. This was the first large-scale study of CMV and HAV serial datasets in Belgium, estimating seroprevalence specified by age and birth cohort. GSAS was supported by the Research Foundation Flanders - (FWO Aspirant), Brussels, Belgium. NH gratefully acknowledges support from the University of Antwerp scientific chair in Evidence-Based Vaccinology, financed by a gift from Pfizer (2009-2017) and GSK (2016). This research was supported by the Antwerp Study Centre for Infectious Diseases (ASCID) and is part of a project that has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement 682540 - TransMID).

Clinical trials covering the immunogenicity of a vaccine aim to study the longitudinal dynamics of certain immune cells after vaccination. The corresponding immunogenicity datasets are mainly analyzed by the use of statistical (mixed effects) models. This paper proposes the use of mathematical ordinary differential equation (ODE) models, combined with a mixed effects approach. ODE models are capable of translating underlying immunological post vaccination processes into mathematical formulas thereby enabling a testable data analysis. Mixed models include both population-averaged parameters (fixed effects) and individual-specific parameters (random effects) for dealing with inter- and intra-individual variability, respectively. This paper models B-cell and T-cell datasets of a phase I/II, open-label, randomized, parallel-group study (NCT00492648) in which the immunogenicity of a new Herpes Zoster vaccine (Shingrix) is compared with the original Varicella Zoster Virus vaccine (Varilrix). Since few significant correlations were found between the B-cell and T-cell datasets, each dataset was modeled separately. By following a general approach to both the formulation of several different models and the procedure of selecting the most suitable model, we were able to propose a mathematical ODE mixed-effects model for each dataset. As such, the use of ODE-based mixed effects models offers a suitable framework for handling longitudinal vaccine immunogenicity data. Moreover, this approach allows testing for differences in immunological processes between vaccines or schedules. We found that the Shingrix vaccination schedule led to a more pronounced proliferation of T-cells, without a difference in T-cell decay rate compared to the Varilrix vaccination schedule. (C) 2019 Elsevier Ltd. All rights reserved. This research was funded by the University of Antwerp [BOF Concerted Research Action, Methusalem funding], NH acknowledges support from the chair in evidence-based vaccinology sponsored by a gift from Pfizer (2009-2018) and GSK (2016) and from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement 682540 - TransMID). This research was supported by the Antwerp Study Centre for Infectious Diseases (BID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Pathogens of past and current infections have been identified directly by means of PCR or indirectly by measuring a specific immune response (e.g., antibody titration). Using a novel approach, Emerson and colleagues showed that the cytomegalovirus serostatus can also be accurately determined by using a T cell receptor repertoire data mining approach. In this study, we have sequenced the CD4+ memory T cell receptor repertoire of a Belgian cohort with known cytomegalovirus serostatus. A random forest classifier was trained on the CMV specific T cell receptor repertoire signature and used to classify individuals in the Belgian cohort. This study shows that the novel approach can be reliably replicated with an equivalent performance as that reported by Emerson and colleagues. Additionally, it provides evidence that the T cell receptor repertoire signature is to a large extent present in the CD4+ memory repertoire.

Background Despite the increasing popularity of multi-model comparison studies and their ability to inform policy recommendations, clear guidance on how to conduct multi-model comparisons is not available. Herein, we present guidelines to provide a structured approach to comparisons of multiple models of interventions against infectious diseases. The primary target audience for these guidelines are researchers carrying out model comparison studies and policy-makers using model comparison studies to inform policy decisions. Methods The consensus process used for the development of the guidelines included a systematic review of existing model comparison studies on effectiveness and cost-effectiveness of vaccination, a 2-day meeting and guideline development workshop during which mathematical modellers from different disease areas critically discussed and debated the guideline content and wording, and several rounds of comments on sequential versions of the guidelines by all authors. Results The guidelines provide principles for multi-model comparisons, with specific practice statements on what modellers should do for six domains. The guidelines provide explanation and elaboration of the principles and practice statements as well as some examples to illustrate these. The principles are (1) the policy and research question – the model comparison should address a relevant, clearly defined policy question; (2) model identification and selection – the identification and selection of models for inclusion in the model comparison should be transparent and minimise selection bias; (3) harmonisation – standardisation of input data and outputs should be determined by the research question and value of the effort needed for this step; (4) exploring variability – between- and within-model variability and uncertainty should be explored; (5) presenting and pooling results – results should be presented in an appropriate way to support decision-making; and (6) interpretation – results should be interpreted to inform the policy question. Conclusion These guidelines should help researchers plan, conduct and report model comparisons of infectious diseases and related interventions in a systematic and structured manner for the purpose of supporting health policy decisions. Adherence to these guidelines will contribute to greater consistency and objectivity in the approach and methods used in multi-model comparisons, and as such improve the quality of modelled evidence for policy. Electronic supplementary material The online version of this article (10.1186/s12916-019-1403-9) contains supplementary material, which is available to authorized users.

Background: Faced with the resurgence of malaria, malaria surveillance in the Peruvian Amazon incorporated consecutive active case detection (ACD) interventions using light microscopy (LM) as reactive measure in communities with an unusual high number of cases during high transmission season (HTS). We assessed the effectiveness in malaria detection of this local ACD-based strategy. Methods: A cohort study was conducted in June&ndash, July 2015 in Mazan, Loreto. Four consecutive ACD interventions at intervals of 10 days were conducted in four riverine communities (Gamitanacocha, Primero de Enero, Libertad and Urco Mira&ntilde, o). In each intervention, all inhabitants were visited at home, and finger-prick blood samples collected for immediate diagnosis by LM and on filter paper for later analysis by quantitative real-time polymerase chain reaction (qPCR). Effectiveness was calculated by dividing the number of malaria infections detected using LM by the number of malaria infections detected by delayed qPCR. Results: Most community inhabitants (88.1%, 822/933) were present in at least one of the four ACD interventions. A total of 451 infections were detected by qPCR in 446 participants (54.3% of total participants), five individuals had two infections. Plasmodium vivax was the predominant species (79.8%), followed by P. falciparum (15.3%) and P. vivax-P. falciparum co-infections (4.9%). Most qPCR-positive infections were asymptomatic (255/448, 56.9%). The ACD-strategy using LM had an effectiveness of 22.8% (detection of 103 of the total qPCR-positive infections). Children aged 5&ndash, 14 years, and farming as main economic activity were associated with P. vivax infections. Conclusions: Although the ACD-strategy using LM increased the opportunity of detecting and treating malaria infections during HTS, the number of detected infections was considerably lower than the real burden of infections (those detected by qPCR).

IntroductionEffective management of seasonal and pandemic influenza is a high priority internationally. Guidelines in many countries recommend antiviral treatment for older people and individuals with comorbidity at increased risk of complications. However, antivirals are not often prescribed in primary care in Europe, partly because its clinical and cost effectiveness has been insufficiently demonstrated by non-industry funded and pragmatic studies.Methods and analysisAntivirals for influenza-Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE is a European multinational, multicentre, open-labelled, non-industry funded, pragmatic, adaptive-platform, randomised controlled trial. Initial trial arms will be best usual primary care and best usual primary care plus treatment with oseltamivir for 5 days. We aim to recruit at least 2500 participants ≥1 year presenting with influenza-like illness (ILI), with symptom duration ≤72 hours in primary care over three consecutive periods of confirmed high influenza incidence. Participant outcomes will be followed up to 28 days by diary and telephone. The primary objective is to determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity with fever, headache and muscle ache reduced to minor severity or less. Secondary objectives include estimating cost-effectiveness, benefits in subgroups according to age (64 years), severity of symptoms at presentation (low, medium and high), comorbidity (yes/no), duration of symptoms (≤48 hours/>48–72 hours), complications (hospital admission and pneumonia), use of additional prescribed medication including antibiotics, use of over-the-counter medicines and self-management of ILI symptoms.Ethics and disseminationResearch ethics committee (REC) approval was granted by the NRES Committee South Central (Oxford B) and Clinical Trial Authority (CTA) approval by The Medicines and Healthcare products Regulatory Agency. All participating countries gained national REC and CTA approval as required. Dissemination of results will be through peer-reviewed scientific journals and conference presentations.Trial registration numberISRCTN27908921; Pre-results.

Background: Large measles and mumps outbreaks recently occurred throughout Europe and the United States. Aim: Our aim was to estimate and map the risk of resurgence for measles, mumps and rubella in France. Methods: We used a multi-cohort model combining seroprevalence information, vaccine coverage and social contact data. Results: The overall outbreak risk for France in 2018 was highest for mumps, remained significant for measles despite a recent measles outbreak and was low for rubella. Outbreak risks were heterogeneous between departments, as the effective reproduction numbers for 2018 ranged from 1.08 to 3.66. The seroprevalence, and therefore the risk of measles and rubella infection, differed significantly between mates and females. There was a lower seroprevalence, and therefore a higher risk, for males. Infants of less thane year would be seriously affected in a future outbreak of measles, mumps or rubella, but the highest overall caseload contribution would come from teenagers and young adults (10-25 years old). Conclusions: The high risk for teenagers and young adults is of concern in view of their vulnerability to more severe measles, mumps and rubella disease and complications. NH gratefully acknowledges the support from the University of Antwerp scientific chair in Evidence-Based Vaccinology, which was financed by a gift from Pfizer (2009-2017) and GlaxoSmithKline (2016). This project was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement 682540 - TransMID). GB gratefully acknowledges special research funding provided by Hasselt University (BOF14BL07). SA gratefully acknowledges support by the Research Fund of Hasselt University (Grant BOF11NI31). GB gratefully acknowledges special research funding provided by Hasselt University (BOF14BL07). SA gratefully acknowledges support by the Research Fund of Hasselt University (Grant BOF11NI31).

Clinical trials covering the immunogenicity of a vaccine aim to study the longitudinal dynamics of certain immune cells after vaccination. The corresponding immunogenicity datasets are mainly analyzed by the use of statistical (mixed effects) models. This paper proposes the use of mathematical ordinary differential equation (ODE) models, combined with a mixed effects approach. ODE models are capable of translating underlying immunological post vaccination processes into mathematical formulas thereby enabling a testable data analysis. Mixed models include both population-averaged parameters (fixed effects) and individual-specific parameters (random effects) for dealing with inter-and intra-individual variability, respectively.This paper models B-cell and T-cell datasets of a phase I/II, open-label, randomized, parallel-group study in which the immunogenicity of a new Herpes Zoster vaccine (Shingrix) is compared with the original Varicella Zoster Virus vaccine (Varilrix).Since few significant correlations were assessed between the B-cell datasets and T-cell datasets, each dataset was modeled separately. By following a general approach to both the formulation of several different models and the procedure of selecting the most suitable model, we were able propose a mathematical ODE mixed-effects model for each dataset. As such, the use of ODE-based mixed effects models offers a suitable framework for handling longitudinal vaccine immunogenicity data. Moreover, it is possible to test differences in immunological processes between the two vaccines.We found that the Shingrix vaccination schedule led to a more pronounced proliferation of T-cells, without a difference in T-cell decay rate compared to the Varilrix vaccination schedule.Author summaryUpon vaccination, B-cells and T-cells are activated to induce an immune response against the vaccine antigen at hand. In this paper, we study and compare the longitudinal dynamics of the specific immune response based on a vaccine trial in which the immunogenicity of a new Herpes Zoster vaccine (Shingrix) is compared with the original Varicella Zoster Virus vaccine (Varilrix). We combine the use of ordinary differential equations (ODEs), i.e. mathematical models which are used to describe the dynamics of the immune response, with advanced regression analyses enabling us to infer the model parameters describing these dynamics. The resulting ODE-based mixed effects models enable describing the immune response dynamics allowing for both inter-and intra-individual variability; comparing the dynamics induced by the two vaccines and studying the B-and T-cell interactions. We found a more pronounced proliferation of T-cells for the Shingrix vaccination schedule as compared to the Varilrix vaccination schedule. The proposed methodology offers a suitable framework for better understanding the immunogenicity of vaccines.

ALIC4E is the first publicly funded, multicountry, pragmatic study determining whether antivirals should be routinely prescribed for influenza-like illness in primary care. The trial aims to go beyond determining the average treatment effect in a population to determining effects in patients with combinations of participant characteristics (age, symptom duration, illness severity, and comorbidities). It is one of the first platform, response-adaptive, open trial designs implemented in primary care, and this article aims to provide an accessible description of key aspects of the study design. 1) The platform design allows the study to remain relevant to evolving circumstances, with the ability to add treatment arms. 2) Response adaptation allows the proportion of participants with key characteristics allocated to study arms to be altered during the course of the trial according to emerging outcome data, so that participants' information will be most useful, and increasing their chances of receiving the trial intervention that will be most effective for them. 3) Because the possibility of taking placebos influences participant expectations about their treatment, and determining effects of the interventions on patient help seeking and adherence behaviour in real-world care is critical to estimates of cost-effectiveness, ALIC4E is an open-label trial., A platform, response-adaptive, open trial design allows for flexibility and may enhance efficiency in determining cost-effectiveness of interventions for acute infections http://ow.ly/NODY30jACb7

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.

Objective Adolescent vaccination coverage under a system of non school-based vaccination is likely to be suboptimal, but might be increased by targeted encouragement campaigns. We analysed the effect on human papillomavirus (HPV) vaccination initiation by girls aged 1218 of two campaigns set up in Flanders (Belgium) in 2007 and 2009: a personal information campaign and a combined personal information and financial incentive campaign. Methods We analysed (objective) data on HPV vaccination behaviour from the National Alliance of Christian Mutualities (NACM), Flanders largest sickness fund. We used z-scores to compare the monthly proportion of girls initiating HPV vaccination over time between carefully selected intervention and control groups. Separate analyses were done for older and younger girls. Total sample sizes of the intervention (control) groups were 221 (243) for the personal information campaign and 629 (5,322) for the combined personal information and financial incentive campaign. Results The personal information campaign significantly increased vaccination initiation, with older girls reacting faster. One year after the campaign the percentages of vaccination initiation for the oldest girls were 64.6 and 42.8 % in the intervention and control group, respectively (z = 3.35, p = 0.0008); for the youngest girls the percentages were 78.4 and 68.1 % (z = 1.71, p = 0.09). The combined personal information and financial incentive campaign increased vaccination initiation among certain age groups. One year after the campaign the difference in percentage points for HPV vaccination initiation between intervention and control groups varied between 18.5 % (z = 3.65, p = 0.0002) and 5.1 % (z = 1.12, p = 0.26). Conclusion Under a non school-based vaccination system, personal information and removing out-of-pocket costs had a significant positive effect on HPV vaccination initiation, although the effect substantially varied in magnitude. Overall, the obtained vaccination rates remained far below those realised under school-based HPV vaccination.

In many settings, serotype changes as a result of infant 13-valent pneumococcal conjugate vaccine (PCV13) programs are likely to continue after the introduction of adult PCV13 programs. We applied a multi-cohort model to explore how potential serotype changes may impact on the cost-effectiveness of PCV13 use in Australian adults aged over 65 years. We found assumptions around continued herd protection from infant PCV13 programs to be critical when assessing the cost-effectiveness of adult PCV13 vaccination in Australia. Future cost-effectiveness analyses of adult PCV13 programs need to carefully consider how to predict these future changes in serotypes, with Australian data suggesting that the changes post-PCV13 use in infants may be different than post-PCV7. (C) 2018 Elsevier Ltd. All rights reserved.

Streptococcus pneumoniae causes a high disease burden including pneumonia, meningitis and septicemia. Both a polysaccharide vaccine targeting 23serotypes (PPV23) and a 13-valent conjugate vaccine (PCV13) are indicated for persons aged over 50years. We developed and parameterized a static multi-cohort model to estimate the incremental cost-effectiveness and budget-impact of these vaccines at different uptake levels. Using three different vaccine efficacy scenarios regarding non-invasive pneumococcal pneumonia and extensive uni- and multivariate sensitivity analyses, we found a strong preference for PPV23 over PCV13 in all age groups at willingness to pay levels below Euro300 000 per quality adjusted life year (QALY). PPV23 vaccination would cost on average about Euro83000, Euro60000 and Euro52000 per QALY gained in 50-64, 65-74 and 75-84year olds, whereas for PCV13 this is about Euro171000, Euro201000 and Euro338000, respectively. Strategies combining PPV23 and PCV13 vaccines were most effective but generally less cost-effective. When assuming a combination of increased duration of PCV13 protection, increased disease burden preventable by PCV13 and a 75% reduction of the PCV13 price, PCV13 could become more attractive in

Social contact data are increasingly being used to inform models for infectious disease spread with the aim of guiding effective policies on disease prevention and control. In this paper, we undertake a systematic review of the study design, statistical analyses and outcomes of the many social contact surveys that have been published. Our primary focus is to identify the designs that have worked best and the most important determinants and to highlight the most robust findings.Two publicly accessible online databases were systematically searched for articles regarding social contact surveys. PRISMA guidelines were followed as closely as possible. In total, 64 social contact surveys were identified. These surveys were conducted in 24 countries, and more than 80% of the surveys were conducted in high-income countries. Study settings included general population (58%), schools/universities (37%) and health care/conference/research institutes (5%). The majority of studies did not focus on a specific age group (38%), whereas others focused on adults (32%) or children (19%). Retrospective and prospective designs were used mostly (45% and 41% of the surveys, respectively) with 6% using both for comparison purposes. The definition of a contact varied among surveys, e.g. a non-physical contact may require conversation, close proximity or both. Age, time schedule (e.g., weekday/weekend) and household size were identified as relevant determinants for contact pattern across a large number of studies. The surveys present a wide range of study designs. Throughout, we found that the overall contact patterns were remarkably robust for the study details. By considering the most common approach in each aspect of design (e.g., sampling schemes, data collection, definition of contact), we could identify a common practice approach that can be used to facilitate comparison between studies and for benchmarking future studies.

Background: The Australian infant pneumococcal vaccination program was funded in 2005 using the 7-valent pneumococcal conjugate vaccine (PCV7) and the 13-valent conjugate vaccine (PCV13) in 2011. The PCV7 and PCV13 programs resulted in herd immunity effects across all age-groups, including older adults. Coincident with the introduction of the PCV7 program in 2005, 23-valent pneumococcal polysaccharide vaccine (ppv23) was funded for all Australian adults aged over 65 years. Methods: A multi-cohort Markov model with a cycle length of one year was developed to retrospectively evaluate the cost-effectiveness of the PPV23 immunisation program from 2005 to 2015. The analysis was performed from the healthcare system perspective with costs and quality -adjusted life years discounted at 5% annually. The incremental cost-effectiveness ratio (ICER) for PPV23 doses provided from 2005 to 2015 was calculated separately for each year when compared to no vaccination. Parameter uncertainty was explored using deterministic and probabilistic sensitivity analysis. Results: It was estimated that PPV23 doses given out over the 11-year period from 2005 to 2015 prevented 771 hospitalisations and 99 deaths from invasive pneumococcal disease Opro. However, the estimated IPD cases and deaths prevented by PPV23 declined by more than 50% over this period (e.g. from 12.9 deaths for doses given out in 2005 to 6.1 in 2015), likely driven by herd effects from infant PCV programs. The estimated ICER over the period 2005 to 2015 was approximately A$224,000/QALY gained compared to no vaccination. When examined per year, the ICER for each individual year worsened from $140,000/QALY in 2005 to $238,000/QALY in 2011 to $286,000/Q,ALY in 2015. Conclusion: The cost-effectiveness of the PPV23 program in older Australians was estimated to have worsened over time. It is unlikely to have been cost-effective, unless PPV23 provided protection against non-invasive pneumococcal pneumonia and/or a low vaccine price was negotiated. A key policy priority should be to review of the future use of PPV23 in Australia, which is likely to be more cost-effective in certain high-risk groups. (C) 2018 Elsevier Ltd. All rights reserved.

Postherpetic neuralgia (PHN) is the most common complication of herpes zoster and is typified by a lingering pain that can last months or years after the characteristic herpes zoster rash disappears. It is well known that there are risk factors for the development of PHN, such as its association with certain HLA alleles. In this study, previous HLA genotyping results were collected and subjected to a meta-analysis with increased statistical power. This work shows that the alleles HLA-A*33 and HLA-B*44 are significantly enriched in PHN patients, while HLA-A*02 and HLA-B*40 are significantly depleted. Prediction of the varicella-zoster virus (VZV) peptide affinity for these four HLA variants by using one in-house-developed and two existing state-of-the-art major histocompatibility complex (MHC) class I ligand prediction methods reveals that there is a great difference in their absolute and relative peptide binding repertoires. It was observed that HLA-A*02 displays a high affinity for an ∼7-fold-higher number of VZV peptides than HLA-B*44. Furthermore, after correction for HLA allele-specific limitations, the relative affinity of HLA-A*33 and HLA-B*44 for VZV peptides was found to be significantly lower than those of HLA-A*02 and HLA-B*40. In addition, HLA peptide affinity calculations indicate strong trends for VZV to avoid high-affinity peptides in some of its proteins, independent of the studied HLA allele. IMPORTANCE Varicella-zoster virus can cause two distinct diseases: chickenpox (varicella) and shingles (herpes zoster). Varicella is a common disease in young children, while herpes zoster is more frequent in older individuals. A common complication of herpes zoster is postherpetic neuralgia, a persistent and debilitating pain that can remain months up to years after the resolution of the rash. In this study, we show that the relative affinity of HLA variants associated with higher postherpetic neuralgia risk for varicella-zoster virus peptides is lower than that of variants with a lower risk. These results provide new insight into the development of postherpetic neuralgia and strongly support the hypothesis that one of its possible underlying causes is a suboptimal anti-VZV immune response due to weak HLA binding peptide affinity.