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Non-communicable diseases (NCD) are the most important cause of death in the world. The socio-economic costs associated with NCDs makes it imperative to prevent and control them in the 21st century. The severe toll that the COVID-19 pandemic has taken worldwide is an unfortunate illustration of our limited insight into the infectious risk for the global population. Co-incidence between NCD and infection offers an underexplored opportunity to design preventive policies. In a pilot survey, we observed that the NCD population displays a substantial reduction in their social contacting behavior as compared to the general population. This indicates that existing mathematical models based on contact surveys in the general population are not applicable to the NCD population and that the risk of acquiring an infection following a contact is probably underestimated. Our demonstration of reduced social mixing in several chronic conditions, raises the question to what extent the social mixing is influenced by the burden of disease. We advocate the design of disease-specific contact surveys to address how the burden of disease associates with social contact behavior and the risk of infection. The SARS-CoV-2 pandemic offers an unprecedented opportunity to gain insight into the importance of infection in the NCD population and to find ways to improve healthcare procedures.

The COVID-19 pandemic led to unprecedented changes in behaviour. To estimate if these persisted, a final round of the CoMix social contact survey was conducted in four countries at a time when all societal restrictions had been lifted for several months. We conducted a survey on a nationally representative sample in the UK, Netherlands (NL), Belgium (BE), and Switzerland (CH). Participants were asked about their contacts and behaviours on the previous day. We calculated contact matrices and compared the contact levels to a pre-pandemic baseline to estimate R0. Data collection occurred from 17 November to 7 December 2022. 7477 participants were recruited. Some were asked to undertake the survey on behalf of their children. Only 14.4 % of all participants reported wearing a facemask on the previous day. Self-reported vaccination rates in adults were similar for each country at around 86 %. Trimmed mean recorded contacts were highest in NL with 9.9 (95 % confidence interval [CI] 9.0–10.8) contacts per person per day and lowest in CH at 6.0 (95 % CI 5.4–6.6). Contacts at work were lowest in the UK (1.4 contacts per person per day) and highest in NL at 2.8 contacts per person per day. Other contacts were also lower in the UK at 1.6 per person per day (95 % CI 1.4–1.9) and highest in NL at 3.4 recorded per person per day (95 % CI 43.0–4.0). The next-generation approach suggests that R0 for a close-contact disease would be roughly half pre-pandemic levels in the UK, 80 % in NL and intermediate in the other two countries. The pandemic appears to have resulted in lasting changes in contact patterns expected to have an impact on the epidemiology of many different pathogens. Further post-pandemic surveys are necessary to confirm this finding.

Abstract Background When formulating and evaluating COVID-19 vaccination strategies, an emphasis has been placed on preventing severe disease that overburdens healthcare systems and leads to mortality. However, more conventional outcomes such as quality-adjusted life years (QALYs) and inequality indicators are warranted as additional information for policymakers. Methods We adopted a mathematical transmission model to describe the infectious disease dynamics of SARS-COV-2, including disease mortality and morbidity, and to evaluate (non)pharmaceutical interventions. Therefore, we considered temporal immunity levels, together with the distinct transmissibility of variants of concern (VOCs) and their corresponding vaccine effectiveness. We included both general and age-specific characteristics related to SARS-CoV-2 vaccination. Our scenario study is informed by data from Belgium, focusing on the period from August 2021 until February 2022, when vaccination for children aged 5-11 years was initially not yet licensed and first booster doses were administered to adults. More specifically, we investigated the potential impact of an earlier vaccination programme for children and increased or reduced historical adult booster dose uptake. Results Through simulations, we demonstrate that increasing vaccine uptake in children aged 5-11 years in August–September 2021 could have led to reduced disease incidence and ICU occupancy, which was an essential indicator for implementing non-pharmaceutical interventions and maintaining healthcare system functionality. However, an enhanced booster dose regimen for adults from November 2021 onward could have resulted in more substantial cumulative QALY gains, particularly through the prevention of elevated levels of infection and disease incidence associated with the emergence of Omicron VOC. In both scenarios, the need for non-pharmaceutical interventions could have decreased, potentially boosting economic activity and mental well-being. Conclusions When calculating the impact of measures to mitigate disease spread in terms of life years lost due to COVID-19 mortality, we highlight the impact of COVID-19 on the health-related quality of life of survivors. Our study underscores that disease-related morbidity could constitute a significant part of the overall health burden. Our quantitative findings depend on the specific setup of the interventions under review, which is open to debate or should be contextualised within future situations.

Abstract Background The complex management of health needs in multimorbid patients, alongside limited cost data, presents challenges in developing cost-effective patient-care pathways. We estimated the costs of managing 171 dyads and 969 triads in Belgium, taking into account the influence of morbidity interactions on costs. Methods We followed a retrospective longitudinal study design, using the linked Belgian Health Interview Survey 2018 and the administrative claim database 2017–2020 hosted by the Intermutualistic Agency. We included people aged 15 and older, who had complete profiles (N = 9753). Applying a system costing perspective, the average annual direct cost per person per dyad/triad was presented in 2022 Euro and comprised mainly direct medical costs. We developed mixed models to analyse the impact of single chronic conditions, dyads and triads on healthcare costs, considering two-/three-way interactions within dyads/triads, key cost determinants and clustering at the household level. Results People with multimorbidity constituted nearly half of the study population and their total healthcare cost constituted around three quarters of the healthcare cost of the study population. The most common dyad, arthropathies + dorsopathies, with a 14% prevalence rate, accounted for 11% of the total national health expenditure. The most frequent triad, arthropathies + dorsopathies + hypertension, with a 5% prevalence rate, contributed 5%. The average annual direct costs per person with dyad and triad were €3515 (95% CI 3093–3937) and €4592 (95% CI 3920–5264), respectively. Dyads and triads associated with cancer, diabetes, chronic fatigue, and genitourinary problems incurred the highest costs. In most cases, the cost associated with multimorbidity was lower or not substantially different from the combined cost of the same conditions observed in separate patients. Conclusion Prevalent morbidity combinations, rather than high-cost ones, made a greater contribution to total national health expenditure. Our study contributes to the sparse evidence on this topic globally and in Europe, with the aim of improving cost-effective care for patients with diverse needs.

To mitigate the spread of SARS-CoV-2, the Swiss government enacted restrictions on social contacts from 2020 to 2022. In addition, individuals changed their social contact behavior to limit the risk of COVID-19. In this study, we aimed to investigate the changes in social contact patterns of the Swiss population. As part of the CoMix study, we conducted a survey consisting of 24 survey waves from January 2021 to May 2022. We collected data on social contacts and constructed contact matrices for the age groups 0–4, 5–14, 15–29, 30–64, and 65 years and older. We estimated the change in contact numbers during the COVID-19 pandemic to a synthetic pre-pandemic contact matrix. We also investigated the association of the largest eigenvalue of the social contact and transmission matrices with the stringency of pandemic measures, the effective reproduction number (Re), and vaccination uptake. During the pandemic period, 7084 responders reported an average number of 4.5 contacts (95% confidence interval, CI: 4.5–4.6) per day overall, which varied by age and survey wave. Children aged 5–14 years had the highest number of contacts with 8.5 (95% CI: 8.1–8.9) contacts on average per day and participants that were 65 years and older reported the fewest (3.4, 95% CI: 3.2–3.5) per day. Compared with the pre-pandemic baseline, we found that the 15–29 and 30–64 year olds had the largest reduction in contacts. We did not find statistically significant associations between the largest eigenvalue of the social contact and transmission matrices and the stringency of measures, Re, or vaccination uptake. The number of social contacts in Switzerland fell during the COVID-19 pandemic and remained below pre-pandemic levels after contact restrictions were lifted. The collected social contact data will be critical in informing modeling studies on the transmission of respiratory infections in Switzerland and to guide pandemic preparedness efforts.

Background: Collaborative comparisons and combinations of epidemic models are used as policy-relevant evidence during epidemic outbreaks. In the process of collecting multiple model projections, such collaborations may gain or lose relevant information. Typically, modellers contribute a probabilistic summary at each time-step. We compared this to directly collecting simulated trajectories. We aimed to explore information on key epidemic quantities; ensemble uncertainty; and performance against data, investigating potential to continuously gain information from a single cross-sectional collection of model results. Methods: We compared projections from the European COVID-19 Scenario Modelling Hub. Five teams modelled incidence in Belgium, the Netherlands, and Spain. We compared July 2022 projections by incidence, peaks, and cumulative totals. We created a probabilistic ensemble drawn from all trajectories, and compared to ensembles from a median across each model’s quantiles, or a linear opinion pool. We measured the predictive accuracy of individual trajectories against observations, using this in a weighted ensemble. We repeated this sequentially against increasing weeks of observed data. We evaluated these ensembles to reflect performance with varying observed data. Results: By collecting modelled trajectories, we showed policy-relevant epidemic characteristics. Trajectories contained a right-skewed distribution well represented by an ensemble of trajectories or a linear opinion pool, but not models’ quantile intervals. Ensembles weighted by performance typically retained the range of plausible incidence over time, and in some cases narrowed this by excluding some epidemic shapes. Conclusions: We observed several information gains from collecting modelled trajectories rather than quantile distributions, including potential for continuously updated information from a single model collection. The value of information gains and losses may vary with each collaborative effort’s aims, depending on the needs of projection users. Understanding the differing information potential of methods to collect model projections can support the accuracy, sustainability, and communication of collaborative infectious disease modelling efforts.

Summary: The role of T cell receptor (TCR) diversity in infectious disease susceptibility is not well understood. We use a systems immunology approach on three cohorts of herpes zoster (HZ) patients and controls to investigate whether TCR diversity against varicella-zoster virus (VZV) influences the risk of HZ. We show that CD4+ T cell TCR diversity against VZV glycoprotein E (gE) and immediate early 63 protein (IE63) after 1-week culture is more restricted in HZ patients. Single-cell RNA and TCR sequencing of VZV-specific T cells shows that T cell activation pathways are significantly decreased after stimulation with VZV peptides in convalescent HZ patients. TCR clustering indicates that TCRs from HZ patients co-cluster more often together than TCRs from controls. Collectively, our results suggest that not only lower VZV-specific TCR diversity but also reduced functional TCR affinity for VZV-specific proteins in HZ patients leads to lower T cell activation and consequently affects the susceptibility for viral reactivation.

Abstract Background Increasing life expectancy and persistently low fertility levels have led to old population age structures in most high-income countries, and population ageing is expected to continue or even accelerate in the coming decades. While older adults on average have few interactions that potentially could lead to disease transmission, their morbidity and mortality due to infectious diseases, respiratory infections in particular, remain substantial. We aim to explore how population ageing affects the future transmission dynamics and mortality burden of emerging respiratory infections. Methods Using longitudinal individual-level data from population registers, we model the Belgian population with evolving age and household structures, and explicitly consider long-term care facilities (LTCFs). Three scenarios are presented for the future proportion of older adults living in LTCFs. For each demographic scenario, we simulate outbreaks of SARS-CoV-2 and a novel influenza A virus in 2020, 2030, 2040 and 2050 and distinguish between household and community transmission. We estimate attack rates by age and household size/type, as well as disease-related deaths and the associated quality-adjusted life-years (QALYs) lost. Results As the population is ageing, small households and LTCFs become more prevalent. Additionally, families with children become smaller (i.e. low fertility, single-parent families). The overall attack rate slightly decreases as the population is ageing, but to a larger degree for influenza than for SARS-CoV-2 due to differential age-specific attack rates. Nevertheless, the number of deaths and QALY losses per 1,000 people is increasing for both infections and at a speed influenced by the share living in LTCFs. Conclusion Population ageing is associated with smaller outbreaks of COVID-19 and influenza, but at the same time it is causing a substantially larger burden of mortality, even if the proportion of LTCF residents were to decrease. These relationships are influenced by age patterns in epidemiological parameters. Not only the shift in the age distribution, but also the induced changes in the household structures are important to consider when assessing the potential impact of population ageing on the transmission and burden of emerging respiratory infections.

Abstract Purpose Policymakers have struggled to maintain SARS-CoV-2 transmission at levels that are manageable to contain the COVID-19 disease burden while enabling a maximum of societal and economic activities. One of the tools that have been used to facilitate this is the so-called “COVID-19 pass”. We aimed to document current evidence on the effectiveness of COVID-19 passes, distinguishing their indirect effects by improving vaccination intention and uptake from their direct effects on COVID-19 transmission measured by the incidence of cases, hospitalizations, and deaths. Methods We performed a scoping review on the scientific literature of the proposed topic covering the period January 2021 to September 2022, in accordance with the PRISMA-ScR guidelines for scoping reviews. Results Out of a yield of 4,693 publications, 45 studies from multiple countries were retained for full-text review. The results suggest that implementing COVID-19 passes tends to reduce the incidence of cases, hospitalizations, and deaths due to COVID-19. The use of COVID-19 passes was also shown to improve overall vaccination uptake and intention, but not in people who hold strong anti-COVID-19 vaccine beliefs. Conclusion The evidence from the literature we reviewed tends to indicate positive direct and indirect effects from the use of COVID-19 passes. A major limitation to establishing this firmly is the entanglement of individual effects of multiple measures being implemented simultaneously.

Abstract Background Burden of disease estimates have become important population health metrics over the past decade to measure losses in health. In Belgium, the disease burden caused by COVID-19 has not yet been estimated, although COVID-19 has emerged as one of the most important diseases. Therefore, the current study aims to estimate the direct COVID-19 burden in Belgium, observed despite policy interventions, during 2020 and 2021, and compare it to the burden from other causes. Methods Disability-adjusted life years (DALYs) are the sum of Years Lived with Disability (YLDs) and Years of Life Lost (YLLs) due to disease. DALYs allow comparing the burden of disease between countries, diseases, and over time. We used the European Burden of Disease Network consensus disease model for COVID-19 to estimate DALYs related to COVID-19. Estimates of person-years for (a) acute non-fatal disease states were calculated from a compartmental model, using Belgian seroprevalence, social contact, hospital, and intensive care admission data, (b) deaths were sourced from the national COVID-19 mortality surveillance, and (c) chronic post-acute disease states were derived from a Belgian cohort study. Results In 2020, the total number of COVID-19 related DALYs was estimated at 253,577 [252,541 − 254,739], which is higher than in 2021, when it was 139,281 [136,704 − 142,306]. The observed COVID-19 burden was largely borne by the elderly, and over 90% of the burden was attributable to premature mortality (i.e., YLLs). In younger people, morbidity (i.e., YLD) contributed relatively more to the DALYs, especially in 2021, when vaccination was rolled out. Morbidity was mainly attributable to long-lasting post-acute symptoms. Conclusion COVID-19 had a substantial impact on population health in Belgium, especially in 2020, when COVID-19 would have been the main cause of disease burden if all other causes had maintained their 2019 level.

Background: To date, it is not fully understood to what extent COVID-19 has burdened society in Japan. This study aimed to estimate the total disease burden due to COVID-19 in Japan during 2020–2021. Methods: We stratify disease burden estimates by age group and present it as absolute Quality Adjusted Life Years (QALYs) lost and QALYs lost per 100,000 persons. The total estimated value of QALYs lost consists of (1) QALYs lost brought by deaths due to COVID-19, (2) QALYs lost brought by inpatient cases, (3) QALYs lost brought by outpatient cases, and (4) QALYs lost brought by long-COVID. Results: The total QALYs lost due to COVID-19 was estimated as 286,782 for two years, 114.0 QALYs per 100,000 population per year. 71.3% of them were explained by the burden derived from deaths. Probabilistic sensitivity analysis showed that the burden of outpatient cases was the most sensitive factor. Conclusions: The large part of disease burden due to COVID-19 in Japan from the beginning of 2020 to the end of 2021 was derived from Wave 3, 4, and 5 and the proportion of QALYs lost due to morbidity in the total burden increased gradually. The estimated disease burden was smaller than that in other high-income countries. It will be our future challenge to take other indirect factors into consideration.

Abstract Background The SARS-CoV-2 transmission dynamics have been greatly modulated by human contact behaviour. To curb the spread of the virus, global efforts focused on implementing both Non-Pharmaceutical Interventions (NPIs) and pharmaceutical interventions such as vaccination. This study was conducted to explore the influence of COVID-19 vaccination status and risk perceptions related to SARS-CoV-2 on the number of social contacts of individuals in 16 European countries. Methods We used data from longitudinal surveys conducted in the 16 European countries to measure social contact behaviour in the course of the pandemic. The data consisted of representative panels of participants in terms of gender, age and region of residence in each country. The surveys were conducted in several rounds between December 2020 and September 2021 and comprised of 29,292 participants providing a total of 111,103 completed surveys. We employed a multilevel generalized linear mixed effects model to explore the influence of risk perceptions and COVID-19 vaccination status on the number of social contacts of individuals. Results The results indicated that perceived severity played a significant role in social contact behaviour during the pandemic after controlling for other variables (p-value < 0.001). More specifically, participants who had low or neutral levels of perceived severity reported 1.25 (95% Confidence intervals (CI) 1.13 - 1.37) and 1.10 (95% CI 1.00 - 1.21) times more contacts compared to those who perceived COVID-19 to be a serious illness, respectively. Additionally, vaccination status was also a significant predictor of contacts (p-value < 0.001), with vaccinated individuals reporting 1.31 (95% CI 1.23 - 1.39) times higher number of contacts than the non-vaccinated. Furthermore, individual-level factors played a more substantial role in influencing contact behaviour than country-level factors. Conclusion Our multi-country study yields significant insights on the importance of risk perceptions and vaccination in behavioral changes during a pandemic emergency. The apparent increase in social contact behaviour following vaccination would require urgent intervention in the event of emergence of an immune escaping variant.

Abstract Background During the COVID-19 pandemic, the CoMix study, a longitudinal behavioral survey, was designed to monitor social contacts and public awareness in multiple countries, including Belgium. As a longitudinal survey, it is vulnerable to participants’ “survey fatigue”, which may impact inferences. Methods A negative binomial generalized additive model for location, scale, and shape (NBI GAMLSS) was adopted to estimate the number of contacts reported between age groups and to deal with under-reporting due to fatigue within the study. The dropout process was analyzed with first-order auto-regressive logistic regression to identify factors that influence dropout. Using the so-called next generation principle, we calculated the effect of under-reporting due to fatigue on estimating the reproduction number. Results Fewer contacts were reported as people participated longer in the survey, which suggests under-reporting due to survey fatigue. Participant dropout is significantly affected by household size and age categories, but not significantly affected by the number of contacts reported in any of the two latest waves. This indicates covariate-dependent missing completely at random (MCAR) in the dropout pattern, when missing at random (MAR) is the alternative. However, we cannot rule out more complex mechanisms such as missing not at random (MNAR). Moreover, under-reporting due to fatigue is found to be consistent over time and implies a 15-30% reduction in both the number of contacts and the reproduction number ( $$R_0$$ R 0 ) ratio between correcting and not correcting for under-reporting. Lastly, we found that correcting for fatigue did not change the pattern of relative incidence between age groups also when considering age-specific heterogeneity in susceptibility and infectivity. Conclusions CoMix data highlights the variability of contact patterns across age groups and time, revealing the mechanisms governing the spread/transmission of COVID-19/airborne diseases in the population. Although such longitudinal contact surveys are prone to the under-reporting due to participant fatigue and drop-out, we showed that these factors can be identified and corrected using NBI GAMLSS. This information can be used to improve the design of similar, future surveys.

Abstract Background Several decision support tools have been developed to aid policymaking regarding the adoption of pneumococcal conjugate vaccine (PCV) into national pediatric immunization programs. The lack of critical appraisal of these tools makes it difficult for decision makers to understand and choose between them. With the aim to guide policymakers on their optimal use, we compared publicly available decision-making tools in relation to their methods, influential parameters and results. Methods The World Health Organization (WHO) requested access to several publicly available cost-effectiveness (CE) tools for PCV from both public and private provenance. All tools were critically assessed according to the WHO's guide for economic evaluations of immunization programs. Key attributes and characteristics were compared and a series of sensitivity analyses was performed to determine the main drivers of the results. The results were compared based on a standardized set of input parameters and assumptions. Results Three cost-effectiveness modeling tools were provided, including two cohort-based (Pan-American Health Organization (PAHO) ProVac Initiative TriVac, and PneumoADIP) and one population-based model (GlaxoSmithKline's SUPREMES). They all compared the introduction of PCV into national pediatric immunization program with no PCV use. The models were different in terms of model attributes, structure, and data requirement, but captured a similar range of diseases. Herd effects were estimated using different approaches in each model. The main driving parameters were vaccine efficacy against pneumococcal pneumonia, vaccine price, vaccine coverage, serotype coverage and disease burden. With a standardized set of input parameters developed for cohort modeling, TriVac and PneumoADIP produced similar incremental costs and health outcomes, and incremental cost-effectiveness ratios. Conclusions Vaccine cost (dose price and number of doses), vaccine efficacy and epidemiology of critical endpoint (for example, incidence of pneumonia, distribution of serotypes causing pneumonia) were influential parameters in the models we compared. Understanding the differences and similarities of such CE tools through regular comparisons could render decision-making processes in different countries more efficient, as well as providing guiding information for further clinical and epidemiological research. A tool comparison exercise using standardized data sets can help model developers to be more transparent about their model structure and assumptions and provide analysts and decision makers with a more in-depth view behind the disease dynamics. Adherence to the WHO guide of economic evaluations of immunization programs may also facilitate this process. Please see related article: http://www.biomedcentral.com/1741-7007/9/55

Abstract Background Most countries around the world enforced non-pharmaceutical interventions against COVID-19. Italy was one of the first countries to be affected by the pandemic, imposing a hard lockdown, in the first epidemic wave. During the second wave, the country implemented progressively restrictive tiers at the regional level according to weekly epidemiological risk assessments. This paper quantifies the impact of these restrictions on contacts and on the reproduction number. Methods Representative (with respect to age, sex, and region of residence) longitudinal surveys of the Italian population were undertaken during the second epidemic wave. Epidemiologically relevant contact patterns were measured and compared with pre-pandemic levels and according to the level of interventions experienced by the participants. Contact matrices were used to quantify the reduction in the number of contacts by age group and contact setting. The reproduction number was estimated to evaluate the impact of restrictions on the spread of COVID-19. Results The comparison with the pre-pandemic baseline shows a significant decrease in the number of contacts, independently from the age group or contact settings. This decrease in the number of contacts significantly depends on the strictness of the non-pharmaceutical interventions. For all levels of strictness considered, the reduction in social mixing results in a reproduction number smaller than one. In particular, the impact of the restriction on the number of contacts decreases with the severity of the interventions. Conclusions The progressive restriction tiers implemented in Italy reduced the reproduction number, with stricter interventions associated with higher reductions. Readily collected contact data can inform the implementation of mitigation measures at the national level in epidemic emergencies to come.

Abstract Background Most countries have enacted some restrictions to reduce social contacts to slow down disease transmission during the COVID-19 pandemic. For nearly two years, individuals likely also adopted new behaviours to avoid pathogen exposure based on personal circumstances. We aimed to understand the way in which different factors affect social contacts – a critical step to improving future pandemic responses. Methods The analysis was based on repeated cross-sectional contact survey data collected in a standardized international study from 21 European countries between March 2020 and March 2022. We calculated the mean daily contacts reported using a clustered bootstrap by country and by settings (at home, at work, or in other settings). Where data were available, contact rates during the study period were compared with rates recorded prior to the pandemic. We fitted censored individual-level generalized additive mixed models to examine the effects of various factors on the number of social contacts. Results The survey recorded 463,336 observations from 96,456 participants. In all countries where comparison data were available, contact rates over the previous two years were substantially lower than those seen prior to the pandemic (approximately from over 10 to

Abstract The COVID-19 pandemic was in 2020 and 2021 for a large part mitigated by reducing contacts in the general population. To monitor how these contacts changed over the course of the pandemic in the Netherlands, a longitudinal survey was conducted where participants reported on their at-risk contacts every two weeks, as part of the European CoMix survey. The survey included 1659 participants from April to August 2020 and 2514 participants from December 2020 to September 2021. We categorized the number of unique contacted persons excluding household members, reported per participant per day into six activity levels, defined as 0, 1, 2, 3–4, 5–9 and 10 or more reported contacts. After correcting for age, vaccination status, risk status for severe outcome of infection, and frequency of participation, activity levels increased over time, coinciding with relaxation of COVID-19 control measures.

Abstract Background Respiratory syncytial virus (RSV) causes a substantial burden of acute lower respiratory infection in children under 5 years, particularly in low- and middle-income countries (LMICs). Maternal vaccine (MV) and next-generation monoclonal antibody (mAb) candidates have been shown to reduce RSV disease in infants in phase 3 clinical trials. The cost-effectiveness of these biologics has been estimated using disease burden data from global meta-analyses, but these are sensitive to the detailed age breakdown of paediatric RSV disease, for which there have previously been limited data. Methods We use original hospital-based incidence data from South Africa (ZAF) and Kenya (KEN) collected between 2010 and 2018 of RSV-associated acute respiratory infection (ARI), influenza-like illness (ILI), and severe acute respiratory infection (SARI) as well as deaths with monthly age-stratification, supplemented with data on healthcare-seeking behaviour and costs to the healthcare system and households. We estimated the incremental cost per DALY averted (incremental cost-effectiveness ratio or ICER) of public health interventions by MV or mAb for a plausible range of prices (5–50 USD for MV, 10–125 USD for mAb), using an adjusted version of a previously published health economic model of RSV immunisation. Results Our data show higher disease incidence for infants younger than 6 months of age in the case of Kenya and South Africa than suggested by earlier projections from community incidence-based meta-analyses of LMIC data. Since MV and mAb provide protection for these youngest age groups, this leads to a substantially larger reduction of disease burden and, therefore, more favourable cost-effectiveness of both interventions in both countries. Using the latest efficacy data and inferred coverage levels based on antenatal care (ANC-3) coverage (KEN: 61.7%, ZAF: 75.2%), our median estimate of the reduction in RSV-associated deaths in children under 5 years in Kenya is 10.5% (95% CI: 7.9, 13.3) for MV and 13.5% (10.7, 16.4) for mAb, while in South Africa, it is 27.4% (21.6, 32.3) and 37.9% (32.3, 43.0), respectively. Starting from a dose price of 5 USD, in Kenya, net cost (for the healthcare system) per (undiscounted) DALY averted for MV is 179 (126, 267) USD, rising to 1512 (1166, 2070) USD at 30 USD per dose; for mAb, it is 684 (543, 895) USD at 20 USD per dose and 1496 (1203, 1934) USD at 40 USD per dose. In South Africa, a MV at 5 USD per dose would be net cost-saving for the healthcare system and net cost per DALY averted is still below the ZAF’s GDP per capita at 40 USD dose price (median: 2350, 95% CI: 1720, 3346). For mAb in ZAF, net cost per DALY averted is 247 (46, 510) USD at 20 USD per dose, rising to 2028 (1565, 2638) USD at 50 USD per dose and to 6481 (5364, 7959) USD at 125 USD per dose. Conclusions Incorporation of new data indicating the disease burden is highly concentrated in the first 6 months of life in two African settings suggests that interventions against RSV disease may be more cost-effective than previously estimated.

Abstract Background Mathematical modelling of infectious disease is increasingly used to help guide public health policy. As directly transmitted infections, such as influenza and tuberculosis, require contact between individuals, knowledge about contact patterns is a necessary pre-requisite of accurate model predictions. Of particular interest is the potential impact of school closure as a means of controlling pandemic influenza (and potentially other pathogens). Methods This paper uses a population-based prospective survey of mixing patterns in eight European countries to study the relative change in the basic reproduction number (R0 - the average number of secondary cases from a typical primary case in a fully susceptible population) on weekdays versus weekends and during regular versus holiday periods. The relative change in R0 during holiday periods and weekends gives an indication of the impact collective school closures (and prophylactic absenteeism) may have during a pandemic. Results Social contact patterns differ substantially when comparing weekdays to the weekend and regular to holiday periods mainly due to the reduction in work and/or school contacts. For most countries the basic reproduction number decreases from the week to weekends and regular to holiday periods by about 21% and 17%, respectively. However for other countries no significant decrease was observed. Conclusion We use a large-scale social contact survey in eight different European countries to gain insights in the relative change in the basic reproduction number on weekdays versus weekends and during regular versus holiday periods. The resulting estimates indicate that school closure can have a substantial impact on the spread of a newly emerging infectious disease that is transmitted via close (non sexual) contacts.

Abstract Background Until recently, mathematical models of person to person infectious diseases transmission had to make assumptions on transmissions enabled by personal contacts by estimating the so-called WAIFW-matrix. In order to better inform such estimates, a population based contact survey has been carried out in Belgium over the period March-May 2006. In contrast to other European surveys conducted simultaneously, each respondent recorded contacts over two days. Special attention was given to holiday periods, and respondents with large numbers of professional contacts. Methods Participants kept a paper diary with information on their contacts over two different days. A contact was defined as a two-way conversation of at least three words in each others proximity. The contact information included the age of the contact, gender, location, duration, frequency, and whether or not touching was involved. For data analysis, we used association rules and classification trees. Weighted generalized estimating equations were used to analyze contact frequency while accounting for the correlation between contacts reported on the two different days. A contact surface, expressing the average number of contacts between persons of different ages was obtained by a bivariate smoothing approach and the relation to the so-called next-generation matrix was established. Results People mostly mixed with people of similar age, or with their offspring, their parents and their grandparents. By imputing professional contacts, the average number of daily contacts increased from 11.84 to 15.70. The number of reported contacts depended heavily on the household size, class size for children and number of professional contacts for adults. Adults living with children had on average 2 daily contacts more than adults living without children. In the holiday period, the daily contact frequency for children and adolescents decreased with about 19% while a similar observation is made for adults in the weekend. These findings can be used to estimate the impact of school closure. Conclusion We conducted a diary based contact survey in Belgium to gain insights in social interactions relevant to the spread of infectious diseases. The resulting contact patterns are useful to improve estimating crucial parameters for infectious disease transmission models.

Abstract Background The increasing availability of data on social contact patterns and time use provides invaluable information for studying transmission dynamics of infectious diseases. Social contact data provide information on the interaction of people in a population whereas the value of time use data lies in the quantification of exposure patterns. Both have been used as proxies for transmission risks within in a population and the combination of both sources has led to investigate which contacts are more suitable to describe these transmission risks. Methods We used social contact and time use data from 1707 participants from a survey conducted in Flanders, Belgium in 2010–2011. We calculated weighted exposure time and social contact matrices to analyze age- and gender-specific mixing patterns and to quantify behavioral changes by distance from home. We compared the value of both separate and combined data sources for explaining seroprevalence and incidence data on parvovirus-B19, Varicella-Zoster virus (VZV) and influenza like illnesses (ILI), respectively. Results Assortative mixing and inter-generational interaction is more pronounced in the exposure matrix due to the high proportion of time spent at home. This pattern is less pronounced in the social contact matrix, which is more impacted by the reported contacts at school and work. The average number of contacts declined with distance. On the individual-level, we observed an increase in the number of contacts and the transmission potential by distance when travelling. We found that both social contact data and time use data provide a good match with the seroprevalence and incidence data at hand. When comparing the use of different combinations of both data sources, we found that the social contact matrix based on close contacts of at least 4 h appeared to be the best proxy for parvovirus-B19 transmission. Social contacts and exposure time were both on their own able to explain VZV seroprevalence data though combining both scored best. Compared with the contact approach, the time use approach provided the better fit to the ILI incidence data. Conclusions Our work emphasises the common and complementary value of time use and social contact data for analysing mixing behavior and analysing infectious disease transmission. We derived spatial, temporal, age-, gender- and distance-specific mixing patterns, which are informative for future modelling studies.

Abstract Background Lyme borreliosis (LB) is the most common tick-borne disease in Europe and North America, yet its economic burden remains largely unknown. This study aimed to estimate the economic cost associated with the different clinical manifestations of LB in Belgium. Methods An incidence approach and societal perspective were used to estimate the total cost-of-illness for LB in Belgium. Costs were calculated for patients with erythema migrans (EM) or disseminated/late LB, including patients who developed post-treatment Lyme disease syndrome (PTLDS). Direct medical, direct non-medical (transportation & paid help) and indirect non-medical costs (productivity losses) were included in the analysis. Ambulatory cost data were collected through a prospective cohort study from June 2016 to March 2020, in which patients with LB were followed up 6 to 12 months after diagnosis. Hospitalization costs were retrieved from the Minimal Clinical Data registry, a mandatory registry for all Belgian hospitals, linked to the Minimal Financial Data registry. Costs were expressed in 2019 euros. Results The total annual cost associated with clinical manifestations of LB in Belgium was estimated at €5.59 million (95% UI 3.82–7.98). Of these, €3.44 million (95% UI 2.05–5.48) or 62% was related to disseminated/late LB diagnoses and €2.15 million (95% UI 1.30–3.26) to EM. In general, direct medical costs and productivity losses accounted for 49.8% and 46.4% of the total costs, respectively, while direct non-medical costs accounted for only 3.8%. The estimated mean costs were €193 per EM patient and €5,148 per disseminated/late LB patient. While patients with PTLDS seemed to have somewhat higher costs compared to patients without PTLDS, the number of patients was too small to have representative estimates. Conclusions We estimate the total annual direct medical costs, direct non-medical and indirect non-medical costs associated with LB to exceed €5.5 million per year, almost evenly distributed between EM (40%) and disseminated/late LB (60%). EM costs 26 times less per patient but occurs also 16 times more frequently than disseminated/late LB. The cost burden remains limited by comparison to other infectious diseases due to the relative lower incidence.

Abstract Background Evidence and advice for pregnant women evolved during the COVID-19 pandemic. We studied social contact behaviour and vaccine uptake in pregnant women between March 2020 and September 2021 in 19 European countries. Methods In each country, repeated online survey data were collected from a panel of nationally-representative participants. We calculated the adjusted mean number of contacts reported with an individual-level generalized additive mixed model, modelled using the negative binomial distribution and a log link function. Mean proportion of people in isolation or quarantine, and vaccination coverage by pregnancy status and gender were calculated using a clustered bootstrap. Findings We recorded 4,129 observations from 1,041 pregnant women, and 115,359 observations from 29,860 non-pregnant individuals aged 18–49. Pregnant women made slightly fewer contacts (3.6, 95%CI = 3.5–3.7) than non-pregnant women (4.0, 95%CI = 3.9–4.0), driven by fewer work contacts but marginally more contacts in non-essential social settings. Approximately 15–20% pregnant and 5% of non-pregnant individuals reported to be in isolation and quarantine for large parts of the study period. COVID-19 vaccine coverage was higher in pregnant women than in non-pregnant women between January and April 2021. Since May 2021, vaccination in non-pregnant women began to increase and surpassed that in pregnant women. Interpretation Limited social contact to avoid pathogen exposure during the COVID-19 pandemic has been a challenge to many, especially women going through pregnancy. More recognition of maternal social support desire is needed in the ongoing pandemic. As COVID-19 vaccination continues to remain an important pillar of outbreak response, strategies to promote correct information can provide reassurance and facilitate informed pregnancy vaccine decisions in this vulnerable group.

BackgroundRespiratory syncytial virus (RSV) infections are among the primary causes of death for children under 5 years of age worldwide. A notable challenge with many of the upcoming prophylactic interventions against RSV is their short duration of protection, making the age profile of key interest to the design of prevention strategies.Methods and findingsWe leverage the RSV data collected on cases, hospitalizations, and deaths in a systematic review in combination with flexible generalized additive mixed models (GAMMs) to characterize the age burden of RSV incidence, hospitalization, and hospital-based case fatality rate (hCFR). Due to the flexible nature of GAMMs, we estimate the peak, median, and mean incidence of infection to inform discussions on the ideal "window of protection" of prophylactic interventions. In a secondary analysis, we reestimate the burden of RSV in all low- and middle-income countries. The peak age of community-based incidence is 4.8 months, and the mean and median age of infection is 18.9 and 14.7 months, respectively. Estimating the age profile using the incidence coming from hospital-based studies yields a slightly younger age profile, in which the peak age of infection is 2.6 months and the mean and median age of infection are 15.8 and 11.6 months, respectively. More severe outcomes, such as hospitalization and in-hospital death have a younger age profile. Children under 6 months of age constitute 10% of the population under 5 years of age but bear 20% to 29% of cases, 28% to 39% of hospitalizations, and 38% to 50% of deaths. On an average year, we estimate 28.23 to 31.34 million cases of RSV, between 2.95 to 3.35 million hospitalizations, and 16,835 to 19,909 in-hospital deaths in low, lower- and upper middle-income countries. In addition, we estimate 17,254 to 23,875 deaths in the community, for a total of 34,114 to 46,485 deaths. Globally, evidence shows that community-based incidence may differ by World Bank Income Group, but not hospital-based incidence, probability of hospitalization, or the probability of in-hospital death (p ≤ 0.01, p = 1, p = 0.86, 0.63, respectively). Our study is limited mainly due to the sparsity of the data, especially for low-income countries (LICs). The lack of information for some populations makes detecting heterogeneity between income groups difficult, and differences in access to care may impact the reported burden.ConclusionsWe have demonstrated an approach to synthesize information on RSV outcomes in a statistically principled manner, and we estimate that the age profile of RSV burden depends on whether information on incidence is collected in hospitals or in the community. Our results suggest that the ideal prophylactic strategy may require multiple products to avert the risk among preschool children.

Abstract 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.

Intro: The burden of infectious diseases is influenced by the structure of the population at risk. Population ageing may have implications for the disease burden of future epidemics. Moreover, changing household structures induced by population ageing may influence the dynamics of disease transmission and burden of infections transmitted via close contact interactions. We aim to investigate the impact of demographic change on the disease transmission dynamics and future disease burden and illustrate this for COVID-19 and influenza-like illness (ILI). Methods: We simulate the Belgian population between 2020 and 2050 using an individual-based model with census data. The simulated population structures were used as input for an infectious disease model that distinguishes between exposure to infection in the household versus exposure in the community at large. We mimicked outbreaks of COVID-19 and ILI of varying total final size. Findings: The simulated population ages between 2020 and 2050, which also affects household size and composition. As the proportion of elderly people in the population increases, the overall attack rate slightly decreases because older age groups have fewer contacts and are therefore less likely to incur and transmit infections. Despite the lower per-person attack rate, the estimated disease burden increases as morbidity and mortality increases with the age at infection. Conclusion: The demographic changes induced by population ageing have an impact on the burden of future outbreaks of COVID-19 and ILI in Belgium. The shifting age distribution implies that the elderly, a population group with increased morbidity and mortality in case of infection, make up an increasing proportion of the total population. Population ageing also leads to an increasing proportion of single-person households and collective households (e.g. nursing homes) in the population. Since the household attack rate varies by household size and composition, the living arrangements of the elderly population influences the disease burden of future epidemics to some extent.

BackgroundNon-typeable Haemophilus influenzae has become increasingly important as a causative agent of invasive diseases following vaccination against H. influenzae type b. The emergence of antibiotic resistance underscores the necessity to investigate typeable non-b carriage and non-typeable H. influenzae (NTHi) in children.MethodsNasopharyngeal swab samples were taken over a three-year period (2016–2018) from 336 children (6–30 months of age) attending daycare centers (DCCs) in Belgium, and from 218 children with acute otitis media (AOM). Biotype, serotype, and antibiotic resistance of H. influenzae strains were determined phenotypically. Mutations in the ftsI gene were explored in 129 strains that were resistant or had reduced susceptibility to beta-lactam antibiotics. Results were compared with data obtained during overlapping time periods from 94 children experiencing invasive disease.ResultsOverall, NTHi was most frequently present in both carriage (DCC, AOM) and invasive group. This was followed by serotype “f” (2.2%) and “e” (1.4%) in carriage, and “b” (16.0%), “f” (11.7%), and “a” (4.3%) in invasive strains. Biotype II was most prevalent in all studied groups, followed by biotype III in carriage and I in invasive strains. Strains from both groups showed highest resistance to ampicillin (26.7% in carriage vs. 18.1% in invasive group). A higher frequency of ftsI mutations were found in the AOM group than the DCC group (21.6 vs. 14.9% – p = 0.056). Even more so, the proportion of biotype III strains that carried a ftsI mutation was higher in AOM compared to DCC (50.0 vs. 26.3% – p