Diagnosing Viral Infections Through T-Cell Receptor Sequencing of Activated CD8+ T Cells.

T-cell-based diagnostic tools identify pathogen exposure but lack differentiation between recent and historical exposures in acute infectious diseases. Here, T-cell receptor (TCR) RNA sequencing was performed on HLA-DR+/CD38+CD8+ T-cell subsets of hospitalized coronavirus disease 2019 (COVID-19) patients (n = 30) and healthy controls (n = 30; 10 of whom had previously been exposed to severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]). CDR3α and CDR3ß TCR regions were clustered separately before epitope specificity annotation using a database of SARS-CoV-2-associated CDR3α and CDR3ß sequences corresponding to >1000 SARS-CoV-2 epitopes. The depth of the SARS-CoV-2-associated CDR3α/ß sequences differentiated COVID-19 patients from the healthy controls with a receiver operating characteristic area under the curve of 0.84 ± 0.10. Hence, annotating TCR sequences of activated CD8+ T cells can be used to diagnose an acute viral infection and discriminate it from historical exposure. In essence, this work presents a new paradigm for applying the T-cell repertoire to accomplish TCR-based diagnostics.

A Comparison of Items and Constructs of Standardized Health-Related Quality of Life and Mental Well-Being Measures.

OBJECTIVES: This study aimed to explore the internal constructs of the concepts being measured by EQ-5D-5L (a health-related quality of life measure that can produce preference-based utility values) and the 12-item General Health Questionnaire (GHQ-12, a mental well-being measure) and to understand to what extent the items of EQ-5D-5L and GHQ-12 associate with each other. METHODS: We used data from 12 701 respondents participating in a Belgian survey in 2022. Correlation coefficients between GHQ-12 and EQ-5D-5L were calculated at both the aggregate and item levels. Multidimensional scaling, exploratory factor analysis, and regression models were performed to investigate the underlying constructs that are associated with the items. RESULTS: Despite a moderate correlation (0.39) between the EQ-5D-5L and GHQ-12 total scores, only a trivial or weak correlation (<0.3) was observed between the first 4 EQ-5D-5L items and any GHQ-12 item. Multidimensional scaling and exploratory factor analysis showed the first 4 EQ-5D-5L dimensions were clustered together with EuroQol visual analog scale and positively phrased GHQ-12 items were close to each other, whereas EQ-anxiety/depression and negatively phrased GHQ-12 items were grouped with overall life satisfaction. In the regression models, not all GHQ-12 items had a significant coefficient to predict EQ-5D-5L responses. CONCLUSIONS: To the best of our knowledge, we present the first comparison of items and underlying constructs of GHQ-12 and EQ-5D-5L. The results showed that GHQ-12 can only partially predict the responses of EQ-5D-5L and the 2 instruments measure different constructs. Researchers should carefully consider conceptual legitimacy while applying the mapping technique and consider sensitivity analyses for the mapping estimates.

COVID-19-related health utility values and changes in COVID-19 patients and the general population: a scoping review.

PURPOSE: To summarise the diverse literature reporting the impact of COVID-19 on health utility in COVID-19 patients as well as in general populations being affected by COVID-19 control policies. METHODS: A literature search up to April 2023 was conducted to identify papers reporting health utility in COVID-19 patients or in COVID-19-affected general populations. We present a narrative synthesis of the health utility values/losses of the retained studies to show the mean health utility values/losses with 95% confidence intervals. Mean utility values/losses for categories defined by medical attendance and data collection time were calculated using random-effects models. RESULTS: In total, 98 studies-68 studies on COVID-19 patients and 30 studies on general populations-were retained for detailed review. Mean (95% CI) health utility values were 0.83 (0.81, 0.86), 0.78 (0.73, 0.83), 0.82 (0.78, 0.86) and 0.71 (0.65, 0.78) for general populations, non-hospitalised, hospitalised and ICU patients, respectively, irrespective of the data collection time. Mean utility losses in patients and general populations ranged from 0.03 to 0.34 and from 0.02 to 0.18, respectively. CONCLUSIONS: This scoping review provides a summary of the health utility impact of COVID-19 and COVID-19 control policies. COVID-19-affected populations were reported to have poor health utility, while a high degree of heterogeneity was observed across studies. Population- and/or country-specific health utility is recommended for use in future economic evaluation on COVID-19-related interventions.

The impact of quality-adjusted life years on evaluating COVID-19 mitigation strategies: lessons from age-specific vaccination roll-out and variants of concern in Belgium (2020-2022).

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.

Multimorbidity healthcare expenditure in Belgium: a 4-year analysis (COMORB study).

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.

The age profile of respiratory syncytial virus burden in preschool children of low- and middle-income countries: A semi-parametric, meta-regression approach.

BACKGROUND: Respiratory 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 FINDINGS: We 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. CONCLUSIONS: We 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.

Estimating the cost-effectiveness of maternal vaccination and monoclonal antibodies for respiratory syncytial virus in Kenya and South Africa.

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.

Inferring age-specific differences in susceptibility to and infectiousness upon SARS-CoV-2 infection based on Belgian social contact data.

Several important aspects related to SARS-CoV-2 transmission are not well known due to a lack of appropriate data. However, mathematical and computational tools can be used to extract part of this information from the available data, like some hidden age-related characteristics. In this paper, we present a method to investigate age-specific differences in transmission parameters related to susceptibility to and infectiousness upon contracting SARS-CoV-2 infection. More specifically, we use panel-based social contact data from diary-based surveys conducted in Belgium combined with the next generation principle to infer the relative incidence and we compare this to real-life incidence data. Comparing these two allows for the estimation of age-specific transmission parameters. Our analysis implies the susceptibility in children to be around half of the susceptibility in adults, and even lower for very young children (preschooler). However, the probability of adults and the elderly to contract the infection is decreasing throughout the vaccination campaign, thereby modifying the picture over time.

Different forms of superspreading lead to different outcomes: Heterogeneity in infectiousness and contact behavior relevant for the case of SARS-CoV-2.

Superspreading events play an important role in the spread of several pathogens, such as SARS-CoV-2. While the basic reproduction number of the original Wuhan SARS-CoV-2 is estimated to be about 3 for Belgium, there is substantial inter-individual variation in the number of secondary cases each infected individual causes-with most infectious individuals generating no or only a few secondary cases, while about 20% of infectious individuals is responsible for 80% of new infections. Multiple factors contribute to the occurrence of superspreading events: heterogeneity in infectiousness, individual variations in susceptibility, differences in contact behavior, and the environment in which transmission takes place. While superspreading has been included in several infectious disease transmission models, research into the effects of different forms of superspreading on the spread of pathogens remains limited. To disentangle the effects of infectiousness-related heterogeneity on the one hand and contact-related heterogeneity on the other, we implemented both forms of superspreading in an individual-based model describing the transmission and spread of SARS-CoV-2 in a synthetic Belgian population. We considered its impact on viral spread as well as on epidemic resurgence after a period of social distancing. We found that the effects of superspreading driven by heterogeneity in infectiousness are different from the effects of superspreading driven by heterogeneity in contact behavior. On the one hand, a higher level of infectiousness-related heterogeneity results in a lower risk of an outbreak persisting following the introduction of one infected individual into the population. Outbreaks that did persist led to fewer total cases and were slower, with a lower peak which occurred at a later point in time, and a lower herd immunity threshold. Finally, the risk of resurgence of an outbreak following a period of lockdown decreased. On the other hand, when contact-related heterogeneity was high, this also led to fewer cases in total during persistent outbreaks, but caused outbreaks to be more explosive in regard to other aspects (such as higher peaks which occurred earlier, and a higher herd immunity threshold). Finally, the risk of resurgence of an outbreak following a period of lockdown increased. We found that these effects were conserved when testing combinations of infectiousness-related and contact-related heterogeneity.

Cost-Effectiveness of Respiratory Syncytial Virus Preventive Interventions in Children: A Model Comparison Study.

OBJECTIVES: Model-based cost-effectiveness analyses on maternal vaccine (MV) and monoclonal antibody (mAb) interventions against respiratory syncytial virus (RSV) use context-specific data and produce varied results. Through model comparison, we aim to characterize RSV cost-effectiveness models and examine drivers for their outputs. METHODS: We compared 3 static and 2 dynamic models using a common input parameter set for a hypothetical birth cohort of 100 000 infants. Year-round and seasonal programs were evaluated for MV and mAb interventions, using available evidence during the study period (eg, phase III MV and phase IIb mAb efficacy). RESULTS: Three static models estimated comparable medically attended (MA) cases averted versus no intervention (MV, 1019-1073; mAb, 5075-5487), with the year-round MV directly saving ∼€1 million medical and €0.3 million nonmedical costs, while gaining 4 to 5 discounted quality-adjusted life years (QALYs) annually in <1-year-olds, and mAb resulting in €4 million medical and €1.5 million nonmedical cost savings, and 21 to 25 discounted QALYs gained. In contrast, both dynamic models estimated fewer MA cases averted (MV, 402-752; mAb, 3362-4622); one showed an age shift of RSV cases, whereas the other one reported many non-MA symptomatic cases averted, especially by MV (2014). These differences can be explained by model types, assumptions on non-MA burden, and interventions' effectiveness over time. CONCLUSIONS: Our static and dynamic models produced overall similar hospitalization and death estimates, but also important differences, especially in non-MA cases averted. Despite the small QALY decrement per non-MA case, their larger number makes them influential for the costs per QALY gained of RSV interventions.

Exploring the impact of population ageing on the spread of emerging respiratory infections and the associated burden of mortality.

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.

Social contact patterns during the COVID-19 pandemic in 21 European countries - evidence from a two-year study.

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 < 5), predominantly due to fewer contacts outside the home. Government restrictions imposed immediate effect on contacts, and these effects lingered after the restrictions were lifted. Across countries, the relationships between national policy, individual perceptions, or personal circumstances determining contacts varied. CONCLUSIONS: Our study, coordinated at the regional level, provides important insights into the understanding of the factors associated with social contacts to support future infectious disease outbreak responses.

Assessing the impact of COVID-19 passes and mandates on disease transmission, vaccination intention, and uptake: a scoping review.

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.

Impact of tiered measures on social contact and mixing patterns of in Italy during the second wave of COVID-19.

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.

The influence of COVID-19 risk perception and vaccination status on the number of social contacts across Europe: insights from the CoMix study.

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.

Longitudinal social contact data analysis: insights from 2 years of data collection in Belgium during the COVID-19 pandemic.

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 ([Formula: see text]) 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.

The direct disease burden of COVID-19 in Belgium in 2020 and 2021.

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.

A spatial model to jointly analyze self-reported survey data of COVID-19 symptoms and official COVID-19 incidence data.

This work presents a joint spatial modeling framework to improve estimation of the spatial distribution of the latent COVID-19 incidence in Belgium, based on test-confirmed COVID-19 cases and crowd-sourced symptoms data as reported in a large-scale online survey. Correction is envisioned for stochastic dependence between the survey's response rate and spatial COVID-19 incidence, commonly known as preferential sampling, but not found significant. Results show that an online survey can provide valuable auxiliary data to optimize spatial COVID-19 incidence estimation based on confirmed cases in situations with limited testing capacity. Furthermore, it is shown that an online survey on COVID-19 symptoms with a sufficiently large sample size per spatial entity is capable of pinpointing the same locations that appear as test-confirmed clusters, approximately 1 week earlier. We conclude that a large-scale online study provides an inexpensive and flexible method to collect timely information of an epidemic during its early phase, which can be used by policy makers in an early phase of an epidemic and in conjunction with other monitoring systems.

Cost-effectiveness of Respiratory Syncytial Virus Disease Prevention Strategies: Maternal Vaccine Versus Seasonal or Year-Round Monoclonal Antibody Program in Norwegian Children.

BACKGROUND: Every winter, respiratory syncytial virus (RSV) disease results in thousands of cases in Norwegian children under 5 years of age. We aim to assess the RSV-related economic burden and the cost-effectiveness of upcoming RSV disease prevention strategies including year-round maternal immunization and year-round and seasonal monoclonal antibody (mAb) programs. METHODS: Epidemiological and cost data were obtained from Norwegian national registries, while quality-adjusted life-years (QALYs) lost and intervention characteristics were extracted from literature and phase 3 clinical trials. A static model was used and uncertainty was accounted for probabilistically. Value of information was used to assess decision uncertainty. Extensive scenario analyses were conducted, including accounting for long-term consequences of RSV disease. RESULTS: We estimate an annual average of 13 517 RSV cases and 1572 hospitalizations in children under 5, resulting in 79.6 million Norwegian kroner (~€8 million) treatment costs. At €51 per dose for all programs, a 4-month mAb program for neonates born in November to February is the cost-effective strategy for willingness to pay (WTP) values up to €40 000 per QALY gained. For higher WTP values, the longer 6-month mAb program that immunizes neonates from October to March becomes cost-effective. Sensitivity analyses show that year-round maternal immunization can become a cost-effective strategy if priced lower than mAb. CONCLUSIONS: Assuming the same pricing, seasonal mAb programs are cost-effective over year-round programs in Norway. The timing and duration of the cost-effective seasonal program are sensitive to the pattern of the RSV season in a country, so continued RSV surveillance data are essential.

Economic Burden and Health-Related Quality of Life of Respiratory Syncytial Virus and Influenza Infection in European Community-Dwelling Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) and influenza virus infections result in a considerable mortality and morbidity among the aging population globally. Influenza vaccination for older adults before the seasonal influenza epidemic has been evaluated to be cost-effective in many countries. Interventions against RSV in older adults are in the pipeline, and evaluating their cost-effectiveness is crucial for decision making. To inform such evaluations, our aim was to estimate average costs and health-related quality of life (HRQoL) in older adults with RSV and influenza infection. METHODS: The European RESCEU observational cohort study followed 1040 relatively healthy community-dwelling older adults aged 60 years and older during 2 consecutive winter seasons. Health care resource use and HRQoL were collected and analyzed during RSV episodes, and also during influenza episodes. Country-specific unit cost data were mainly obtained from national databases. Direct costs were estimated from a patient, health care provider, and health care payers' perspective, whereas indirect costs were estimated from a societal perspective. Due to small sample size, no formal statistical comparisons were made. RESULTS: Thirty-six RSV and 60 influenza episodes were reported, including 1 hospitalization. Means (median; first-third quartile) of €26.4 (€5.5; 0-47.3) direct and €4.4 (€0; 0-0) indirect costs were reported per nonhospitalized RSV episode, and €42.5 (€36; 3.3-66.7) direct and €32.1 (€0; 0-0) indirect costs per nonhospitalized influenza episode. For RSV episodes, the utility value decreased from 0.896 (0.928; 0.854-0.953) to 0.801 (0.854; 0.712-0.937) from preseason to 1 week after symptom onset; for influenza, the change was from 0.872 (0.895; 0.828-0.953) to 0.664 (0.686; 0.574-0.797). CONCLUSIONS: The average costs and HRQoL estimates of older adults treated outside the hospital can be used to inform the design of future studies and the decision making regarding interventions to prevent RSV infection in older adults. Larger studies are needed to provide better country-specific and complementary cost estimates and to allow for formal statistical comparison of costs between RSV and influenza. CLINICAL TRIALS REGISTRATION: NCT03621930.