Predicting subnational incidence of COVID-19 cases and deaths in EU countries.

BACKGROUND: Recurring COVID-19 waves highlight the need for tools able to quantify transmission risk, and identify geographical areas at risk of outbreaks. Local outbreak risk depends on complex immunity patterns resulting from previous infections, vaccination, waning and immune escape, alongside other factors (population density, social contact patterns). Immunity patterns are spatially and demographically heterogeneous, and are challenging to capture in country-level forecast models. METHODS: We used a spatiotemporal regression model to forecast subnational case and death counts and applied it to three EU countries as test cases: France, Czechia, and Italy. Cases in local regions arise from importations or local transmission. Our model produces age-stratified forecasts given age-stratified data, and links reported case counts to routinely collected covariates (e.g. test number, vaccine coverage). We assessed the predictive performance of our model up to four weeks ahead using proper scoring rules and compared it to the European COVID-19 Forecast Hub ensemble model. Using simulations, we evaluated the impact of variations in transmission on the forecasts. We developed an open-source RShiny App to visualise the forecasts and scenarios. RESULTS: At a national level, the median relative difference between our median weekly case forecasts and the data up to four weeks ahead was 25% (IQR: 12-50%) over the prediction period. The accuracy decreased as the forecast horizon increased (on average 24% increase in the median ranked probability score per added week), while the accuracy of death forecasts was more stable. Beyond two weeks, the model generated a narrow range of likely transmission dynamics. The median national case forecasts showed similar accuracy to forecasts from the European COVID-19 Forecast Hub ensemble model, but the prediction interval was narrower in our model. Generating forecasts under alternative transmission scenarios was therefore key to capturing the range of possible short-term transmission dynamics. DISCUSSION: Our model captures changes in local COVID-19 outbreak dynamics, and enables quantification of short-term transmission risk at a subnational level. The outputs of the model improve our ability to identify areas where outbreaks are most likely, and are available to a wide range of public health professionals through the Shiny App we developed.

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 impact of local vaccine coverage and recent incidence on measles transmission in France between 2009 and 2018.

BACKGROUND: Subnational heterogeneity in immunity to measles can create pockets of susceptibility and result in long-lasting outbreaks despite high levels of national vaccine coverage. The elimination status defined by the World Health Organization aims to identify countries where the virus is no longer circulating and can be verified after 36 months of interrupted transmission. However, since 2018, numerous countries have lost their elimination status soon after reaching it, showing that the indicators defining elimination may not be associated with lower risks of outbreaks. METHODS: We quantified the impact of local vaccine coverage and recent levels of incidence on the dynamics of measles in each French department between 2009 and 2018, using mathematical models based on the "Endemic-Epidemic" regression framework. After fitting the models using daily case counts, we simulated the effect of variations in the vaccine coverage and recent incidence on future transmission. RESULTS: High values of local vaccine coverage were associated with fewer imported cases and lower risks of local transmissions, but regions that had recently reported high levels of incidence were also at a lower risk of local transmission. This may be due to additional immunity accumulated during recent outbreaks. Therefore, the risk of local transmission was not lower in areas fulfilling the elimination criteria. A decrease of 3% in the 3-year average vaccine uptake led to a fivefold increase in the average annual number of cases in simulated outbreaks. CONCLUSIONS: Local vaccine uptake was a reliable indicator of the intensity of transmission in France, even if it only describes yearly coverage in a given age group, and ignores population movements. Therefore, spatiotemporal variations in vaccine coverage, caused by disruptions in routine immunisation programmes, or lower trust in vaccines, can lead to large increases in both local and cross-regional transmission. The incidence indicator used to define the elimination status was not associated with a lower number of local transmissions in France, and may not illustrate the risks of imminent outbreaks. More detailed models of local immunity levels or subnational seroprevalence studies may yield better estimates of local risk of measles outbreaks.

Determinants of Transmission Risk During the Late Stage of the West African Ebola Epidemic.

Understanding risk factors for Ebola transmission is key for effective prediction and design of interventions. We used data on 860 cases in 129 chains of transmission from the latter half of the 2013-2016 Ebola epidemic in Guinea. Using negative binomial regression, we determined characteristics associated with the number of secondary cases resulting from each infected individual. We found that attending an Ebola treatment unit was associated with a 38% decrease in secondary cases (incidence rate ratio (IRR) = 0.62, 95% confidence interval (CI): 0.38, 0.99) among individuals that did not survive. Unsafe burial was associated with a higher number of secondary cases (IRR = 1.82, 95% CI: 1.10, 3.02). The average number of secondary cases was higher for the first generation of a transmission chain (mean = 1.77) compared with subsequent generations (mean = 0.70). Children were least likely to transmit (IRR = 0.35, 95% CI: 0.21, 0.57) compared with adults, whereas older adults were associated with higher numbers of secondary cases. Men were less likely to transmit than women (IRR = 0.71, 95% CI: 0.55, 0.93). This detailed surveillance data set provided an invaluable insight into transmission routes and risks. Our analysis highlights the key role that age, receiving treatment, and safe burial played in the spread of EVD.

Long-term waning of vaccine-induced immunity to measles in England: a mathematical modelling study.

BACKGROUND: Among people infected with measles in England between 2010 and 2019, the proportion of cases who had previously received two doses of vaccine has increased, especially among young adults. Possible explanations include rare infections in vaccinated individuals who did not gain immunity upon vaccination, made more common because fewer individuals in the population were born in the endemic era, before vaccination was introduced, and exposed as part of endemic transmission, or the waning of vaccine-induced immunity, which would present new challenges for measles control in near-elimination settings. We aimed to evaluate whether measles dynamics observed in England between 2010 and 2019 were in line with a waning of vaccine-induced immunity. METHODS: We used a compartmental mathematical model stratified by age group, region, and vaccine status, fitted to individual-level case data reported in England from 2010 to 2019 and collected by the UK Health Security Agency. The deterministic model was fitted using Monte Carlo Markov Chains under three scenarios: without the waning of vaccine-induced immunity, with waning depending on time since vaccination, and with waning depending on time since vaccination, starting in 2000. We generated stochastic simulations from the fitted parameter sets to evaluate which scenarios could replicate the transmission dynamics observed in vaccinated cases in England. FINDINGS: The scenario without waning overestimated the number of one-dose recipients among measles cases, and underestimated the number of two-dose recipients among cases older than 15 years (median 75 cases [95% simulation interval (SI) 44-124] in simulations without waning, 196 [95% SI 122-315] in simulations when waning was included, 188 [95% SI 118-301] in simulations when waning started in 2000, and 202 observed cases). The number of onward transmissions from vaccinated cases was 83% (95% credible interval 72-91%) of the number of transmissions from unvaccinated cases. The estimated waning rate was slow (0·039% per year of age; 95% credible interval 0·034-0·044% per year in the best-fitting scenario with waning starting in 2000), but sufficient to increase measles burden. INTERPRETATION: Measles case dynamics in England are consistent with scenarios assuming the waning of vaccine-induced immunity. Since measles is highly infectious, slow waning leads to a heightened burden in outbreaks, increasing the number of measles cases in people who are both vaccinated and unvaccinated. Our findings show that although the vaccine remains highly protective against measles infections for decades and most transmission is connected to people who are unvaccinated, breakthrough infections are increasingly frequent for individuals aged 15 years and older who have been vaccinated twice. FUNDING: National Institute for Health and Care Research and Wellcome Trust.

Transmission dynamics of seasonal influenza in a remote island population.

Seasonal influenza outbreaks remain an important public health concern, causing large numbers of hospitalizations and deaths among high-risk groups. Understanding the dynamics of individual transmission is crucial to design effective control measures and ultimately reduce the burden caused by influenza outbreaks. In this study, we analyzed surveillance data from Kamigoto Island, Japan, a semi-isolated island population, to identify the drivers of influenza transmission during outbreaks. We used rapid influenza diagnostic test (RDT)-confirmed surveillance data from Kamigoto island, Japan and estimated age-specific influenza relative illness ratios (RIRs) over eight epidemic seasons (2010/11 to 2017/18). We reconstructed the probabilistic transmission trees (i.e., a network of who-infected-whom) using Bayesian inference with Markov-chain Monte Carlo method and then performed a negative binomial regression on the inferred transmission trees to identify the factors associated with onwards transmission risk. Pre-school and school-aged children were most at risk of getting infected with influenza, with RIRs values consistently above one. The maximal RIR values were 5.99 (95% CI 5.23, 6.78) in the 7-12 aged-group and 5.68 (95%CI 4.59, 6.99) in the 4-6 aged-group in 2011/12. The transmission tree reconstruction suggested that the number of imported cases were consistently higher in the most populated and busy districts (Tainoura-go and Arikawa-go) ranged from 10-20 to 30-36 imported cases per season. The number of secondary cases generated by each case were also higher in these districts, which had the highest individual reproduction number (Reff: 1.2-1.7) across the seasons. Across all inferred transmission trees, the regression analysis showed that cases reported in districts with lower local vaccination coverage (incidence rate ratio IRR = 1.45 (95% CI 1.02, 2.05)) or higher number of inhabitants (IRR = 2.00 (95% CI 1.89, 2.12)) caused more secondary transmissions. Being younger than 18 years old (IRR = 1.38 (95%CI 1.21, 1.57) among 4-6 years old and 1.45 (95% CI 1.33, 1.59) 7-12 years old) and infection with influenza type A (type B IRR = 0.83 (95% CI 0.77, 0.90)) were also associated with higher numbers of onwards transmissions. However, conditional on being infected, we did not find any association between individual vaccination status and onwards transmissibility. Our study showed the importance of focusing public health efforts on achieving high vaccine coverage throughout the island, especially in more populated districts. The strong association between local vaccine coverage (including neighboring regions), and the risk of transmission indicate the importance of achieving homogeneously high vaccine coverage. The individual vaccine status may not prevent onwards transmission, though it may reduce the severity of infection.

Quantifying the value of viral genomics when inferring who infected whom in the 2014-16 Ebola virus outbreak in Guinea.

Transmission trees can be established through detailed contact histories, statistical or phylogenetic inference, or a combination of methods. Each approach has its limitations, and the extent to which they succeed in revealing a 'true' transmission history remains unclear. In this study, we compared the transmission trees obtained through contact tracing investigations and various inference methods to identify the contribution and value of each approach. We studied eighty-six sequenced cases reported in Guinea between March and November 2015. Contact tracing investigations classified these cases into eight independent transmission chains. We inferred the transmission history from the genetic sequences of the cases (phylogenetic approach), their onset date (epidemiological approach), and a combination of both (combined approach). The inferred transmission trees were then compared to those from the contact tracing investigations. Inference methods using individual data sources (i.e. the phylogenetic analysis and the epidemiological approach) were insufficiently informative to accurately reconstruct the transmission trees and the direction of transmission. The combined approach was able to identify a reduced pool of infectors for each case and highlight likely connections among chains classified as independent by the contact tracing investigations. Overall, the transmissions identified by the contact tracing investigations agreed with the evolutionary history of the viral genomes, even though some cases appeared to be misclassified. Therefore, collecting genetic sequences during outbreak is key to supplement the information contained in contact tracing investigations. Although none of the methods we used could identify one unique infector per case, the combined approach highlighted the added value of mixing epidemiological and genetic information to reconstruct who infected whom.

o2geosocial: Reconstructing who-infected-whom from routinely collected surveillance data.

Reconstructing the history of individual transmission events between cases is key to understanding what factors facilitate the spread of an infectious disease. Since conducting extended contact-tracing investigations can be logistically challenging and costly, statistical inference methods have been developed to reconstruct transmission trees from onset dates and genetic sequences. However, these methods are not as effective if the mutation rate of the virus is very slow, or if sequencing data is sparse. We developed the package o2geosocial to combine variables from routinely collected surveillance data with a simple transmission process model. The model reconstructs transmission trees when full genetic sequences are not available, or uninformative. Our model incorporates the reported age-group, onset date, location and genotype of infected cases to infer probabilistic transmission trees. The package also includes functions to summarise and visualise the inferred cluster size distribution. The results generated by o2geosocial can highlight regions where importations repeatedly caused large outbreaks, which may indicate a higher regional susceptibility to infections. It can also be used to generate the individual number of secondary transmissions, and show the features associated with individuals involved in high transmission events. The package is available for download from the Comprehensive R Archive Network (CRAN) and GitHub.

Probabilistic reconstruction of measles transmission clusters from routinely collected surveillance data.

Pockets of susceptibility resulting from spatial or social heterogeneity in vaccine coverage can drive measles outbreaks, as cases imported into such pockets are likely to cause further transmission and lead to large transmission clusters. Characterizing the dynamics of transmission is essential for identifying which individuals and regions might be most at risk. As data from detailed contact-tracing investigations are not available in many settings, we developed an R package called o2geosocial to reconstruct the transmission clusters and the importation status of the cases from their age, location, genotype and onset date. We compared our inferred cluster size distributions to 737 transmission clusters identified through detailed contact-tracing in the USA between 2001 and 2016. We were able to reconstruct the importation status of the cases and found good agreement between the inferred and reference clusters. The results were improved when the contact-tracing investigations were used to set the importation status before running the model. Spatial heterogeneity in vaccine coverage is difficult to measure directly. Our approach was able to highlight areas with potential for local transmission using a minimal number of variables and could be applied to assess the intensity of ongoing transmission in a region.

Control of Ebola virus disease outbreaks: Comparison of health care worker-targeted and community vaccination strategies.

BACKGROUND: Health care workers (HCW) are at risk of infection during Ebola virus disease outbreaks and therefore may be targeted for vaccination before or during outbreaks. The effect of these strategies depends on the role of HCW in transmission which is understudied. METHODS: To evaluate the effect of HCW-targeted or community vaccination strategies, we used a transmission model to explore the relative contribution of HCW and the community to transmission. We calibrated the model to data from multiple Ebola outbreaks. We quantified the impact of ahead-of-time HCW-targeted strategies, and reactive HCW and community vaccination. RESULTS: We found that for some outbreaks (we call "type 1″) HCW amplified transmission both to other HCW and the community, and in these outbreaks prophylactic vaccination of HCW decreased outbreak size. Reactive vaccination strategies had little effect because type 1 outbreaks ended quickly. However, in outbreaks with longer time courses ("type 2 outbreaks"), reactive community vaccination decreased the number of cases, with or without prophylactic HCW-targeted vaccination. For both outbreak types, we found that ahead-of-time HCW-targeted strategies had an impact at coverage of 30%. CONCLUSIONS: The vaccine strategies tested had a different impact depending on the transmission dynamics and previous control measures. Although we will not know the characteristics of a new outbreak, ahead-of-time HCW-targeted vaccination can decrease the total outbreak size, even at low vaccine coverage.

Combined Effect of Chain Extension and Supramolecular Interactions on Rheological and Adhesive Properties of Acrylic Pressure-Sensitive Adhesives.

A new approach for the elaboration of low molecular weight pressure-sensitive adhesives based on supramolecular chemistry is explored. The synthesis of model systems coupled with probe-tack tests and rheological experiments highlights the influence of the transient network formed by supramolecular bonds on the adhesion energy. The first step of our approach consists of synthesizing poly(butyl acrylate-co-glycidyl methacrylate) copolymers from a difunctional initiator able to self-associate by four hydrogen bonds between urea groups. Linear copolymers with a low dispersity (Mn = 10 kg/mol, Ip < 1.4) have been synthesized via atom transfer radical polymerization. Films of the copolymers were then partially cross-linked through reaction of the epoxy functions with a diamine. The systematic variation of the average ratio of glycidyl methacrylate and diamine per copolymer shed light on the respective role played by the supramolecular interactions (between bis-urea groups and with the side chains) and by the chain extension and branching induced by the diamine/epoxy reaction. In this strategy, the adhesive performance can be optimized by modifying the strength of "stickers" (via the structure of the supramolecular initiator, for instance) and the polymer network (e.g., via the length and level of branching of the copolymer chains) in order to approach commercial PSA-like properties (high debonding energy and clean removal).