Emergence and spread of SARS-CoV-2 variants of concern in Canada: a retrospective analysis from clinical and wastewater data.

BACKGROUND: The spread of SARS-CoV-2 has been studied at unprecedented levels worldwide. In jurisdictions where molecular analysis was performed on large scales, the emergence and competition of numerous SARS-CoV-2lineages have been observed in near real-time. Lineage identification, traditionally performed from clinical samples, can also be determined by sampling wastewater from sewersheds serving populations of interest. Variants of concern (VOCs) and SARS-CoV-2 lineages associated with increased transmissibility and/or severity are of particular interest. METHOD: Here, we consider clinical and wastewater data sources to assess the emergence and spread of VOCs in Canada retrospectively. RESULTS: We show that, overall, wastewater-based VOC identification provides similar insights to the surveillance based on clinical samples. Based on clinical data, we observed synchrony in VOC introduction as well as similar emergence speeds across most Canadian provinces despite the large geographical size of the country and differences in provincial public health measures. CONCLUSION: In particular, it took approximately four months for VOC Alpha and Delta to contribute to half of the incidence. In contrast, VOC Omicron achieved the same contribution in less than one month. This study provides significant benchmarks to enhance planning for future VOCs, and to some extent for future pandemics caused by other pathogens, by quantifying the rate of SARS-CoV-2 VOCs invasion in Canada.

Forward-looking serial intervals correctly link epidemic growth to reproduction numbers.

The reproduction number R and the growth rate r are critical epidemiological quantities. They are linked by generation intervals, the time between infection and onward transmission. Because generation intervals are difficult to observe, epidemiologists often substitute serial intervals, the time between symptom onset in successive links in a transmission chain. Recent studies suggest that such substitution biases estimates of R based on r. Here we explore how these intervals vary over the course of an epidemic, and the implications for R estimation. Forward-looking serial intervals, measuring time forward from symptom onset of an infector, correctly describe the renewal process of symptomatic cases and therefore reliably link R with r. In contrast, backward-looking intervals, which measure time backward, and intrinsic intervals, which neglect population-level dynamics, give incorrect R estimates. Forward-looking intervals are affected both by epidemic dynamics and by censoring, changing in complex ways over the course of an epidemic. We present a heuristic method for addressing biases that arise from neglecting changes in serial intervals. We apply the method to early (21 January to February 8, 2020) serial interval-based estimates of R for the COVID-19 outbreak in China outside Hubei province; using improperly defined serial intervals in this context biases estimates of initial R by up to a factor of 2.6. This study demonstrates the importance of early contact tracing efforts and provides a framework for reassessing generation intervals, serial intervals, and R estimates for COVID-19.

Age-dependence of healthcare interventions for COVID-19 in Ontario, Canada.

BACKGROUND: Patient age is one of the most salient clinical indicators of risk from COVID-19. Age-specific distributions of known SARS-CoV-2 infections and COVID-19-related deaths are available for many regions. Less attention has been given to the age distributions of serious medical interventions administered to COVID-19 patients, which could reveal sources of potential pressure on the healthcare system should SARS-CoV-2 prevalence increase, and could inform mass vaccination strategies. The aim of this study is to quantify the relationship between COVID-19 patient age and serious outcomes of the disease, beyond fatalities alone. METHODS: We analysed 277,555 known SARS-CoV-2 infection records for Ontario, Canada, from 23 January 2020 to 16 February 2021 and estimated the age distributions of hospitalizations, Intensive Care Unit admissions, intubations, and ventilations. We quantified the probability of hospitalization given known SARS-CoV-2 infection, and of survival given COVID-19-related hospitalization. RESULTS: The distribution of hospitalizations peaks with a wide plateau covering ages 60-90, whereas deaths are concentrated in ages 80+. The estimated probability of hospitalization given known infection reaches a maximum of 27.8% at age 80 (95% CI 26.0%-29.7%). The probability of survival given hospitalization is nearly 100% for adults younger than 40, but declines substantially after this age; for example, a hospitalized 54-year-old patient has a 91.7% chance of surviving COVID-19 (95% CI 88.3%-94.4%). CONCLUSIONS: Our study demonstrates a significant need for hospitalization in middle-aged individuals and young seniors. This need is not captured by the distribution of deaths, which is heavily concentrated in very old ages. The probability of survival given hospitalization for COVID-19 is lower than is generally perceived for patients over 40. If acute care capacity is exceeded due to an increase in COVID-19 prevalence, the distribution of deaths could expand toward younger ages. These results suggest that vaccine programs should aim to prevent infection not only in old seniors, but also in young seniors and middle-aged individuals, to protect them from serious illness and to limit stress on the healthcare system.

Temporal estimates of case-fatality rate for COVID-19 outbreaks in Canada and the United States.

BACKGROUND: Estimates of the case-fatality rate (CFR) associated with coronavirus disease 2019 (COVID-19) vary widely in different population settings. We sought to estimate and compare the COVID-19 CFR in Canada and the United States while adjusting for 2 potential biases in crude CFR. METHODS: We used the daily incidence of confirmed COVID-19 cases and deaths in Canada and the US from Jan. 31 to Apr. 22, 2020. We applied a statistical method to minimize bias in the crude CFR by accounting for the survival interval as the lag time between disease onset and death, while considering reporting rates of COVID-19 cases less than 50% (95% confidence interval 10%-50%). RESULTS: Using data for confirmed cases in Canada, we estimated the crude CFR to be 4.9% on Apr. 22, 2020, and the adjusted CFR to be 5.5% (credible interval [CrI] 4.9%-6.4%). After we accounted for various reporting rates less than 50%, the adjusted CFR was estimated at 1.6% (CrI 0.7%-3.1%). The US crude CFR was estimated to be 5.4% on Apr. 20, 2020, with an adjusted CFR of 6.1% (CrI 5.4%-6.9%). With reporting rates of less than 50%, the adjusted CFR for the US was 1.78 (CrI 0.8%-3.6%). INTERPRETATION: Our estimates suggest that, if the reporting rate is less than 50%, the adjusted CFR of COVID-19 in Canada is likely to be less than 2%. The CFR estimates for the US were higher than those for Canada, but the adjusted CFR still remained below 2%. Quantification of case reporting can provide a more accurate measure of the virulence and disease burden of severe acute respiratory syndrome coronavirus 2.

Intrinsic and realized generation intervals in infectious-disease transmission.

The generation interval is the interval between the time when an individual is infected by an infector and the time when this infector was infected. Its distribution underpins estimates of the reproductive number and hence informs public health strategies. Empirical generation-interval distributions are often derived from contact-tracing data. But linking observed generation intervals to the underlying generation interval required for modelling purposes is surprisingly not straightforward, and misspecifications can lead to incorrect estimates of the reproductive number, with the potential to misguide interventions to stop or slow an epidemic. Here, we clarify the theoretical framework for three conceptually different generation-interval distributions: the 'intrinsic' one typically used in mathematical models and the 'forward' and 'backward' ones typically observed from contact-tracing data, looking, respectively, forward or backward in time. We explain how the relationship between these distributions changes as an epidemic progresses and discuss how empirical generation-interval data can be used to correctly inform mathematical models.

Estimations du taux de létalité de la COVID-19 au Canada et aux États-Unis sur une période donnée.

CONTEXTE: Les estimations du taux de létalité de la maladie à coronavirus 2019 (COVID-19) varient grandement selon les populations. L'objectif était d'estimer et de comparer ce taux pour le Canada et les États-Unis en tenant compte de 2 sources de biais potentiel du taux brut. MÉTHODES: Pour ce faire, nous sommes partis du nombre quotidien de cas confirmés et de décès au Canada et aux États-Unis pour la période du 31 janvier au 22 avril 2020. Nous y avons appliqué une méthode statistique qui réduit au minimum les biais du taux de létalité brut de 2 façons : en intégrant la durée de survie, soit le délai entre le début de la maladie et le décès, et en considérant que moins de 50 % des cas de COVID-19 sont confirmés (intervalle de confiance à 95 % 10 %­50 %). RÉSULTATS: À partir du nombre de cas confirmés au Canada, nous avons évalué le taux brut en date en 22 avril 2020 à 4,9 %, et le taux ajusté à 5,5 % (intervalle de crédibilité [ICr] 4,9 %­6,4 %). En appliquant divers taux de cas confirmés inférieurs à 50 %, nous avons obtenu un taux ajusté de 1,6 % (ICr 0,7 %­3,1 %). Pour les États-Unis, le taux brut en date du 20 avril 2020 était de 5,4 %, et le taux ajusté, de 6,1 % (ICr 5,4 %­6,9 %). Combiné à des taux de cas confirmés inférieurs à 50 %, le taux ajusté est passé à 1,78 % (ICr 0,8 %­3,6 %). INTERPRÉTATION: Nos estimations montrent que si le taux de cas confirmés est de moins de 50 %, le taux de létalité ajusté de la COVID-19 est vraisemblablement inférieur à 2 % au Canada. Aux États-Unis, les estimations sont plus élevées, mais le taux ajusté reste sous la barre des 2 %. Si le taux de cas confirmés était connu, nous pourrions mieux évaluer la virulence du coronavirus du syndrome respiratoire aigu sévère 2 et la charge associée.

The effect of sexually transmitted co-infections on HIV viral load amongst individuals on antiretroviral therapy: a systematic review and meta-analysis.

BACKGROUND: Antiretroviral therapy (ART) markedly reduces HIV transmission, and testing and treatment programs have been advocated as a method for decreasing transmission at the population level. Little is known, however, about the extent to which sexually transmitted infections (STIs), which increase the HIV infectiousness of untreated individuals, may decrease the effectiveness of treatment as prevention. METHODS: We searched major bibliographic databases to August 12(th), 2014 and identified studies reporting differences in HIV transmission rate or in viral load between individuals on ART who either were or were not co-infected with another STI. We used hierarchical Bayesian models to estimate viral load differences between individuals with and without STI co-infections. RESULTS: The search strategy retrieved 1630 unique citations of which 14 studies (reporting on 4607 HIV viral load measurements from 2835 unique individuals) met the inclusion criteria. We did not find any suitable studies that estimated transmission rates directly in both groups. Our meta-analysis of HIV viral load measurements among treated individuals did not find a statistically significant effect of STI co-infection; viral loads were, on average, 0.11 log10 (95% CI -0.62 to 0.83) higher among co-infected versus non-co-infected individuals. CONCLUSIONS: Direct evidence about the effects of STI co-infection on transmission from individuals on ART is very limited. Available data suggests that the average effect of STI co-infection on HIV viral load in individuals on ART is less than 1 log10 difference, and thus unlikely to decrease the effectiveness of treatment as prevention. However, there is not enough data to rule out the possibility that particular STIs pose a larger threat.

ern: An [Formula: see text] package to estimate the effective reproduction number using clinical and wastewater surveillance data.

The effective reproduction number, [Formula: see text], is an important epidemiological metric used to assess the state of an epidemic, as well as the effectiveness of public health interventions undertaken in response. When [Formula: see text] is above one, it indicates that new infections are increasing, and thus the epidemic is growing, while an [Formula: see text] is below one indicates that new infections are decreasing, and so the epidemic is under control. There are several established software packages that are readily available to statistically estimate [Formula: see text] using clinical surveillance data. However, there are comparatively few accessible tools for estimating [Formula: see text] from pathogen wastewater concentration, a surveillance data stream that cemented its utility during the COVID-19 pandemic. We present the [Formula: see text] package ern that aims to perform the estimation of the effective reproduction number from real-world wastewater or aggregated clinical surveillance data in a user-friendly way.

SUP: a probabilistic framework to propagate genome sequence uncertainty, with applications.

Genetic sequencing is subject to many different types of errors, but most analyses treat the resultant sequences as if they are known without error. Next generation sequencing methods rely on significantly larger numbers of reads than previous sequencing methods in exchange for a loss of accuracy in each individual read. Still, the coverage of such machines is imperfect and leaves uncertainty in many of the base calls. In this work, we demonstrate that the uncertainty in sequencing techniques will affect downstream analysis and propose a straightforward method to propagate the uncertainty. Our method (which we have dubbed Sequence Uncertainty Propagation, or SUP) uses a probabilistic matrix representation of individual sequences which incorporates base quality scores as a measure of uncertainty that naturally lead to resampling and replication as a framework for uncertainty propagation. With the matrix representation, resampling possible base calls according to quality scores provides a bootstrap- or prior distribution-like first step towards genetic analysis. Analyses based on these re-sampled sequences will include a more complete evaluation of the error involved in such analyses. We demonstrate our resampling method on SARS-CoV-2 data. The resampling procedures add a linear computational cost to the analyses, but the large impact on the variance in downstream estimates makes it clear that ignoring this uncertainty may lead to overly confident conclusions. We show that SARS-CoV-2 lineage designations via Pangolin are much less certain than the bootstrap support reported by Pangolin would imply and the clock rate estimates for SARS-CoV-2 are much more variable than reported.

Coupling wastewater-based epidemiological surveillance and modelling of SARS-COV-2/COVID-19: Practical applications at the Public Health Agency of Canada.

Wastewater-based surveillance (WBS) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) offers a complementary tool for clinical surveillance to detect and monitor coronavirus disease 2019 (COVID-19). Since both symptomatic and asymptomatic individuals infected with SARS-CoV-2 can shed the virus through the fecal route, WBS has the potential to measure community prevalence of COVID-19 without restrictions from healthcare-seeking behaviours and clinical testing capacity. During the Omicron wave, the limited capacity of clinical testing to identify COVID-19 cases in many jurisdictions highlighted the utility of WBS to estimate disease prevalence and inform public health strategies; however, there is a plethora of in-sewage, environmental and laboratory factors that can influence WBS outcomes. The implementation of WBS, therefore, requires a comprehensive framework to outline a pipeline that accounts for these complex and nuanced factors. This article reviews the framework of the national WBS conducted at the Public Health Agency of Canada to present WBS methods used in Canada to track and monitor SARS-CoV-2. In particular, we focus on five Canadian cities-Vancouver, Edmonton, Toronto, Montréal and Halifax-whose wastewater signals are analyzed by a mathematical model to provide case forecasts and reproduction number estimates. The goal of this work is to share our insights on approaches to implement WBS. Importantly, the national WBS system has implications beyond COVID-19, as a similar framework can be applied to monitor other infectious disease pathogens or antimicrobial resistance in the community.

A wastewater-based risk index for SARS-CoV-2 infections among three cities on the Canadian Prairie.

Wastewater surveillance (WWS) is useful to better understand the spreading of coronavirus disease 2019 (COVID-19) in communities, which can help design and implement suitable mitigation measures. The main objective of this study was to develop the Wastewater Viral Load Risk Index (WWVLRI) for three Saskatchewan cities to offer a simple metric to interpret WWS. The index was developed by considering relationships between reproduction number, clinical data, daily per capita concentrations of virus particles in wastewater, and weekly viral load change rate. Trends of daily per capita concentrations of SARS-CoV-2 in wastewater for Saskatoon, Prince Albert, and North Battleford were similar during the pandemic, suggesting that per capita viral load can be useful to quantitatively compare wastewater signals among cities and develop an effective and comprehensible WWVLRI. The effective reproduction number (Rt) and the daily per capita efficiency adjusted viral load thresholds of 85 × 106 and 200 × 106 N2 gene counts (gc)/population day (pd) were determined. These values with rates of change were used to categorize the potential for COVID-19 outbreaks and subsequent declines. The weekly average was considered 'low risk' when the per capita viral load was 85 × 106 N2 gc/pd. A 'medium risk' occurs when the per capita copies were between 85 × 106 and 200 × 106 N2 gc/pd. with a rate of change <100 %. The start of an outbreak is indicated by a 'medium-high' risk classification when the week-over-week rate of change was >100 %, and the absolute magnitude of concentrations of viral particles was >85 × 106 N2 gc/pd. Lastly, a 'high risk' occurs when the viral load exceeds 200 × 106 N2 gc/pd. This methodology provides a valuable resource for decision-makers and health authorities, specifically given the limitation of COVID-19 surveillance based on clinical data.

Implications of the unexpected persistence of human rhinovirus/enterovirus during the COVID-19 pandemic in Canada.

Stringent public health measures imposed across Canada to control the COVID-19 pandemic have nearly suppressed most seasonal respiratory viruses, with the notable exception of human rhinovirus/enterovirus (hRV/EV). Thanks to this unexpected persistence, we highlight that hRV/EV could serve as a sentinel for levels of contact rate in populations to inform on the efficiency, or the need of, public health measures to control the subsequent COVID-19 epidemic, but also for future epidemics from other seasonal or emerging respiratory pathogens.

Antigenic drift and epidemiological severity of seasonal influenza in Canada.

Seasonal influenza epidemics circulate globally every year with varying levels of severity. One of the major drivers of this seasonal variation is thought to be the antigenic drift of influenza viruses, resulting from the accumulation of mutations in viral surface proteins. In this study, we aimed to investigate the association between the genetic drift of seasonal influenza viruses (A/H1N1, A/H3N2 and B) and the epidemiological severity of seasonal epidemics within a Canadian context. We obtained hemagglutinin protein sequences collected in Canada between the 2006/2007 and 2019/2020 flu seasons from GISAID and calculated Hamming distances in a sequence-based approach to estimating inter-seasonal antigenic differences. We also gathered epidemiological data on cases, hospitalizations and deaths from national surveillance systems and other official sources, as well as vaccine effectiveness estimates to address potential effect modification. These aggregate measures of disease severity were integrated into a single seasonal severity index. We performed linear regressions of our severity index with respect to the inter-seasonal antigenic distances, controlling for vaccine effectiveness. We did not find any evidence of a statistical relationship between antigenic distance and seasonal influenza severity in Canada. Future studies may need to account for additional factors, such as co-circulation of other respiratory pathogens, population imprinting, cohort effects and environmental parameters, which may drive seasonal influenza severity.

Statistical framework to support the epidemiological interpretation of SARS-CoV-2 concentration in municipal wastewater.

The ribonucleic acid (RNA) of the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is detectable in municipal wastewater as infected individuals can shed the virus in their feces. Viral concentration in wastewater can inform the severity of the COVID-19 pandemic but observations can be noisy and sparse and hence hamper the epidemiological interpretation. Motivated by a Canadian nationwide wastewater surveillance data set, unlike previous studies, we propose a novel Bayesian statistical framework based on the theories of functional data analysis to tackle the challenges embedded in the longitudinal wastewater monitoring data. By employing this framework to analyze the large-scale data set from the nationwide wastewater surveillance program covering 15 sampling sites across Canada, we successfully detect the true trends of viral concentration out of noisy and sparsely observed viral concentrations, and accurately forecast the future trajectory of viral concentrations in wastewater. Along with the excellent performance assessment using simulated data, this study shows that the proposed novel framework is a useful statistical tool and has a significant potential in supporting the epidemiological interpretation of noisy viral concentration measurements from wastewater samples in a real-life setting.

A wastewater-based epidemic model for SARS-CoV-2 with application to three Canadian cities.

The COVID-19 pandemic has stimulated wastewater-based surveillance, allowing public health to track the epidemic by monitoring the concentration of the genetic fingerprints of SARS-CoV-2 shed in wastewater by infected individuals. Wastewater-based surveillance for COVID-19 is still in its infancy. In particular, the quantitative link between clinical cases observed through traditional surveillance and the signals from viral concentrations in wastewater is still developing and hampers interpretation of the data and actionable public-health decisions. We present a modelling framework that includes both SARS-CoV-2 transmission at the population level and the fate of SARS-CoV-2 RNA particles in the sewage system after faecal shedding by infected persons in the population. Using our mechanistic representation of the combined clinical/wastewater system, we perform exploratory simulations to quantify the effect of surveillance effectiveness, public-health interventions and vaccination on the discordance between clinical and wastewater signals. We also apply our model to surveillance data from three Canadian cities to provide wastewater-informed estimates for the actual prevalence, the effective reproduction number and incidence forecasts. We find that wastewater-based surveillance, paired with this model, can complement clinical surveillance by supporting the estimation of key epidemiological metrics and hence better triangulate the state of an epidemic using this alternative data source.

Salivary testing for SARS-CoV-2 in the pediatric population: a diagnostic accuracy study.

BACKGROUND: Accurate and timely testing for SARS-CoV-2 in the pediatric population is crucial to control the COVID-19 pandemic; saliva testing has been proposed as a less invasive alternative to nasopharyngeal swabs. We sought to compare the detection of SARS-CoV-2 using saliva versus nasopharyngeal swab in the pediatric population, and to determine the optimum time of testing for SARS-CoV-2 using saliva. METHODS: We conducted a longitudinal diagnostic study in Ottawa, Canada, from Jan. 19 to Mar. 26, 2021. Children aged 3-17 years were eligible if they exhibited symptoms of COVID-19, had been identified as a high-risk or close contact to someone confirmed positive for SARS-CoV-2 or had travelled outside Canada in the previous 14 days. Participants provided both nasopharyngeal swab and saliva samples. Saliva was collected using a self-collection kit (DNA Genotek, OM-505) or a sponge-based kit (DNA Genotek, ORE-100) if they could not provide a saliva sample into a tube. RESULTS: Among 1580 paired nasopharyngeal and saliva tests, 60 paired samples were positive for SARS-CoV-2. Forty-four (73.3%) were concordant-positive results and 16 (26.6%) were discordant, among which 8 were positive only on nasopharyngeal swab and 8 were positive only on saliva testing. The sensitivity of saliva was 84.6% (95% confidence interval 71.9%-93.1%). INTERPRETATION: Salivary testing for SARS-CoV-2 in the pediatric population is less invasive and shows similar detection of SARS-CoV-2 to nasopharyngeal swabs. It may therefore provide a feasible alternative for diagnosis of SARS-CoV-2 infection in children.

Effectiveness of non-pharmaceutical interventions to reduce SARS-CoV-2 transmission in Canada and their association with COVID-19 hospitalization rates.

Background: Non-pharmaceutical interventions (NPIs) aim to reduce the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections mostly by limiting contacts between people where virus transmission can occur. However, NPIs limit social interactions and have negative impacts on economic, physical, mental and social well-being. It is, therefore, important to assess the impact of NPIs on reducing the number of coronavirus disease 2019 (COVID-19) cases and hospitalizations to justify their use. Methods: Dynamic regression models accounting for autocorrelation in time series data were used with data from six Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Québec) to assess 1) the effect of NPIs (measured using a stringency index) on SARS-CoV-2 transmission (measured by the effective reproduction number), and 2) the effect of the number of hospitalized COVID-19 patients on the stringency index. Results: Increasing stringency index was associated with a statistically significant decrease in the transmission of SARS-CoV-2 in Alberta, Saskatchewan, Manitoba, Ontario and Québec. The effect of stringency on transmission was time-lagged in all of these provinces except for Ontario. In all provinces except for Saskatchewan, increasing hospitalization rates were associated with a statistically significant increase in the stringency index. The effect of hospitalization on stringency was time-lagged. Conclusion: These results suggest that NPIs have been effective in Canadian provinces, and that their implementation has been, in part, a response to increasing hospitalization rates of COVID-19 patients.

Simple mathematical modelling approaches to assessing the transmission risk of SARS-CoV-2 at gatherings.

BACKGROUND: Gatherings may contribute significantly to the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For this reason, public health interventions have sought to constrain unrepeated or recurrent gatherings to curb the coronavirus disease 2019 (COVID-19) pandemic. Unfortunately, the range of different types of gatherings hinders specific guidance from setting limiting parameters (e.g. total size, number of cohorts, the extent of physical distancing). METHODS: We used a generic modelling framework, based on fundamental probability principles, to derive simple formulas to assess introduction and transmission risks associated with gatherings, as well as the potential efficiency of some testing strategies to mitigate these risks. RESULTS: Introduction risk can be broadly assessed with the population prevalence and the size of the gathering, while transmission risk at a gathering is mainly driven by the gathering size. For recurrent gatherings, the cohort structure does not have a significant impact on transmission between cohorts. Testing strategies can mitigate risk, but frequency of testing and test performance are factors in finding a balance between detection and false positives. CONCLUSION: The generality of the modelling framework used here helps to disentangle the various factors affecting transmission risk at gatherings and may be useful for public health decision-making.

Effectiveness and cost-effectiveness of a Clostridium difficile vaccine candidate in a hospital setting.

Toxoid vaccines against Clostridium difficile infections (CDI) appear promising in reducing the risk of developing toxin-mediated symptoms. We sought to evaluate the effectiveness and cost-effectiveness of a vaccine candidate in a hospital setting. We developed an agent-based simulation model of nosocomial CDI in a 300-bed hospital. Targeting high-risk patients for vaccination, we estimated the reduction of symptomatic CDI. Using the net reduction of CDI-associated isolation days, we evaluated the vaccine's cost-effectiveness from a healthcare provider perspective over a 2-year period with an average monthly incidence of 5 cases per 10,000 patient-days pre-vaccination. Assuming a vaccine efficacy in the range 60-90%, vaccinating 40% of high-risk patients pre-admission reduced symptomatic CDI by 16.6% (95% CI: 15.2, 17.9). When the vaccine coverage increased to 80%, the reduction of symptomatic CDI was 34.6% (95% CI: 33.7, 35.9). For a willingness to pay (WTP) of CDN$1000 (corresponding to the average costs of case isolation per day), vaccine was cost-effective for vaccination costs per individual (VCPI) up to CDN$111 in the scenario of 40% vaccine coverage. With the same WTP, vaccine was cost-effective for VCPI up to CDN$121 when the vaccine coverage increased to 80%. A significant portion (~80%) of hospital colonization is caused by environmental transmission of C. difficile, which markedly reduced the effectiveness of vaccine below its assumed efficacy. However, due to the number of CDI-associated isolation days averted, vaccination of high-risk patients can be cost-effective depending on the WTP and the VCPI.

Inferring generation-interval distributions from contact-tracing data.

Generation intervals, defined as the time between when an individual is infected and when that individual infects another person, link two key quantities that describe an epidemic: the initial reproductive number, [Formula: see text], and the initial rate of exponential growth, r. Generation intervals can be measured through contact tracing by identifying who infected whom. We study how realized intervals differ from 'intrinsic' intervals that describe individual-level infectiousness and identify both spatial and temporal effects, including truncating (due to observation time), and the effects of susceptible depletion at various spatial scales. Early in an epidemic, we expect the variation in the realized generation intervals to be mainly driven by truncation and by the population structure near the source of disease spread; we predict that correcting realized intervals for the effect of temporal truncation but not for spatial effects will provide the initial forward generation-interval distribution, which is spatially informed and correctly links r and [Formula: see text]. We develop and test statistical methods for temporal corrections of generation intervals, and confirm our prediction using individual-based simulations on an empirical network.