Individual Infectiousness Research Articles

Interplay between viral shedding, age, and symptoms on individual infectiousness of influenza cases in households.

Understanding factors affecting the infectiousness of influenza cases is crucial for disease prevention and control. Viral shedding is expected to correlate with infectiousness of cases, but it is strongly associated with age and the presence of symptoms. To elucidate this complex interplay, we analyze with an individual-based household transmission model a detailed household transmission study of influenza with 442 households and 1710 individuals from 2008 to 2017 in Hong Kong, to characterize the household transmission dynamics and identify factors affecting transmissions. We estimate that age, fever symptoms and viral load were all associated with higher infectiousness. However, by model comparison, the best model includes age and fever as factors affecting individual infectiousness, and estimates that pre-school and school-age children were 317% (95% credible interval (CrI): 103%, 1042%) and 161% (95% CrI: 33%, 601%) more infectious than adults respectively, and patients having fever had 146% (95% CrI: 37%, 420%) higher infectiousness. Adding heterogeneity on individual infectiousness of cases does not improve the model fit, suggesting these factors could explain the difference in individual infectiousness. Our study clarifies the contribution of age, symptoms and viral shedding to individual infectiousness of influenza cases in households.

Generalized epidemic model incorporating non-Markovian infection processes and waning immunity.

The Markovian approach, which assumes exponentially distributed interinfection times, is dominant in epidemic modeling. However, this assumption is unrealistic as an individual's infectiousness depends on its viral load and varies over time. In this paper, we present a Susceptible-Infected-Recovered-Vaccinated-Susceptible epidemic model incorporating non-Markovian infection processes. The model can be easily adapted to accurately capture the generation time distributions of emerging infectious diseases, which is essential for accurate epidemic prediction. We observe noticeable variations in the transient behavior under different infectiousness profiles and the same basic reproduction number R_{0}. The theoretical analyses show that only R_{0} and the mean immunity period of the vaccinated individuals have an impact on the critical vaccination rate needed to achieve herd immunity. A vaccination level at the critical vaccination rate can ensure a very low incidence among the population in the case of future epidemics, regardless of the infectiousness profiles.

The effect of variation of individual infectiousness on SARS-CoV-2 transmission in households.

Quantifying variation of individual infectiousness is critical to inform disease control. Previous studies reported substantial heterogeneity in transmission of many infectious diseases including SARS-CoV-2. However, those results are difficult to interpret since the number of contacts is rarely considered in such approaches. Here, we analyze data from 17 SARS-CoV-2 household transmission studies conducted in periods dominated by ancestral strains, in which the number of contacts was known. By fitting individual-based household transmission models to these data, accounting for number of contacts and baseline transmission probabilities, the pooled estimate suggests that the 20% most infectious cases have 3.1-fold (95% confidence interval: 2.2- to 4.2-fold) higher infectiousness than average cases, which is consistent with the observed heterogeneity in viral shedding. Household data can inform the estimation of transmission heterogeneity, which is important for epidemic management.

Factors driving norovirus transmission in long-term care facilities: A case-level analysis of 107 outbreaks

Norovirus is the most common cause of gastroenteritis outbreaks in long-term care facilities (LTCFs) in the United States, causing a high burden of disease in both residents and staff. Understanding how case symptoms and characteristics contribute to norovirus transmission can lead to more informed outbreak control measures in LTCFs. We examined line lists for 107 norovirus outbreaks that took place in LTCFs in five U.S. states from 2015 to 2019. We estimated the individual effective reproduction number, Ri, to quantify individual case infectiousness and examined the contribution of vomiting, diarrhea, and being a resident (vs. staff) to case infectiousness. The associations between case characteristics and Ri were estimated using a multivariable, log-linear mixed model with inverse variance weighting. We found that cases with vomiting infected 1.28 (95 % CI: 1.11, 1.48) times the number of secondary cases compared to cases without vomiting, and LTCF residents infected 1.31 (95 % CI: 1.15, 1.50) times the number of secondary cases compared to staff. There was no difference in infectiousness between cases with and without diarrhea (1.07; 95 % CI: 0.90, 1.29). This suggests that vomiting, particularly by LTCF residents, was a primary driver of norovirus transmission. These results support control measures that limit exposure to vomitus during norovirus outbreaks in LTCFs.

Aligning staff schedules, testing, and isolation reduces the risk of COVID-19 outbreaks in carceral and other congregate settings: A simulation study.

COVID-19 outbreaks in congregate settings remain a serious threat to the health of disproportionately affected populations such as people experiencing incarceration or homelessness, the elderly, and essential workers. An individual-based model accounting for individual infectiousness over time, staff work schedules, and testing and isolation schedules was developed to simulate community transmission of SARS-CoV-2 to staff in a congregate facility and subsequent transmission within the facility that could cause an outbreak. Systematic testing strategies in which staff are tested on the first day of their workweek were found to prevent up to 16% more infections than testing strategies unrelated to staff schedules. Testing staff at the beginning of their workweek, implementing timely isolation following testing, limiting test turnaround time, and increasing test frequency in high transmission scenarios can supplement additional mitigation measures to aid outbreak prevention in congregate settings.

Coupling the Within-Host Process and Between-Host Transmission of COVID-19 Suggests Vaccination and School Closures are Critical.

Most models of COVID-19 are implemented at a single micro or macro scale, ignoring the interplay between immune response, viral dynamics, individual infectiousness and epidemiological contact networks. Here we develop a data-driven model linking the within-host viral dynamics to the between-host transmission dynamics on a multilayer contact network to investigate the potential factors driving transmission dynamics and to inform how school closures and antiviral treatment can influence the epidemic. Using multi-source data, we initially determine the viral dynamics and estimate the relationship between viral load and infectiousness. Then, we embed the viral dynamics model into a four-layer contact network and formulate an agent-based model to simulate between-host transmission. The results illustrate that the heterogeneity of immune response between children and adults and between vaccinated and unvaccinated infections can produce different transmission patterns. We find that school closures play a significant effect on mitigating the pandemic as more adults get vaccinated and the virus mutates. If enough infected individuals are diagnosed by testing before symptom onset and then treated quickly, the transmission can be effectively curbed. Our multiscale model reveals the critical role played by younger individuals and antiviral treatment with testing in controlling the epidemic.

Characterizing superspreading potential of infectious disease: Decomposition of individual transmissibility.

In the context of infectious disease transmission, high heterogeneity in individual infectiousness indicates that a few index cases can generate large numbers of secondary cases, a phenomenon commonly known as superspreading. The potential of disease superspreading can be characterized by describing the distribution of secondary cases (of each seed case) as a negative binomial (NB) distribution with the dispersion parameter, k. Based on the feature of NB distribution, there must be a proportion of individuals with individual reproduction number of almost 0, which appears restricted and unrealistic. To overcome this limitation, we generalized the compound structure of a Poisson rate and included an additional parameter, and divided the reproduction number into independent and additive fixed and variable components. Then, the secondary cases followed a Delaporte distribution. We demonstrated that the Delaporte distribution was important for understanding the characteristics of disease transmission, which generated new insights distinct from the NB model. By using real-world dataset, the Delaporte distribution provides improvements in describing the distributions of COVID-19 and SARS cases compared to the NB distribution. The model selection yielded increasing statistical power with larger sample sizes as well as conservative type I error in detecting the improvement in fitting with the likelihood ratio (LR) test. Numerical simulation revealed that the control strategy-making process may benefit from monitoring the transmission characteristics under the Delaporte framework. Our findings highlighted that for the COVID-19 pandemic, population-wide interventions may control disease transmission on a general scale before recommending the high-risk-specific control strategies.

Robust models of disease heterogeneity and control, with application to the SARS-CoV-2 epidemic.

In light of the continuing emergence of new SARS-CoV-2 variants and vaccines, we create a robust simulation framework for exploring possible infection trajectories under various scenarios. The situations of primary interest involve the interaction between three components: vaccination campaigns, non-pharmaceutical interventions (NPIs), and the emergence of new SARS-CoV-2 variants. Additionally, immunity waning and vaccine boosters are modeled to account for their growing importance. New infections are generated according to a hierarchical model in which people have a random, individual infectiousness. The model thus includes super-spreading observed in the COVID-19 pandemic which is important for accurate uncertainty prediction. Our simulation functions as a dynamic compartment model in which an individual's history of infection, vaccination, and possible reinfection all play a role in their resistance to further infections. We present a risk measure for each SARS-CoV-2 variant, [Formula: see text], that accounts for the amount of resistance within a population and show how this risk changes as the vaccination rate increases. [Formula: see text] highlights that different variants may become dominant in different countries-and in different times-depending on the population compositions in terms of previous infections and vaccinations. We compare the efficacy of control strategies which act to both suppress COVID-19 outbreaks and relax restrictions when possible. We demonstrate that a controller that responds to the effective reproduction number in addition to case numbers is more efficient and effective in controlling new waves than monitoring case numbers alone. This not only reduces the median total infections and peak quarantine cases, but also controls outbreaks much more reliably: such a controller entirely prevents rare but large outbreaks. This is important as the majority of public discussions about efficient control of the epidemic have so far focused primarily on thresholds for case numbers.

Modeling to inform economy‐wide pandemic policy: Bringing epidemiologists and economists together

Modeling to inform economy‐wide pandemic policy: Bringing epidemiologists and economists together

In vivo kinetics of SARS-CoV-2 infection and its relationship with a person's infectiousness.

The within-host viral kinetics of SARS-CoV-2 infection and how they relate to a person's infectiousness are not well understood. This limits our ability to quantify the impact of interventions on viral transmission. Here, we develop viral dynamic models of SARS-CoV-2 infection and fit them to data to estimate key within-host parameters such as the infected cell half-life and the within-host reproductive number. We then develop a model linking viral load (VL) to infectiousness and show a person's infectiousness increases sublinearly with VL and that the logarithm of the VL in the upper respiratory tract is a better surrogate of infectiousness than the VL itself. Using data on VL and the predicted infectiousness, we further incorporated data on antigen and RT-PCR tests and compared their usefulness in detecting infection and preventing transmission. We found that RT-PCR tests perform better than antigen tests assuming equal testing frequency; however, more frequent antigen testing may perform equally well with RT-PCR tests at a lower cost but with many more false-negative tests. Overall, our models provide a quantitative framework for inferring the impact of therapeutics and vaccines that lower VL on the infectiousness of individuals and for evaluating rapid testing strategies.

Understanding why superspreading drives the COVID-19 pandemic but not the H1N1 pandemic

Understanding why superspreading drives the COVID-19 pandemic but not the H1N1 pandemic

Heterogeneity in transmissibility and shedding SARS-CoV-2 via droplets and aerosols.

Which virological factors mediate overdispersion in the transmissibility of emerging viruses remains a long-standing question in infectious disease epidemiology. Here, we use systematic review to develop a comprehensive dataset of respiratory viral loads (rVLs) of SARS-CoV-2, SARS-CoV-1 and influenza A(H1N1)pdm09. We then comparatively meta-analyze the data and model individual infectiousness by shedding viable virus via respiratory droplets and aerosols. The analyses indicate heterogeneity in rVL as an intrinsic virological factor facilitating greater overdispersion for SARS-CoV-2 in the COVID-19 pandemic than A(H1N1)pdm09 in the 2009 influenza pandemic. For COVID-19, case heterogeneity remains broad throughout the infectious period, including for pediatric and asymptomatic infections. Hence, many COVID-19 cases inherently present minimal transmission risk, whereas highly infectious individuals shed tens to thousands of SARS-CoV-2 virions/min via droplets and aerosols while breathing, talking and singing. Coughing increases the contagiousness, especially in close contact, of symptomatic cases relative to asymptomatic ones. Infectiousness tends to be elevated between 1 and 5 days post-symptom onset. Intrinsic case variation in rVL facilitates overdispersion in the transmissibility of emerging respiratory viruses. Our findings present considerations for disease control in the COVID-19 pandemic as well as future outbreaks of novel viruses. Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant program, NSERC Senior Industrial Research Chair program and the Toronto COVID-19 Action Fund.

Inferencing superspreading potential using zero-truncated negative binomial model: exemplification with COVID-19

BackgroundIn infectious disease transmission dynamics, the high heterogeneity in individual infectiousness indicates that few index cases generate large numbers of secondary cases, which is commonly known as superspreading events. The heterogeneity in transmission can be measured by describing the distribution of the number of secondary cases as a negative binomial (NB) distribution with dispersion parameter, k. However, such inference framework usually neglects the under-ascertainment of sporadic cases, which are those without known epidemiological link and considered as independent clusters of size one, and this may potentially bias the estimates.MethodsIn this study, we adopt a zero-truncated likelihood-based framework to estimate k. We evaluate the estimation performance by using stochastic simulations, and compare it with the baseline non-truncated version. We exemplify the analytical framework with three contact tracing datasets of COVID-19.ResultsWe demonstrate that the estimation bias exists when the under-ascertainment of index cases with 0 secondary case occurs, and the zero-truncated inference overcomes this problem and yields a less biased estimator of k. We find that the k of COVID-19 is inferred at 0.32 (95%CI: 0.15, 0.64), which appears slightly smaller than many previous estimates. We provide the simulation codes applying the inference framework in this study.ConclusionsThe zero-truncated framework is recommended for less biased transmission heterogeneity estimates. These findings highlight the importance of individual-specific case management strategies to mitigate COVID-19 pandemic by lowering the transmission risks of potential super-spreaders with priority.

Adequacy of SEIR models when epidemics have spatial structure: Ebola in Sierra Leone.

Dynamic SEIR (Susceptible, Exposed, Infectious, Removed) compartmental models provide a tool for predicting the size and duration of both unfettered and managed outbreaks-the latter in the context of interventions such as case detection, patient isolation, vaccination and treatment. The reliability of this tool depends on the validity of key assumptions that include homogeneity of individuals and spatio-temporal homogeneity. Although the SEIR compartmental framework can easily be extended to include demographic (e.g. age) and additional disease (e.g. healthcare workers) classes, dependence of transmission rates on time, and metapopulation structure, fitting such extended models is hampered by both a proliferation of free parameters and insufficient or inappropriate data. This raises the question of how effective a tool the basic SEIR framework may actually be. We go some way here to answering this question in the context of the 2014-2015 outbreak of Ebola in West Africa by comparing fits of an SEIR time-dependent transmission model to both country- and district-level weekly incidence data. Our novel approach in estimating the effective-size-of-the-populations-at-risk ( Neff) and initial number of exposed individuals ( E0) at both district and country levels, as well as the transmission function parameters, including a time-to-halving-the-force-of-infection ( tf/2) parameter, provides new insights into this Ebola outbreak. It reveals that the estimate R0 ≈ 1.7 from country-level data appears to seriously underestimate R0 ≈ 3.3 - 4.3 obtained from more spatially homogeneous district-level data. Country-level data also overestimate tf/2 ≈ 22 weeks, compared with 8-10 weeks from district-level data. Additionally, estimates for the duration of individual infectiousness is around two weeks from spatially inhomogeneous country-level data compared with 2.4-4.5 weeks from spatially more homogeneous district-level data, which estimates are rather high compared with most values reported in the literature. This article is part of the theme issue 'Modelling infectious disease outbreaks in humans, animals and plants: approaches and important themes'. This issue is linked with the subsequent theme issue 'Modelling infectious disease outbreaks in humans, animals and plants: epidemic forecasting and control'.

Understanding the Importance of Contact Heterogeneity and Variable Infectiousness in the Dynamics of a Large Norovirus Outbreak.

Large norovirus (NoV) outbreaks are explosive in nature and vary widely in final size and duration, suggesting that superspreading combined with heterogeneous contact may explain these dynamics. Modeling tools that can capture heterogeneity in infectiousness and contact are important for NoV outbreak prevention and control, yet they remain limited. Data from a large NoV outbreak at a Dutch scout jamboree, which resulted in illness among 326 (of 4500 total) individuals from 7 separate camps, were used to examine the contributions of individual variation in infectiousness and clustered contact patterns to the transmission dynamics. A Bayesian hierarchical model of heterogeneous, clustered outbreak transmission was applied to represent (1) between-individual heterogeneity in infectiousness and (2) heterogeneous patterns of contact. We found wide heterogeneity in infectiousness across individuals, suggestive of superspreading. Nearly 50% of individual infectiousness was concentrated in the individual's subcamp of residence, with the remainder distributed over other subcamps. This suggests a source-and-sink dynamic in which subcamps with greater average infectiousness fed cases to those with a lower transmission rate. Although the per capita transmission rate within camps was significantly greater than that between camps, the large pool of susceptible individuals across camps enabled similar numbers of secondary cases generated between versus within camps. The consideration of clustered transmission and heterogeneous infectiousness is important for understanding NoV transmission dynamics. Models including these mechanisms may be useful for providing early warning and guiding outbreak response.

Quantifying Transmission.

Transmissibility is the defining characteristic of infectious diseases. Quantifying transmission matters for understanding infectious disease epidemiology and designing evidence-based disease control programs. Tracing individual transmission events can be achieved by epidemiological investigation coupled with pathogen typing or genome sequencing. Individual infectiousness can be estimated by measuring pathogen loads, but few studies have directly estimated the ability of infected hosts to transmit to uninfected hosts. Individuals' opportunities to transmit infection are dependent on behavioral and other risk factors relevant given the transmission route of the pathogen concerned. Transmission at the population level can be quantified through knowledge of risk factors in the population or phylogeographic analysis of pathogen sequence data. Mathematical model-based approaches require estimation of the per capita transmission rate and basic reproduction number, obtained by fitting models to case data and/or analysis of pathogen sequence data. Heterogeneities in infectiousness, contact behavior, and susceptibility can have substantial effects on the epidemiology of an infectious disease, so estimates of only mean values may be insufficient. For some pathogens, super-shedders (infected individuals who are highly infectious) and super-spreaders (individuals with more opportunities to transmit infection) may be important. Future work on quantifying transmission should involve integrated analyses of multiple data sources.

The role of symptomatic presentation in influenza A transmission risk.

Computer models can be useful in planning interventions against novel strains of influenza. However such models sometimes make unsubstantiated assumptions about the relative infectivity of asymptomatic and symptomatic cases, or conversely assume there is no impact at all. Using household-level data from known-index studies of virologically confirmed influenza A infection, the relationship between an individual's infectiousness and their symptoms was quantified using a discrete-generation transmission model and Bayesian Markov chain Monte Carlo methods. It was found that the presence of particular respiratory symptoms in an index case does not influence transmission probabilities, with the exception of child-to-child transmission where the donor has phlegm or a phlegmy cough.

Heterogeneity in pathogen transmission: mechanisms and methodology

SummaryHeterogeneity in the ability of hosts to transmit pathogens is among the most fundamental concepts in disease dynamics and has major implications for disease control strategies.The number of secondary infections produced by an infected individual is a function of three components: an individual's infectiousness, the rate at which it contacts susceptible individuals and the duration of infection. Individual‐level variation can emerge in each of these components through a combination of behavioural and physiological mechanisms.In this review, we describe mechanisms that promote variation in the number of individuals to which an individual transmits a pathogen,emphasizing insights that can be gained by understanding which components of transmission (infectiousness, contact rate, infection duration) are primarily affected. We also discuss how behavioural and physiological processes generate transmission heterogeneities across multiple scales, from individual‐level variation to heterogeneity among species.Strategies for quantifying each transmission component are presented, and we discuss why studies focusing on only one component of the infection process may be misleading.To conclude, we describe how future research focusing on variation in transmission across all three components can provide a more holistic view of heterogeneity in pathogen transmission.

The Potential Impact of Routine Immunization with Inactivated Poliovirus Vaccine on Wild-type or Vaccine-derived Poliovirus Outbreaks in a Posteradication Setting

The "endgame" for worldwide poliomyelitis eradication will entail eventual cessation of the use of oral poliovirus vaccine (OPV) in all countries to prevent the reintroduction of vaccine-derived polioviruses--exposing some populations to an unprecedented, albeit low, risk of poliovirus outbreaks. Inactivated poliovirus vaccine (IPV) is likely to play a large part in post--OPV management of poliovirus risks by reducing the consequences of any reintroduction of poliovirus. In this article, we examine the impact IPV would have on an outbreak in a partially susceptible population after OPV cessation, using a mathematical model of poliovirus transmission with a realistic natural history and case reporting. We explore a range of assumptions about the impact of IPV on an individual's infectiousness, given the lack of knowledge about this parameter. We show that routine use of IPV is beneficial under most conditions, increasing the chance of fadeout and reducing the expected prevalence of infection at the time of detection. The duration of "silent" poliovirus circulation prior to detection lengthens with increasing coverage of IPV, although this only increases the expected prevalence of infection at the time of the OPV response if IPV has a very limited impact on infectiousness. Overall, the model predicts that routine use of IPV will be advantageous for the posteradication management of poliovirus.

Transmission dynamics of primary pneumonic plague in the USA

Plague is thought to have killed millions during three catastrophic pandemics. Primary pneumonic plague, the most severe form of the disease, is transmissible from person-to-person and has the potential for propagating epidemics. Efforts to quantify its transmission potential have relied on published data from large outbreaks, an approach that artificially inflates the basic reproductive number (R(0)) and skews the distribution of individual infectiousness. Using data for all primary pneumonic plague cases reported in the USA from 1900 to 2009, we determined that the majority of cases will fail to transmit, even in the absence of antimicrobial treatment or prophylaxis. Nevertheless, potential for sustained outbreaks still exists due to superspreading events. These findings challenge current concepts regarding primary pneumonic plague transmission.