Age-structured Transmission Model Research Articles

Role of the dengue vaccine TAK-003 in an outbreak response: Modeling the Sri Lanka experience.

Outbreaks of dengue can overburden hospital systems, drastically reducing capacity for other care. The 2017 dengue serotype 2 (DENV-2) outbreak in Sri Lanka coincided with vaccination in an ongoing phase 3 efficacy trial of a tetravalent dengue vaccine, TAK-003 (NCT02747927). Here, we present data on the efficacy of TAK-003 following two doses of the vaccine administered 3 months apart in participants aged 4-16 years in Sri Lanka. In addition, we have used the 2017 outbreak dynamics to model the potential impact of TAK-003 on virologically confirmed dengue (VCD) cases and hospitalizations during an outbreak situation. Modeling was performed using an age-structured, host-vector, spatial and stochastic transmission model, assuming 65% vaccine coverage and 30 days until initiation of vaccination. Efficacy of TAK-003 against VCD and hospitalized VCD cases was based on data against DENV-2 from the first year of the phase 3 trial. Vaccine efficacy and safety findings in Sri Lanka were in line with those of the overall trial population. The efficacy estimates in Sri Lanka up to the first 12 months after the second dose of TAK-003 were 94.7% and 95.7% against VCD and hospitalized VCD cases, respectively. Modeling of the trial data over an extended geographic area showed a substantial reduction in cases and a flattening of outbreak curves from TAK-003 use. The baseline vaccination scenario (initiation at 30 days, 65% target coverage, vaccine effective at 14 days, 70% hospitalization rate, VE of 95% for VCD and 97% for hospitalized VCD, and 47% for asymptomatic) resulted in a 69.1% reduction in VCD cases and 72.7% reduction in VCD hospitalizations compared with no vaccination. An extreme high scenario (vaccination initiated at Day 15, 80% coverage rate, baseline VE) resulted in 80.3% and 82.3% reduction in VCD and VCD hospitalizations, respectively. Vaccine performance, speed of vaccination campaign initiation, and vaccine coverage were key drivers in reducing VCD cases and hospitalizations. Overall, the study and modelling results indicate that TAK-003 has the potential of meaningful utility in dengue outbreaks in endemic areas.

Social vs. individual age-dependent costs of imperfect vaccination

In diseases with long-term immunity, vaccination is known to increase the average age at infection as a result of the decrease in the pathogen circulation. This implies that a vaccination campaign can have negative effects when a disease is more costly (financial or health-related costs) for higher ages. This work considers an age-structured population transmission model with imperfect vaccination. We aim to compare the social and individual costs of vaccination, assuming that disease costs are age-dependent, while the disease’s dynamic is age-independent. A model for pathogen deterministic dynamics in a population consisting of juveniles and adults, assumed to be rational agents, is introduced. The parameter region for which vaccination has a positive social impact is fully characterized and the Nash equilibrium of the vaccination game is obtained. Finally, collective strategies designed to promote voluntary vaccination, without compromising social welfare, are discussed.

Numerical threshold stability of a nonlinear age-structured reaction diffusion heroin transmission model

This paper deals with the numerical threshold stability of a nonlinear age-space structured heroin transmission model. A semi-discrete system is established by spatially domain discretization of the original nonlinear age-space structured model. A threshold value is proposed in stability analysis of the semi-discrete system and named as a numerical basic reproduction number. Besides the role it plays in numerical threshold stability analysis, the numerical basic reproduction number can preserve qualitative properties of the exact basic reproduction number and converge to the latter while stepsizes vanish. A fully discrete system is established via a time discretization of the semi-discrete system, in which an implicit-explicit technique is implemented to ensure the preservation of the biological meanings (such as positivity) without CFL restriction. Some numerical experiments are exhibited in the end to confirm the conclusions and explore the final state.

Cost-Effectiveness of Adjuvanted Quadrivalent Influenza Vaccine for Adults over 65 in France.

In France, influenza accounts for an average of over one million consultations with GPs, 20,000 hospitalizations, and 9000 deaths per year, particularly among the over-65s. This study evaluates the cost-effectiveness of the adjuvanted quadrivalent influenza vaccine (aQIV) compared to standard (SD-QIV) and high-dose (HD-QIV) quadrivalent influenza vaccines for individuals aged 65 and older in France. The age-structured SEIR transmission model, calibrated to simulate a mean influenza season, incorporates a contact matrix to estimate intergroup contact rates. Epidemiological, economic, and utility outcomes are evaluated. Vaccine effectiveness and costs are derived from literature and national insurance data. Quality of life adjustments for influenza attack rates and hospitalizations are applied. Deterministic and probabilistic analyses are also conducted. Compared to SD-QIV, aQIV demonstrates substantial reductions in healthcare utilization and mortality, avoiding 89,485 GP consultations, 2144 hospitalizations, and preventing 1611 deaths. Despite an investment of EUR 110 million, aQIV yields a net saving of EUR 14 million in healthcare spending. Compared to HD-QIV, aQIV saves 62 million euros on vaccination costs. Cost-effectiveness analysis reveals an incremental cost-effectiveness ratio of EUR 7062 per QALY. This study highlights the cost-effectiveness of aQIV versus SD-QIV and HD-QIV, preventing influenza cases, hospitalizations, and deaths.

Evaluation of Strategies for Transitioning to Annual SARS-CoV-2 Vaccination Campaigns in the United States.

The U.S. Food and Drug Administration has proposed administering annual SARS-CoV-2 vaccines. To evaluate the effectiveness of an annual SARS-CoV-2 vaccination campaign, quantify the health and economic benefits of a second dose provided to children younger than 2 years and adults aged 50 years or older, and optimize the timing of a second dose. An age-structured dynamic transmission model. United States. A synthetic population reflecting demographics and contact patterns in the United States. Vaccination against SARS-CoV-2 with age-specific uptake similar to that of influenza vaccination. Incidence, hospitalizations, deaths, and direct health care cost. The optimal timing between the first and second dose delivered to children younger than 2 years and adults aged 50 years or older in an annual vaccination campaign was estimated to be 5 months. In direct comparison with a single-dose campaign, a second booster dose results in 123 869 fewer hospitalizations (95% uncertainty interval [UI], 121 994 to 125 742 fewer hospitalizations) and 5524 fewer deaths (95% UI, 5434 to 5613 fewer deaths), averting $3.63 billion (95% UI, $3.57 billion to $3.69 billion) in costs over a single year. Population immunity is subject to degrees of immune evasion for emerging SARS-CoV-2 variants. The model was implemented in the absence of nonpharmaceutical interventions and preexisting vaccine-acquired immunity. The direct health care costs of SARS-CoV-2, particularly among adults aged 50 years or older, would be substantially reduced by administering a second dose 5 months after the initial dose. Natural Sciences and Engineering Research Council of Canada, Notsew Orm Sands Foundation, National Institutes of Health, Centers for Disease Control and Prevention, and National Science Foundation.

Projecting COVID-19 intensive care admissions for policy advice, the Netherlands, February 2020 to January 2021.

BackgroundModel projections of coronavirus disease 2019 (COVID-19) incidence help policymakers about decisions to implement or lift control measures. During the pandemic, policymakers in the Netherlands were informed on a weekly basis with short-term projections of COVID-19 intensive care unit (ICU) admissions.AimWe aimed at developing a model on ICU admissions and updating a procedure for informing policymakers.MethodThe projections were produced using an age-structured transmission model. A consistent, incremental update procedure integrating all new surveillance and hospital data was conducted weekly. First, up-to-date estimates for most parameter values were obtained through re-analysis of all data sources. Then, estimates were made for changes in the age-specific contact rates in response to policy changes. Finally, a piecewise constant transmission rate was estimated by fitting the model to reported daily ICU admissions, with a changepoint analysis guided by Akaike's Information Criterion.ResultsThe model and update procedure allowed us to make weekly projections. Most 3-week prediction intervals were accurate in covering the later observed numbers of ICU admissions. When projections were too high in March and August 2020 or too low in November 2020, the estimated effectiveness of the policy changes was adequately adapted in the changepoint analysis based on the natural accumulation of incoming data.ConclusionThe model incorporates basic epidemiological principles and most model parameters were estimated per data source. Therefore, it had potential to be adapted to a more complex epidemiological situation with the rise of new variants and the start of vaccination.

Wildlife vaccination strategies for eliminating bovine tuberculosis in white-tailed deer populations.

Many pathogens of humans and livestock also infect wildlife that can act as a reservoir and challenge disease control or elimination. Efficient and effective prioritization of research and management actions requires an understanding of the potential for new tools to improve elimination probability with feasible deployment strategies that can be implemented at scale. Wildlife vaccination is gaining interest as a tool for managing several wildlife diseases. To evaluate the effect of vaccinating white-tailed deer (Odocoileus virginianus), in combination with harvest, in reducing and eliminating bovine tuberculosis from deer populations in Michigan, we developed a mechanistic age-structured disease transmission model for bovine tuberculosis with integrated disease management. We evaluated the impact of pulse vaccination across a range of vaccine properties. Pulse vaccination was effective for reducing disease prevalence rapidly with even low (30%) to moderate (60%) vaccine coverage of the susceptible and exposed deer population and was further improved when combined with increased harvest. The impact of increased harvest depended on the relative strength of transmission modes, i.e., direct vs indirect transmission. Vaccine coverage and efficacy were the most important vaccine properties for reducing and eliminating disease from the local population. By fitting the model to the core endemic area of bovine tuberculosis in Michigan, USA, we identified feasible integrated management strategies involving vaccination and increased harvest that reduced disease prevalence in free-ranging deer. Few scenarios led to disease elimination due to the chronic nature of bovine tuberculosis. A long-term commitment to regular vaccination campaigns, and further research on increasing vaccines efficacy and uptake rate in free-ranging deer are important for disease management.

Dynamical analysis of an age-structured cholera transmission model on complex networks

Cholera is a water- and food-borne infectious disease caused by the bacterium Vibrio cholerae. In this paper, we present a novel modeling framework to investigate the effect of infection age on cholera transmission in a heterogeneous population. Our model is constructed on a system with infection age on complex networks, including both direct and indirect transmission routes and demographics. The basic reproduction number R0 is derived as the spectral radius of the next generation operator, and it is verified that R0 is a sharp threshold that determines whether cholera becomes extinct or not. Numerical simulations are performed to confirm the theoretical results. Furthermore, the sensitivity analysis of the basic reproduction number to the parameters suggests that the implementation of effective drug treatment for infected individuals and the timely removal of pathogens from contaminated water are beneficial to control the spread of cholera.

The interplay between age structure and cultural transmission.

Empirical work has shown that human cultural transmission can be heavily influenced by population age structure. We aim to explore the role of such age structure in shaping the cultural composition of a population when cultural transmission occurs in an unbiased way. In particular, we are interested in understanding the effect induced by the interplay between age structure and the cultural transmission process by allowing cultural transmission from individuals within a limited age range only. To this end we develop an age-structured cultural transmission model and find that age-structured and non age-structured populations evolving through unbiased transmission possess very similar cultural compositions (at a single point in time) at the population and sample level if the copy pool consists of a sufficiently large fraction of the population. If, however, an age constraint-a structural constraint restricting the pool of potential role models to individuals of a limited age range- exists, the cultural compositions of age-structured and non age-structured population show stark differences. This may have drastic consequences for our ability to correctly analyse cultural data sets. Rejections of tests of neutrality, blind to age structure and, importantly, the interaction between age structure and cultural transmission, are only indicative of biased transmission if it is known a priori that there are no or only weak age constraints acting on the pool of role models. As this knowledge is rarely available for specific empirical case studies we develop a generative inference approach based on our age-structured cultural transmission model and machine learning techniques. We show that in some circumstances it is possible to simultaneously infer the characteristics of the age structure, the nature of the transmission process, and the interplay between them from observed samples of cultural variants. Our results also point to hard limits on inference from population-level data at a single point in time, regardless of the approach used.

Global age-structured spatial modeling for emerging infectious diseases like COVID-19.

Modeling the global dynamics of emerging infectious diseases (EIDs) like COVID-19 can provide important guidance in the preparation and mitigation of pandemic threats. While age-structured transmission models are widely used to simulate the evolution of EIDs, most of these studies focus on the analysis of specific countries and fail to characterize the spatial spread of EIDs across the world. Here, we developed a global pandemic simulator that integrates age-structured disease transmission models across 3,157 cities and explored its usage under several scenarios. We found that without mitigations, EIDs like COVID-19 are highly likely to cause profound global impacts. For pandemics seeded in most cities, the impacts are equally severe by the end of the first year. The result highlights the urgent need for strengthening global infectious disease monitoring capacity to provide early warnings of future outbreaks. Additionally, we found that the global mitigation efforts could be easily hampered if developed countries or countries near the seed origin take no control. The result indicates that successful pandemic mitigations require collective efforts across countries. The role of developed countries is vitally important as their passive responses may significantly impact other countries.

Transmission modeling to infer tuberculosis incidence prevalence and mortality in settings with generalized HIV epidemics

Tuberculosis (TB) killed more people globally than any other single pathogen over the past decade. Where surveillance is weak, estimating TB burden estimates uses modeling. In many African countries, increases in HIV prevalence and antiretroviral therapy have driven dynamic TB epidemics, complicating estimation of burden, trends, and potential intervention impact. We therefore develop a novel age-structured TB transmission model incorporating evolving demographic, HIV and antiretroviral therapy effects, and calibrate to TB prevalence and notification data from 12 African countries. We use Bayesian methods to include uncertainty for all TB model parameters, and estimate age-specific annual risks of TB infection, finding up to 16.0%/year in adults, and the proportion of TB incidence from recent (re)infection, finding a mean across countries of 34%. Rapid reduction of the unacceptably high burden of TB in high HIV prevalence settings will require interventions addressing progression as well as transmission.

Preparing for the upcoming 2022/23 influenza season: A modelling study of the susceptible population in Australia, France, Germany, Italy, Spain and the United Kingdom

We analysed the influenza epidemic that occurred in Australia during the 2022 winter using an age-structured dynamic transmission model, which accounts for past epidemics to estimate the population susceptibility to an influenza infection. We applied the same model to five European countries. Our analysis suggests Europe might experience an early and moderately large influenza epidemic. Also, differences may arise between countries, with Germany and Spain experiencing larger epidemics, than France, Italy and the United Kingdom, especially in children.

Predicted effectiveness of vaccines and extended half-life monoclonal antibodies against RSV hospitalizations in children

Several vaccines and extended half-life monoclonal antibodies (mAbs) against respiratory syncytial virus (RSV) have shown promise in clinical trials. We used age-structured transmission models to predict the possible impact of various RSV prevention strategies including maternal immunization, live-attenuated vaccines, and long-lasting mAbs. Our results suggest that maternal immunization and long-lasting mAbs are likely to be highly effective in preventing RSV hospitalizations in infants under 6 months of age, averting more than half of RSV hospitalizations in neonates. Live-attenuated vaccines could reduce RSV hospitalizations in vaccinated age groups and are also predicted to have a modest effect in unvaccinated age groups because of disruptions to transmission. Compared to year-round vaccination, a seasonal vaccination program at the country level provides at most a minor advantage regarding efficiency. Our findings highlight the substantial public health impact that upcoming RSV prevention strategies may provide.

Epidemiological impact and cost-effectiveness analysis of COVID-19 vaccination in Kenya

BackgroundA few studies have assessed the epidemiological impact and the cost-effectiveness of COVID-19 vaccines in settings where most of the population had been exposed to SARS-CoV-2 infection.MethodsWe conducted a cost-effectiveness...

Determinants of RSV epidemiology following suppression through pandemic contact restrictions

IntroductionCOVID-19 related non-pharmaceutical interventions (NPIs) led to a suppression of RSV circulation in winter 2020/21 in the UK and an off-season resurgence in Summer 2021. We explore how the parameters of RSV epidemiology shape the size and dynamics of post-suppression resurgence and what we can learn about them from the resurgence patterns observed so far. MethodsWe developed an age-structured dynamic transmission model of RSV and sampled the parameters governing RSV seasonality, infection susceptibility and post-infection immunity, retaining simulations fitting the UK’s pre-pandemic epidemiology by a set of global criteria consistent with likelihood calculations. From Spring 2020 to Summer 2021 we assumed a reduced contact frequency, returning to pre-pandemic levels from Spring 2021. We simulated transmission forwards until 2023 and evaluated the impact of the sampled parameters on the projected trajectories of RSV hospitalisations and compared these to the observed resurgence. ResultsSimulations replicated an out-of-season resurgence of RSV in 2021. If unmitigated, paediatric RSV hospitalisation incidence in the 2021/22 season was projected to increase by 30–60% compared to pre-pandemic levels. The increase was larger if infection risk was primarily determined by immunity acquired from previous exposure rather than age-dependent factors, exceeding 90 % and 130 % in 1–2 and 2–5 year old children, respectively. Analysing the simulations replicating the observed early outbreak in 2021 in addition to pre-pandemic RSV data, we found they were characterised by weaker seasonal forcing, stronger age-dependence of infection susceptibility and higher baseline transmissibility. ConclusionCOVID-19 mitigation measures in the UK stopped RSV circulation in the 2020/21 season and generated immunity debt leading to an early off-season RSV epidemic in 2021. A stronger dependence of infection susceptibility on immunity from previous exposure increases the size of the resurgent season. The early onset of the RSV resurgence in 2021, its marginally increased size relative to previous seasons and its decline by January 2022 suggest a stronger dependence of infection susceptibility on age-related factors, as well as a weaker effect of seasonality and a higher baseline transmissibility. The pattern of resurgence has been complicated by contact levels still not back to pre-pandemic levels. Further fitting of RSV resurgence in multiple countries incorporating data on contact patterns will be needed to further narrow down these parameters and to better predict the pathogen’s future trajectory, planning for a potential expansion of new immunisation products against RSV in the coming years.

The backward bifurcation of an age-structured cholera transmission model with saturation incidence.

In this paper, we consider an age-structured cholera model with saturation incidence, vaccination age of vaccinated individuals, infection age of infected individuals, and biological age of pathogens. First, the basic reproduction number is calculated. When the basic reproduction number is less than one, the disease-free equilibrium is locally stable. Further, the existence of backward bifurcation of the model is obtained. Numerically, we also compared the effects of various control measures, including basic control measures and vaccination, on the number of infected individuals.

The Epidemiological and Economic Impact of a Cell-Based Quadrivalent Influenza Vaccine in Adults in the US: A Dynamic Modeling Approach.

Mutations of the H3N2 vaccine strain during the egg-based vaccine manufacturing process partly explain the suboptimal effectiveness of traditional seasonal influenza vaccines. Cell-based influenza vaccines improve antigenic match and vaccine effectiveness by avoiding such egg-adaptation. This study evaluated the public health and economic impact of a cell-based quadrivalent influenza vaccine (QIVc) in adults (18–64 years) compared to the standard egg-based quadrivalent influenza vaccine (QIVe) in the US. The impact of QIVc over QIVe in public health and cost outcomes was estimated using a dynamic age-structured SEIR transmission model, which accounted for four circulating influenza strains [A/H1N1pdm9, A/H3N2, B(Victoria), and B(Yamagata)] and was calibrated on the 2013–2018 influenza seasons. The robustness of the results was assessed in univariate and probabilistic sensitivity analyses. Switching from QIVe to QIVc in 18- to 64-year-olds may prevent 5.7 million symptomatic cases, 1.8 million outpatient visits, 50,000 hospitalizations, and 5453 deaths annually. The switch could save 128,000 Quality-Adjusted Life Years (QALYs) and US $ 845 M in direct costs, resulting in cost-savings in a three-year time horizon analysis. Probabilistic sensitivity analyses confirmed the robustness of the cost-saving result. The analysis shows that QIVc is expected to prevent hospitalizations and deaths, and result in substantial savings in healthcare costs.

Controlling the pandemic during the SARS-CoV-2 vaccination rollout

There is a consensus that mass vaccination against SARS-CoV-2 will ultimately end the COVID-19 pandemic. However, it is not clear when and which control measures can be relaxed during the rollout of vaccination programmes. We investigate relaxation scenarios using an age-structured transmission model that has been fitted to age-specific seroprevalence data, hospital admissions, and projected vaccination coverage for Portugal. Our analyses suggest that the pressing need to restart socioeconomic activities could lead to new pandemic waves, and that substantial control efforts prove necessary throughout 2021. Using knowledge on control measures introduced in 2020, we anticipate that relaxing measures completely or to the extent as in autumn 2020 could launch a wave starting in April 2021. Additional waves could be prevented altogether if measures are relaxed as in summer 2020 or in a step-wise manner throughout 2021. We discuss at which point the control of COVID-19 would be achieved for each scenario.

Antibody and Antigen Prevalence as Indicators of Ongoing Transmission or Elimination of Visceral Leishmaniasis: A Modeling Study.

BackgroundControl of visceral leishmaniasis (VL) on the Indian subcontinent has been highly successful. Control efforts such as indoor residual spraying and active case detection will be scaled down or even halted over the coming years. We explored how after scale-down, potential recurrence of VL cases may be predicted based on population-based surveys of antibody or antigenemia prevalence.MethodsUsing a stochastic age-structured transmission model of VL, we predicted trends in case incidence and biomarker prevalence over time after scaling down control efforts when the target of 3 successive years without VL cases has been achieved. Next, we correlated biomarker prevalence with the occurrence of new VL cases within 10 years of scale-down.ResultsOccurrence of at least 1 new VL case in a population of 10 000 was highly correlated with the seroprevalence and antigenemia prevalence at the moment of scale-down, or 1 or 2 years afterward. Receiver operating characteristic curves indicated that biomarker prevalence in adults provided the most predictive information, and seroprevalence was a more informative predictor of new VL cases than antigenemia prevalence. Thresholds for biomarker prevalence to predict occurrence of new VL cases with high certainty were robust to variation in precontrol endemicity.ConclusionsThe risk of recrudescence of VL after scaling down control efforts can be monitored and mitigated by means of population-based surveys. Our findings highlight that rapid point-of-care diagnostic tools to assess (preferably) seroprevalence or (otherwise) antigenemia in the general population could be a key ingredient of sustainable VL control.

Simulated Identification of Silent COVID-19 Infections Among Children and Estimated Future Infection Rates With Vaccination

A significant proportion of COVID-19 transmission occurs silently during the presymptomatic and asymptomatic stages of infection. Children, although important drivers of silent transmission, are not included in the current COVID-19 vaccination campaigns. To estimate the benefits of identifying silent infections among children as a proxy for their vaccination. This study used an age-structured disease transmission model, parameterized with census data and estimates from published literature, to simulate the estimated synergistic effect of interventions in reducing attack rates during the course of 1 year among a synthetic population representative of the US demographic composition. The population included 6 age groups of 0 to 4, 5 to 10, 11 to 18, 19 to 49, 50 to 64, and 65 years or older based on US census data. Data were analyzed from December 12, 2020, to February 26, 2021. In addition to the isolation of symptomatic cases within 24 hours of symptom onset, vaccination of adults was implemented to reach a 40% to 60% coverage during 1 year with an efficacy of 95% against symptomatic and severe COVID-19. The combinations of proportion and speed for detecting silent infections among children that would suppress future attack rates to less than 5%. In the base-case scenarios with an effective reproduction number Re = 1.2, a targeted approach that identifies 11% of silent infections among children within 2 days and 14% within 3 days after infection would bring attack rates to less than 5% with 40% vaccination coverage of adults. If silent infections among children remained undetected, achieving the same attack rates would require an unrealistically high vaccination coverage (≥81%) of this age group, in addition to 40% vaccination coverage of adults. The estimated effect of identifying silent infections was robust in sensitivity analyses with respect to vaccine efficacy against infection and reduced susceptibility of children to infection. In this simulation modeling study of a synthetic US population, in the absence of vaccine availability for children, a targeted approach to rapidly identify silent COVID-19 infections in this age group was estimated to significantly mitigate disease burden. These findings suggest that without measures to interrupt transmission chains from silent infections, vaccination of adults is unlikely to contain the outbreaks in the near term.