Minimal within-host dengue models highlight the specific roles of the immune response in primary and secondary dengue infections

Rotem Ben-Shachar and Katia Koelle

Journal of the Royal Society, Interface

December 17, 2015


In recent years, the within-host viral dynamics of dengue infections have been increasingly characterized, and the relationship between aspects of these dynamics and the manifestation of severe disease has been increasingly probed. Despite this progress, there are few mathematical models of within-host dengue dynamics, and the ones that exist focus primarily on the general role of immune cells in the clearance of infected cells, while neglecting other components of the immune response in limiting viraemia. Here, by considering a suite of mathematical within-host dengue models of increasing complexity, we aim to isolate the critical components of the innate and the adaptive immune response that suffice in the reproduction of several well-characterized features of primary and secondary dengue infections. By building up from a simple target cell limited model, we show that only the innate immune response is needed to recover the characteristic features of a primary symptomatic dengue infection, while a higher rate of viral infectivity (indicative of antibody-dependent enhancement) and infected cell clearance by T cells are further needed to recover the characteristic features of a secondary dengue infection. We show that these minimal models can reproduce the increased risk of disease associated with secondary heterologous infections that arises as a result of a cytokine storm, and, further, that they are consistent with virological indicators that predict the onset of severe disease, such as the magnitude of peak viraemia, time to peak viral load, and viral clearance rate. Finally, we show that the effectiveness of these virological indicators to predict the onset of severe disease depends on the contribution of T cells in fuelling the cytokine storm.

Seven challenges for model-driven data collection in experimental and observational studies

J. Lessler,  W.J. Edmunds, M.E. Halloran, T.D. Hollingsworth,  A.L. Lloyd


December 16, 2014


Infectious disease models are both concise statements of hypotheses and powerful techniques for creating tools from hypotheses and theories. As such, they have tremendous potential for guiding data collection in experimental and observational studies, leading to more efficient testing of hypotheses and more robust study designs. In numerous instances, infectious disease models have played a key role in informing data collection, including the Garki project studying malaria, the response to the 2009 pandemic of H1N1 influenza in the United Kingdom and studies of T-cell immunodynamics in mammals. However, such synergies remain the exception rather than the rule; and a close marriage of dynamic modeling and empirical data collection is far from the norm in infectious disease research. Overcoming the challenges to using models to inform data collection has the potential to accelerate innovation and to improve practice in how we deal with infectious disease threats.

Opinion: Mathematical models: A key tool for outbreak response

E. Lofgren, M.E. Halloran, C.M. Rivers, J.M. Drake, T.C. Porco, B. Lewis, W. Yang, A. Vespignani, J. Shaman, J.N.S. Eisenberg, M.C. Eisenberg, M. Marathe, S.V. Scarpino, K.A. Alexander, R. Meza, M.J. Ferrari, J.M. Hyman, L.A. Meyers, S. Eubank 


December 10, 2014


The 2014 outbreak of Ebola in West Africa is unprecedented in its size and geographic range, and demands swift, effective action from the international community. Understanding the dynamics and spread of Ebola is critical for directing interventions and extinguishing the epidemic; however, observational studies of local conditions have been incomplete and limited by the urgent need to direct resources to patient care.

Mathematical and computational models can help address this deficiency through work with sparse observations, inference on missing data, and incorporation of the latest information. These models can clarify how the disease is spreading and provide timely guidance to policymakers. However, the use of models in public health often meets resistance (1), from doubts in peer review about the utility of such analyses to public skepticism that models can contribute when the means to control an epidemic are already known (2). Even when they are discussed in a positive light, models are often portrayed as arcane and largely inaccessible thought experiments (3). However, the role of models is crucial: they can be used to quantify the effect of mitigation efforts, provide guidance on the scale of interventions required to achieve containment, and identify factors that fundamentally influence the course of an outbreak.


School-Located Influenza Vaccination Reduces Community Risk for Influenza and Influenza-Like Illness Emergency Care Visits

C.H. Tran, J.D. Sugimoto, J.R.C. Pulliam, K.A. Ryan, P.D. Myers, 
J.B. Castleman, R. Doty, J. Johnson, J. Stringfellow, 
N. Kovacevich, J. Brew, L.L. Cheung, B. Caron, G. Lipori, 
C.A. Harle, C. Alexander, Y. Yang, I.M. Longini Jr., 
M.E. Halloran, J.G. Morris Jr., P.A. Small Jr.


December 9, 2014


School-located influenza vaccination (SLIV) programs can substantially enhance the sub-optimal coverage achieved under existing delivery strategies. Randomized SLIV trials have shown these programs reduce laboratory-confirmed influenza among both vaccinated and unvaccinated children. This work explores the effectiveness of a SLIV program in reducing the community risk of influenza and influenza-like illness (ILI) associated emergency care visits.


For the 2011/12 and 2012/13 influenza seasons, we estimated age-group specific attack rates (AR) for ILI from routine surveillance and census data. Age-group specific SLIV program effectiveness was estimated as one minus the AR ratio for Alachua County versus two comparison regions: the 12 county region surrounding Alachua County, and all non-Alachua counties in Florida.


Vaccination of ~50% of 5–17 year-olds in Alachua reduced their risk of ILI-associated visits, compared to the rest of Florida, by 79% (95% confidence interval: 70, 85) in 2011/12 and 71% (63, 77) in 2012/13. The greatest indirect effectiveness was observed among 0–4 year-olds, reducing AR by 89% (84, 93) in 2011/12 and 84% (79, 88) in 2012/13. Among all non-school age residents, the estimated indirect effectiveness was 60% (54, 65) and 36% (31, 41) for 2011/12 and 2012/13. The overall effectiveness among all age-groups was 65% (61, 70) and 46% (42, 50) for 2011/12 and 2012/13.


Wider implementation of SLIV programs can significantly reduce the influenza-associated public health burden in communities.

Comparative Effectiveness of Different Strategies of Oral Cholera Vaccination in Bangladesh: A Modeling Study

Dobromir T. Dimitrov , Christopher Troeger , M. Elizabeth Halloran, Ira M. Longini , Dennis L. Chao

Neglected Tropical Diseases

December 4, 2014


Killed, oral cholera vaccines have proven safe and effective, and several large-scale mass cholera vaccination efforts have demonstrated the feasibility of widespread deployment. This study uses a mathematical model of cholera transmission in Bangladesh to examine the effectiveness of potential vaccination strategies.

Methods & Findings

We developed an age-structured mathematical model of cholera transmission and calibrated it to reproduce the dynamics of cholera in Matlab, Bangladesh. We used the model to predict the effectiveness of different cholera vaccination strategies over a period of 20 years. We explored vaccination programs that targeted one of three increasingly focused age groups (the entire vaccine-eligible population of age one year and older, children of ages 1 to 14 years, or preschoolers of ages 1 to 4 years) and that could occur either as campaigns recurring every five years or as continuous ongoing vaccination efforts. Our modeling results suggest that vaccinating 70% of the population would avert 90% of cholera cases in the first year but that campaign and continuous vaccination strategies differ in effectiveness over 20 years. Maintaining 70% coverage of the population would be sufficient to prevent sustained transmission of endemic cholera in Matlab, while vaccinating periodically every five years is less effective. Selectively vaccinating children 1–14 years old would prevent the most cholera cases per vaccine administered in both campaign and continuous strategies.


We conclude that continuous mass vaccination would be more effective against endemic cholera than periodic campaigns. Vaccinating children averts more cases per dose than vaccinating all age groups, although vaccinating only children is unlikely to control endemic cholera in Bangladesh. Careful consideration must be made before generalizing these results to other regions.

Ebola: Mobility data

M.E. Halloran, A. Vespignani, N. Bharti, L.R. Feldstein, K.A. Alexander, M. Ferrari, J. Shaman, J.M. Drake, T. Porco, J.N.S. Eisenberg, S.Y. Del Valle, E. Lofgren, S.V. Scarpino, M.C. Eisenberg, D. Gao, J.M. Hyman, S. Eubank, I.M. Longini


October 24, 2014

Understanding human movement and mobility is important for characterizing, forecasting, and controlling the spatial and temporal spread of infectious diseases. Unfortunately, the current West African Ebola outbreak is taking place in a region where mobility has changed considerably in recent years. Efforts must be made to better understand these mobility patterns. For example, mobile phone call records provide insight into how people move within countries, particularly if they move from hotspots of disease. Analyses of Orange Telecom data have produced initial maps of movement in Senegal and Ivory Coast (1, 2), and endeavors are under way to obtain similar data for Sierra Leone, Guinea, and Liberia.


Assessing the impact of travel restrictions on international spread of the 2014 West African Ebola epidemic

C. Poletto, M.F. Gomes, A. Pastore y Piontti, L. Rossi, L. Bioglio, D.L. Chao, I.M. Longini, M.E. Halloran, V. Colizza, A. Vespignani

Euro Surveillance

October 23, 2014


The quick spread of an Ebola outbreak in West Africa has led a number of countries and airline companies to issue travel bans to the affected areas. Considering data up to 31 Aug 2014, we assess the impact of the resulting traffic reductions with detailed numerical simulations of the international spread of the epidemic. Traffic reductions are shown to delay by only a few weeks the risk that the outbreak extends to new countries.