Maíra Aguiar

The role of seasonality and import in a minimalistic multi-strain dengue model capturing differences between primary and secondary infections: complex dynamics and its implications for data analysis.

In many countries in Asia and South-America dengue fever (DF) and dengue hemorrhagic fever (DHF) has become a substantial public health concern leading to serious social-economic costs. Mathematical models describing the transmission of dengue viruses have focussed on the so-called antibody-dependent enhancement (ADE) effect and temporary cross-immunity trying to explain the irregular behavior of dengue epidemics by analyzing available data. However, no systematic investigation of the possible dynamical structures has been performed so far. Our study focuses on a seasonally forced (non-autonomous) model with temporary cross-immunity and possible secondary infection, motivated by dengue fever epidemiology. The notion of at least two different strains is needed in a minimalistic model to describe differences between primary infections, often asymptomatic, and secondary infection, associated with the severe form of the disease. We extend the previously studied non-seasonal (autonomous) model by adding seasonal forcing, mimicking the vectorial dynamics, and a low import of infected individuals, which is realistic in the dynamics of dengue fever epidemics. A comparative study between three different scenarios (non-seasonal, low seasonal and high seasonal with a low import of infected individuals) is performed. The extended models show complex dynamics and qualitatively a good agreement between empirical DHF monitoring data and the obtained model simulation. We discuss the role of seasonal forcing and the import of infected individuals in such systems, the biological relevance and its implications for the analysis of the available dengue data. At the moment only such minimalistic models have a chance to be qualitatively understood well and eventually tested against existing data. The simplicity of the model (low number of parameters and state variables) offer a promising perspective on parameter values inference from the DHF case notifications.

The Impact of the Newly Licensed Dengue Vaccine in Endemic Countries

Background With approximately 3 billion people at risk of acquiring the infection, dengue fever is now considered the most important mosquito-borne viral disease in the world, with 390 million dengue infections occurring every year, of which 96 million manifest symptoms with any level of disease severity. Treatment of uncomplicated dengue cases is only supportive and severe dengue cases require hospital intensive care. A vaccine now licensed in several countries and developed by Sanofi Pasteur (CYD-TDV, named Dengvaxia), was able to protect, in the first 25 months of the two Phase III, 66% of a subset of 9–16 year old participants. However, a significantly lower efficacy (including negative vaccine efficacy) was noted for children younger than 9 years of age. Methodology/Principal Findings Analysis of year 3 results of phase III trials of Dengvaxia suggest high rates of protection of vaccinated partial dengue immunes but high rates of hospitalizations during breakthrough dengue infections of persons who were vaccinated when seronegative, with vaccine appearing to induce enhancing antibodies (ADE). An age structured model was developed based on Sanofi’s recommendation to vaccinate persons age 945 years in dengue endemic countries. The model was used to explore the clinical burden of two vaccination strategies: 1) Vaccinate 4 or 20% of individuals, ages 9–45 years, seropositives and seronegatives, and 2) vaccinate 4 or 20% of individuals, ages 9–45 years, who are dengue immune only. Conclusions/Significance Our results show that vaccinating dengue monotypic immune individuals prevents dengue hospitalizations, but at the same time dengue infections of vaccine-sensitized persons increases hospitalizations. When the vaccine is given only to partial immune individuals, after immunological screening of the population, disease burden decreases considerably.

Dynamic noise, chaos and parameter estimation in population biology

We revisit the parameter estimation framework for population biological dynamical systems, and apply it to calibrate various models in epidemiology with empirical time series, namely influenza and dengue fever. When it comes to more complex models such as multi-strain dynamics to describe the virus–host interaction in dengue fever, even the most recently developed parameter estimation techniques, such as maximum likelihood iterated filtering, reach their computational limits. However, the first results of parameter estimation with data on dengue fever from Thailand indicate a subtle interplay between stochasticity and the deterministic skeleton. The deterministic system on its own already displays complex dynamics up to deterministic chaos and coexistence of multiple attractors.

Torus bifurcations, isolas and chaotic attractors in a simple dengue fever model with ade and temporary cross immunity.

We analyse an epidemiological model of competing strains of pathogens and hence differences in transmission for first versus secondary infection due to interaction of the strains with previously aquired immunities, as has been described for dengue fever, is known as antibody dependent enhancement (ADE). These models show a rich variety of dynamics through bifurcations up to deterministic chaos. Including temporary cross-immunity even enlarges the parameter range of such chaotic attractors, and also gives rise to various coexisting attractors, which are difficult to identify by standard numerical bifurcation programs using continuation methods. A combination of techniques, including classical bifurcation plots and Lyapunov exponent spectra, has to be applied in comparison to get further insight into such dynamical structures. Here we present for the first time multi-parameter studies in a range of biologically plausible values for dengue. The multi-strain interaction with the immune system is expected to have implications for the epidemiology of other diseases also.

The risks behind Dengvaxia recommendation

882 www.thelancet.com/infection Vol 16 August 2016 3 Capeding MR, Tran NH, Hadinegoro SRS, et al. Clinical effi cacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet 2014; 384: 1358–65. 4 Villar L, Dayan GH, Arredondo-García JL, et al. Effi cacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med 2014; 372: 113–23. 5 Wilder-Smith A, Gubler D. Dengue vaccines at a crossroads. Science 2015; 350: 626–27. 1 WHO. Global Strategy for Dengue Prevention and Control. 2012–2020. Geneva: World Health Organization, 2012. http://apps.who.int/iris/ bitstream/10665/75303/1/9789241504034_eng.pdf?ua=1 (accessed April 20, 2016). 2 WHO. Summary of the April 2016 meeting of the Strategic Advisory Group of Experts on immunization (SAGE). Geneva: World Health Organization, 2016. http://www.who.int/immunization/sage/ meetings/2016/april/SAGE_April_2016_Meeting_Web_summary. pdf?ua=1 (accessed April 20, 2016).

Scale-free network of a dengue epidemic

Abstract In this work we show that the dengue epidemic in the city of Singapore organized itself into a scale-free network of transmission as the 2000–2005 outbreaks progressed. This scale-free network of cluster comprised geographical breeding places for the aedes mosquitoes, acting as super-spreaders nodes in a network of transmission. The geographical organization of the network was analysed by the corresponding distribution of weekly number of new cases. Therefore, our hypothesis is that the distribution of dengue cases reflects the geographical organization of a transmission network, which evolved towards a power law as the epidemic intensity progressed until 2005.

Carnival or football, is there a real risk for acquiring dengue fever in Brazil during holidays seasons?

More than 600,000 football fans, coming from all over the world, were expected to visit Brazil during the FIFA World Cup 2014. International travel can become a public health problem when the visitors start to become sick, needing medical intervention and eventually hospitalization. The occurrence of dengue fever infections in Brazil is persistent and has been increasing since the 1980s, and the health authorities were expected to take preventive measures and to warn the visitors about the risks during the tournament period. Before the World Cup started, studies have been published stating that dengue could be a significant problem in some of the Brazilian cities hosting the games. These conclusions were taken after a brief observation of the available data, analyzing its mean and standard deviation only, or based on seasonal climate forecasts, causing alarm for the world cup in Brazil. Here, with a more careful data analysis, we show that the seasonality of the disease plays a major role in dengue transmission. The density of dengue cases in Brazil is residual during winter in the Southern hemisphere (mid June to mid September) and the fans of football were not likely to get dengue during the tournament period.

Time-scale separation and centre manifold analysis describing vector-borne disease dynamics

In vector-borne diseases, the human hosts’ epidemiology often acts on a much slower time scales than the one of the mosquitos transmitting as a vector from human to human, due to their vastly different life cycles. We investigate in how far the fast time scale of the mosquito epidemiology can be slaved by the slower human epidemiology, so that for the understanding of human disease data mainly the dynamics of the human time scale is essential and only slightly perturbed by the mosquito dynamics.

Bifurcation analysis of a family of multi-strain epidemiology models

In this paper we use bifurcation theory to analyze three multi-strain compartmental models, motivated by dengue fever epidemiology. The models are extensions of the classical SIR model where the notion of two different strains is needed to describe primary and secondary infections. Ferguson et al. formulate and analyzed in Ferguson et al. (1999) [1] a two-strain model with Antibody Dependent Enhancement (ade), where the pre-existing antibodies to previous dengue infection cannot neutralize but rather enhance the new infection. No cross-immunity is assumed and therefore co-infection is possible and moreover individuals can belong to multiple compartments. In the modeling approach proposed by Billings et al. in (2007) [2] cross-infection is not possible as long as an individual is primarily infected. As a result all compartments are distinct. In the third model Aguiar et al. (2011) [9] starting from the Billings et al. model, temporary cross-immunity is introduced by additional compartments for the recovered from the primary infection. The study of the different models gives insight into how different long-term dynamic behavior originate. We use the same parameter set for all models, except the duration of the cross-immunity period in the last model which will be a bifurcation parameter. Another bifurcation parameter is the ade factor. Besides endemic equilibria and periodic solutions there is also chaotic behavior originating via different routes. Numerical bifurcation analysis, Lyapunov exponent calculation and simulation techniques (quantitative results) as well as symbolic analysis (qualitative results) are used to unravel the different types of long-term dynamics. When the cross-immunity period is moderately long or short the predictions show, besides similar chaotic dynamics as in the two models without temporal cross-immunity, a new chaotic attractor with a different origin.

Consider stopping dengvaxia administration without immunological screening

Developed by Sanofi Pasteur, a tetravalent dengue vaccine, Dengvaxia, was recently recommended by the World Health Organization (WHO) Strategic Advisory Group of Experts (SAGE) on Immunization, bas...