The Hidden Burden of Dengue and Chikungunya in Chennai,India

Background

Dengue and chikungunya are rapidly expanding viruses transmitted by mosquitoes of the genus Aedes. Few epidemiological studies have examined the extent of transmission of these infections in South India despite an increase in the number of reported cases, and a high suitability for transmission.

Methods and findings

We conducted a household-based seroprevalence survey among 1010 individuals aged 5-40 years living in fifty randomly selected spatial locations in Chennai, Tamil Nadu. Participants were asked to provide a venous blood sample and to complete a brief questionnaire with basic demographic and daily activity information. Previous exposure to dengue and chikungunya was determined using IgG indirect ELISA (Panbio) and IgG ELISA (Novatec), respectively. We used this data to estimate key transmission parameters (force of infection and basic reproductive number) and to explore factors associated with seropositivity. While only 1% of participants reported history of dengue and 20% of chikungunya, we found that 93% (95%CI 89-95%) of participants were seropositive to dengue virus, and 44% (95%CI 37-50%) to chikungunya. Age-specific seroprevalence was consistent with long-tem, endemic circulation of dengue and suggestive of epidemic chikungunya transmission. Seropositivity to dengue and chikungunya were significantly correlated, even after adjusting for individual and household factors. We estimate that 23% of the susceptible population gets infected by dengue each year, corresponding to approximately 228,000 infections. This transmission intensity is significantly higher than that estimated in known hyperendemic settings in Southeast Asia and the Americas.

Conclusions

These results provide unprecedented insight into the very high transmission potential of dengue and chikungunya in Chennai and underscore the need for enhanced surveillance and control methods.     

The Effects of Vector Movement and Distribution in a Mathematical Model of Dengue Transmission

Background

Mathematical models have been used to study the dynamics of infectious disease outbreaks and predict the effectiveness of potential mass vaccination campaigns. However, models depend on simplifying assumptions to be tractable, and the consequences of making such assumptions need to be studied. Two assumptions usually incorporated by mathematical models of vector-borne disease transmission is homogeneous mixing among the hosts and vectors and homogeneous distribution of the vectors.

Methodology/Principal Findings

We explored the effects of mosquito movement and distribution in an individual-based model of dengue transmission in which humans and mosquitoes are explicitly represented in a spatial environment. We found that the limited flight range of the vector in the model greatly reduced its ability to transmit dengue among humans. A model that does not assume a limited flight range could yield similar attack rates when transmissibility of dengue was reduced by 39%. A model in which mosquitoes are distributed uniformly across locations behaves similarly to one in which the number of mosquitoes per location is drawn from an exponential distribution with a slightly higher mean number of mosquitoes per location. When the models with different assumptions were calibrated to have similar human infection attack rates, mass vaccination had nearly identical effects.

Conclusions/Significance

Small changes in assumptions in a mathematical model of dengue transmission can greatly change its behavior, but estimates of the effectiveness of mass dengue vaccination are robust to some simplifying assumptions typically made in mathematical models of vector-borne disease.     

A mathematical model for malaria involving differential susceptibility, exposedness and infectivity of human host

The main purpose of this article is to formulate a deterministic mathematical model for the transmission of malaria that considers two host types in the human population. The first type is called "non-immune" comprising all humans who have never acquired immunity against malaria and the second type is called "semi-immune". Non-immune are divided into susceptible, exposed and infectious and semi-immune are divided into susceptible, exposed, infectious and immune. We obtain an explicit formula for the reproductive number, R(0) which is a function of the weight of the transmission semi-immune-mosquito-semi-immune, R(0a), and the weight of the transmission non-immune-mosquito-non-immune, R(0e). Then, we study the existence of endemic equilibria by using bifurcation analysis. We give a simple criterion when R(0) crosses one for forward and backward bifurcation. We explore the possibility of a control for malaria through a specific sub-group such as non-immune or semi-immune or mosquitoes.     

Comparison of Vector Competence of Aedes mediovittatus and Aedes aegypti for Dengue Virus: Implications for Dengue Control in the Caribbean

Background

Aedes mediovittatus mosquitoes are found throughout the Greater Antilles in the Caribbean and often share the same larval habitats with Ae. Aegypti, the primary vector for dengue virus (DENV). Implementation of vector control measures to control dengue that specifically target Ae. Aegypti may not control DENV transmission in Puerto Rico (PR). Even if Ae. Aegypti is eliminated or DENV refractory mosquitoes are released, DENV transmission may not cease when other competent mosquito species like Ae. Mediovittatus are present. To compare vector competence of Ae. Mediovittatus and Ae. Aegypti mosquitoes, we studied relative infection and transmission rates for all four DENV serotypes.

Methods

To compare the vector competence of Ae. Mediovittatus and Ae. Aegypti, mosquitoes were exposed to DENV 1–4 per os at viral titers of 5–6 logs plaque-forming unit (pfu) equivalents. At 14 days post infectious bloodmeal, viral RNA was extracted and tested by qRT-PCR to determine infection and transmission rates. Infection and transmission rates were analyzed with a generalized linear model assuming a binomial distribution.

Results

Ae. Aegypti had significantly higher DENV-4 infection and transmission rates than Ae. mediovittatus.

Conclusions

This study determined that Ae. Mediovittatus is a competent DENV vector. Therefore dengue prevention programs in PR and the Caribbean should consider both Ae. Mediovittatus and Ae. Aegypti mosquitoes in their vector control programs.     

Modelling the Use of Wolbachia to Control Dengue Fever Transmission

Experiments and field trials have shown that the intracellular bacterium Wolbachia may be introduced into populations of the mosquito Aedes aegypti, the primary vector for dengue fever. In the absence of Wolbachia, a mosquito acquiring the dengue virus from an infected human enters an exposed (infected but not infectious) period before becoming infectious itself. A Wolbachia-infected mosquito that acquires dengue (i) may have a reduced lifespan, so that it is less likely to survive the exposed period and become infectious, and (ii) may have a reduced ability to transmit dengue, even if it has survived the exposed period. Wolbachia introduction has therefore been suggested as a potential dengue control measure. We set up a mathematical model for the system to investigate this suggestion and to evaluate the desirable properties of the Wolbachia strain to be introduced. We show that Wolbachia has excellent potential for dengue control in areas where R ₀ is not too large. However, if R ₀ is large, Wolbachia strains that reduce but do not eliminate dengue transmission have little effect on endemic steady states or epidemic sizes. Unless control measures to reduce R ₀ by reducing mosquito populations are also put in place, it may be worth the extra effort in such cases to introduce Wolbachia strains that eliminate dengue transmission completely.     

Transmission dynamics of West Nile virus in mosquitoes and corvids and non-corvids

There are more than 300 avian species that can transmit West Nile virus (WNv). In general, the corvid and non-corvid families of birds have different responses to the virus, with corvids suffering a higher disease-induced mortality rate. By taking both corvids and non-corvids as the primary reservoir hosts and mosquitoes as vectors; we formulate and study a system of ordinary differential equations to model a single season of the transmission dynamics of WNv in the mosquito–bird cycle. We calculate the basic reproduction number and analyze the existence and stability of the equilibria. The existence of a backward bifurcation gives a further sub-threshold condition beyond the basic reproduction number for the spread of the virus. We also discuss the role of corvids and non-corvids in spreading the virus. We conclude that knowledge of the relative abundance of corvid bird species and other mammals assist us in accurate estimation of the epidemic of WNv.     

The Interactive Roles of Aedes aegypti Super-Production and Human Density in Dengue Transmission

Background

A. aegypti production and human density may vary considerably in dengue endemic areas. Understanding how interactions between these factors influence the risk of transmission could improve the effectiveness of the allocation of vector control resources. To evaluate the combined impacts of variation in A. aegypti production and human density we integrated field data with simulation modeling.

Methodology/Principal Findings

Using data from seven censuses of A. aegypti pupae (2007–2009) and from demographic surveys, we developed an agent-based transmission model of the dengue transmission cycle across houses in 16 dengue-endemic urban ‘patches’ (1–3 city blocks each) of Armenia, Colombia. Our field data showed that 92% of pupae concentrated in only 5% of houses, defined as super-producers. Average secondary infections (R₀) depended on infrequent, but highly explosive transmission events. These super-spreading events occurred almost exclusively when the introduced infectious person infected mosquitoes that were produced in super-productive containers. Increased human density favored R₀, and when the likelihood of human introduction of virus was incorporated into risk, a strong interaction arose between vector production and human density. Simulated intervention of super-productive containers was substantially more effective in reducing dengue risk at higher human densities.

Significance/Conclusions

These results show significant interactions between human population density and the natural regulatory pattern of A. aegypti in the dynamics of dengue transmission. The large epidemiological significance of super-productive containers suggests that they have the potential to influence dengue viral adaptation to mosquitoes. Human population density plays a major role in dengue transmission, due to its potential impact on human-A. aegypti contact, both within a person''s home and when visiting others. The large variation in population density within typical dengue endemic cities suggests that it should be a major consideration in dengue control policy.     

Meteorologically Driven Simulations of Dengue Epidemics in San Juan,PR

Meteorological factors influence dengue virus ecology by modulating vector mosquito population dynamics, viral replication, and transmission. Dynamic modeling techniques can be used to examine how interactions among meteorological variables, vectors and the dengue virus influence transmission. We developed a dengue fever simulation model by coupling a dynamic simulation model for Aedes aegypti, the primary mosquito vector for dengue, with a basic epidemiological Susceptible-Exposed-Infectious-Recovered (SEIR) model. Employing a Monte Carlo approach, we simulated dengue transmission during the period of 2010–2013 in San Juan, PR, where dengue fever is endemic. The results of 9600 simulations using varied model parameters were evaluated by statistical comparison (r²) with surveillance data of dengue cases reported to the Centers for Disease Control and Prevention. To identify the most influential parameters associated with dengue virus transmission for each period the top 1% of best-fit model simulations were retained and compared. Using the top simulations, dengue cases were simulated well for 2010 (r² = 0.90, p = 0.03), 2011 (r² = 0.83, p = 0.05), and 2012 (r² = 0.94, p = 0.01); however, simulations were weaker for 2013 (r² = 0.25, p = 0.25) and the entire four-year period (r² = 0.44, p = 0.002). Analysis of parameter values from retained simulations revealed that rain dependent container habitats were more prevalent in best-fitting simulations during the wetter 2010 and 2011 years, while human managed (i.e. manually filled) container habitats were more prevalent in best-fitting simulations during the drier 2012 and 2013 years. The simulations further indicate that rainfall strongly modulates the timing of dengue (e.g., epidemics occurred earlier during rainy years) while temperature modulates the annual number of dengue fever cases. Our results suggest that meteorological factors have a time-variable influence on dengue transmission relative to other important environmental and human factors.     

Human Social Behavior and Demography Drive Patterns of Fine-Scale Dengue Transmission in Endemic Areas of Colombia

Dengue is known to transmit between humans and A. aegypti mosquitoes living in neighboring houses. Although transmission is thought to be highly heterogeneous in both space and time, little is known about the patterns and drivers of transmission in groups of houses in endemic settings. We carried out surveys of PCR positivity in children residing in 2-block patches of highly endemic cities of Colombia. We found high levels of heterogeneity in PCR positivity, varying from less than 30% in 8 of the 10 patches to 56 and 96%, with the latter patch containing 22 children simultaneously PCR positive (PCR22) for DEN2. We then used an agent-based model to assess the likely eco-epidemiological context of this observation. Our model, simulating daily dengue dynamics over a 20 year period in a single two block patch, suggests that the observed heterogeneity most likely derived from variation in the density of susceptible people. Two aspects of human adaptive behavior were critical to determining this density: external social relationships favoring viral introduction (by susceptible residents or infectious visitors) and immigration of households from non-endemic areas. External social relationships generating frequent viral introduction constituted a particularly strong constraint on susceptible densities, thereby limiting the potential for explosive outbreaks and dampening the impact of heightened vectorial capacity. Dengue transmission can be highly explosive locally, even in neighborhoods with significant immunity in the human population. Variation among neighborhoods in the density of local social networks and rural-to-urban migration is likely to produce significant fine-scale heterogeneity in dengue dynamics, constraining or amplifying the impacts of changes in mosquito populations and cross immunity between serotypes.     

Synchrony of Sylvatic Dengue Isolations: A Multi-Host,Multi-Vector SIR Model of Dengue Virus Transmission in Senegal

Isolations of sylvatic dengue-2 virus from mosquitoes, humans and non-human primates in Senegal show synchronized multi-annual dynamics over the past 50 years. Host demography has been shown to directly affect the period between epidemics in other pathogen systems, therefore, one might expect unsynchronized multi-annual cycles occurring in hosts with dramatically different birth rates and life spans. However, in Senegal, we observe a single synchronized eight-year cycle across all vector species, suggesting synchronized dynamics in all vertebrate hosts. In the current study, we aim to explore two specific hypotheses: 1) primates with different demographics will experience outbreaks of dengue at different periodicities when observed as isolated systems, and that coupling of these subsystems through mosquito biting will act to synchronize incidence; and 2) the eight-year periodicity of isolations observed across multiple primate species is the result of long-term cycling in population immunity in the host populations. To test these hypotheses, we develop a multi-host, multi-vector Susceptible, Infected, Removed (SIR) model to explore the effects of coupling multiple host-vector systems of dengue virus transmission through cross-species biting rates. We find that under small amounts of coupling, incidence in the host species synchronize. Long-period multi-annual dynamics are observed only when prevalence in troughs reaches vanishingly small levels (), suggesting that these dynamics are inconsistent with sustained transmission in this setting, but are consistent with local dengue virus extinctions followed by reintroductions. Inclusion of a constant introduction of infectious individuals into the system causes the multi-annual periods to shrink, while the effects of coupling remain the same. Inclusion of a stochastic rate of introduction allows for multi-annual periods at a cost of reduced synchrony. Thus, we conclude that the eight-year period separating amplifications of dengue may be explained by cycling in immunity with stochastic introductions.     

Dengue Virus Type 2 Infections of Aedes aegypti Are Modulated by the Mosquito's RNA Interference Pathway

A number of studies have shown that both innate and adaptive immune defense mechanisms greatly influence the course of human dengue virus (DENV) infections, but little is known about the innate immune response of the mosquito vector Aedes aegypti to arbovirus infection. We present evidence here that a major component of the mosquito innate immune response, RNA interference (RNAi), is an important modulator of mosquito infections. The RNAi response is triggered by double-stranded RNA (dsRNA), which occurs in the cytoplasm as a result of positive-sense RNA virus infection, leading to production of small interfering RNAs (siRNAs). These siRNAs are instrumental in degradation of viral mRNA with sequence homology to the dsRNA trigger and thereby inhibition of virus replication. We show that although dengue virus type 2 (DENV2) infection of Ae. aegypti cultured cells and oral infection of adult mosquitoes generated dsRNA and production of DENV2-specific siRNAs, virus replication and release of infectious virus persisted, suggesting viral circumvention of RNAi. We also show that DENV2 does not completely evade RNAi, since impairing the pathway by silencing expression of dcr2, r2d2, or ago2, genes encoding important sensor and effector proteins in the RNAi pathway, increased virus replication in the vector and decreased the extrinsic incubation period required for virus transmission. Our findings indicate a major role for RNAi as a determinant of DENV transmission by Ae. aegypti.     

Modeling the Geographic Spread of Rabies in China

In order to investigate how the movement of dogs affects the geographically inter-provincial spread of rabies in Mainland China, we propose a multi-patch model to describe the transmission dynamics of rabies between dogs and humans, in which each province is regarded as a patch. In each patch the submodel consists of susceptible, exposed, infectious, and vaccinated subpopulations of both dogs and humans and describes the spread of rabies among dogs and from infectious dogs to humans. The existence of the disease-free equilibrium is discussed, the basic reproduction number is calculated, and the effect of moving rates of dogs between patches on the basic reproduction number is studied. To investigate the rabies virus clades lineages, the two-patch submodel is used to simulate the human rabies data from Guizhou and Guangxi, Hebei and Fujian, and Sichuan and Shaanxi, respectively. It is found that the basic reproduction number of the two-patch model could be larger than one even if the isolated basic reproduction number of each patch is less than one. This indicates that the immigration of dogs may make the disease endemic even if the disease dies out in each isolated patch when there is no immigration. In order to reduce and prevent geographical spread of rabies in China, our results suggest that the management of dog markets and trades needs to be regulated, and transportation of dogs has to be better monitored and under constant surveillance.     

Analysis of rabies in China: transmission dynamics and control

Human rabies is one of the major public-health problems in China. The number of human rabies cases has increased dramatically in the last 15 years, partially due to the poor understanding of the transmission dynamics of rabies and the lack of effective control measures of the disease. In this article, in order to explore effective control and prevention measures we propose a deterministic model to study the transmission dynamics of rabies in China. The model consists of susceptible, exposed, infectious, and recovered subpopulations of both dogs and humans and describes the spread of rabies among dogs and from infectious dogs to humans. The model simulations agree with the human rabies data reported by the Chinese Ministry of Health. We estimate that the basic reproduction number for the rabies transmission in China and predict that the number of the human rabies is decreasing but may reach another peak around 2030. We also perform some sensitivity analysis of in terms of the model parameters and compare the effects of culling and immunization of dogs. Our study demonstrates that (i) reducing dog birth rate and increasing dog immunization coverage rate are the most effective methods for controlling rabies in China; and (ii) large scale culling of susceptible dogs can be replaced by immunization of them.     

The impact of maturation delay of mosquitoes on the transmission of West Nile virus

We formulate and analyze a delay differential equation model for the transmission of West Nile virus between vector mosquitoes and avian hosts that incorporates maturation delay for mosquitoes. The maturation time from eggs to adult mosquitoes is sensitive to weather conditions, in particular the temperature, and the model allows us to investigate the impact of this maturation time on transmission dynamics of the virus among mosquitoes and birds. Numerical results of the model show that a combination of the maturation time and the vertical transmission of the virus in mosquitoes has substantial influence on the abundance and number of infection peaks of the infectious mosquitoes.     

埃及伊蚊对登革Ⅱ型病毒感染Balb/C实验小鼠的增强

以Balb/C小鼠为实验动物,探讨了埃及伊蚊Aedes aegypti唾液对登革病毒感染宿主的影响。结果显示,在皮下接种剂量相同的情况下,如果Balb/C实验小鼠预先被一定数量的埃及伊蚊叮咬以后,实验小鼠感染病毒的程度有所提高,血清中的抗体滴度明显降低,腹腔巨噬细胞感染登革病毒的阳性率及感染的时间动态曲线也有明显差异,感染高峰期延迟。这些说明实验小鼠被媒介蚊虫叮咬以后变得相对容易被登革病毒感染,可能是媒介蚊虫叮咬小鼠时分泌的唾液对宿主的免疫反应系统有一定作用。因此可以初步肯定埃及伊蚊在登革病毒的感染传播过程中,影响了Balb/C实验小鼠的免疫功能,对登革病毒的感染有一定推动作用。     

Threshold Dynamics of a Temperature-Dependent Stage-Structured Mosquito Population Model with Nested Delays

Mosquito-borne diseases remain a significant threat to public health and economics. Since mosquitoes are quite sensitive to temperature, global warming may not only worsen the disease transmission case in current endemic areas but also facilitate mosquito population together with pathogens to establish in new regions. Therefore, understanding mosquito population dynamics under the impact of temperature is considerably important for making disease control policies. In this paper, we develop a stage-structured mosquito population model in the environment of a temperature-controlled experiment. The model turns out to be a system of periodic delay differential equations with periodic delays. We show that the basic reproduction number is a threshold parameter which determines whether the mosquito population goes to extinction or remains persistent. We then estimate the parameter values for Aedes aegypti, the mosquito that transmits dengue virus. We verify the analytic result by numerical simulations with the temperature data of Colombo, Sri Lanka where a dengue outbreak occurred in 2017.     

Controlling Dengue with Vaccines in Thailand

Background

Dengue is a mosquito-borne infectious disease that constitutes a growing global threat with the habitat expansion of its vectors Aedes aegyti and A. albopictus and increasing urbanization. With no effective treatment and limited success of vector control, dengue vaccines constitute the best control measure for the foreseeable future. With four interacting dengue serotypes, the development of an effective vaccine has been a challenge. Several dengue vaccine candidates are currently being tested in clinical trials. Before the widespread introduction of a new dengue vaccine, one needs to consider how best to use limited supplies of vaccine given the complex dengue transmission dynamics and the immunological interaction among the four dengue serotypes.

Methodology/Principal Findings

We developed an individual-level (including both humans and mosquitoes), stochastic simulation model for dengue transmission and control in a semi-rural area in Thailand. We calibrated the model to dengue serotype-specific infection, illness and hospitalization data from Thailand. Our simulations show that a realistic roll-out plan, starting with young children then covering progressively older individuals in following seasons, could reduce local transmission of dengue to low levels. Simulations indicate that this strategy could avert about 7,700 uncomplicated dengue fever cases and 220 dengue hospitalizations per 100,000 people at risk over a ten-year period.

Conclusions/Significance

Vaccination will have an important role in controlling dengue. According to our modeling results, children should be prioritized to receive vaccine, but adults will also need to be vaccinated if one wants to reduce community-wide dengue transmission to low levels.     

A mathematical model for malaria involving differential susceptibility,exposedness and infectivity of human host

The main purpose of this article is to formulate a deterministic mathematical model for the transmission of malaria that considers two host types in the human population. The first type is called “non-immune” comprising all humans who have never acquired immunity against malaria and the second type is called “semi-immune”. Non-immune are divided into susceptible, exposed and infectious and semi-immune are divided into susceptible, exposed, infectious and immune. We obtain an explicit formula for the reproductive number, R ₀ which is a function of the weight of the transmission semi-immune-mosquito-semi-immune, R _0a , and the weight of the transmission non-immune-mosquito-non-immune, R _0e . Then, we study the existence of endemic equilibria by using bifurcation analysis. We give a simple criterion when R ₀ crosses one for forward and backward bifurcation. We explore the possibility of a control for malaria through a specific sub-group such as non-immune or semi-immune or mosquitoes.