Why are dengue virus serotypes so distantly related? Enhancement and limiting serotype similarity between dengue virus strains

145

173

Dengue hemorrhagic fever (DHF) is a potentially fatal manifestation of an infection with the mosquito-borne dengue virus. Because of the social and economic costs of DHF, many countries in Asia and South America have initiated public health measures aimed at vector control. Despite these measures, DHF incidence rates do not appear to be declining. The effectiveness of vector control in reducing dengue transmissibility has thereby been questioned. Here, we revisit this conclusion using epidemiological data from Thailand. We first show, with age incidence data, that dengue transmission rates have fallen since 1981; surprisingly, however, these declines are not associated with decreases in DHF incidence. Instead, district-level analyses indicate a nonmonotonic relationship between the basic reproductive number R 0 and DHF incidence. To understand this relationship, we formulated three mathematical models, which differ in their assumptions of transient between-serotype cross-protection. Unlike the first two models, the previously unconsidered third model with clinical cross-protection can reproduce this nonmonotonic relationship. Simulation of this model with nonstationary R 0 reproduces several previously unexplained patterns of dengue dynamics, including a transition from a Ϸ2-year cycle to a Ϸ4-year cycle and a transient trough in DHF incidence in provinces with rapid R 0 declines. These results imply that DHF incidence can be effectively controlled with a sufficiently large reduction in R 0 but that moderate reductions may be counterproductive. More broadly, these results show that assuming parameter stationarity in systems with approximate stationarity in disease incidence is unjustified and may result in missed opportunities to understand the drivers of disease variability.dengue dynamics ͉ interannual disease variability ͉ multistrain dynamics

Section: Resultsmentioning

confidence: 97%

Decreases in dengue transmission may act to increase the incidence of dengue hemorrhagic fever

Nagao

Koelle

2008

145

173

“…The precise immunological consequences of ADE are not fully understood, but there are two alternative assumptions that can be made: (i) ADE can result in increased transmission, by either increased susceptibility to infection after a primary infection (32) or increased infectiousness with a secondary infection (25), perhaps through an increase in viral titers (ref. 33; both variations lead to similar results); or (ii) ADE can result in increased mortality after a secondary infection (27). Here, we focus on assumption i: increased susceptibility to infection after a primary infection, regulated by the parameter .…”

Section: Methodsmentioning

confidence: 92%

“…Previous theoretical work has demonstrated that if ADE is assumed to increase transmission, then coexistence and cyclic, possibly chaotic, strain fluctuations are promoted (25,26). However, if ADE is instead assumed to increase mortality and shorten the effective infectious period, it may decrease persistence (27).…”

Section: Alternative Hypothesesmentioning

confidence: 99%

Ecological and immunological determinants of dengue epidemics

Wearing¹,

Rohani

2006

285

286

The management of infectious diseases is an increasingly important public health issue, the effective implementation of which is often complicated by difficulties in teasing apart the relative roles of extrinsic and intrinsic factors influencing transmission. Dengue, a vector-borne strain polymorphic disease, is one such infection where transmission dynamics are affected by environmental variables as well as immune-mediated serotype interactions. To understand how alternative hypotheses concerning dengue infection and transmission may explain observed multiannual cycles in disease incidence, we adopt a theoretical approach that combines both ecological and immunological mechanisms. We demonstrate that, contrary to perceived wisdom, patterns generated solely by antibody-dependent enhancement or heterogeneity in virus virulence are not consistent with serotype-specific notification data in important ways. Furthermore, to generate epidemics with the characteristic signatures observed in data, we find that a combination of seasonal variation in vector demography and, crucially, a short-lived period of cross-immunity is sufficient. We then show how understanding the persistence and eradication of dengue serotypes critically depends on the alternative assumed mechanisms.antibody-dependent enhancement ͉ multistrain dynamics ͉ transient cross-immunity ͉ vector-transmitted disease

“…We believe this assumption is a reasonable because of the low case fatality rate of DHF (Ϸ0.01) and the much lower fatality rate of dengue infection (Ϸ0.0001) in Thailand (34). The work of Kawaguchi and Rohani (30,35) suggests that the dynamics of dengue are significantly impacted by dengue-induced mortality only at much higher levels of mortality than are observed. The rate of recovery, given by , is assumed to be equal for primary and secondary infections.…”

Section: Methodsmentioning

confidence: 94%

“…Research groups have explored the effects of ADE on the dynamics of dengue transmission by using several different approaches (25,27,29,30). Feng (29) examined the effect of ADE in a two-serotype model via the inclusion of a parameter that increased the susceptibility of those individuals who had previously been exposed to one serotype.…”

mentioning

confidence: 99%

Dynamic effects of antibody-dependent enhancement on the fitness of viruses

Cummings

Schwartz

Billings

et al. 2005

136

148

Antibody-dependent enhancement (ADE), a phenomenon in which viral replication is increased rather than decreased by immune sera, has been observed in vitro for a large number of viruses of public health importance, including flaviviruses, coronaviruses, and retroviruses. The most striking in vivo example of ADE in humans is dengue hemorrhagic fever, a disease in which ADE is thought to increase the severity of clinical manifestations of dengue virus infection by increasing virus replication. We examine the epidemiological impact of ADE on the prevalence and persistence of viral serotypes. Using a dynamical system model of n cocirculating dengue serotypes, we find that ADE may provide a competitive advantage to those serotypes that undergo enhancement compared with those that do not, and that this advantage increases with increasing numbers of cocirculating serotypes. Paradoxically, there are limits to the selective advantage provided by increasing levels of ADE, because greater levels of enhancement induce large amplitude oscillations in incidence of all dengue virus infections, threatening the persistence of both the enhanced and nonenhanced serotypes. Although the models presented here are specifically designed for dengue, our results are applicable to any epidemiological system in which partial immunity increases pathogen replication rates. Our results suggest that enhancement is most advantageous in settings where multiple serotypes circulate and where a large host population is available to support pathogen persistence during the deep troughs of ADE-induced large amplitude oscillations of virus replication.dengue ͉ adaptive ͉ trade-off