Series
Dengue: knowledge gaps, unmet needs, and research priorities

https://doi.org/10.1016/S1473-3099(16)30473-XGet rights and content

Summary

Dengue virus is a mosquito-borne pathogen that causes up to about 100 million cases of disease each year, placing a major public health, social, and economic burden on numerous low-income and middle-income countries. Major advances by investigators, vaccine developers, and affected communities are revealing new insights and enabling novel interventions and approaches to dengue prevention and control. Such research has highlighted further questions about both the basic understanding of dengue and efforts to develop new tools. In this report, the third in a Series on dengue, we discuss existing approaches to dengue diagnostics, disease prognosis, surveillance, and vector control in low-income and middle-income countries, as well as potential consequences of vaccine introduction. We also summarise current knowledge and recent insights into dengue epidemiology, immunology, and pathogenesis, and their implications for understanding natural infection and current and future vaccines.

Introduction

Dengue is the most prevalent arboviral disease in human beings, with 3·6 billion people living in areas with risk of disease transmission, and with an estimated 390 million dengue virus infections and 96 million dengue cases annually.1 Dengue is endemic to the tropical belt of Asia, Latin America, and the Pacific, it circulates across Africa, and it has recently caused local outbreaks in the USA and parts of Europe.1, 2, 3 Dengue has expanded globally since the 1960s, driven by population growth, urbanisation, increased travel, and insufficient vector control programmes. Despite increased funding and advances in dengue research, dengue epidemics are intensifying in frequency, magnitude, and geographical reach.4 The global burden of dengue is estimated at 25·5 disability-adjusted life-years per 100 000 individuals, with major economic, social, and political effects.5, 6 Public health systems are strained by the relentless spread of dengue virus and other arboviruses, such as chikungunya virus and Zika virus, and they are discouraged by decades of failed vector control programmes and absence of new interventions.

However, never before has the level of resources and commitment from diverse researchers and stakeholders been as great, or as focused on increasing basic knowledge, potential treatments and vaccines, and new vector control strategies, with the ultimate goal of conquering dengue. In this paper, we address existing tools and needs for dengue diagnostics and surveillance in low-income and middle-income countries, and review current knowledge and research gaps in immunology, epidemiology, dengue pathogenesis, and vector control in the context of natural infection and vaccines. Many of these insights call into question existing paradigms in the dengue field, and raise many new and exciting questions.

Section snippets

Case management

Dengue is caused by four dengue virus serotypes (DENV1–4), transmitted by the daytime-biting mosquitoes Aedes aegypti and Aedes albopictus. Dengue fever is characterised by debilitating symptoms, including high fever, arthralgia, myalgia, anorexia, petechiae or rash, and retro-orbital pain. Because symptoms are non-specific and overlap with those of many other infections, such as chikungunya virus and Zika virus, laboratory diagnosis is required. Upon defervescence, during the critical phase

Surveillance, outbreak response, and sero-epidemiogical studies

Most dengue-endemic countries rely on syndromic dengue surveillance, with laboratory-based confirmation of a subset of cases. Laboratory-enhanced sentinel surveillance systems provide more precise information to public health authorities on time, location, serotype, and disease severity, thus enabling an earlier trigger for interventions to mitigate outbreaks. Functional laboratory-based surveillance systems will be crucial for deployment of vaccine trials and for eventual vaccine rollout.

Vector control

Excellent vector control reviews have recently been written;16 in this section, we discuss key points in the context of vaccination programmes. To date, preventing or reducing dengue virus transmission has depended entirely on controlling the mosquito vectors. Even after vaccine deployment, vector control will continue to be part of control strategies to reduce disease risk and burden. The concept of integrated dengue management is now widely accepted.17, 18

The recent chikungunya and Zika virus

Modelling dengue transmission

Modelling dengue transmission enables the evaluation of the benefits and limitations of different dengue control methods; this is increasingly important as interventions such as vaccine and new vector control strategies come closer to implementation (table 2). Mathematical models have been developed to identify determinants of the oscillations of dengue virus serotypes in endemic settings, including the parts played by the mosquito vector and by immune enhancement from previous exposure to

The virus: serotypes, genotypes, and strains

Dengue virus serotypes, genotypes, and clades can differ in intrinsic virulence and epidemic capacity.14, 35, 44, 45, 46 A better understanding of the genetic basis for virulence and enhanced replication in mosquitoes and people would improve our ability to predict epidemics that pose a greater risk of disease. A further question is whether epidemic force (the symptomatic:inapparent infection ratio) affects the threshold of neutralising antibodies or other immune correlates that protect against

Post-primary infections

The interval of time between first and second dengue virus infection modulates infection and disease outcome (figure). The average period of cross-protection is 1·6–2 years against symptomatic dengue virus infection and 2·6 years against severe disease;15, 65, 66 these observations are consistent with long-term follow-up data from vaccine trials.40 Hypotheses to explain these observations include waning of cross-serotype neutralising antibodies, epidemic force, increased risk of being exposed

Neutralising antibodies

A crucial metric of protection is the potency of neutralising antibodies against future infecting strains; thus, neutralisation assays are a key tool for decision-making by clinicians, epidemiologists, vaccine developers, and policy makers. However, current assays do not adequately capture the full complexity of the neutralising antibody response, and results are highly variable across laboratories. Moreover, the results of recent clinical trials of Sanofi's tetravalent dengue vaccine showed

Pathogenesis

Host genetics, dengue virus immune history, infection sequence with particular dengue virus serotypes and strains, and viral genetics modulate the immune response and affect disease outcome. A dominant theory has been that immunopathogenic mechanisms result in a so-called cytokine storm that leads to vascular leak and thus contributes to severe dengue disease in secondary infections.121 However, severe disease does develop in some instances after primary dengue virus infection, and many

Dengue vaccines

Of the dengue vaccines in development, live-attenuated vaccines are the most advanced, with three candidates in phase 2/3 (NIH TV003/TV005 and Takeda TDV vaccines) or phase 4 (Sanofi Dengvaxia) trials. Other approaches in preclinical or early clinical development include non-replicating or single-replication vectored vaccines packaged in dengue virus structural proteins, purified, inactivated virus vaccines, subunit-based vaccines (eg, EDIII or NS1 protein), and DNA-based vaccines.146 Novel

Conclusion

We have reviewed progress in diagnostics, clinical research, epidemiology, entomology, virology, immunology, pathogenesis, and vaccine development, as well as the results of multiple high-quality clinical studies and field sites, in the context of understanding natural dengue virus infections and current and future vaccination efforts. In addition, we have highlighted knowledge gaps (panel) and the urgent need for translational research. With the recent licensure of the first dengue vaccine and

Search strategy and selection criteria

We identified articles published in English and Spanish by searching PubMed for the section headings: “case management”, “surveillance”, “outbreak response”, “epidemiology”, “vector control”, “modeling”, “transmission”, “genotypes”, “evolution”, “neutralisation”, “antibody-dependent enhancement”, “B cell”, “CD4+ T cell”, “CD8+ T cell”, “innate immunity”, “pathogenesis”, and “dengue vaccines”. These articles were reviewed for relevant references. Historical articles describing major discoveries,

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