Dengue vaccines: progress and challenges

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With several dengue vaccine candidates progressing through clinical trials, several options for controlling this disease appear feasible. This would represent a major achievement and reflect decades of research and development activities. The challenges associated with the limited understanding of protective responses and those factors which determine disease severity remain, but with prospective studies ongoing in various dengue endemic areas and the initiation of dengue vaccine efficacy trials, immune responses are being evaluated in the context of protection and severe disease and these studies are highly likely to provide additional insights.

Highlights

► There is an important unmet medical need for vaccines to prevent dengue. ► New studies of human immune responses demonstrate that most responses are cross-reactive. ► Several vaccine candidates are in clinical development with the most advanced in Phase 3. ► New insights into the basis of protection/exacerbated disease are likely to come from ongoing studies.

Introduction

Dengue vaccine development has been an area of active research and major challenges for over 50 years. Significant advances have occurred over the past 10 years such that several vaccine candidates are now showing promise in clinical studies, with the most advanced candidate having entered Phase 3 testing. While our understanding of dengue virus biology and the potential for immunopathogenesis has also progressed, there are still many areas that are unresolved and the object of significant investigation. Not the least of these is our understanding, or lack thereof, of what constitutes a protective response in humans. With a number of studies focusing on the human immune response to dengue infection and the launch of the first field efficacy trials, we are closer to understanding this fundamental question and to the registration and introduction of safe and effective dengue vaccines.

Section snippets

Disease and epidemiology

Dengue is the most important vector-borne viral disease in terms of morbidity and mortality with an estimated 2.5 billion people throughout the tropics and subtropics at risk of infection (Figure 1, Figure 2). Worldwide, an estimated 50 million infections with dengue occur annually, with approximately 500,000 cases of severe dengue and 20,000 deaths [1, 2, 3, 4]. Evaluations of the economic impact of dengue suggest that it has a tremendous impact in endemic countries that can approach that of

Immunology and immunopathology

Dengue is caused by any one of the four dengue viruses. While infection with one type of dengue virus provides life-long immunity against that virus type, it does not provide long-term protection against infection from the other dengue virus types. Furthermore, while the more severe forms of the disease occur at a lower frequency relative to classic dengue fever, the vast majority of DHF cases occur following secondary infection. Several hypotheses exist regarding the mechanisms that result in

Vaccines in clinical development

Safe and efficacious vaccines for monotypic flaviviruses such as Yellow Fever, Japanese encephalitis, and tick-borne encephalitis viruses demonstrate the potential for the development of protective vaccines for this family of viruses. However, for dengue the complications posed by the four independent virus targets and the accepted need for balanced tetravalent responses have presented challenges that have stymied the field until recently. Clinical testing of classically attenuated vaccine

Challenges

While progress towards the development of a safe and effective dengue vaccine is significant, the key challenges remain the lack of understanding of protective immune responses in humans as described above and the ability of vaccine candidates to induce long-lasting, balanced, tetravalent responses. While the initial data from the phase II clinical trials of ChimeriVax-Dengue appear promising, a challenge for this product, and perhaps for all live-attenuated dengue virus vaccines, is the

Conclusions

With several dengue vaccine candidates progressing through clinical trials, several options for controlling this disease appear feasible. This would represent a major achievement and reflect decades of research and development activities. The challenges associated with the limited understanding of protective responses and those factors that determine disease severity remain, but with prospective studies ongoing in various dengue endemic areas and the initiation of dengue vaccine efficacy

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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