Dengue vaccine

Abstract

Dengue has emerged as one of the major global public health problems. The disease has broken out of its shell and has spread due to increased international travel and climatic changes. Globally, over 2.5 billion people accounting for >40% of the world's population are at risk from dengue. Since the 1940s, dengue vaccines have been under investigation. A live-attenuated tetravalent vaccine based on chimeric yellow fever-dengue virus (CYD-TDV) has progressed to phase III efficacy studies. Dengue vaccine has been found to be a cost-effective intervention to reduce morbidity and mortality. Current dengue vaccine candidates aim to protect against the 4 dengue serotypes, but the recent discovery of a fifth serotype could complicate vaccine development. In recent years, an urgent need has been felt for a vaccine to prevent the morbidity and mortality from this disease in a cost-effective way.

Keywords: :

• dengue
• vaccine
• initiative
• cost effective
• CYD-TDV
• arboviral

Introduction

Dengue has emerged as one of the major global public health problems. It is vector-borne disease that is prevalent mainly in tropical and subtropical areas. Dengue virus (DENV) has 4 antigenically distinct serotypes (DENV1–4) based on neutralization assay, and belongs to the Flavivirus genus of the Flaviviriade family. DENV is transmitted to humans mainly by Aedes mosquitoes (Aedes aegypti and Aedes albopictus). Dengue fever is manifest in a wide variation of symptoms from asymptomatic to life-threatening dengue shock syndrome. It has been famously known as “breakbone fever” and characterized by fever, headache, muscle and joint pains, and a characteristic skin rash that is similar to that of measles. In a small proportion of cases, the disease develops into the life-threatening dengue hemorrhagic fever, resulting in bleeding, low levels of blood platelets and blood plasma leakage, or into dengue shock syndrome, where dangerously low blood pressure occurs.

The disease has broken its geographic shell and is no longer confined to any boundary owing to increased international travel and climatic changes. Globally, ~50 million dengue infections have been estimated annually with ~500 000 cases of severe dengue and 20 000 deaths per year.¹ In countries with a high burden of dengue fever, it has been documented that the annual cost of dengue could be as high as $46 million ($12.47 per capita).²

There are no specific preventive measures; thus, disease prevention has been limited to vector control measures. The development of a dengue vaccine is an immediate need, which will help in taking a step toward disease control.³

Global Burden

The global incidence of dengue has grown dramatically in recent decades, such that >2.5 billion people accounting for >40% of the world's population are at risk from dengue. There are 50–100 million annual dengue infections worldwide. The disease is endemic in more than 100 countries in Africa, the Americas, the eastern Mediterranean basin, South-east Asia, and the Western Pacific. The Americas, South-east Asia, and the Western Pacific regions are the most seriously affected.⁴

Current Scenario

Dengue vaccines have been investigated since the 1940s, but due to the limited appreciation of the global disease burden and of potential markets for dengue vaccine, industrial interest languished throughout much of the 20th century.⁵

While no licensed vaccine is available, several vaccine candidates are being evaluated in clinical studies.⁶ These include live attenuated virus, live chimeric or recombinant virus, inactivated virus, subunit, and DNA vaccines.⁷ A live-attenuated tetravalent vaccine based on chimeric yellow fever-dengue virus (CYD-TDV) has reached phase III efficacy studies.⁶

An efficacy rate of 30% has been documented in a randomized, controlled, phase 2b trial among healthy Thai school children. The vaccine was found to be well tolerated, with no safety signals after 2 y of follow-up. With an excellent short-term safety profile, it has been further documented that one or more doses of vaccine reduced the incidence of DENV 3 and febrile diseases by 80–90%, with a smaller reduction of cases due to DENV1, but no efficacy against DENV-2 infection.⁸ Phase III efficacy studies of CYD-TDV are ongoing in 31 000 children and adolescents in 10 countries in Asia and Latin America.⁹

Dengue vaccine has been found to be a cost-effective intervention for reducing dengue morbidity and mortality. A pediatric vaccine in SE Asia showed a cost per disability adjusted life year (DALY) saved by a pediatric vaccine at $50, making a potential vaccine highly cost-effective.¹⁰

Dengue v2V (vaccine to vaccination) was established in 2009 to lay the groundwork for the accelerated introduction of effective dengue vaccines to endemic countries following regulatory approval.¹¹ Dengue Vaccine Initiative (DVI), a Bill and Melinda Gates-funded project launched in February 2014, is aimed toward an early introduction of dengue vaccine.¹² DVI continues the work of the pediatric dengue initiative launched in 2001 to stimulate the development of safe and effective vaccine for children in developing countries.¹³

Challenges

Infection by 1 of the 4 DENV serotypes confers lasting immunity against homotypic re-infection, but only transient protection against a secondary heterotypic infection. Furthermore, secondary heterotypic infection often is associated with an increase in severity. Additional challenges are posed by the lack of an adequate animal disease model and the resulting uncertainty around correlates of protection.⁶ Incomplete understanding of which “immune profile” will lead to a protective or pathogenic response following a DENV infection poses another challenge to vaccine developers.¹⁴ Current dengue vaccines aim to protect against the 4 DENV serotypes but the recent discovery of a fifth serotype could complicate vaccine development.¹⁵

Conclusion

Dengue fever is a dreadful disease, and is an emerging public health problem. In recent years, an urgent need has been appreciated for a vaccine to prevent the morbidity and mortality from this disease in a cost-effective way. In spite of many challenges, vaccine development has made remarkable progress, and the current dengue vaccine pipeline is advanced, diverse, and overall promising with hope to bring relief worldwide.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

10.4161/hv.28953