Dengue vaccine: Come let's fight the menace

Abstract

Although dengue has a global distribution, the World Health Organization (WHO) South-East Asia region together with Western Pacific region bears nearly 75% of the current global disease burden. Globally, the societal burden has been estimated to be approximately 528 to 1300 disability-adjusted life years (DALY) per million to populations in endemic regions Dengue is believed to infect 50 to 100 million people worldwide a year with half a million life-threatening infections requiring hospitalization, resulting in approximately 12,500 to 25,000 deaths. Despite being known for decades and nearly half the world's population is at risk for infection with as many as 100 million cases occurring annually, the pitiable state is that we still have no antiviral drugs to treat it and no vaccines to prevent it. In recent years, however, the development of dengue vaccines has accelerated dramatically in tandem with the burgeoning dengue problem with a rejuvenated vigour. However, recent progress in molecular-based vaccine strategies, as well as a renewed commitment by the World Health Organization (WHO) to co-ordinate global efforts on vaccine development, finally provides hope that control of this serious disease may be at hand. Today, several vaccines are in various stages of advanced development, with clinical trials currently underway on 5 candidate vaccines. Trials in the most advanced stages are showing encouraging preliminary data, and the leading candidate could be licensed as early as 2015.

Keywords:

• Dengue
• endemic
• tetravalent
• trials
• vaccine

Introduction

Dengue fever has amassed its importance in this modern world as one of the most common emerging diseases particularly of the tropical and subtropical regions. The history of dengue may be many decades old but recent paradigm of shift in the epidemiology of dengue has drawn attention worldwide. Dengue is caused by a virus belonging to the flaviviridae group which has 4 serotypes of DV (DV-1 to DV-4) and is transmitted primarily by Aedes aegypti mosquitoes. Half of the world's population lives in countries endemic for dengue, underscoring the urgency to find solutions for dengue control. Dengue infection can cause a myriad of symptoms ranging from mild, undifferentiated fever to complicated Dengue Hemorrhagic Fever (DHF) and the potentially fatal Dengue Shock Syndrome (DSS).The consequence of severe illness is high mortality rate, since tertiary level care required for DHF/DSS management is beyond the reach of most of the persons at risk.

Epidemiology and problem statement

Although dengue has a global distribution, the World Health Organization (WHO) South-East Asia region together with Western Pacific region bears nearly 75% of the current global disease burden. The South East Asia region is currently experiencing an upsurge in reported cases of dengue in a number of countries which includes India, Sri Lanka, and Thailand.1 Globally, the societal burden has been estimated to be approximately 528 to 1300 disability-adjusted life years (DALY) per million to populations in endemic regions.^2-5 According to the report of Directorate of National Vector Borne Disease Control Program,Dte.GHS / MOHFW, GOI the number of dengue cases is on a steady increase with 12561 cases in 2008 to 18059 cases in 2011-2012 (47029 cases,242 deaths) with about 119 deaths among those.⁶

The global prevalence of dengue has grown dramatically in recent decade. The disease is now endemic in more than 100 countries of WHO region Africa, the Americas, the eastern Mediterranean, Southeast Asia, and the Western Pacific, threatening more than 2.5 billion people.¹ Dengue is believed to infect 50 to 100 million people worldwide a year with half a million life-threatening infections requiring hospitalization, resulting in approximately 12,500 to 25,000 deaths.¹

Can vaccines be of any help?

Why has a genuine dengue vaccine eluded us so far? The unique challenge with dengue fever is that 4 dengue serotypes circulate globally, and infection with one dengue serotype confers life-long protection against re-infection with the same serotype, but only short-term protection against the other 3 serotypes. Moreover, dengue is peculiar as the sequential infections with different serotypes increase the risk of developing severe and potentially lethal disease. There is limited understanding of how the virus interacts with the immune system and how certain types of pre-existing immunity can exacerbate disease. These immunopathological mechanisms create a conundrum for vaccine developers: since sequential infection and heterotypic antibodies cause dengue hemorrhagic fever, a successful vaccine must simultaneously generate long-lasting protective immunity against all 4 dengue serotypes.⁷ This baffling problem is the reason that no dengue vaccine has yet been approved for use, despite considerable efforts and substantial funding.

Dengue vaccines have been under development since the 1940s, but due to the limited appreciation of global dengue disease burden and of the potential markets for dengue vaccines, the industry's interest languished throughout much of the 20th century. Despite being known for decades and nearly half the world's population is at risk for infection with as many as 100 million cases occurring annually, the pitiable state is that we still have no antiviral drugs to treat it and no vaccines to prevent it. The treatment if any is only supportive management and transfusions if severe. Although a vaccine has been developed and successfully implemented for yellow fever, a closely related but much more lethal mosquito-borne virus, an effective dengue vaccine is still not in the horizon.

In recent years, however, the development of dengue vaccines has accelerated dramatically in tandem with the burgeoning dengue problem with a rejuvenated vigour. However, recent progress in molecular-based vaccine strategies, as well as a renewed commitment by the World Health Organization (WHO) to coordinate global efforts on vaccine development, finally provides hope that control of this serious disease may be at hand.

There had been various approaches on the part of scientists in the quest for a potential and effective dengue vaccine.

1. Live attenuated dengue vaccine

2. Live attenuated Chimeric Dengue Vaccine

3. Inactivated/Subunit dengue vaccine

First in this series was in the early 2000s, when GSK and the Walter Reed Army Research Institute (WRAIR) started the joint development of a tetravalent, live-attenuated dengue vaccine. Tetravalent dengue vaccine formulations produced by the Mahidol group were used for Phase I and II clinical trials in Thai adults and children. Not all of the volunteers seroconverted to all 4 DENV serotypes and some showed unacceptable reactogenicity. Consequently, further clinical testing was stopped.^8-10 The WRAIR-produced tetravalent dengue vaccine formulation also showed problems of unbalanced immunogenicity and reactogenicity.¹¹ New formulations seem safe and immunogenic in a Phase II study, however, the protective efficacy needs to be further evaluated.^12,13 Next in line came the live-attenuated tetravalent vaccine based on chimeric yellow fever-dengue virus (CYD-TDV), yellow fever vaccine strain genomic backbone with substitutions of 2 genes encoding dengue proteins. It is the yellow fever/dengue chimeric vaccine (CYD), initially developed by Acambis and Sanofi Pasteur, which had been the most successful and promising strategy so far.

The Phase IIb trial of the vaccine was conducted at Ratchaburi Province, Thailand with the study of 4,002 children aged 4 to 11 y This was the first study conducted to evaluate the efficacy of any dengue vaccine candidate against clinical dengue disease in a population naturally exposed to dengue, which represents a significant advance for the field of dengue vaccine research. First results of a Phase 2b efficacy study in Thailand showed the vaccine was safe, though poorly effective – failing to protect against DEN-2 and overall showing only a 30% effectiveness against all serotypes, with a large variation in protection between serotypes.

According to a WHO advisory group of experts, the recently published data from this IIb phase study yet do not prove nor disprove efficacy of CYD-TDV against diseases caused by any of the 4 dengue virus serotypes. Phase III efficacy studies of CYD-TDV are currently underway in 31,000 children and adolescents in 10 countries in Asia and Latin America.¹⁴ The Phase 3 result will allow for a full evaluation of vaccine efficacy.

The National Institute of Health's (NIH) tetravalent formulation TV003 in Phase 1 trials has shown promising response after 2 doses with 91% of subjects showing tetravalent antibody response.TV003 vaccine has entered Phase II trials in Brazil and Thailand. Similarly the CDC/ InViragen vaccine, DENVax has entered Phase IIb trials with a encouraging response after the Phase I and IIa trials.

Recent advances in molecular biology have spurred dengue vaccine efforts using live recombinant, DNA and subunit vaccines. One of these concepts has been the subunit vaccine in which recombinant 80E subunits from all 4 DENV serotypes were expressed in the DrosophilaS2 cell expression system. Merck along with Hawaii Biotech are now conducting a phase I trial of tetravalent 80E vaccine adjuvanted with ISCOM in Australia. Recombinant subunit-based vaccines may offer significant advantages over other approaches currently being pursued for development of a dengue vaccine. In terms of yields and cost effectiveness for a vaccine targeting primarily developing areas of the world, a high yielding, highly immunogenic, recombinant subunit may offer an attractive alternative to vaccines based on virus replication (live attenuated or killed) where yields may be lower than required.¹⁵ Today, several vaccines are in various stages of advanced development, with clinical trials currently underway on 5 candidate vaccines. Trials in the most advanced stages are showing encouraging preliminary data, and the leading candidate could be licensed as early as 2015.

Although no licensed dengue vaccine is yet available, the ever-increasing knowledge of dengue pathogenesis and novel approaches are providing a formidable background into improved vaccine design. There is an urgent need to transform the results of clinical trials to path breaking effective approaches which may help to curtail if not terminate the menace. Dengue vaccines, when a reality, will complement, but not replace the prevention methods, already in place, such as vector control. According to the WHO, drawing on the experiences of other vaccine-preventable vector-borne diseases, effective surveillance, prevention and outbreak response tools (vector control and vaccines) must continue to complement each other in reducing the burden of the disease.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed. 

Table 1. Dengue vaccines in various stages of development

Phase I	Phase IIa	Phase IIb	Phase III
DENV ax	CYD-TDV	CYD-TDV	CYD-TDV
DPIV	DENV ax
80% E proteins (subunit)