Dengue fever has the highest and fastest-rising morbidity and mortality of any vector-borne viral disease. The growing global impact of dengue is a public health challenge with an economic burden that is currently unmet by licensed vaccines or vector control strategies. Therefore, effective, efficient, safe, and sustainable interventions are a public health priority. However, interventions also must be applicable to tropical and less developed regions where dengue is prevalent. Vector control, the principal method for dengue prevention, is not sustainable because current methodology is expensive and of limited effectiveness. Innovative candidate vaccines, including live-chimeric, live-attenuated, inactivated, subunit, and DNA vaccines, and vector control approaches, such as the release of mosquitoes carrying the dominant-lethal allele or Wolbachia, are in trials.  The most advanced and promising new dengue control measures are the Sanofi Pasteur live-attenuated ChimeriVax vaccine (CYD-TDV) and infection of the Aedes mosquito vector with the endosymbiotic Wolbachia bacteria. While vaccination shows slightly more promise than vector control, in terms of effectiveness and sustainability, integration of both interventions may be more effective than either approach alone.

Relevance to medical students

The rapid pace of development of vaccines for dengue fever will rapidly reduce the over-100-million dengue fever cases and their associated morbidity and mortality within the next few years. A candidate vaccine against dengue viruses called, CYD-TDV, could reach registration and review by the World Health Organization in 2016. If countries do license CYD-TDV, future doctors will need to understand the costs and benefits of vaccination, particularly any undesirable outcomes after vaccination, and whether alternatives exist.

Introduction

There are more than 100 million dengue cases annually and the financial cost of this disease has been estimated to be more than $2 billion in the Americas and $1 billion in South-East Asia each year. [1] The 30-fold increase in the incidence of dengue in the last 50 years has highlighted the failure of existing vector control strategies and the need for new vaccine or vector control approaches. [1] The most advanced of these are the mosquito-infecting bacteria Wolbachia, and Sanofi Pasteur’s chimeric tetravalent dengue vaccine (CYD-TDV). A comparison of their problems and prospects based on effectiveness, efficiency, safety, sustainability, economy, and universality may guide their adoption. While these approaches have been developed in isolation, their combination may help achieve the World Health Organization (WHO) goals of reducing dengue mortality by 50% and morbidity by 25% by 2020. [2]

Vaccinations

Prospects

The ideal dengue fever vaccine would induce a neutralising and balanced response for all four dengue serotypes, provide long-lasting or life-long protection, be safe and stable, balance reactogenicity and immunogenicity, and be cost-effective and context-appropriate.  A more universal vaccine would confer “herd immunity” to the general population by reducing the reservoir of infected individuals and infection transmission. Vaccine candidates should be evaluated in trials spanning different populations and patterns of dengue transmission. [2] Several vaccine types are under development, including live-attenuated, live-chimeric, inactivated, subunit, and DNA vaccines (Table 1). [3] Inactivated and subunit vaccines are safer, in principle, due to a lower risk of reversion to virulence and are under evaluation in pre-clinical or early clinical trials. [4] Several more cost-effective and immunogenic live viral vaccines are under evaluation in late-stage clinical trials. [17]

Table 1: Candidate vaccine approaches.

Vaccine type	Developer	Process	Progress
Live, attenuated chimeric (recombinant)	Acambis / Sanofi Pasteur	Insertion of genes coding for DENV structural proteins into a yellow fever virus (17D) backbone. [5]	Phase III tetravalent – leading candidate [4]
	Centre for Disease Control (CDC) / Inviragen	Insertion of serotype genes into serotype II (DENV2-PDK53) DNA backbone. [6]	Phase II monovalent [7]
	National Institutes of Health (NIH) / University of Maryland	Insertion of serotype II and III genes into safer, more immunogenic serotype I and IV DNA backbone. Live attenuated DENV Delta-30 mutation. [8]	Phase I tetravalent
Live, traditionally attenuated	Walter-Reed Army Institute of Research (WRAIR) / GlaxoSmithKline (GSK)	Attenuation achieved by growing the virus in cultured cells and selecting strains	Phase II tetravalent; technical issues [6]
	Mahidol Institute / Sanofi Pasteur		Phase II tetravalent
Inactivated	GSK	Viruses cultured and killed [9]	Phase I tetravalent
Subunit	Hawaii Biotech	Viral immunogenic envelope is combined with viral non-structural protein antigens to produce recombinant 80% E subunit vaccine [10]	Phase I tetravalent [11]
DNA	WRAIR	Dengue prM-E DNA vaccine incorporating membrane and envelope genes into a plasmid vector [12]	Phase I monovalent

 

The leading vaccine candidate is the tetravalent Sanofi CYD-TDV that recently completed phase III clinical trials. [4] Phase I and II trials have established the vaccine is safe and immunogenic, inducing neutralising antibody responses in 77–100% of recipients receiving three doses of the vaccine. [13] A neutralising immune response is achieved through inserting dengue structural protein genes for the four serotypes onto a yellow fever virus backbone. [14] The multi-centre Phase III efficacy studies have further supported this effectiveness and safety. [17] The vaccine reduces dengue fever incidence by 56% and dengue haemorrhagic fever by 88%. [15] More than 28,000 subjects have been immunised with this vaccine. [16,17] CYD-TDV is based on the safe and effective YF-17D vaccine. [18] Pre-clinical and phase I studies have suggested that the incorporation of four dengue serotypes into the YF-17D RNA backbone has not come at the cost of the vaccine’s stability. [19] The reactogenicity profile is similar to the YF-17D control. [20] A more robust immune response, with no adverse reactions, has been observed post-injection in flavivirus-vaccinated individuals. No cases of dengue-like disease that could arise from reversion of live vaccine strains to virulence were observed in studies on younger subjects. [21] There was a low vaccine viraemia and similar rates of adverse events compared to the YF-17D control. The vaccine’s commercial prospects are still uncertain, but it has a low production cost. [22] Over 20 clinical trials and 20,000 subjects have therefore found the Sanofi vaccine safe and immunogenic. [16]

Problems

The major challenge with the Sanofi Pasteur vaccine has been to induce a balanced immune response against all four dengue virus serotypes (DENV 1-4). The vaccine has needed to elicit protective responses against all four serotypes and not produce sub-neutralising levels of antibody that might enhance subsequent DENV infections. ChimeriVax proved notably inefficient in protecting against DENV-2. [23] The efficacy of ChimeriVax was found to be 61%, 82%, and 90% against DENV-1, DENV-3, and DENV-4, respectively, and only 3.5% against DENV-2 after a single dose and 9.2% against DENV-2 after three doses. [24] Other challenges are the three six-monthly doses of vaccine, which could reduce patient compliance and reduce its utility as a traveller’s vaccine.

Vector control

Prospects

Vector control methods, which seek to eliminate the hosts of disease-transmitting pathogens, need to reduce dengue incidence in an efficient and economical manner without burdening local health infrastructure. While transient control has value in dengue prevention, ideal methods should be sustainable, require minimal reapplication of insecticide, and account for external factors, such as climate change. [15] Safety is paramount and the effects of preventive interventions on health and ecology should be monitored or the strategy may be limited in its use, for example, in the case of the carcinogenic, toxic, and polluting, but highly efficient insecticide, dichlorodiphenyltrichloroethane (DDT). [25] Ultimately, the proposed intervention will need to be based on scientific evidence as well as public and government support. Current chemical, environmental, biological, and genetic vector control methods are not successfully mitigating dengue’s increasing prevalence, geographical distribution, and severity (Table 2). [26] Whether inserting the endosymbiotic Wolbachia bacteria into A. aegypti mosquitoes will be effective in controlling dengue remains to be seen.

Table 2: Candidate vector control approaches

Vector control type	Process	Progress
Chemical [27]	Insecticides, larvicides, pest control	Popular and evidence-based
		Concerns about significant financial and logistical costs, contamination and toxicity and insecticide resistance
Environmental [28]	Eliminating mosquito breeding grounds, screens, water and waste management	Appropriate strategies have the potential to reduce vector transmission and benefit overall health of people and the environment
		Significant infrastructure needed
Biological [29]	Natural predators and pathogens, (for example, Wolbachia)	Successful in local elimination of mosquitoes
		Significant infrastructure needed
Genetic	Release of insects carrying dominant-lethal allele (RIDL), Sterile insect technique (SIT), HE gene, RNAi	Limited field trials and mixed data on effects in reducing target populations in field trials. Large release numbers required

 

Wolbachia promises to be the equivalent of a human “vaccine” for dengue vectors, by inducing a natural biologic resistance to dengue infection in dengue-carrying A. aegypti mosquito populations. Wolbachia occurs naturally in approximately 40% of arthropods and reduces A. aegypti’s ability to respond to viruses, life-span, and reproduction. [30, 31] All three forms of Wolbachia (wAlbB, wMelPop, and wMel), inhibit DENV replication and dissemination within the host mosquito and may block viral transmission. [32, 33] Wolbachia strains can dramatically reduce the lifespan of the female A. aegypti mosquito so that virus transmission may not occur before the insect dies. [34, 35] However, some Wolbachia strains are transmitted from mother to offspring in A. aegypti populations resulting in rapid spread throughout a population. [35] Risk assessments failed to identify significant risks associated with releasing Wolbachia-infected A. aegypti. [36] Safety concerns relate to the possible transfer of Wolbachia to humans by mosquito bites, and to non-target species and mosquito predators. [37] Wolbachia infection rates remain at 100% one year after Wolbachia wMel release in Cairns. [38] This intervention has now received regulatory approval. The success of field trials such as this would allow this innovation to move to countries where dengue is endemic.

Problems

The challenge now remains to make Wolbachia-based vector control strategies more universally applicable and sustainable. Some effects of specific Wolbachia strains on DENV transmission may be inappropriate for certain contexts. For example, wMelPop has a more significant impact on DENV transmission in dengue-endemic settings than wMel due to a stronger DENV transmission-blocking effect. [39] However, the wMelPop strain reduces the fitness of A. aegypti more than wMel, so would require additional Wolbachia mosquito deployment to maintain sufficient levels of Wolbachia-infected vectors to prevent dengue transmission. The sustainability of Wolbachia-based strategies is challenged by the significant financial and operational costs for rearing, releasing and re-establishing Wolbachia-infected mosquito populations. [40] As with insecticides, the evolution of resistance poses a risk. [41] A. aegypti could evolve resistance against particular strains of Wolbachia, similar to the resistance of Drosophila simulans after transinfection with Wolbachia wMelPop. [42] Furthermore, dengue virus strains could develop a means of evading Wolbachia-based transmission blocking. Longer-term, larger-scale trials are needed to assess how Wolbachia can reduce the burden of dengue in a sustainable manner.

Comparisons

Table 3. Overview of promising vaccine and vector control approaches.

	Vaccination – Sanofi Pasteur	Vector control – Wolbachia
Mechanism	1.      Vaccine contains strains against the four dengue virus serotypes 2.      Dendritic cells carry strains to lymph nodes to activate B cell proliferation and antibody production 3.      When bitten by infected mosquitos, antibodies neutralise the virus	1.      Natural arthropod Wolbachia bacteria injected into A. Aegypti eggs 2.      Reduce mosquito reproduction, lifespan and pathogen replication 3.      Wolbachia passed between generations
Efficacy/efficiency	Neutralising and immunogenic; reduces dengue fever by 56% and dengue hemorrhagic fever by 88%; inefficient in tackling DENV-2 in trials	Inhibits DENV replication and dissemination and reduces vector lifespan and reproduction; predicted to reduce transmission by 60–100%
Safety	YF-17D is a safe, stable vaccine backbone; low viraemia, reactogenicity, and adverse events	Minimal safety concerns, such as Wolbachia transfer to humans, non-target species, and mosquito predators
Sustainability	Long-term waning of vaccine-elicited immunity may require boosters	Stable in short-term, but potential for Wolbachia resistance in the long-term
Economy	Low production cost	Large operational and re-establishment costs
Universality	Most useful in tropical regions, rather than as a traveller’s vaccine	Mainly effective in urban centers and tropical regions

 

Vaccination and vector control have the potential to be effective, safe, and sustainable, despite their failure to control dengue to date (Table 3). Two large-scale phase III trials in the Americas and Asia involving 40,000 participants have demonstrated an efficacy of 60.8% for CYD-TDV. [16] However, Wolbachia-based vector control is still at the small-scale trial stage in Australia in order to refine methods with further large-scale trials in Indonesia, Vietnam, and Brazil. Small scale trials have been completed in Vietnam. Licensing of the Sanofi Pasteur vaccine is expected with Australian Pesticides and Veterinary Medicines Authority (AVPMA) approval already achieved in Australia. [4] Licensing of Wolbachia will require further field trials, risk assessment, and time. Both vaccination and Wolbachia involve fixed, front-loaded establishment costs that are significantly lower than traditional vector control methods. The risk of adverse events is increased with the Sanofi Pasteur CYD-TDV vaccine that had an efficacy ranging from 56 to 100% against DENV-1, DENV-3 and DENV-4, but not against DENV-2. It may be that incomplete protection can be achieved through combining vaccine and vector control approaches to reduce DENV-2 transmission.

Combinations

Modelling shows that combining vector control with vaccination could increase intervention effectiveness by reducing vector density and therefore infections. One compartmental model found that an imperfect vaccine could reduce dengue incidence by 57%, ten years post-vaccination, but when combined with other strategies, there was a greater reduction in incidence with a rate of 81%, ten years post-vaccination. [43] Another model demonstrated that less efficacious vaccines should not be applied without concurrently applying vector control approaches. [44] Computer simulations suggest that in areas of high mosquito density, vector control followed by vaccination programs could reduce potential surges in dengue virulence. [45] Vector control and vaccination approaches therefore need context-sensitive and coordinated integration. Applied together, vector control and vaccination interventions could reduce DENV transmission significantly and prove to be cost effective. [46] Vaccines for other diseases have previously been paired with vector control methods with few safety issues, better protection against disease risk, and extended efficacy. [47]

Conclusion

The development of safe, effective, and affordable dengue vaccines and new vector control methods promise to rapidly reduce dengue incidence and therefore morbidity and mortality. The most advanced vaccine candidate has proven safe and protective against three of the four dengue virus serotypes. Of the emerging genetic, biological, and environmental vector control methods, the closest to clinical application is the release of mosquitoes infected with specific strains of Wolbachia that can reduce dengue virus replication, reproduction, and life span. The vaccine shows slightly more promise than the Wolbachia vector control method. History has shown that no single approach is able to control dengue and the future of dengue fever prevention may be integrated immunisation, vector control, and social mobilisation.

Conflict of Interest

None declared.

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