The first licensed dengue vaccine: an important tool for integrated preventive strategies against dengue virus infection

KEYWORDS:

• Dengue
• vaccine
• CYD-TDV
• preventive strategies
• health planning

1. Introduction

Dengue poses a significant social and economic burden to endemic countries in the tropics and subtropics. The first dengue vaccine, a recombinant yellow fever-17D–dengue virus, live, attenuated, tetravalent dengue vaccine (CYD-TDV; Dengvaxia^®, Sanofi Pasteur, Singapore, Singapore), has recently been licensed for use in individuals aged from 9 to 45 years in Mexico, Brazil, the Philippines, El Salvador, and Paraguay. This represents a long-awaited addition to existing disease prevention strategies that have focused mainly on vector control.

Dengue is a vector-borne infectious disease caused by four antigenically distinct dengue virus serotypes (DENV serotypes 1–4) transmitted principally by Aedes aegypti. There are an estimated 390 million annual dengue virus infections globally, of which about one quarter become symptomatic or severe [1]. The risk of developing severe disease has historically been greater in children aged ≤15 years [2,3]. A gradual upward age shift in the burden of severe dengue has occurred in the last decades in Asia towards those aged ≥15 years [3]. Conservative estimates from a societal perspective suggest an economic burden of US$ 2.1 billion (2010 US$) annually in the Americas [4] and US$ 950 million (2010 US$) annually in 12 countries in Southeast Asia [5]. Rapid urbanization leading to overcrowding with inadequate water supply and sanitation has created ideal environments for A. aegypti mosquitoes, leading to resurgence of dengue epidemics in many tropical and subtropical countries [6].

There are many challenges for dengue vaccine development, for example, lack of animal model and no known correlates of protection and concern around immune enhancement. The first licensed vaccine is the one developed by Sanofi Pasteur; several others are in development.

2. A recombinant yellow fever-17D–dengue virus, live, attenuated, tetravalent dengue vaccine (CYD-TDV)

CYD-TDV has recently been approved in several endemic countries and is under review in many more. The vaccine consists of four monovalent recombinant viruses based on the yellow fever vaccine 17D (YFV 17D) backbone, expressing wild-type dengue serotype pre-membrane and envelope proteins for each of the four serotypes [7]. It is administered subcutaneously as three injections given 6 months apart in a schedule of 0, 6 and 12 months. Vaccine schedule optimization and need for boosters are under assessment through additional studies. CYD-TDV is genetically stable, with lower hepatotropism and neurovirulence than YFV 17D. Low vaccine viremia (detected by polymerase chain reaction) may be observed within a few days after the first dose in some recipients but is considered insufficient to infect mosquitoes [8,9]. In addition, mosquitoes are unable to transmit the vaccine viruses after feeding [9].

3. Clinical profile of CYD-TDV

The efficacy and safety of CYD-TDV was demonstrated in two efficacy studies involving ≥31,000 children aged 2–16 years in Asia and Latin America [10,11]. During the first 25 months, pooled analyses of these two trials in children 9 years and above show that CYD-TDV significantly reduced the incidence of virologically confirmed dengue by 65.6% (95% confidence interval [CI], 60.7–69.9) and hospitalizations by 80.8% (95% CI, 70.1–87.7) [12]. No safety concerns were identified in the population aged >9 years. Although vaccine efficacy differed by serotype, there was no evidence of more severe breakthrough disease. A comparison of the individual studies showed that vaccine efficacy was slightly lower in Asian countries, and age-adjusted efficacy was remarkably consistent across the studies. Vaccine efficacy was higher among those previously exposed to wild-type dengue and as such increases with age [12]. Long-term safety follow-up based on hospital surveillance and a phase IIb trial up to 3 years after the first injection indicated a 50% reduction in the relative risk of hospitalization among those aged ≥9 years during the third year, in contrast to a 58% increase in those with younger age (<9 years) [12]. This long-term surveillance is ongoing and will continue for 6 years after first injection. The reasons for this difference between the age groups are under further investigation [13]. The efficacy observed in those aged ≥9 years formed the basis for the approval of CYD-TDV. Coadministration of CYD-TDV with other age-appropriate vaccines in the population aged ≥9 years remains to be investigated. As national immunization programs for relatively older children exist in many countries and can be more complex. Coadministration with influenza, human papilloma virus, and Tdap might make vaccination programs more feasible.

4. Challenges of dengue vaccine introduction

4.1. Role of vaccination in dengue prevention and control

The dengue vaccine has long been awaited, and its introduction remains a high priority for many endemic countries. The first countries that approved its license are endemic for part or all of their territories; more countries are considering licensing. Nevertheless, dengue disease control necessitates a holistic approach whereby the vaccine is integrated into existing strategic interventions including vector control and educational initiatives to reduce the risk of exposure, in addition to optimized treatment of severe cases and good surveillance. This integrated approach has the added benefit of simultaneously targeting several vector-borne diseases (malaria, chikungunya, Zika, Japanese encephalitis, and yellow fever) using the same vector-control infrastructure, thus allowing for maximized benefit of limited funds available.

4.2. Preparation for dengue vaccine introduction

The Strategic Advisory Group of Experts on immunization, World Health Organization (WHO), and the Dengue Vaccine Initiative have published recommendations designed to assist country decision-makers ascertain the capabilities required for dengue vaccine introduction and on whether and how to introduce such a vaccine [14,15].

4.2.1. Evidence for decision-making and impact modeling

The decision to introduce the dengue vaccine into national programs poses a challenge to policy makers. A decision based on the burden of disease in the country alone may warrant vaccine introduction even though robust epidemiological and economic evidence may not be available. Health economic aspects are to be considered in a comprehensive cost–benefit analysis. Important decisions need to be made regarding target age groups for routine vaccination and catch-up vaccination to achieve the most efficient strategy. Mathematical models that incorporate host–vector transmission dynamics at a population level and parameters related to vaccine efficacy help address some of these issues. The most efficient vaccination strategy depends on population demographics, dengue seroprevalence, and intensity of transmission and, as such, is unique to the epidemiology of each country [16].

4.2.2. Immunization systems

The success of vaccine introduction depends on a number of factors including its effectiveness, safety, coverage in target population, duration of efficacy, herd immunity, health-care workforce, and the ability for vaccine delivery systems to rapidly facilitate vaccine distribution [17]. Raising public awareness using social mobilization strategies, along with planning for crisis communications in case of unexpected adverse events, is critical.

There are dengue infections in children aged <9 years in many endemic countries, which will be out of reach with this first vaccine. However, the proportion of the population at risk above age 9 years remains a substantial majority. School-based vaccination programs may be suitable as the vaccine is indicated for children from age ≥9 years. These programs may also facilitate acceptance of dengue vaccination as part of a comprehensive school health program. However, this approach may be problematic in some countries where a sizable proportion of children do not attend school. The WHO has published a tool to help health ministries determine, monitor, and improve their readiness for school-based vaccination programs [18].

Achieving coverage levels ≥90% at the national level (and ≥80% in districts or equivalent units) is the target endorsed by the WHO and United Nations Children’s Fund [19]. Several challenges may arise. In school-based programs, older children may attend vaccination without a parent, posing challenges for the informed consent process. Use of ‘dear parent’ letters may be considered in this case. Inclusion of adults in catch-up vaccination campaigns may be problematic as there is no set mechanism for vaccination in this group. Compliance and coverage data need to be closely monitored as they may help determine the cause of subsequent outbreaks (poor coverage or compliance and vaccine failure).

4.2.3. Post-licensure disease surveillance

Continued surveillance of dengue disease and circulating serotypes is critical in quantifying the impact of vaccination. However, a lack of harmonization in dengue case definitions, diagnostic methodology, and surveillance may make cross-country comparisons of vaccination impact difficult [20]. There are two WHO case definitions and severe disease classification systems currently in widespread use (published in 1997 and 2009, respectively) [21,22]. These have since been adapted by countries to meet their national requirements. In addition, not all countries have access to the latest diagnostic tests, and some rely on clinical symptoms for a diagnosis, giving less reliable results. Serological assays for anti-dengue immunoglobulin (Ig) M and IgG antibodies are generally easier and cheaper to perform than other dengue diagnostic methods and are widely used in surveillance. Reliance on these serological assessments to identify breakthrough disease in vaccine recipients would lead to a significant number of false positives in the postvaccination period, which may have implications for surveillance (Plennevaux et al. Submitted) [23], as well as interference from cross-reactivity with other flaviviruses.

Most countries use passive dengue surveillance systems. Irrespective, surveillance systems considerably underreport the number of dengue cases, limiting their capacity to detect epidemics and to predict trends. Assessing the impact of vaccination on local and global disease patterns would continue to remain a challenge unless more efficient ways of gaining centralized access to disaggregated surveillance data across all countries can be established [24].

4.2.4. Pharmacovigilance

Post-licensure vaccine surveillance will be vital to better define vaccine safety at a population level. Most national regulatory authorities have mandated passive pharmacovigilance systems that include surveillance of adverse events following vaccinations, but this may not be the case in all.

A theoretical safety concern following dengue vaccine introduction would be the decrease in antibodies over time and the theoretical risk of antibody-dependent enhancement leading to severe disease [13]. However, this phenomenon was not seen in the ongoing phase III studies [13]; it is important to continuously monitor all vaccine recipients through phase IV studies. As people in highly endemic countries have significant exposure to wild-type dengue, this risk might not be easily observed or will be very low due to natural boosting. All safety aspects of vaccination, whether related to vaccine quality, associated delivery and storage logistics, or handling and administration, need to be monitored post-licensure to allow rapid rectification when problems arise [24].

4.2.5. Financing

Given the growing list of vaccine-preventable diseases and other competing demands for health-care resources, well-informed evidence-based decision-making is required to ensure that vaccine use following introduction is sustainable. The introduction of dengue vaccine should be integrated into existing vaccine campaigns to economize on operating costs. Short- and longer-term operational costs should be evaluated along with potential benefits and overall impact on national health budgets [25]. Ensuring long-term financial sustainability following dengue vaccine introduction is essential.

5. Conclusions

The approval of the first dengue vaccine represents a major milestone in the prevention of this disease. The vaccine should be complementary to existing integrated intervention strategies for dengue prevention and educational initiatives to minimize risk of exposure. Post-licensure surveillance will help better define vaccine effectiveness, safety in special populations, long-term safety, and options for coadministration with other vaccines in the approved population. A consistent approach to dengue surveillance across countries would be needed to better define vaccination impact.

Declaration of interest

P Pitisuttithum is an investigator at one of the study sites in Thailand that participated in the CYD14 study. A Bouckenooghe is an employee of Sanofi Pasteur. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgments

We thank Richard Glover of inScience Communications, Springer Healthcare, for assistance with the preparation of this manuscript through support from Sanofi Pasteur.