Elsevier

Vaccine

Volume 37, Issue 36, 23 August 2019, Pages 5137-5146
Vaccine

Conference report
Pre-vaccination screening strategies for the use of the CYD-TDV dengue vaccine: A meeting report

https://doi.org/10.1016/j.vaccine.2019.07.016Get rights and content

Abstract

The first licensed dengue vaccine, CYD-TDV (Dengvaxia) is efficacious in seropositive individuals, but increases the risk for severe dengue in seronegative persons about two years after administration of the first dose. For countries considering the introduction of Dengvaxia, WHO recommends a pre-vaccination screening strategy whereby only persons with evidence of a past dengue infection would be vaccinated. Policy-makers need to consider the risk-benefit of vaccination strategies based on such screening tests, the optimal age to introduce the vaccine, communication and implementation strategies. To address these questions, the Global Dengue and Aedes-transmitted diseases Consortium (GDAC) organized a 3-day workshop in January 2019 with country representatives from Asia and Latin America.

The meeting discussions highlighted many challenges in introducing Dengvaxia, in terms of screening test characteristics, costs of such tests combined with a 3-dose schedule, logistics, achieving high coverage rates, vaccine confidence and communication; more challenges than for any other vaccine introduction programme. A screening test would require a high specificity to minimize individual risk, and at the same time high sensitivity to maximize individual and population benefit. The underlying seroprevalence dependent positive predictive value is the best indicator for an acceptable safety profile of a pre-vaccination screening strategy. The working groups discussed many possible implementation strategies. Addressing the bottlenecks in school-based vaccine introduction for Dengvaxia will also benefit other vaccines such as HPV and booster doses for tetanus and pertussis. Levels of public trust are highly variable and context specific, and understanding of population perceptions and concerns is essential to tailor interventions, monitor and mitigate risks.

Introduction

Dengue is a major public health problem with more than 3.6 billion people living in areas at risk for dengue virus (DENV) infection and an estimated 390 million infections annually in over 120 tropical and sub-tropical countries [1], [2]. Effective vector control strategies that are easily scalable remain elusive [3], community-based approaches have had mixed results, but have been generally unreliable and unsustainable [4], [5], compliance with personal protective measures is difficult on a daily basis [6], [7], and novel vector control measures, such as Wolbachia [8], [9], if effective, will take years to implement [9]. Dengue is also increasingly affecting travelers and migrants [10], [11], [12], [13], [14]. An effective vaccine could do much to reduce the global burden of disease.

The first licensed dengue vaccine, CYD-TDV by Sanofi Pasteur, is a live attenuated recombinant tetravalent vaccine that has been evaluated in Phase 3 efficacy trials as a 3-dose 0/6/12 month schedule [15]. It was first licensed in 2015 in Mexico, and is now registered in 20 dengue endemic countries for use in individuals 9–45 or 9–60 years of age living in endemic areas [16]. In 2017, new evidence emerged highlighting the serostatus-dependent vaccine performance of CYD-TDV. Serostatus refers to whether a vaccinee had been infected by dengue (seropositive) or not (seronegative) prior to receiving the vaccine. In seropositive vaccine recipients, the vaccine was efficacious and safe, but in seronegative vaccinees, CYD-TDV was associated with an excess risk of severe dengue observed from about 3 years after the first vaccine dose [17]. WHO‘s Strategic Advisory Group of Experts on Immunization therefore recommended that countries considering the introduction of CYD-TDV should only do so if minimization of risk in seronegative individuals could be assured [18]. Pre-vaccination screening was recommended whereby only persons with evidence of a past dengue infection would be vaccinated.

To support a pre-vaccination screening strategy, WHO highlighted the urgent need for rapid diagnostic tests (RDTs) to determine serostatus. In addition to target product profiles for such RDTs, and providing access to RDTs, policy-makers need to consider the risk-benefit of vaccination strategies based on such screening tests, as no test will be 100% sensitive and specific. What may be considered as an acceptable level of specificity will depend on risk perceptions in different countries, as well as background seroprevalence.

The Partnership for Dengue Control (PDC) [19], as part of the Global Dengue and Aedes-transmitted diseases Consortium (GDAC), organized a 3-day workshop in January 2019, hosted by the Mérieux Foundation at Les Pensières, Annecy, France. PDC has organised previous think-tanks on dengue such as on immune correlates for dengue protection and enhancement [20], best practices for vector control [21], dengue and other flavivirus diagnostics [22], and development of standard clinical endpoints for the use in interventional studies [23], [24].

The pre-vaccination strategy workshop was attended by policy-makers from dengue-endemic countries, epidemiologists, modellers, public health and laboratory scientists, an ethicist, communication specialists, and representatives of vaccine manufacturers and diagnostic companies.

The objectives of the workshop were to

  • review the rationale for the pre-vaccination screening strategy and to learn from the experience of countries where CYD-TDV had been introduced, and

  • discuss rapid diagnostic tests (RDT) for screening for past dengue infection (dengue serostatus), including to:

    • o

      discuss a draft target product profile for RDTs to support a pre-vaccination screening strategy;

    • o

      present a landscape analysis on RDT characteristics, and their sensitivity and specificity in different flavivirus endemic settings;

    • o

      elaborate on population level benefit versus individual risk; and

    • o

      address policy-makers‘ perceptions and views on risk-benefit assessment of an RDT as a pre-vaccination screening tool under different scenarios (high versus low seroprevalence)

  • discuss implementation strategies for pre-vaccination screening programmes for dengue vaccines, including:

    • o

      practical issues for programmatic roll-out;

    • o

      the optimal age for vaccine introduction;

    • o

      communication strategies with regards to vaccine confidence, both for policy makers, the medical community and the lay public; and

    • o

      school-based campaigns

Section snippets

Country experiences with CYD-TDV to date

CYD-TDV dengue vaccine was first licensed in Mexico in December 2015, quickly followed by the Philippines and Brazil. It is now registered in 20 dengue-endemic countries in Asia, Latin America, and the Pacific. Furthermore, the European Medicine Agency (EMA) issued marketing authorization throughout the European Union in December 2018 (https://www.ema.europa.eu/en/documents/product-information/CYD-TDV-epar-product-information_en.pdf) for the indication of prevention of dengue disease caused by

Desired characteristics of screening tests

A screening test would require a high specificity to minimize individual risk and the inadvertent use of vaccine in seronegative persons by reducing the number of false positive test results, and at the same time high sensitivity to maximize individual and population benefit by identifying a high a proportion of previously exposed persons who will benefit from vaccination. The required sensitivity to achieve a high positive predictive value (PPV) will depend on the seroprevalence in the

Interactive workshop on countries opinions and preferences on the pre-vaccination screening strategy

Workshops were conducted with regional country representatives to discuss acceptable test performance thresholds and programmatic strategies.

Conclusions and outlook

Both working groups highlighted many challenges in introducing CYD-TDV, in terms of costs, logistics, achieving high coverage rates and communication; more challenges than for any other vaccine introduction programme. Implementation of a pre-vaccination screening strategy in all dengue-endemic countries is delayed due to the fact that a screening test is not yet available. Among the most critical challenges and rate-limiting steps to bringing new diagnostic tools to the market are the

Contributions

AWS, DJG, RL, MC, CK-C, AD, IKY served on the organizing committee for this workshop. All authors gave presentations during the workshop. AWS wrote the first draft. All authors contributed to the final draft.

Disclaimer

AWS serves as consultant to the World Health Organization (WHO), Initiative for Vaccine Research. SF and PGS served as members of the WHO SAGE working group on dengue vaccines. I-KY is an ad-hoc expert invited to the SAGE working group. CK-C is employed by FIND, RL serves as a consultant to WHO and FIND.

The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions or policies of WHO or FIND.

Funding

The meeting was financially supported through unrestricted grants by Sanofi Pasteur, bioMérieux and Chembio Diagnostic Systems. The funders did not play a role in the organization of the workshop, nor in the writing of the meeting report.

Declaration of Competing Interest

AWS, HL, RL, MC, CK-C, SF, PT and DC have nothing to declare. PGS is a member of the Independent Data Monitoring Committee for trials of the Sanofi-Pasteur dengue vaccine (Dengvaxia). I-KY’s institution received unrestricted grants from Sanofi Pasteur related to dengue vaccines. AD is the Principal Investigator of several trials and studies related to the TV003/005 dengue vaccine. DJG holds shares with Takeda. DC’s institution has received restricted grants from Sanofi Pasteur for its weekly

References (55)

  • H.J. Larson

    The state of vaccine confidence

    Lancet

    (2018)
  • S. Bhatt et al.

    The global distribution and burden of dengue

    Nature

    (2013)
  • E.S. Jentes et al.

    Evidence-based risk assessment and communication: a new global dengue-risk map for travellers and clinicians

    J Travel Med

    (2016)
  • P. Kittayapong et al.

    Mitigating diseases transmitted by aedes mosquitoes: a cluster-randomised trial of permethrin-impregnated school uniforms

    PLoS Negl Trop Dis

    (2017)
  • N. Andersson et al.

    Evidence based community mobilization for dengue prevention in Nicaragua and Mexico (Camino Verde, the Green Way): cluster randomized controlled trial

    BMJ

    (2015)
  • L. Goodyer et al.

    Mosquito repellents for the traveller: does picaridin provide longer protection than DEET?

    J Travel Med.

    (2018)
  • T. Lalani et al.

    A comparison of compliance rates with anti-vectorial protective measures during travel to regions with dengue or chikungunya activity, and regions endemic for Plasmodium falciparum malaria

    J Travel Med

    (2016)
  • S.L. O'Neill

    The use of wolbachia by the world mosquito program to interrupt transmission of aedes aegypti transmitted viruses

    Adv Exp Med Biol

    (2018)
  • S.A. Ritchie

    Wolbachia and the near cessation of dengue outbreaks in Northern Australia despite continued dengue importations via travellers

    J Travel Med

    (2018)
  • S. Masyeni et al.

    Dengue infection in international travellers visiting Bali, Indonesia

    J Travel Med

    (2018)
  • A. Neuberger et al.

    Dengue fever among Israeli expatriates in Delhi, 2015: implications for dengue incidence in Delhi, India

    J Travel Med.

    (2016)
  • A. Riddell et al.

    Imported dengue fever in East London: a 6-year retrospective observational study

    J Travel Med.

    (2017)
  • S. Rabinowicz et al.

    Morbidity among Israeli paediatric travellers

    J Travel Med

    (2017)
  • S.P. Sadarangani et al.

    Infectious diseases and migrant worker health in Singapore: a receiving country's perspective

    J Travel Med

    (2017)
  • S.R. Hadinegoro et al.

    Efficacy and long-term safety of a dengue vaccine in regions of endemic disease

    N Engl J Med

    (2015)
  • A. Wilder-Smith et al.

    Population perspectives and World Health Organization recommendations for CYD-TDV dengue vaccine

    J Infect Dis.

    (2016)
  • S. Sridhar et al.

    Effect of dengue serostatus on dengue vaccine safety and efficacy

    N Engl J Med

    (2018)
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