Conference reportPre-vaccination screening strategies for the use of the CYD-TDV dengue vaccine: A meeting report
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
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review the rationale for the pre-vaccination screening strategy and to learn from the experience of countries where CYD-TDV had been introduced, and
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discuss rapid diagnostic tests (RDT) for screening for past dengue infection (dengue serostatus), including to:
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discuss a draft target product profile for RDTs to support a pre-vaccination screening strategy;
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present a landscape analysis on RDT characteristics, and their sensitivity and specificity in different flavivirus endemic settings;
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elaborate on population level benefit versus individual risk; and
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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)
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discuss implementation strategies for pre-vaccination screening programmes for dengue vaccines, including:
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practical issues for programmatic roll-out;
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the optimal age for vaccine introduction;
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communication strategies with regards to vaccine confidence, both for policy makers, the medical community and the lay public; and
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school-based campaigns
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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
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Evaluation of a new point-of-care test to determine prior dengue infection for potential use in pre-vaccination screening
2021, Clinical Microbiology and InfectionAccuracy and efficacy of pre-dengue vaccination screening for previous dengue infection with five commercially available immunoassays: a retrospective analysis of phase 3 efficacy trials
2021, The Lancet Infectious DiseasesCitation Excerpt :Vaccine efficacy estimates against hospitalised virologically confirmed dengue are also consistent with interim data in seropositive participants from these studies.10 The ideal immunoassay for dengue pre-vaccination screening should have very high specificity to minimise the safety risk of inadvertently vaccinating individuals who are seronegative but have tested as positive.19,20 The very high specificity across the EUROIMMUN ELISA, Panbio ELISA, TELL ME FAST RDT, and OnSite RDT suggests that these tests would be of value in minimising inadvertent vaccination of dengue-seronegative individuals.
Dengue vaccine development by the year 2020: challenges and prospects
2020, Current Opinion in VirologyThe potential impact of dengue vaccination with, and without, pre-vaccination screening
2020, VaccineCitation Excerpt :These data might, however, not be relevant for every setting. We also did not directly address specifically the feasibility aspects of a screen-and-vaccinate approach which could be complicated to implement since it differs from traditional immunization programs and could generate costs not covered in our analysis [18]. Finally, we present results for specific transmission settings but, as previously noted, seroprevalence estimation can by itself be difficult to achieve in practice [25].