Target product profile for a dengue pre-vaccination screening test

Abstract

With increasing geographic spread, frequency, and magnitude of outbreaks, dengue continues to pose a major public health threat worldwide. Dengvaxia, a dengue live-attenuated tetravalent vaccine, was licensed in 2015, but post hoc analyses of long-term data showed serostatus-dependent vaccine performance with an excess risk of hospitalized and severe dengue in seronegative vaccine recipients. The World Health Organization (WHO) recommended that only persons with evidence of past dengue infection should receive the vaccine. A test for pre-vaccination screening for dengue serostatus is needed. To develop the target product profile (TPP) for a dengue pre-vaccination screening test, face-to-face consultative meetings were organized with follow-up regional consultations. A technical working group was formed to develop consensus on a reference test against which candidate pre-vaccination screening tests could be compared. The group also reviewed current diagnostic landscape and the need to accelerate the evaluation, regulatory approval, and policy development of tests that can identify seropositive individuals and maximize public health impact of vaccination while avoiding the risk of hospitalization in dengue-naive individuals. Pre-vaccination screening strategies will benefit from rapid diagnostic tests (RDTs) that are affordable, sensitive, and specific and can be used at the point of care (POC). The TPP described the minimum and ideal characteristics of a dengue pre-vaccination screening RDT with an emphasis on high specificity. The group also made suggestions for accelerating access to these RDTs through streamlining regulatory approval and policy development. Risk and benefit based on what can be achieved with RDTs meeting minimal and optimal characteristics in the TPP across a range of seroprevalences were defined. The final choice of RDTs in each country will depend on the performance of the RDT, dengue seroprevalence in the target population, tolerance of risk, and cost-effectiveness.

Performance Evaluation of a Dengue IgG Rapid Diagnostic Test Designed to Determine Dengue Serostatus as Part of Prevaccination Screening

“…The OnSite dengue IgG RDT fills a diagnostic gap for a simple, highly accurate dengue immunoassay that can be used at point-of-care as part of prevaccination screening for dengue serostatus before administering CYD-TDV, as recommended by WHO ( 4 ) and in conformance with the optimal test performance characteristics recently proposed for this diagnostic indication ( 13 ). The test displayed very high specificity and minimal-to-no cross-reactivity to any of the diseases or conditions tested.…”

“…Flasche et al ( 15 ) and Rodriguez-Barraquer et al ( 5 ) have proposed that the range over which a dengue screening test is safely “fit for purpose” is the span over which PPV exceeds 90% and NPV exceeds 75%, in the case of this new RDT from 16% to 87% dengue seroprevalence (see Table S2). Fongwen et al have proposed that under optimal circumstances, both PPV and NPV would be ≥90%, where the false discovery rate and false omission rate would both be <10% ( 13 ). For the OnSite Dengue IgG Rapid Test, this would correspond to dengue seroprevalence spanning 16% to 69%.…”

Dengue Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2021

“…Other ways to establish previous DENV infection include documentation of either a positive dengue RT-PCR test result, a positive NS1 antigen test result, or a positive anti-DENV IgM test result in geographic areas without co-circulation of other flaviviruses (e.g., Zika) (30). The guidance presented in this report on optimal test performance for anti-DENV IgG screening for U.S. territories and freely associated states is adapted from the international target product profile developed by the Partnership for Dengue Control and the Global Dengue and Aedes-transmitted Diseases Consortium (72). Key areas are discussed where modification of the international target product profile is recommended for U.S. territories and freely associated states.…”

“…At a stated sensitivity and specificity, tests are more likely to misclassify seronegative persons in low seroprevalence geographic areas than in high seroprevalence areas (Table 2) (72,73). For example, in populations with seroprevalence of <30%, jurisdictions should use tests with high specificity (>98%) to ensure <10% (1 -PPV) of persons who have positive test results will be misclassified and erroneously vaccinated (Table 2) (72,73). Conversely, high sensitivity ensures that most seropositive persons would be correctly identified as positive, particularly in high prevalence areas (Table 1).…”

“…CDC recommends that an evaluation of new and existing tests for prevaccination screening should be done with a wellcharacterized panel that includes remote DENV infections (i.e., 1-3 years after documented exposure) of all four DENV serotypes, Zika, and epidemiologically relevant flavivirus infections found in the geographic area where the vaccine is proposed to be used. This evaluation should include samples from persons who received flavivirus vaccines, as well as negative control samples, and should follow international standards (72). The evaluation panel should be assessed with 50% and 90% plaque reduction neutralization tests (PRNT50 and PRNT90) to establish test performance in detecting remote DENV monotypic infections.…”