Accuracy and efficacy of pre-dengue vaccination screening for previous dengue infection with five commercially available immunoassays: a retrospective analysis of phase 3 efficacy trials

Abstract

Background: The tetravalent dengue vaccine (CYD-TDV) has been shown to provide protection against dengue disease over 5-year follow-up in participants with previous dengue infection, but increased the risk of dengue hospitalisation and severe dengue during long-term follow-up in those without previous dengue infection. WHO recommended pre-vaccination screening to identify those with previous dengue infection (ie, dengue seropositive) who would benefit from vaccination. We re-evaluated CYD-TDV efficacy in those identified as dengue seropositive using five commercially available immunoassays, and assessed immunoassay performance.

Methods: We included participants in the immunogenicity subsets of the phase 3 CYD14 (NCT01373281) and CYD15 (NCT01374516) CYD-TDV efficacy trials, which enrolled children aged 2-16 years in 2011-12 in five countries in the Asia-Pacific region (CYD14) and five Latin American countries (CYD15). Participants assessed had received at least one injection of study drug (CYD-TDV or placebo) and had baseline samples available. We tested baseline samples by IgG-based immunoassays to classify baseline dengue serostatus, using two ELISAs (EUROIMMUN and Panbio) and three rapid diagnostic tests (RDTs; TELL ME FAST, SD BIOLINE, and OnSite). Vaccine efficacy in preventing symptomatic, hospitalised, and severe virologically confirmed dengue was determined for participants who tested positive by each immunoassay. The specificity and sensitivity of each immunoassay was determined as percentage negative and positive agreement compared with the reference algorithm, which used dengue plaque reduction neutralisation test with 50% and 90% cutoffs and non-structural protein 1 IgG ELISA results to assign baseline serostatus.

Findings: Samples were available for 3967 participants, 2735 (69·0%) of whom were classified as seropositive by the reference algorithm. Vaccine efficacy against symptomatic virologically confirmed dengue in immunoassay-positive participants was high across all five immunoassays (EUROIMMUN ELISA 88·2% [95% CI 77·3 to 93·9], Panbio ELISA 87·6% [76·7 to 93·4], TELL ME FAST RDT 88·8% [67·0 to 96·2], SD BIOLINE RDT 82·8% [66·9 to 91·1], and OnSite RDT 89·7% [64·6 to 97·0]), as was vaccine efficacy against hospitalised virologically confirmed dengue (EUROIMMUN-ELISA 72·8% [38·9 to 87·9], Panbio ELISA 77·5% [52·8 to 89·3], TELL ME FAST RDT 92·4% [37·8 to 99·1], SD BIOLINE RDT 87·2% [54·5 to 96·4], and OnSite RDT 73·7% [-5·1 to 93·4]) and severe virologically confirmed dengue (EUROIMMUN ELISA 86·9% [-16·8 to 98·5], Panbio ELISA 91·3% [27·6 to 99·0], TELL ME FAST RDT 100·0% [not estimable to 100·0%], SD BIOLINE RDT 89·4% [9·6 to 98·8], and OnSite RDT 73·4% [-193·7 to 97·6]). The immunoassays exhibited high specificity (≥98·8% for all immunoassays apart from SD BIOLINE RDT) but variable sensitivities, with higher sensitivities observed for the ELISAs (EUROIMMUN 89·2% [87·9 to 90·3] and Panbio 92·5 [91·4 to 93·5]) than the RDTs (TELL ME FAST 52·5% [50·6 to 54·4], SD BIOLINE 71·1% [69·3 to 72·8], and OnSite 47·6% [45·7 to 49·5]).

Interpretation: Our findings suggest that these immunoassays could be used for pre-vaccination screening for CYD-TDV as tools to assist risk stratification until more sensitive and convenient tests become available.

Funding: Sanofi Pasteur.

Figure 1

CYD-TDV efficacy against symptomatic virologically confirmed dengue up to month 25 in immunoassay-positive participants Data are pooled from CYD14 and CYD15 studies from participants aged 2–16 years. Density incidence is per 100 person-years, with the person-years at risk being the sum of the individual years for which the participants contributed to the analysis. RDT=rapid diagnostic test. *Immunoassay-positive participants.

Figure 2

CYD-TDV efficacy against hospitalised virologically confirmed dengue up to month 72 in immunoassay-positive participants Density incidence is per 100 person-years, with the person-years at risk being the sum of the individual years for which the participants contributed to the analysis. RDT=rapid diagnostic test. *Immunoassay-positive participants.

Figure 3

CYD-TDV vaccine efficacy against severe virologically confirmed dengue up to month 72 in immunoassay-positive participants Density incidence is per 100 person-years, with the person-years at risk being the sum of the individual years for which the participants contributed to the analysis. RDT=rapid diagnostic test. *Immunoassay-positive participants.

Figure 4

Immunoassay performance for dengue serostatus classification Values presented here are specific for the observed dengue seropositivity by the reference algorithm in this study (69·1%); PPVs and NPVs for other seroprevalences would differ from the estimates presented here. NPV=negative predictive value. PPV=positive predictive value. RDT=rapid diagnostic test.