---
title: "Single Dengvaxia dose gives transient protection in dengue‑naïve children"
id: "frontiers-in-immunology-7-a-single-dose-of-dengvaxia-is-associated-with-transient-reduction-in-dengue"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-7-a-single-dose-of-dengvaxia-is-associated-with-transient-reduction-in-dengue"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1959704"
published_at: "2026-10-14T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Single Dengvaxia dose gives transient protection in dengue‑naïve children
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-7-a-single-dose-of-dengvaxia-is-associated-with-transient-reduction-in-dengue
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1959704)
- **Published At:** 2026-10-14T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The study followed 186 dengue‑naïve children with complete samples at baseline, ~20 months (T1) and ~40 months (T2); 114 received a single dose of **Dengvaxia** and 72 remained unvaccinated. - Investigators used YFV NS1 antibody assays (expressed by the vaccine but not wild‑type DENV) plus DENV ED3/NS1 and neutralization assays to distinguish vaccine‑associated responses from WT DENV infections. - At T1, 61% of vaccinated children met predefined criteria for vaccine responders; low‑level YFV NS1 signals were detected in some originally classified non‑responders when using a more sensitive Luminex dilution. - A ≥4‑fold increase in YFV NS1 at 1:50 dilution was used to classify vaccine‑associated responses; this cutoff gave 82.7% sensitivity and 92.7% specificity in the study dataset (ROC AUC 0.94). - During baseline→T1, vaccination associated with reduced risk of wild‑type DENV infection (vaccine effectiveness = 45%); during T1→T2 no difference in infection risk was detected between vaccinated and unvaccinated groups. - Breakthrough WT DENV infection during baseline→T1 produced larger magnitude and broader serotype‑specific antibody responses in vaccinated children compared with unvaccinated children with primary infection, consistent with vaccine priming. - Those differences in post‑infection antibody magnitude and breadth were not observed during T1→T2. - Assays: focus reduction neutralization test (FRNT) for NAb, Luminex multiplex for ED3 and NS1 (DENV1–4 and YFV NS1). - Statistical approaches included nonparametric tests, probabilistic index effect sizes, and binomial regression to estimate risk ratios and VE for each study interval. - Limitations reported by the authors include the analytic subset (186 of originally enrolled dengue‑naïve children) selected because of complete longitudinal sampling, variable sampling windows across participants, and that sex was not analyzed as a biological variable. - Key unanswered questions in the manuscript: durability of low‑level vaccine‑associated responses beyond 40 months, clinical relevance of low‑level YFV NS1 signals in non‑responders, and mechanisms underlying loss of apparent protection in the second study period.
## Clinical Analysis & Structured Key Points
Frontiers | A single dose of Dengvaxia is associated with transient reduction in dengue infection risk among dengue-naïve children ORIGINAL RESEARCH article Front. Immunol. , 14 October 2026 Sec. Vaccines and Molecular Therapeutics Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1959704 Published in Frontiers in Immunology Vaccines and Molecular Therapeutics 7 impact factor 11.3 citescore Editor & Reviewers Edited by S T Selidji Todagbe AGNANDJI Reviewed by R N Ramtin Naderian I P Iman Pouladi Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Table 1 Cohort characteristics for children with longitudinal samples at T1 and T2. View in article Table 2 Risk of wild-type DENV infection during the first (BL–T1) and second (T1–T2) study periods across vaccination and immunological subgroups. View in article ORIGINAL RESEARCH article Front. Immunol. , 14 October 2026 Sec. Vaccines and Molecular Therapeutics Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1959704 A single dose of Dengvaxia is associated with transient reduction in dengue infection risk among dengue-naïve children M A Maria Abad Fernandez 1 * J V Jedas Veronica Daag 2 L D Lindsay D. Hein 1 K A Kristal An Agrupis 2 M V Maria Vinna Crisostomo 2 M Y Michelle Ylade 2 J D Jacqueline Deen 2 L J Laura J. White 1 L P Lakshmanane Premkumar 1 A L Ana Lena Lopez 2 † +2 more A M Aravinda M. de Silva 1 1. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, United States 2. Institute of Child Health and Human Development, University of the Philippines Manila, Manila, Philippines Article metrics View details Abstract Dengvaxia ® induces antibody responses in dengue virus (DENV)-naïve children, but the durability of these responses and their impact on subsequent wild-type (WT) DENV infection remain unclear. Although previous studies have primarily evaluated vaccine efficacy against dengue disease, the impact of Dengvaxia ® on susceptibility to WT DENV infection and subsequent immune responses remains less well defined. We evaluated vaccine-induced immunity and susceptibility to WT DENV infection in a longitudinal cohort of 186 seronegative children, including 114 who received a single dose of Dengvaxia ® and 72 who remained unvaccinated, followed for 40 months. Samples collected at baseline and two follow-up time points (20 months [T1] and 40 months [T2]) were analyzed using yellow fever virus (YFV) non-structural protein 1 (NS1) antibody assays, which is expressed by Dengvaxia ® but not by WT DENV, enabling discrimination between vaccine-associated and WT infection-induced responses. At T1, 61% of vaccinated children were responders. Additional low-level YFV NS1 antibody responses were detected in some children originally classified as vaccine non-responders, suggesting that the predefined binary classification may not capture the full range of vaccine-associated antibody responses. Low-level YFV NS1 responses remained detectable through T2. During the first follow-up period (baseline-T1), vaccination was associated with a reduced risk of WT DENV infection (vaccine effectiveness [VE]=45%). During the second period (T1-T2), no difference in infection risk was detected between groups. Following breakthrough infection during the first follow-up period, vaccinated children developed antibody responses with greater magnitude and broader serotype breadth than unvaccinated children with primary infection, consistent with vaccine-associated immune priming following WT DENV infection. In contrast, during the second period (T1-T2), differences in antibody magnitude and breadth following infection were no longer detected between groups. Together, these findings suggest that a single dose of Dengvaxia ® in DENV-seronegative children was associated with a reduced risk of WT DENV infection and with differences in subsequent antibody responses during the first follow-up period, but these associations were no longer observed during the second period. Introduction Dengue virus (DENV), a mosquito-borne flavivirus with four antigenically distinct serotypes (DENV1–4), causes a broad spectrum of clinical outcomes, ranging from asymptomatic infection to severe, life-threatening disease ( 1 ). Globally, an estimated 400 million DENV infections occur annually, predominantly in tropical and subtropical regions ( 2 ). Natural infection induces long-lived protection against the infecting serotype; however, subsequent secondary infection with another serotype is associated with increased risk of severe disease, a phenomenon often attributed to antibody-dependent enhancement (ADE) ( 3 ). These immunological dynamics pose unique challenges for dengue vaccine development, requiring the induction of both breadth and durability of protective immunity. Dengvaxia ® (CYD-TDV) is a live-attenuated, tetravalent dengue vaccine developed to protect against all four DENV serotypes ( 4 ). In 2015, it was approved for use in children aged nine years and older living in areas of high dengue endemicity. However, subsequent analyses of clinical trial data revealed an increased risk of severe dengue and hospitalization among vaccine recipients who were DENV-seronegative at baseline ( 5 ). These findings led to revised recommendations restricting vaccine use to individuals with evidence of prior dengue infection ( 6 ). Limited efficacy in seronegative children has been attributed to unbalanced replication among the vaccine’s tetravalent components, with the DENV4 strain replicating more efficiently than the others, resulting in predominantly DENV4-specific and cross-reactive antibodies to DENV1–3 that may contribute to enhanced disease risk ( 7 ). Prior to revised recommendations restricting the use of Dengvaxia ® to individuals with prior dengue infection, nearly one million children were vaccinated in the Philippines ( 8 ). In parallel with the vaccine rollout, we established a 5-year prospective pediatric cohort in Cebu to assess vaccine immunogenicity and efficacy by baseline dengue serostatus ( 9 ). We previously reported vaccine efficacy against virologically confirmed dengue within this cohort ( 9 ) and subsequently conducted detailed immunological analyses in a subgroup of 138 children who were DENV-seronegative at baseline (BL), focusing on individual-level vaccine responses and their relationship to safety and efficacy ( 10 ). At 20 months of follow-up, 38% of these baseline seronegative vaccinated children lacked detectable DENV-specific antibody responses by standard assays and were classified as vaccine “non-responders” according to the predefined study criteria ( 10 ). Vaccine non-responders are routinely included in efficacy studies and immunogenicity analyses evaluating seroconversion and the heterogeneity of vaccine-induced immune responses ( 5 , 11 , 12 ). However, the absence of detectable antibodies does not necessarily indicate an absence of vaccine-induced immune priming ( 13 – 15 ). In vaccines such as influenza and hepatitis B, post-exposure or booster responses have revealed underlying immune priming despite low or undetectable circulating antibody responses ( 14 , 15 ). In dengue vaccination, however, immunogenicity assessments have largely relied on circulating neutralizing antibodies (NAbs), potentially overlooking low-level antibody responses that may not be captured by standard assays ( 7 ). These limitations highlight the need to better define the spectrum, durability, and characteristics of vaccine-induced immune responses in dengue-naïve children, as well as how these responses are associated with susceptibility to subsequent WT DENV infection. To better understand the durability and characteristics of antibody responses stimulated by Dengvaxia ® in dengue-naïve children and their association with susceptibility to WT DENV infection, we addressed three interrelated questions in this study. First, to better define vaccine responders and individuals with low or undetectable responses by standard assays, we used an enhanced detection approach incorporating YFV NS1 antibody measurements at 20 and 40 months after vaccination (T1 and T2). Second, we evaluated antibody responses following breakthrough WT DENV infection by characterizing DENV-specific antibody magnitude and serotype breadth during the two follow-up periods. Finally, we examined how these immunological patterns related to susceptibility to WT DENV infection during the first (baseline to T1) and second (T1 to T2) study periods. Methods Cebu cohort study and ethics statement Between 2016 and 2017, 2,996 children aged 9–14 years were enrolled in a longitudinal cohort study. Of these, 1,782 children received a single dose of Dengvaxia ® during a mass vaccination campaign, while 1,214 remained unvaccinated. Demographic information and serum samples were collected from all participants at baseline, prior to vaccination. Baseline dengue immune status was assessed using a PanBio indirect IgG ELISA and DENV1–4 standard neutralization assays (two dilutions, 1:40 and 1:200), and 241 children were classified as dengue-naïve, including 148 vaccinated and 93 unvaccinated participants ( 16 ). In this cohort, the PanBio IgG ELISA showed 95.2% sensitivity and 93.4% specificity relative to FRNT for distinguishing DENV-seropositive from DENV-seronegative children ( 16 ). For the present analysis, we focused on a subset of dengue-naïve children from the previously described cohort ( 10 ) for whom serum samples were available at baseline and at two follow-up time points, approximately 20 months (T1) and 40 months (T2) post-baseline. This analytic subset included 186 children (114 vaccinated and 72 unvaccinated), reflecting those with complete longitudinal sampling through T2. The remaining DENV-naïve children were not included because complete longitudinal serum samples through T2 were unavailable. Sex was recorded for all participants and both males and females were included in the study. Sex was not considered as a biological variable in the analyses. Baseline samples were collected prior to vaccination, which occurred approximately two months after enrollment. Follow-up sampling occurred within predefined windows that varied slightly between participants; therefore, time points are reported relative to baseline throughout the manuscript. The study protocol was approved by the University of Manila Research Ethics Board (UPM-REB 2016-435-01) and was registered at ClinicalTrials.gov (NCT03465254). Parents or guardians provided written informed consent and children provided documented oral assent before participating in the study, in accordance with local regulations. Cells and virus Vero cells (CCL-81, ATCC) and furin-overexpressing Vero cells generously received from Dr. Ralph Baric were cultured as monolayers at 37 °C with 5% CO2 in Opti-Pro serum-free medium (Invitrogen), supplemented with 10% fetal bovine serum (FBS) and 4 mM glutamine (Gibco). DENV1–4 strains that match circulating genotypes in the Philippines were produced as previously described ( 17 , 18 ). DENV virus strains used were: DENV1 (2014 Sri Lanka strain, GenBank accession no. KJ726662), DENV2 (2016 Sri Lanka strain, MK579857), DENV3 (1986 Sri Lanka strain, JQ411814) and DENV4 (1992 Sri Lanka strain, KJ160504). Focus reduction neutralization test Neutralization assays were conducted following previously described procedures ( 17 , 18 ). In brief, 1.7x10 4 Vero cells per well were plated one day before infection and incubated overnight at 37 °C. Human immune sera were serially diluted four-fold and mixed with low-passage clinical isolates of DENV1-4, produced in Vero-furin cells. The serum-virus mixtures were incubated at 37 °C for one hour before being added to confluent cells. After an additional hour, a 1% methylcellulose overlay was applied, and the cells were incubated for 2–3 days. The cells were then fixed with 80% methanol, blocked with 5% non-fat dried milk, and immunostained using mouse 4G2 and 2H2 anti-pan flavivirus monoclonal antibodies. Secondary detection was carried out with a horseradish peroxidase (HRP)-labeled goat anti-mouse IgG antibody (Jackson ImmunoResearch Laboratories), and HRP activity was visualized with the TrueBlue substrate. Images of all wells were captured using the Cellular Technology Limited (CTL) imaging system and ImmunoSpot software, and foci were quantified with the Viridot plaque counter in R. Serum neutralization titers were determined by calculating the serum dilution resulting in a 50% reduction in foci relative to control wells with virus without serum. Luminex-based assays to measure binding antibodies to NS1 and EDIII Binding antibodies to DENV envelope protein domain 3 (ED3) and nonstructural protein 1 (NS1) of DENV1–4, as well as YFV NS1, were measured in unvaccinated and vaccinated children using a Luminex-based multiplex assay, as previously described ( 19 ). Briefly, biotinylated ED3 antigens and biotinylated bovine serum albumin (BSA) were coupled to unique MagPlex ® -Avidin Microspheres (Luminex), while His-tagged NS1 antigens (The Native Antigen Company) were immobilized onto avidin-coated microspheres via anti-His tag antibody (Abcam). ED3-, NS1-, and BSA-conjugated microspheres were mixed in equal ratios and plated at 2,500 beads per antigen in 50 µL/well on 96-well plates. Human serum samples were diluted 1:500 for all antigens; in addition, a 1:50 dilution was used for YFV NS1 to enhance detection of low-level antibody responses. Diluted sera were incubated with the antigen-coupled microspheres for 1 hour at 37 °C and 700 rpm, followed by incubation with goat anti-human IgG Fc multi-species SP ads-PE (Southern Biotech) after three washes. Antibody responses were measured using a Luminex 200 analyzer and expressed as median fluorescence intensity (MFI), with non-specific binding to BSA subtracted. For measurements at the 1:500 dilution (all antigens), a seropositivity threshold was applied to facilitate interpretation across individuals. The threshold was calculated from MFI values measured in 136 DENV-naïve children, taking the mean plus three standard deviations (mean + 3 SD). A sample was considered positive if its MFI exceeded this threshold and showed a ≥2-fold increase from baseline to T1. For measurements at 1:50 dilution, YFV NS1 antibody responses were defined based on the fold-increase in Luminex signal between baseline and T1 (T1/BL ratio). Receiver operating characteristic (ROC) analysis comparing originally classified vaccine responders (n=52) and unvaccinated children who remained free of WT DENV infection during the BL-T1 interval (n=41) was performed to determine the optimal threshold for discrimination between these two groups. The area under the curve (AUC) was 0.94 (95% CI 0.89–0.99), and the Youden index identified a 3.55-fold increase as the optimal cutoff within this dataset. For consistency with conventional serologic criteria and to avoid relying on a threshold optimized within the study population, a ≥4-fold increase was applied to classify YFV-specific vaccine responses in all subsequent analyses, yielding 82.7% sensitivity and 92.7% specificity relative to these predefined reference groups. Sensitivity analyses using the ROC-derived 3.55-fold threshold yielded similar results. Definition of vaccine response, non-response and DENV infection Vaccine responders and non-responders were initially classified based on a composite immunological profile integrating multiple assays. Children were considered vaccine responders if they showed YFV NS1 antibody positivity by ELISA and/or Luminex at 1:500, or if they seroconverted to DENV-ED3 antigens without seroconversion to DENV-NS1 antigens. Non-responders were defined as those lacking detectable responses across these criteria. To enhance detection of low-level YFV NS1 responses, children who remained free of breakthrough WT DENV infection through T1 were additionally assessed using Luminex at a 1:50 dilution. DENV infection was defined as previously described based on serological evidence of seroconversion to DENV NS1 and/or serotype-specific antibody profiles in longitudinal paired samples collected over time ( 10 ). For infections identified during the BL-T1 interval, the infecting serotype was inferred from post-infection neutralization profiles based on seroconversion to a single DENV serotype or a ≥4-fold higher neutralizing antibody titer to one serotype relative to the other serotypes. Infections for which no single serotype met either criterion were classified as indeterminate. Both symptomatic and asymptomatic infections were included. Statistical analysis Statistical analyses were performed using GraphPad Prism (version 10.1.2), with probabilistic index effect sizes and 95% confidence intervals calculated in R (version 4.3.2). Paired comparisons between baseline and post-vaccination time points were performed using the Wilcoxon signed-rank test. Longitudinal analyses across three time points (baseline, T1, T2) were conducted using the Friedman test with Dunn’s post-hoc multiple comparisons. All analyses were two-tailed, and p values 0.5 indicating a greater probability of a higher response in the vaccinated group relative to the unvaccinated reference group. Ties were assigned half-weight, and 95% confidence intervals (CI) were estimated using nonparametric bootstrap resampling within groups. As an exploratory sensitivity analysis, post-infection antibody responses were additionally compared between vaccine responders and unvaccinated children with inferred DENV2 infection, the predominant assignable infecting serotype in both groups. Risk ratios (RRs) and 95% CIs were calculated to compare infection risk between groups. RRs were estimated using binomial regression models with a log link, with DENV-naïve unvaccinated individuals as the reference group. Vaccine effectiveness (VE) was calculated as VE= (1−RR) × 100. Confidence intervals for RR were derived from model-based standard errors. Analyses were performed separately for each study period. Comparisons addressing the primary study questions were hypothesis-driven, whereas additional subgroup analyses were exploratory. Study approval The study protocol was approved by the University of the Philippines - Manila Research Ethics Board (UPM REB 2016-435-01) and is registered at clinica
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