Indirect IgG ELISA and serotype-specific neutralizing antibody titers are associated with protection against dengue in children in Cebu, Philippines

Abstract Standard measures of dengue virus (DENV) antibodies have not been established as protective against dengue. We assess whether an indirect dengue IgG ELISA (PanBio; Brisbane, QLD, Australia) and serotype-specific neutralizing antibody titers measured by a two-dilution focus reduction neutralization test (FRNT) are associated with protection against dengue. Healthy children (n = 1,214) aged 9–14 years in Cebu, Philippines were enrolled in a prospective population-based cohort study in May – June 2017 and were tested for dengue when they reported a febrile illness through March 2020. Serum samples were collected at enrollment, and all were tested by ELISA. FRNTs were performed using the WHO DENV1–4 reference strains on a random subset to quantify serotype-specific neutralizing antibodies (nAbs). Inverse probability weighting was used to adjust for subset size. The odds of dengue as predicted by antibody measures were assessed by logistic regressions and adjusted for age, gender, and residential site. Dengue naïve children were used as the reference group in all models. The probability of dengue was 9.2% (95% CI: 4.5 – 17.9) for the naïve group, 9.5% (4.8 – 17.8) for those with ELISA < 2, but 4.5% (2.8 – 7.2) for those with ELISA >= 2 (p=0.04). The probability was even lower at 1.4% (0.6 – 3.1) for those with the highest DENV1–4 geometric mean titers (GMT, p = 0.0001). Pre-vaccine nAbs to DENV2 and DENV3 were protective against a homotypic dengue case (DENV2: OR 0.28, 95% CI 0.12 to 0.65; DENV3: OR 0.27, 95% CI 0.13 to 0.57), but not heterotypic dengue. We show a commercial ELISA and serotype-specific nAbs are associated with the probability of dengue, providing useful assays for use in population and vaccine trials. This work was supported by the Philippine Department of Health, the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), and NIH Extramural Grant: P01AI106695.