Antibody-dependent enhancement of severe dengue disease in humans

By L. Katzelnick, L. Gresh, M. E. Halloran, J. Mercado, G. Kuan, A. Gordon, Á. Balmaseda, E. Harris. Science, 2017

1,056 citations recorded by the source corpus.

Too much or too little—better than some Dengue fever is caused by a mosquito-transmitted flavivirus resembling Zika virus. Both viruses can cause severe diseases in humans with catastrophic sequelae. It has been suspected in humans, and shown in animal models, that the host's immune responses can make disease worse. Katzelnick et al. examined data from a long-term study of Nicaraguan children exposed to dengue virus (see the Perspective by Feinberg and Ahmed). They confirmed that antibody-dependent enhancement of disease occurs at a specific range of antibody concentrations. Low levels of antibody did not enhance disease, intermediate levels exacerbated disease, and high antibody titers protected against severe disease. These findings have major implications for vaccines against flaviviruses. Indeed, recent vaccine trials have shown evidence of severe disease in some recipients who were previously exposed to virus. Science, this issue p. 929; see also p. 865 A long-term Nicaraguan pediatric cohort reveals that a narrow range of preexisting antibody titers increases the risk of severe dengue disease. For dengue viruses 1 to 4 (DENV1-4), a specific range of antibody titer has been shown to enhance viral replication in vitro and severe disease in animal models. Although suspected, such antibody-dependent enhancement of severe disease has not been shown to occur in humans. Using multiple statistical approaches to study a long-term pediatric cohort in Nicaragua, we show that risk of severe dengue disease is highest within a narrow range of preexisting anti-DENV antibody titers. By contrast, we observe protection from all symptomatic dengue disease at high antibody titers. Thus, immune correlates of severe dengue must be evaluated separately from correlates of protection against symptomatic disease. These results have implications for studies of dengue pathogenesis and for vaccine development, because enhancement, not just lack of protection, is of concern.

Subfields: Infectious Diseases, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/fa4dbdafb0e623b4bc139cbabd96f2736089a18f

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Citations in the corpus

Dengue and severe dengue (2025, positive): “…and bind to epitopes on the E protein unique to the homologous DENV and typically strongly neutralize that DENV, but also induce cross-reactive (heterotypic) antibodies that bind to conserved E protein epitopes shared among all four DENVs with varying degrees of neutralizing activity (100, 101).”
Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry (2019, result): “Our study explains an earlier observation that ADE of dengue viruses occurs only at certain concentrations of MAb (5).”
Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. (2020, neutral): “5) 17 (34) 13 (29) 5 (38) Otherh 6 (10) 2 (9) 3 (10) 3 (10) 1 (8) 5 (11) 1 (14) 5 (10) 0 6 (12) 3 (7) 3 (23) Clinical features at presentationi Abdominal pain 31 (53) 13 (57) 18 (62) 13 (45) 2 (15) 29 (64) 1 (14) 30 (59) 2 (33) 29 (58) 24 (55) 7 (50) Diarrhea 30 (52) 10 (44) 19 (66) 11 (38) 7 (54) 2”
COVID-19 and multisystem inflammatory syndrome in children and adolescents (2020, positive): “…might accentuate disease through antibodydependent enhancement of viral entry and amplification of viral replication, as observed in dengue, 92–94 or by triggering a host inflammatory response through the formation of immune complexes or direct antitissue antibody activation or cellular…”
The enemy who sealed the world: effects quarantine due to the COVID-19 on sleep quality, anxiety, and psychological distress in the Italian population (2020, positive): “Our study explains an earlier observation that ADE of dengue viruses occurs only at certain concentrations of MAb (5) .”
COVID-19: immunopathogenesis and Immunotherapeutics (2020, background): “Antibody-dependent enhancement The Antibody-dependent enhancement (ADE) of virus infection is a phenomenon in which preexisting sub-neutralizing antibodies enhance virus entry and replication, and has been observed for various viruses, including the Ebola and Dengue viruses.(54,55) A neutralizing mo”
Global expansion and redistribution of Aedes-borne virus transmission risk with climate change (2017, background): “While viral immunology is complex [46,47], previously unexposed people may have high susceptibility to chikungunya, Zika, and primary dengue infection, although secondary dengue infections are often the most severe [46].”