Dengue virus controlled human challenge reveals that preexisting immunity shapes viral replication and broadly protective responses

Dengue is the canonical viral disease for which immune history is a determinant of protective versus pathogenic responses and immunogenicity. Yet, because of limitations in animal models and clinical presentation after peak viremia, how preinfection and early immune responses affect dengue outcome is not confirmed. We conducted a phase 1 clinical trial with 45 healthy adults to test whether secondary infection challenge with a heterotypic, full-length, attenuated virus increases viremia and immunogenicity compared with primary and tertiary infection. Viremia was associated with more, but still mild, clinical signs and symptoms, and secondary infection resulted in greater viremia, neutralizing antibodies, and protective T cell responses. However, those whose baseline antibodies most efficiently increased dengue virus replication in an in vitro assay experienced delayed inflammatory and adaptive immune activation, the highest viremia, strong acute immune responses, and waning of potent CD8 + T cells and antibodies. In contrast, higher baseline antibodies against the nonstructural protein 1 of multiple serotypes predicted early interferon and balanced immune activation, viremia control, and development of enduring, potent B and T cells, revealing how vaccines can induce broad, long-lasting protection. Last, individuals with potent and neutralizing antibodies and IFN-γ + T cells at baseline experienced minimal viral replication. Together, these findings demonstrate that controlled human challenge with dengue virus can delineate coordinated versus dysregulated acute immune responses and their effects on immunogenicity, informing therapeutic and vaccine strategies for dengue and other viral diseases.

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Publication Details

Journal
Science Translational Medicine
Published
2026-10-28
DOI
https://doi.org/10.1126/scitranslmed.aei5117
Citations
1
Primary Topic
Mosquito-borne diseases and control
Type
article
Field-Weighted Citation Impact
6.43

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article

Dengue virus controlled human challenge reveals that preexisting immunity shapes viral replication and broadly protective responses

Caitlin Jarvis, Jeffrey I. Cohen, Jessica E. Manning, Gitanjali L. Bhushan et al.
1 citations
Science Translational Medicine
Mosquito-borne diseases and control
6.43
article

Dengue virus controlled human challenge reveals that preexisting immunity shapes viral replication and broadly protective responses

Caitlin Jarvis, Jeffrey I. Cohen, Jessica E. Manning, Gitanjali L. Bhushan, Camila D. Odio, María Abad-Fernández, Leah C. Katzelnick, Stephen S. Whitehead, Robbie Kattappuram, Melissa A. Law, Rosemary A. Aogo, Kelsey Elizabeth Lowman, Patrick I. Mpingabo, Daniela Weiskopf, Viviane Callier, Charlie J. Voirin, Anna P. Durbin, Saba Firdous, Sally Hunsberger, Christina Yek, Chloe M. Hasund, Amparo Martínez-Pérez, Aravinda M. de Silva, Silvia Blanco, Ysabelle Broderson, Keerthi Konda, Nhyira Asante
article en
1 citations

Abstract

Dengue is the canonical viral disease for which immune history is a determinant of protective versus pathogenic responses and immunogenicity. Yet, because of limitations in animal models and clinical presentation after peak viremia, how preinfection and early immune responses affect dengue outcome is not confirmed. We conducted a phase 1 clinical trial with 45 healthy adults to test whether secondary infection challenge with a heterotypic, full-length, attenuated virus increases viremia and immunogenicity compared with primary and tertiary infection. Viremia was associated with more, but still mild, clinical signs and symptoms, and secondary infection resulted in greater viremia, neutralizing antibodies, and protective T cell responses. However, those whose baseline antibodies most efficiently increased dengue virus replication in an in vitro assay experienced delayed inflammatory and adaptive immune activation, the highest viremia, strong acute immune responses, and waning of potent CD8 + T cells and antibodies. In contrast, higher baseline antibodies against the nonstructural protein 1 of multiple serotypes predicted early interferon and balanced immune activation, viremia control, and development of enduring, potent B and T cells, revealing how vaccines can induce broad, long-lasting protection. Last, individuals with potent and neutralizing antibodies and IFN-γ + T cells at baseline experienced minimal viral replication. Together, these findings demonstrate that controlled human challenge with dengue virus can delineate coordinated versus dysregulated acute immune responses and their effects on immunogenicity, informing therapeutic and vaccine strategies for dengue and other viral diseases.

Science Translational MedicineVol. 18(873)
University of North Carolina at Chapel Hill (US), National Institutes of Health (US), La Jolla Institute for Immunology (US), Johns Hopkins University (US), University of Cambridge (GB), University of California San Diego (US), Frederick National Laboratory for Cancer Research (US), National Institute of Allergy and Infectious Diseases (US), National Institutes of Health Clinical Center (US)
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 3%
Mosquito-borne diseases and control
6.43
DOISourceOpenAlex
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