Dengue immune defenses

Cross-reactive antibodies against different dengue virus serotypes (DENV1-4) can have either protective or pathogenic effects depending on immune responses to the secondary infection serotype. Dias et al. used systems serology to profile DENV-specific antibody responses of previously infected children in a Nicaraguan cohort study to determine correlates of protection against secondary DENV3 infection. Children protected against secondary symptomatic infection had higher titers of total IgG and IgG4 specific to envelope (E) protein and nonstructural protein 1 (NS1) and had antibodies with greater Fc effector functions relative to symptomatic children. Plasma anti-E and anti-NS1 polyclonal antibodies were associated with protection via Fc-driven complement deposition and lysis of DENV virions or infected cells in vitro. Together, these observations indicate that E- and NS1-specific Abs may have Fc effector functions that serve as correlates of protection against DENV.


Preexisting cross-reactive antibodies have been implicated in both protection and pathogenesis during subsequent infections with different dengue virus (DENV) serotypes (DENV1-4). Nonetheless, humoral immune correlates and mechanisms of protection have remained elusive. Using a systems serology approach to evaluate humoral responses, we profiled plasma collected before inapparent or symptomatic secondary DENV3 infection from our pediatric cohort in Nicaragua. Children protected from symptomatic infections had more anti-envelope (E) and anti–nonstructural protein 1 (NS1) total immunoglobulin G (IgG), IgG4, and greater Fc effector functions than those with symptoms. Fc effector functions were also associated with protection from hemorrhagic manifestations in the pre-symptomatic group. Furthermore, in vitro virological assays using these plasma samples revealed that protection mediated by antibody-dependent complement deposition was associated with both lysis of virions and DENV-infected cells. These data suggest that E- and NS1-specific Fc functions may serve as correlates of protection, which can be potentially applied toward the design and evaluation of dengue vaccines.

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June 2022

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We thank past and present members of the study team based at the Centro de Salud Sócrates Flores Vivas, the National Virology Laboratory in the Centro Nacional de Diagnóstico y Referencia, and the Sustainable Sciences Institute in Nicaragua for their dedication and high-quality work. We are very grateful to the PDCS participants and their families. We thank W. Clay Brown and J. Smith (University of Michigan, USA), L. Premkumar and A. de Silva (University of North Carolina at Chapel Hill, USA), and R. Baric (University of North Carolina at Chapel Hill, USA) for providing us with DENV3 E domain III, full-length recombinant DENV2 NS1 and NS1 wing and β-ladder domains, and a DENV3 infectious clone, respectively. We are also thankful to S. Biering for providing helpful feedback on this manuscript; F. Bustos for discussions on statistical analyses and data presentation; and J. V. Zambrana for providing demographic and infection history data about the samples.
Funding: This research was funded by National Institutes of Health (NIH) grants P01AI106695 (to E.H.) and NIH U19-AI135995 (to D.A.L.). G.A.’s work was supported by Terry and Susan Ragon; the SAMANA Kay MGH Research Scholars award; the Ragon Institute of MGH, MIT and Harvard; the NIH (3R37AI080289-11S1); the Gates Foundation Global Health Vaccine Accelerator Platform funding (OPP1146996 and INV-001650); and the Musk Foundation. The PDCS was supported by the Pediatric Dengue Vaccine Initiative grant VE-1 (to E.H.) from the Bill and Melinda Gates Foundation and NIH subcontract HHSN2722001000026C (to E.H. and A.B.).
Author contributions: E.H., G.A., and A.G.D.J. conceptualized the study. A.G.D.J., C.A., and V.R. conducted systems serology experiments and virological assays. M.M. and P.N. conducted experiments for sample characterization. C.A. and C.L. performed bioinformatic analysis. A.G.D.J, C.A., C.L., S.B., L.K., T.S., D.L., E.H., and G.A. contributed to overall data analysis and visualization. E.H., G.A., and A.B. obtained funding. A.B. and G.K. were responsible for sample acquisition, clinical and laboratory characterization, and generation of databases. E.H., G.A., and D.L. supervised the study. A.G.D.J. and E.H. wrote the first draft of the manuscript. All authors reviewed and edited the manuscript.
Competing interests: G.A. is a founder of Systems Seromyx and an employee of Leyden Labs. E.H.’s laboratory received research funds from Takeda Vaccines Inc. to analyze samples from vaccine recipients. E.H. served on one-time advisory boards for Merck and Takeda. The other authors declare that they have no competing interests.
Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. Materials may be shared with outside investigators subject to availability and following UC Berkeley IRB approval. Please contact the UC Berkeley Center for the Protection of Human Subjects ([email protected]) and E.H. ([email protected]) to arrange for access. The materials used in this study are covered by standard material transfer agreements. There was no unique code generated for this manuscript. Code from this manuscript was adapted from



Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Roles: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
Roles: Conceptualization, Formal analysis, Investigation, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Carolin Loos
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
Massachusetts Institute of Technology, Cambridge, MA, USA.
Roles: Formal analysis, Methodology, Software, Validation, Visualization, and Writing - review & editing.
Magelda Montoya
Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Role: Conceptualization.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
Roles: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Resources, and Validation.
Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Roles: Formal analysis, Investigation, Methodology, Writing - original draft, and Writing - review & editing.
Parnal Narvekar
Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Roles: Formal analysis and Validation.
Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Roles: Formal analysis and Validation.
Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Viral Epidemiology and Immunity Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Roles: Conceptualization, Data curation, Validation, and Writing - review & editing.
Sustainable Sciences Institute, Managua, Nicaragua.
Centro de Salud Sócrates Flores Vivas, Ministerio de Salud, Managua, Nicaragua.
Roles: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Supervision, and Validation.
Douglas A. Lauffenburger
Massachusetts Institute of Technology, Cambridge, MA, USA.
Roles: Methodology, Resources, Supervision, and Writing - review & editing.
Angel Balmaseda
Sustainable Sciences Institute, Managua, Nicaragua.
Laboratorio Nacional de Virología, Centro Nacional de Diagnóstico y Referencia, Ministerio de Salud, Managua, Nicaragua.
Roles: Project administration, Resources, Supervision, and Validation.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
Roles: Conceptualization, Project administration, Supervision, Writing - original draft, and Writing - review & editing.
Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Roles: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Visualization, Writing - original draft, and Writing - review & editing.

Funding Information

National Institutes of Health: HHSN2722001000026C
National Institutes of Health: HHSN2722001000026C
Center for Global Health: 3R37AI080289-11S1
Center for Global Health: HHSN2722001000026C


Corresponding author. Email: [email protected] (E.H.); [email protected] (G.A.)
These authors contributed equally to this work.

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