Patterns of Cellular Immunity Associated with Experimental Infection with rDEN2Δ30 (Tonga/74) Support Its Suitability as a Human Dengue Virus Challenge Strain.
A deletion variant of the dengue virus (DENV) serotype 2 (DENV2) Tonga/74 strain lacking 30 nucleotides from its 3' untranslated region (rDEN2Δ30) has previously been established for use in a controlled human DENV challenge model. To evaluate if this model is appropriate for the derivation of correlates of protection for DENV vaccines on the basis of cellular immunity, we wanted to compare the cellular immune response to this challenge strain to the response induced by natural infection. To achieve this, we predicted HLA class I- and class II-restricted peptides from rDEN2Δ30 and used them in a gamma interferon enzyme-linked immunosorbent spot assay to interrogate CD8+and CD4+T cell responses in healthy volunteers infected with rDEN2Δ30. At the level of CD8 responses, vigorousex vivoresponses were detected in approximately 80% of donors. These responses were similar in terms of the magnitude and the numbers of epitopes recognized to the responses previously observed in peripheral blood mononuclear cells from donors from regions where DENV is hyperendemic. The similarity extended to the immunodominance hierarchy of the DENV nonstructural proteins, with NS3, NS5, and NS1 being dominant in both donor cohorts. At the CD4 level, the responses to rDEN2Δ30 vaccination were less vigorous than those to natural DENV infection and were more focused on nonstructural proteins. The epitopes recognized following rDEN2Δ30 infection and natural infection were largely overlapping for both the CD8 (100%) and CD4 (85%) responses. Finally, rDEN2Δ30 induced stronger CD8 responses than other, more attenuated DENV isolates.IMPORTANCEThe lack of a known correlate of protection and the failure of a neutralizing antibody to correlate with protection against dengue virus have highlighted the need for a human DENV challenge model to better evaluate the candidate live attenuated dengue vaccines. In this study, we sought to characterize the immune profiles of rDEN2Δ30-infected subjects and to compare the profiles with those for subjects from areas where DENV is hyperendemic. Our data demonstrate that T cell responses to rDENV2Δ30 are largely similar to those to natural infection in terms of specificity, highlighting that the response to this virus in humans is appropriate as a model for the T cell response to primary DENV2 infection.
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Alba
A
Grifoni
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Michael
M
Angelo
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
John
J
Sidney
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Sinu
S
Paul
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Bjoern
B
Peters
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.|Genetech Research Institute, Colombo, Sri Lanka.
Aruna D
AD
de Silva
Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia, and Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Elizabeth
E
Phillips
Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia, and Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Simon
S
Mallal
University of Vermont College of Medicine and Vaccine Testing Center, Burlington, Vermont, USA.
Sean A
SA
Diehl
University of Vermont College of Medicine and Vaccine Testing Center, Burlington, Vermont, USA.
Jason
J
Botten
University of Vermont College of Medicine and Vaccine Testing Center, Burlington, Vermont, USA.
Jonathan
J
Boyson
University of Vermont College of Medicine and Vaccine Testing Center, Burlington, Vermont, USA.
Beth D
BD
Kirkpatrick
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Stephen S
SS
Whitehead
Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
Anna P
AP
Durbin
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Alessandro
A
Sette
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA daniela@lji.org.
Daniela
D
Weiskopf
D020413:3' Untranslated Regions; D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003715:Dengue / Q000276:immunology* / Q000821:virology*; D003716:Dengue Virus / Q000235:genetics / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D017384:Sequence Deletion
D020413:3' Untranslated Regions; D000956:Antigens, Viral; D000939:Epitopes; D007371:Interferon-gamma
T cells; dengue virus; human challenge model; vaccine