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Comparative Study
. 2017 Mar 29;91(8):e02133-16.
doi: 10.1128/JVI.02133-16. Print 2017 Apr 15.

Patterns of Cellular Immunity Associated With Experimental Infection With rDEN2Δ30 (Tonga/74) Support Its Suitability as a Human Dengue Virus Challenge Strain

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Free PMC article
Comparative Study

Patterns of Cellular Immunity Associated With Experimental Infection With rDEN2Δ30 (Tonga/74) Support Its Suitability as a Human Dengue Virus Challenge Strain

Alba Grifoni et al. J Virol. .
Free PMC article

Abstract

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, vigorous ex vivo responses 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.IMPORTANCE The 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.

Keywords: T cells; dengue virus; human challenge model; vaccine.

Figures

FIG 1
FIG 1
Protein locations of CD8 epitopes from individuals immunized with rDENV2d30 compared to those from individuals with natural infection (NI). The magnitude of the DENV2 response was analyzed by considering the overall protein composition (in percent). (A) Protein composition of the CD8 T cell response in rDEN2Δ30-immunized individuals; (B) protein composition of the CD8 T cell response in DENV2-infected donors in areas of hyperendemicity (16).
FIG 2
FIG 2
Protein locations of CD4 epitopes from individuals immunized with rDENV2d30 compared to those from individuals with natural infection. The magnitude of the DENV2 response was analyzed by considering the overall protein composition (in percent). (A) Protein composition of the CD4 T cell response in rDEN2Δ30-immunized individuals; (B) protein composition of the CD4 T cell response in DENV2-infected donors in areas of hyperendemicity (17).
FIG 3
FIG 3
CD8 immune response to rDEN2Δ30 compared to that to attenuated DENV vaccine strains. (A) Number of CD8-specific epitopes per donor in response to rDENV2Δ30 and the magnitude of the response in terms of the average number of SFC per donor. (B) Percentage of donors responding to rDENV2Δ30 with respect to that to other monovalent attenuated vaccine strains (12).

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