Human CD4 ⁺ T Cell Responses to an Attenuated Tetravalent Dengue Vaccine Parallel Those Induced by Natural Infection in Magnitude, HLA Restriction, and Antigen Specificity

Abstract

Dengue virus (DENV) is responsible for growing numbers of infections worldwide and has proven to be a significant challenge for vaccine development. We previously demonstrated that CD8 ϩ T cell responses elicited by a dengue live attenuated virus (DLAV) vaccine resemble those observed after natural infection. In this study, we screened peripheral blood mononuclear cells (PBMCs) from donors vaccinated with a tetravalent DLAV vaccine (TV005) with pools of dengue virusderived predicted major histocompatibility complex (MHC) class II binding peptides. The definition of CD4 ϩ T cell responses after live vaccination is important because CD4 ϩ T cells are known contributors to host immunity, including cytokine production, help for CD8 ϩ T and B cells, and direct cytotoxicity against infected cells. While responses to all antigens were observed, DENV-specific CD4 ϩ T cells were focused predominantly on the capsid and nonstructural NS3 and NS5 antigens. Importantly, CD4 ϩ T cell responses in vaccinees were similar in magnitude and breadth to those after natural infection, recognized the same antigen hierarchy, and had similar profiles of HLA restriction. We conclude that TV005 vaccination has the capacity to elicit CD4 ϩ cell responses closely mirroring those observed in a population associated with natural immunity.IMPORTANCE The development of effective vaccination strategies against dengue virus infection is of high global public health interest. Here we study the CD4 T cell responses elicited by a tetravalent live attenuated dengue vaccine and show that they resemble responses seen in humans naturally exposed to dengue virus. This is an important issue, since it is likely that optimal immunity induced by a vaccine requires induction of CD4 ϩ responses against the same antigens as those recognized as dominant in natural infection. Detailed knowledge of the T cell response may further contribute to the identification of robust correlates of protection against dengue virus.

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

“…Here we compared the magnitude and breadth of the response and the response rates of CD8 T cells observed in the monovalent DLAV studies (12) with those of CD8 T cells observed in the current study. A similar analysis at the level of CD4 responses was not feasible since the CD4 immunogenicity of the attenuated viruses was evaluated only with the tetravalent formulation (8).…”

“…This effect has been reported in the context of other viral systems. A similar comparison of the various DLAVs and rDEN2Δ30 at the level of CD4 responses was not feasible since the CD4 immunogenicity of the attenuated viruses was evaluated only with the tetravalent formulation (8). Since no clinical evaluation of monovalent DLAVs is currently ongoing, samples for study were no longer available for our analysis.…”

“…These peptides sets were subdivided into pools of 10 individual peptides and were previously utilized to characterize CD8 responses in the areas of Colombo, Sri Lanka, and Managua, Nicaragua, where dengue is hyperendemic and in the context of vaccination with the tetravalent DENV live attenuated vaccine (TDLAV) (12,16,25). These peptide sets were previously utilized to characterize the CD4 responses in the areas of Colombo, Sri Lanka, and Managua, Nicaragua, where dengue is hyperendemic and in the context of vaccination with TDLAV (8,12,16).…”

“…To analyze DENV-specific HLA-restricted CD4 responses, we utilized sets of DENV peptides predicted to bind HLA-DRB1* allelic variants expressed in the donor population as previously described (8,17). These sets of peptides included 15-mer HLA class II allele-restricted peptides (average, 130 peptides; range, 108 to 172 peptides) subdivided into pools of 20 individual peptides previously utilized to characterize CD4 responses in the area of Colombo, Sri Lanka, where dengue is hyperendemic and in the context of vaccination with TDLAV (8,17).…”

“…In this case, the use of the yellow fever virus backbone encoding the DENV E and prM antigens might be suboptimal, since DENV-specific CD4 and CD8 responses dominantly target the DENV capsid (C) and nonstructural (NS) proteins, respectively (8), which are not contained in the Dengvaxia vaccine. The DENV C and NS proteins are, however, encoded by tetravalent DENV live attenuated vaccine (TDLAV) constructs.…”