Cellular immunity patterns of rDEN2Δ30 (Tonga/74) support its suitability as a human DENV challenge strain.

Abstract

Abstract The need for human DENV challenge model to better evaluate DENV candidate vaccines has become of extreme importance in the past years after neutralizing antibody failure to be a good correlate of protection and the lack of valid alternatives. rDEN2Δ30, a variant of DENV2 Tonga/74 strain lacking 30 nucleotides from its 3′ untranslated region, has been established as DENV human challenge model. In this study, DENV cellular immune responses of rDEN2Δ30 strain have been compared with natural infection to derive correlates of protection for DENV vaccines based on cellular immunity. For this purpose, HLA class I and class II restricted peptides have been predicted and tested in an IFN-gamma ELISPOT assay, to assess CD8+ and CD4+ T cell responses in healthy donors infected with rDEN2Δ30. CD8 and CD4 responses were detected in approximately 80% and 90% of donors respectively. Strong CD8 responses are detected in rDEN2Δ30 recipients and when compared with natural infections similarity in terms of magnitude and numbers of recognized epitopes is observed. In particular, the immunodominance hierarchy of the DENV nonstructural proteins NS3, NS5 is maintained in both analyzed cohorts. On the contrary, CD4 responses were mainly focused on nonstructural proteins and less strong respect to natural infection. Large overlap is observed in the epitopes recognized by rDEN2Δ30 infection and natural infection both for CD8 (100%) and CD4 (85%) responses. Finally, when rDEN2Δ30 CD8 response is compared with the one induced by other attenuated DENV isolates, a stronger response is observed. In conclusion, T cell response of rDENV2D30 has very similar specificity to natural infection supporting its suitability as an appropriate human DENV challenge model.