Vaccine Targeting of Subdominant CD8+ T Cell Epitopes Increases the Breadth of the T Cell Response upon Viral Challenge, but May Impair Immediate Virus Control

Abstract

As a result of the difficulties in making efficient vaccines against genetically unstable viruses such as HIV, it has been suggested that future vaccines should preferentially target subdominant epitopes, the idea being that this should allow a greater breadth of the induced T cell response and, hence, a greater efficiency in controlling escape variants. However, to our knowledge the evidence supporting this concept is limited at best. To improve upon this, we used the murine lymphocytic choriomeningitis virus model and adenoviral vectors to compare a vaccine expressing unmodified Ag to a vaccine expressing the same Ag without its immunodominant epitope. We found that removal of the dominant epitope allowed the induction of CD8+ T cell responses targeting at least two otherwise subdominant epitopes. Importantly, the overall magnitude of the induced T cell responses was similar, allowing us to directly compare the efficiency of these vaccines. Doing this, we observed that mice vaccinated with the vaccine expressing unmodified Ag more efficiently controlled an acute viral challenge. In the course of a more chronic viral infection, mice vaccinated using the vaccine targeting subdominant epitopes caught up with the conventionally vaccinated mice, and analysis of the breadth of the CD8+ T cell response revealed that this was notably greater in the former mice. However, under the conditions of our studies, we never saw any functional advantage of this. This may represent a limitation of our model, but clearly our findings underscore the importance of carefully weighing the pros and cons of changes in epitope targeting before any implementation.

Induction of broad multifunctional CD8+ and CD4+ T cells by hepatitis B virus antigen-based synthetic long peptides ex vivo

“…Such subdominant epitopes may not be cross presented well naturally in vivo from whole viral proteins during ongoing viral infection. Specific stimulation of subdominant conserved epitopes in mice and chimpanzees has been demonstrated to broaden T cell responses and to induce T cells that hold potential to contain viral infections ( 40 – 42 ).…”

Novel Identified HLA-A*0201-Restricted Hantaan Virus Glycoprotein Cytotoxic T-Cell Epitopes Could Effectively Induce Protective Responses in HLA-A2.1/Kb Transgenic Mice May Associate with the Severity of Hemorrhagic Fever with Renal Syndrome

“…Emerging results have revealed that vaccines that strictly elicit immunodominant epitope-specific CTL responses could be more effective against viruses. Vaccines that induce both immunodominant and subdominant epitope responses were significantly less protective than vaccines that only elicited immunodominant epitope-specific responses, suggesting that the increased breadth of T-cell epitope recognition may prevent the induction of optimal protective CTL immunity and reduce the efficiency of host immunity against pathogens ( 43 , 44 ). The secondary CTL expansion in vaccinated mice competes for antigen accessibility on antigen-presenting cells, suppressing the priming of other protective pathogen-specific CTLs ( 45 ) and potentially explaining how subdominant epitope vaccination could reduce immunodominant epitope-induced CTL responses.…”

Identification of HCMV-derived T cell epitopes in seropositive individuals through viral deletion models

“…Moreover, methods such as ribosome profiling will enable the identification of novel ORFs that might be a source of additional viral T cell epitopes ( Erhard et al, 2018 ; Stern-Ginossar et al, 2012 ). The presence of a broad range of specific memory T cells in healthy seropositive individuals suggests that strategies using subdominant epitopes and targeting multiple antigens in vaccination and cellular therapies may be beneficial for sustainable virus control ( Holst et al, 2015 ; Panagioti et al, 2018 ; Steffensen et al, 2016 ). Therefore, the identification of a large number of immunogenic HCMV-derived cytotoxic T cell targets for the most frequent HLA restrictions is, in our opinion, indispensable for the development and improvement of such therapies.…”