DNA/Ad5 vaccination with SIV epitopes induced epitope-specific CD4 ⁺ T cells, but few subdominant epitope-specific CD8 ⁺ T cells

The goals of a T cell-based vaccine for HIV are to reduce viral peak and setpoint and prevent transmission. While it has been relatively straightforward to induce CD8 ⁺ T cell responses against immunodominant T cell epitopes, it has been more difficult to broaden the vaccine-induced CD8 ⁺ T cell response against subdominant T cell epitopes. Additionally, vaccine regimens to induce CD4 ⁺ T cell responses have been studied only in limited settings. In this study, we sought to elicit CD8 ⁺ T cells against subdominant epitopes and CD4 ⁺ T cells using various novel and well-established vaccine strategies. We vaccinated three Mamu-A*01 ⁺ animals with five Mamu-A*01-restricted subdominant SIV-specific CD8 ⁺ T cell epitopes. All three vaccinated animals made high frequency responses against the Mamu-A*01-restricted Env TL9 epitope with one animal making a low frequency CD8 ⁺ T cell response against the Pol LV10 epitope. We also induced SIV-specific CD4 ⁺ T cells against several MHC class II DRBw*606-restricted epitopes. Electroporated DNA with pIL-12 followed by a rAd5 boost was the most immunogenic vaccine strategy. We induced responses against all three Mamu-DRB*w606-restricted CD4 epitopes in the vaccine after the DNA prime. Ad5 vaccination further boosted these responses. Although we successfully elicited several robust epitope-specific CD4 ⁺ T cell responses, vaccination with subdominant MHC class I epitopes elicited few detectable CD8 ⁺ T cell responses. Broadening the CD8 ⁺ T cell response against subdominant MHC class I epitopes was, therefore, more difficult than we initially anticipated.