Adenovirus 5‐ and 35‐based immunotherapy enhances the strength but not breadth or quality of immunity during chronic SIV infection

Heterologous adenovirus‐based vectors hold promise as preventative HIV vaccines but their capacity to induce effective T‐cell immunity in established infection has not been explored. We vaccinated rhesus macaques chronically infected with SIVmac251 and undergoing antiretroviral therapy (ART) with human adenovirus serotype 5‐based vectors expressing SIV Gag, Env, and Nef with and without IL‐15 and evaluated vaccine immunogenicity. Vaccination increased Ag‐specific T cells 20‐fold but did not expand the breadth of epitopes recognized or the quality of response, as the majority of CD8⁺ and CD4⁺ T cells produced only one cytokine irrespective of vaccination. Immunization transiently restored blood CD4⁺ central memory T cells (Tcm) and boosted CD4⁺ and CD8⁺ Tcm and effector cell responses but did not prevent virus rebound upon cessation of ART. Boosting with human adenovirus serotype 35‐based vectors during a second ART cycle increased Ag‐specific T cells to 50‐fold above pre‐vaccination levels and boosted CD4⁺ Tcm numbers but did not expand the breadth or quality of immunity or control virus levels following drug discontinuation. The number of blood CD4⁺ Tcm correlated positively with complexity of T‐cell responses and negatively with virus load, suggesting that more complete restoration of this subset through vaccination would be beneficial.