Long-lasting humoral and cellular immune responses and mucosal dissemination after intramuscular DNA immunization

Abstract

Naïve Indian rhesus macaques were immunized with a mixture of optimized plasmid DNAs expressing several SIV antigens using in vivo electroporation via the intramuscular route. The animals were monitored for the development of SIV-specific systemic (blood) and mucosal (bronchoalveolar lavage) cellular and humoral immune responses. The immune responses were of great magnitude, broad (Gag, Pol, Nef, Tat, Vif), long-lasting (up to 90 weeks post 3rd vaccination) and were boosted with each subsequent immunization, even after an extended 90 week rest period. The SIV-specific cellular immune responses were consistently more abundant in BAL than in blood, and were characterized as predominantly effector memory CD4 + and CD8 + T cells in BAL and as both central and effector memory T cells in blood. SIV-specific T cells containing Granzyme B were readily detected in both blood and BAL, suggesting the presence of effector cells with cytolytic potential. DNA vaccination also elicited long-lasting systemic and mucosal humoral immune responses, including the induction of Gag-specific IgA. The combination of optimized DNA vectors and improved intramuscular delivery by in vivo electroporation has the potential to elicit both cellular and humoral responses and dissemination to the periphery, and thus to improve DNA immunization efficacy.

DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge

“…In contrast to nonpersistent viral vectors, which induce cellular responses with central memory phenotype, the bias induced by CMV vectors toward cellular responses with EM phenotype was considered a substantial advantage, because EM cells react immediately upon encountering the antigen. Similarly, the cellular responses induced in the vaccinated macaques described in the present study were mainly EM T cells (both CD28 + CCR7 − and CD28 − CCR7 − ), and we have previously reported that these cellular responses efficiently migrate into mucosal sites, where they persist for long periods of time after the last vaccination (29).…”

Kinetic and Phenotypic Analysis of CD8 + T Cell Responses after Priming with Alphavirus Replicons and Homologous or Heterologous Booster Immunizations

“…ϩ Tem responses that can be expanded by a heterologous boost with a viral vector (34,69,70). Our studies further demonstrated that DREP induced both Tcm and Tem and that a protein boost preserved Tcm proportions, whereas boosting with MVA preferentially expanded Tem subpopulations.…”

DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV

“…We have demonstrated that HIV/SIV pDNA vaccines induce responses, including CE-induced (X. Hu, A. Valentin, and B.K. Felber, unpublished observations) responses, which efficiently disseminate to mucosal tissues (39,54). In addition, the recent demonstration of therapeutic efficacy of a human papilloma virus vaccine delivered by DNA or electroporation in a Phase IIB randomized study in humans (55)(56)(57) demonstrates the efficacy of a pDNA platform in inducing mucosal T cell responses in humans.…”

“…We previously reported that therapeutic SIV pDNA vaccination induces potent immune responses (as high as ∼10% of T cells in blood) able to reduce viremia by 1 log following interruption of ART in SIV mac251 -infected Indian rhesus macaques (58,59). Importantly, some animals maintained reduced viral a loads for more than 3 y, indicating there is a long-lasting effect of the vaccine-induced T cell responses, another hallmark of the pDNA platform (32,54). Together, these data provide a proof-ofconcept in support of adding pDNA vaccination, and in particular CE followed by CE+gag pDNA booster vaccination to cART regimens to augment potent virus-specific immune responses.…”