DNA Immunization against Herpes Simplex Virus: Enhanced Efficacy Using a Sindbis Virus-Based Vector

Abstract

Previously we reported the development of a plasmid DNA expression vector system derived from Sindbis virus (T. W. Dubensky, Jr., et al., J. Virol. 70:508–519, 1996). In vitro, such vectors exhibit high-level heterologous gene expression via self-amplifying cytoplasmic RNA replication. In the present study, we demonstrated the in vivo efficacy of the Sindbis virus-based pSIN vectors as DNA vaccines. A single intramuscular immunization of BALB/c mice with pSIN vectors expressing the glycoprotein B of herpes simplex virus type 1 induced a broad spectrum of immune responses, including virus-specific antibodies, cytotoxic T cells, and protection from lethal virus challenge in two different murine models. In addition, dosing studies demonstrated that the pSIN vectors were superior to a conventional plasmid DNA vector in the induction of all immune parameters tested. In general, 100- to 1,000-fold-lower doses of pSIN were needed to induce the same level of responsiveness as that achieved with the conventional plasmid DNA vector. In some instances, significant immune responses were induced with a single dose of pSIN as low as 10 ng/mouse. These results indicate the potential usefulness of alphavirus-based vectors for DNA immunization in general and more specifically as a herpes simplex virus vaccine.

Immunogenicity of a DNA-launched replicon-based canine parvovirus DNA vaccine expressing VP2 antigen in dogs

“…Further, the lymphoproliferative response and CPV-specific priming of CD4 + /CD8 + effectors cells were significantly higher with repliconbased CPV DNA vaccine compared to conventional CPV DNA vaccine. Similar enhanced immune responses with replicon-based vaccines over conventional DNA vaccines have been reported earlier for other diseases (Zhou et al, 1994;Dalemans et al, 1995;Hariharan et al, 1998;Vignuzzi et al, 2001;Xiao et al, 2004;Arbele et al, 2005;Saxena et al, 2008).…”

“…RNA replicon-based expression vectors have been developed from representatives of most of the positive-strand RNA virus families, namely, Togaviridae, Flaviviridae and Picornaviridae. Several members of Alphavirus genus of Togaviridae family, including, Sindbis virus (Xiong et al, 1989;Herweijer et al, 1995;Hariharan et al, 1998;Miller et al, 2008;Saxena et al, 2008;Gupta et al, 2009), Semliki Forest virus (Liljestrom and Garoff, 1991;Berglund et al, 1999;Zhao et al, 2009), Venezuelan equine encephalitis virus (Davis et al, 1989;Lee et al, 2003) and Flavivirus genus, including, tickborne encephalitis virus, Kunjin virus (Anraku et al, 2002(Anraku et al, , 2008, Pestivirus-BVDV and Coronavirus-HCoV (Curtis et al, 2002) have received considerable attention. These demonstrated that RNA replicon-based DNA vaccines provide higher levels of protective immunity and break immunological tolerance by activating innate dsRNA-mediated anti-viral pathways (Frolov and Schlesinger, 1994;Diebold et al, 2009) and significant dose-sparing advantages compared with conventional DNA vaccines (Miller et al, 2008;Leitner et al, 2003).…”

Mucosal adjuvants and delivery systems for protein‐, DNA‐ and RNA‐based vaccines

“…95 In two separate investigations using lethalchallenge models of viral infection, plasmid DNA-based alphavirus replicons were shown to be significantly more efficacious in vaccinated mice compared to conventional plasmid DNA expression vectors. 98,99 In both investigations, the immune correlates of protection against lethal virus challenge included humoral and cellular responses. The CD4 + T-cell immune response in the alphavirus plasmid immunized mice was primarily of the Th1 type, as demonstrated by a high IgG2a : IgG1 ratio.…”

“…98 For Sindbis alphavirus basedplasmid (SIN), CTL precursors were induced by replicons expressing HSV glycoprotein B at 1000-fold lower dosage levels of DNA, compared to animals immunized with conventional plasmid. 99 Recently, we have evaluated pSIN encoding HIV gag (SF2) in mice and rhesus macaques. pSINgag was very potent, even when delivered as naked DNA, and comparable to pCMV for priming cellular immune responses (M. Vajdy et al , unpubl.…”

Antigen delivery systems for veterinary vaccine development

“…The use of selfreplicating alphavirus DNA vectors containing RNApol II promoters may provide an alternative to increase the immune stimulation. At least in mice, antigen specific immune responses can be obtained with lower DNA doses with compared to conventional plasmids [262,263]. SIN-based DNA vectors were used to prime immune responses against Aujezsky's disease in pigs [264] or to decrease strongly the quantity of plasmids needed [265].…”