Self‐Replicative RNA Vaccines Elicit Protection against Influenza A Virus, Respiratory Syncytial Virus, and a Tickborne Encephalitis Virus

Abstract

In genetic vaccination, recipients are immunized with antigen-encoding nucleic acid, usually DNA. This study addressed the possibility of using the recombinant alpha virus RNA molecule, which replicates in the cytoplasm of transfected cells, as a novel approach for genetic vaccination. Mice were immunized with recombinant Semliki Forest virus RNA-encoding envelope proteins from one of 3 viruses: influenza A virus, a tickborne flavivirus (louping ill virus), or respiratory syncytial virus (RSV). Serologic analyses showed that antigen-specific antibody responses were elicited. IgG isotyping indicated that predominantly Th1 type immune responses were induced after immunization with RSV F protein-encoding RNA, which is relevant for protection against RSV infection. Challenge infection showed that RNA immunization had elicited significant levels of protection against the 3 model virus diseases.

Induction of an IFN-Mediated Antiviral Response by a Self-Amplifying RNA Vaccine: Implications for Vaccine Design

“…RNA vaccines obviate the potential safety risks associated with other nucleic acid-based vaccines (including genomic integration and cell transformation) (3) and avoid the limitation of antivector immunity that negatively impacts the potency of viral vectors (4). An additional potential benefit in the use of RNA vaccines compared with protein subunit vaccines is the ability to stimulate an innate immune response (5).…”

Modulation of disease, T cell responses, and measles virus clearance in monkeys vaccinated with H-encoding alphavirus replicon particles

“…The subgenomic promoter can be engineered to express foreign genes either by duplicating it in the genome or by substituting the foreign gene for the structural proteins (22)(23)(24). In the latter replicon system, these RNAs can be used directly for vaccination (25)(26)(27) or packaged into particles by supplying the viral structural proteins, selected for delivery to specific target cells, in trans (28)(29)(30). The alphaviruses Semliki Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus (SINV) have all been developed as potential vaccine and gene therapy vectors (13,31).…”

Inhibition of angiogenesis by a Semliki Forest virus vector expressing VEGFR-2 reduces tumour growth and metastasis in mice

“…[24][25][26]30,31 Immune responses against the encoded antigens have been characterized by strong T-cell responses and antibodies principally of the IgG2a subtype. Recently, several studies have demonstrated that active immunization of mice with Salmonella vectors or DC-based vaccines coding for or pulsed with Flk-1 protein/ peptides can inhibit tumour neovascularization and have an antimetastatic effect.…”

“…This is in contrast to previous studies using rSFV coding for foreign antigens, where immune responses have been shown to be TH1-mediated. 24,26,37 Further evidence for the anti-angiogenic effect induced by vaccination with rSFV-Flk-1 VLPs being antibody mediated was shown by pathological examination of tumours from immunized mice. Examination of CT26 tumour sections from treated and control mice revealed that there was no increase in lymphocyte infiltration associated with rSFV-Flk-1 VLP vaccination.…”

“…Immunization of mice with rSFV VLPs coding for foreign antigens has previously been shown to induce strong TH1-mediated antibody and T-cell responses resulting in protection from virus challenge in several models. [24][25][26] SFV vectors have also been used to express high levels of cytokines (interleukin (IL)-12, IL-4, IL-10) in vivo 27,28 for tumour therapy and for delivery to the CNS. Murine IL-12-encoding VLPs have been used successfully to treat solid and metastasizing tumours in mice.…”