In the molecular farming area, transient expression approaches for pharmaceutical proteins production, mainly recombinant monoclonal antibodies and vaccines, were developed almost two decades ago a...

Transient expression systems for plant-derived biopharmaceuticals

Tobacco mosaic virus (TMV) is an RNA virus that typically infects plants but has recently been adapted for vaccine development, owing to the suitability of the virions for modifications as nanoparticles. TMV also has a simple functional structure of a 6.4 Kb (+)-strand RNA encapsidated by a single coat protein, which permits facile genetic manipulation. In this review, we describe recent advances in the manipulation of TMV for the development of several different types of vaccines, including ones that induce antibody and T-cell responses that are protective in pathogen and tumor challenge animal models. Lastly, we describe how TMV self-assembly properties are being used to make a new mammalian RNA pseudovirus, that has unique characteristics for RNA and protein antigen delivery to antigen-presenting cells.

https://www.tandfonline.com/doi/pdf/10.1586/14760584.7.1.33

Genetically engineered Tobacco mosaic virus as nanoparticle vaccines.

Induction of potent antibody is the goal of many vaccines targeted against infections or cancer. Modern vaccine designs that use virus-like particles (VLP) have shown efficacy for prophylactic vaccination against virus-associated cancer in the clinic. Here we used plant viral particles (PVP), which are structurally analogous to VLP, coupled to a weak idiotypic (Id) tumour antigen, as a conjugate vaccine to induce antibody against a murine B-cell malignancy. The Id-PVP vaccine incorporates a natural adjuvant, the viral ssRNA, which acts via TLR7. It induced potent protective anti-Id antibody responses in an in vivo mouse model, superior to the “gold standard” Id vaccine, with prevalence of the IgG2a isotype. Combination with alum further increased antibody levels and maintained the IgG2a bias. Engagement of TLR7 in vivo was followed by secretion of IFN-α by plasmacytoid dendritic cells and by activation of splenic CD11chi conventional dendritic cells. The latter was apparent from up-regulation of co-stimulatory molecules and from secretion of a wide range of inflammatory cytokines and chemokines including the Th1-governing cytokine IL-12, in keeping with the IgG2a antibody isotype distribution. PVP conjugates are a novel cancer vaccine design, offering an attractive molecular form, similar to VLP, and providing T-cell help. In contrast to VLP, they also incorporate a safe “in-built” ssRNA adjuvant.

/pdf/plant-virus-particles-carrying-tumour-antigen-activate-tlr7-368jovt08n.pdf

Plant Virus Particles Carrying Tumour Antigen Activate TLR7 and Induce High Levels of Protective Antibody

A new approach for super-expression of the influenza virus epitope M2e in plants has been developed on the basis of a recombinant Tobacco mosaic virus (TMV, strain U1) genome designed for Agrobacterium-mediated delivery into the plant cell nucleus. The TMV coat protein (CP) served as a carrier and three versions of the M2e sequence were inserted into the surface loop between amino acid residues 155 and 156. Cysteine residues in the heterologous peptide were thought likely to impede efficient assembly of chimeric particles. Therefore, viral vectors TMV-M2e-ala and TMV-M2e-ser were constructed in which cysteine codons 17 and 19 of the M2e epitope were substituted by codons for serine or alanine. Agroinfiltration experiments proved that the chimeric viruses were capable of systemically infecting Nicotiana benthamiana plants. Antisera raised against TMV-M2e-ala virions appear to contain far more antibodies specific to influenza virus M2e than those specific to TMV carrier particle (ratio 5:1). Immunogold electron microscopy showed that the 2-epitopes were uniformly distributed and tightly packed on the surface of the chimeric TMV virions. Apparently, the majority of the TMV CP-specific epitopes in the chimeric TMV-M2e particles are hidden from the immune system by the M2e epitopes exposed on the particle surface. The profile of IgG subclasses after immunization of mice with TMV-M2e-ser and TMV-M2e-ala was evaluated. Immunization with TMV-M2e-ala induced a significant difference between the levels of IgG1 and IgG2a (IgG1/IgG2a=3.2). Mice immunized with the chimeric viruses were resistant to five lethal doses (LD50) of the homologous influenza virus strain, A/PR/8/34 (H1N1) and TMV-M2e-ala also gave partial protection (5LD50, 70% of survival rate) against a heterologous strain influenza A/California/04/2009 (H1N1) (4 amino acid changes in M2e). These results indicate that a new generation candidate universal nanovaccine against influenza based on a recombinant TMV construct has been obtained.

Immunogenicity and protective efficacy of candidate universal influenza A nanovaccines produced in plants by Tobacco mosaic virus-based vectors.

In the last two decades, preparation of infectious RNA or DNA clones of plant viruses has transformed to a standard laboratory technique, providing an excellent tool for the research of viral gene functions and virus-host interactions A full-length clone can be transformed in vitro to a viral vector expressing foreign poly/oligopeptides in soluble form or fused to a viral capsid protein The use of the plants as producers of antigens, allergens, and other pharmaceuticals is cheaper than the use other eukaryotic bioreactors Transient expression of proteins using the vector technique has several advantages in comparison with a transgenic approach Virus-induced gene silencing vectors have been widely adapted for research of plant genes functions and screening of plant genomes for resistance genes The potential instability of the constructs remains the main problem of virus vector-based techniques leading to a wild-type virus recovery by recombination A novel approach including "a deconstructed virus-strategy" may overcome these difficulties A preparative-scale production of numerous biologically active compounds in the various plants using viral vectors are expected in the near future

Infectious full-length clones of plant viruses and their use for construction of viral vectors

Morphology and stability changes of recombinant TMV particles caused by a cysteine residue in the foreign peptide fused to the coat protein.

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Morphology and stability changes of recombinant TMV particles caused by a cysteine residue in the foreign peptide fused to the coat protein.