Incorporation of tetanus-epitope into virus-like particles achieves vaccine responses even in older recipients in models of psoriasis, Alzheimer’s and cat allergy

Abstract

Monoclonal antibodies are widely used to treat non-infectious conditions but are costly. Vaccines could offer a cost-effective alternative but have been limited by sub-optimal T-cell stimulation and/or weak vaccine responses in recipients, for example, in elderly patients. We have previously shown that the repetitive structure of virus-like-particles (VLPs) can effectively bypass self-tolerance in therapeutic vaccines. Their efficacy could be increased even further by the incorporation of an epitope stimulating T cell help. However, the self-assembly and stability of VLPs from envelope monomer proteins is sensitive to geometry, rendering the incorporation of foreign epitopes difficult. We here show that it is possible to engineer VLPs derived from a non human-pathogenic plant virus to incorporate a powerful T-cell-stimulatory epitope derived from Tetanus toxoid. These VLPs (termed CMVTT) retain self-assembly as well as long-term stability. Since Th cell memory to Tetanus is near universal in humans, CMVTT-based vaccines can deliver robust antibody-responses even under limiting conditions. By way of proof of concept, we tested a range of such vaccines against chronic inflammatory conditions (model: psoriasis, antigen: interleukin-17), neurodegenerative (Alzheimer’s, β-amyloid), and allergic disease (cat allergy, Fel-d1), respectively. Vaccine responses were uniformly strong, selective, efficient in vivo, observed even in old mice, and employing low vaccine doses. In addition, randomly ascertained human blood cells were reactive to CMVTT-VLPs, confirming recognition of the incorporated Tetanus epitope. The CMVTT-VLP platform is adaptable to almost any antigen and its features and performance are ideally suited for the design of vaccines delivering enhanced responsiveness in aging populations.

Virus‐like particles for vaccination against cancer

“…The exterior or interior surface of VLPs can be functionalized and modified to display the antigens or epitopes of interest by different means: • Chemical coupling • Genetic fusion and engineering • Peptide conjugation , Brune et al (2016); Kaczmarczyk, Sitaraman, Young, Hughes, and Chatterjee (2011); Martin Caballero et al (2012); Pomwised, Intamaso, Teintze, Young, and Pincus (2016); Pumpens (2016); Tegerstedt et al (2005); Zeltins et al (2017) Immunostimulatory molecules Some VLPs assemble around RNA fragments (noninfectious or replication competent) during the expression process in host cells. VLPs can also be disassembled and reassembled in the presence of different TLR-ligands such as oligodeoxynucleotides (CpGs) (TLR-9 ligand), polyGLU, ssRNA (TLR 7/8 ligand) or dsRNA (TLR-3 ligand) Dash, Federica, Ottenbrite, and Chiellini (2011); Kawano, Matsui, and Handa (2018); Sioud (2006); ; Gomes et al (2019).…”

Recent Advances in the Use of Plant Virus-Like Particles as Vaccines

“…Later, several vaccine candidates were constructed based on AlMV carriers ( Figure 3A A-antigen-coding sequence; 2A-self-processing peptide sequence; Rep, TGB, CP -replicase, triple gene block and coat protein genes [40]. (C) Bacterial system for antigen introduction in plant VLP structure [28]. Antigen (A) and CMV VLPs are obtained from separate bacterial cultures, purified, derivatized and joined in chemical coupling reaction.…”

“…(A) Cucumber mosaic virus (CMV) structure (T = 3 symmetry, diameter = 28 nm). Image of 5OW6 [28]. (B) Cowpea chlorotic mottle virus (CCMV) structure (T = 3 symmetry, diameter = 29 nm).…”

Virus-Like Particles as an Instrument of Vaccine Production

“…These platforms are based on the strategies described above. In particular, they take advantage of the reactivity of the Lys ε-group to immobilize the antigen on the surface of the plant's VLPs [102][103][104][105]. Using the tobacco mosaic virus [106] and potato X virus [104], it has been shown that a considerably large antigen can be immobilized on the surface of the corresponding VLPs via the formation of the streptavidin-biotin complex.…”