Incorporation of tetanus-epitope into virus-like particles achieves vaccine responses even in older recipients in models of psoriasis, Alzheimer\u2019s and cat allergy

Andris Zeltins,Abhay Kotecha,Jonathan West,Gary T Jennings,Martin F Bachmann,Federico Storni,Stefanie Haas,David I Stuart,Franziska Zabel,Ina Balke,Paul Engeroff,John Foerster,Aadil El Turabi,Melanie Maudrich

doi:10.1038/s41541-017-0030-8

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.

Highlights

Vaccines are widely used prophylactically to prevent infectious disease, as well as therapeutically to alter the course of established chronic infections
Inconsistent neutralizing capacity of vaccine-induced targetspecific antibodies has often been found limiting. This may be due to a combination of factors, including the absence of good Th cell epitopes within the vaccine conferring good Th cell help to B cells,[8,9,10] difficulties to bypass self-tolerance, as well as poor vaccine responses in an aging demographic due to immunosenescence
In order to be adaptable to a wide range of applications, the ideal VLP would (1) be derived from a nonhuman parent virus, (2) retain the capacity to incorporate RNA able to serve as immuno-stimulatory TLR agonist RNA,[17,18] and (3) exhibit a large molecular size monomer to increase the overall number of T-cell stimulatory epitopes

Summary

Introduction

Vaccines are widely used prophylactically to prevent infectious disease, as well as therapeutically to alter the course of established chronic infections. Fig. 4 Immunogenicity and specificity of the immune response generated by vaccination with a CMV-based anti IL17A vaccine in mice.

Results

Conclusion