Lytic Polyplex Vaccines Enhance Antigen‐Specific Cytotoxic T Cell Response through Induction of Local Cell Death

Abstract

Endosomolytic vaccine nanocarriers can potentiate cellular immune responses by enhancing cross-presentation. A cationic polymer-lytic peptide conjugate (VIPER) that greatly improves endosomal escape and intracellular activity of nucleic acid cargoes is recently developed; furthermore, it is hypothesized that VIPER's unique mechanism of endosomal disruption can increase cytoplasmic delivery of other biomacromolecules (e.g., peptides). Herein, VIPER is formulated as a polyplex subunit vaccine composed of conjugated peptide antigens and electrostatically complexed poly(I:C) nucleic acid adjuvant and is evaluated to determine whether the presence of the lytic peptide melittin conjugated to the pH-responsive micelle core improves vaccination outcomes. Although VIPER delivers peptide antigens intracellularly, disrupts endosomes in antigen-presenting cells (APCs) in vitro, and generates strong antigen-specific cytotoxic T cell responses in vivo, significantly enhanced cross-presentation is only observed in conjunction with VIPER-induced local cell death. While these results demonstrate that VIPER is a useful platform technology for the study of vaccine delivery, full elucidation of how endosomal disruption by VIPER improves vaccination outcomes will require decoupling of endosomolysis from cytotoxicity, as well as precise targeting of VIPER vaccine formulations to APC populations in vivo.

Inhibition of SARS-CoV-2 replication in the lung with siRNA/VIPER polyplexes

“…This difference in activity is probably linked to the presence of melittin in the structure of VIPER, which is an endosomolytic peptide that has been studied for improving the activity of siRNA delivery agents [ 37 ]. By disrupting the endosomal membrane, melittin helps to release the siRNA in the cytosol and consequently improves the RNAi activity of the siRNA formulation [ 38 ].

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Design and Evaluation of Synthetic Delivery Formulations for Peptide-Based Cancer Vaccines

“…We investigated 20 recently published peptide-based vaccine papers but did not observe an obvious correlation between the percentage of antigen-specific T cells and antitumor capacity [ 9 , 42 , 43 , 45 , 51 , 52 , 54 , 55 , 58 , 61 , 63 , 69 , 82 , 95 , 98 , 99 , 119 , 127 – 129 ]. A number of different factors could contribute to this.…”

Harnessing Nanovaccines for Effective Immunization─A Special Concern on COVID-19: Facts, Fidelity, and Future Prospective

“…The unique ability of the VIPER for endosomal disruption helped in the enhancement of the cytoplasmic delivery to that of the biomacromolecules. 109 Luther et al explored the application of the cationic guanidinium polymer−pDNA polyplex mediated gene transfer as part of the nonviral vaccination. The homopolymer called poly(oxanorbornene)imide (PONI-Guan) functionalized with guanidinium was implemented for the nondisruptive pDNA condensation to generate discrete polyplexes.…”

“…A conjugate was prepared from a lytic peptide and a cationic polymer called VIPER, which was significant for improvising the endosomal escape. The unique ability of the VIPER for endosomal disruption helped in the enhancement of the cytoplasmic delivery to that of the biomacromolecules . Luther et al explored the application of the cationic guanidinium polymer–pDNA polyplex mediated gene transfer as part of the nonviral vaccination.…”