Design and proof of concept for targeted phage-based COVID-19 vaccination strategies with a streamlined cold-free supply chain

Abstract

Development of effective vaccines against coronavirus disease 2019 (COVID-19) is a global imperative. Rapid immunization of the entire human population against a widespread, continually evolving, and highly pathogenic virus is an unprecedented challenge, and different vaccine approaches are being pursued. Engineered filamentous bacteriophage (phage) particles have unique potential in vaccine development due to their inherent immunogenicity, genetic plasticity, stability, cost-effectiveness for large-scale production, and proven safety profile in humans. Herein we report the development and initial evaluation of two targeted phage-based vaccination approaches against SARS-CoV-2: dual ligand peptide-targeted phage and adeno-associated virus/phage (AAVP) particles. For peptide-targeted phage, we performed structure-guided antigen design to select six solvent-exposed epitopes of the SARS-CoV-2 spike (S) protein. One of these epitopes displayed on the major capsid protein pVIII of phage induced a specific and sustained humoral response when injected in mice. These phage were further engineered to simultaneously display the peptide CAKSMGDIVC on the minor capsid protein pIII to enable their transport from the lung epithelium into the systemic circulation. Aerosolization of these “dual-display” phage into the lungs of mice generated a systemic and specific antibody response. In the second approach, targeted AAVP particles were engineered to deliver the entire S protein gene under the control of a constitutive CMV promoter. This induced tissue-specific transgene expression, stimulating a systemic S protein-specific antibody response in mice. With these proof-of-concept preclinical experiments, we show that both targeted phage- and AAVP-based particles serve as robust yet versatile platforms that can promptly yield COVID-19 vaccine prototypes for translational development.

A Bacteriophage-Based, Highly Efficacious, Needle- and Adjuvant-Free, Mucosal COVID-19 Vaccine

“…A noninfectious phage T4-CoV-2 vaccine with no tropism to human cells and no use of adjuvants or chemical stimulants represent significant advantages. Two recent phage-COVID vaccine studies using filamentous AAVP ( 71 ) and Bxb1 phage ( 24 ) also demonstrated the advantages of phage vaccine system, including the low cost of production, the self-adjuvanted nature, and the strong safety profile. In fact, our previous studies showed that adding adjuvants such as alum or liposomes did not further enhance the levels of immune responses ( 20 , 72 ).…”

Treating bacterial infections with bacteriophages in the 21st century

“…Bacteriophages vaccination is an innovative and novel vaccine system. 25,26 This is a bio-engineered structure that entails a DNA vaccine contained within a phage capsule under the expression of a eukaryotic promoter. 21 Once the phage transporting the DNA vaccine is engulfed into a eukaryotic antigen-presenting cell, the vaccine gene is expressed.…”

Bacteriophages as Solid Tumor Theragnostic Agents

“…Another interesting application of phage display related to medicine is their proven role as vaccines at pre-clinical level [ 64 ]. Phage display is used to display viral or bacterial antigenic peptides on phage capsids followed by in vivo administration to induce an immune response [ 77 , 78 ]. Due to the inherent ability of phages to induce balanced innate and adaptive immunity, phage vaccines are shown to impart better synergistic immune response when compared to free subunit antigens, without the use of adjuvants [ 79 ].…”