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1. Phage-like particle vaccines are highly immunogenic and protect against pathogenic coronavirus infection and disease

   https://doi.org/10.1101/2021.11.08.467648  

   Davenport, Bennett J; Catala, Alexis; Weston, Stuart M; Johnson, Robert M; Ardunay, Jeremy; Hammond, Holly L; Dillen, Carly; Frieman, Matthew B; Catalano, Carlos E; Morrison, Thomas E (November 2021, bioRxiv)

   ABSTRACT The response by vaccine developers to the COVID-19 pandemic has been extraordinary with effective vaccines authorized for emergency use in the U.S. within one year of the appearance of the first COVID-19 cases. However, the emergence of SARS-CoV-2 variants and obstacles with the global rollout of new vaccines highlight the need for platforms that are amenable to rapid tuning and stable formulation to facilitate the logistics of vaccine delivery worldwide. We developed a “designer nanoparticle” platform using phage-like particles (PLPs) derived from bacteriophage lambda for multivalent display of antigens in rigorously defined ratios. Here, we engineered PLPs that display the receptor binding domain (RBD) protein from SARS-CoV-2 and MERS-CoV, alone (RBD_SARS-PLPs, RBD_MERS-PLPs) and in combination (hCoV-RBD PLPs). Functionalized particles possess physiochemical properties compatible with pharmaceutical standards and retain antigenicity. Following primary immunization, BALB/c mice immunized with RBD_SARS- or RBD_MERS-PLPs display serum RBD-specific IgG endpoint and live virus neutralization titers that, in the case of SARS-CoV-2, were comparable to those detected in convalescent plasma from infected patients. Further, these antibody levels remain elevated up to 6 months post-prime. In dose response studies, immunization with as little as one microgram of RBD_SARS-PLPs elicited robust neutralizing antibody responses. Finally, animals immunized with RBD_SARS-PLPs, RBD_MERS-PLPs, and hCoV-RBD PLPs were protected against SARS-CoV-2 and/or MERS-CoV lung infection and disease. Collectively, these data suggest that the designer PLP system provides a platform for facile and rapid generation of single and multi-target vaccines. 

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2. Phage-like particle vaccines are highly immunogenic and protect against pathogenic coronavirus infection and disease

   Davenport, Bennett J.; Catala, Alexis; Weston, Stuart M.; Johnson, Robert M.; Ardunay, Jeremy; Hammond, Holly L.; Dillen, Carly; Frieman, Matthew B.; Catalano, Carlos E.; Morrison, Thomas E. (November 2021, bioRxiv)

   The response by vaccine developers to the COVID-19 pandemic has been extraordinary with effective vaccines authorized for emergency use in the United States within 1 year of the appearance of the first COVID-19 cases. However, the emergence of SARS-CoV-2 variants and obstacles with the global rollout of new vaccines highlight the need for platforms that are amenable to rapid tuning and stable formulation to facilitate the logistics of vaccine delivery worldwide. We developed a “designer nanoparticle” platform using phage-like particles (PLPs) derived from bacteriophage lambda for a multivalent display of antigens in rigorously defined ratios. Here, we engineered PLPs that display the receptor-binding domain (RBD) protein from SARS-CoV-2 and MERS-CoV, alone (RBDSARS-PLPs and RBDMERS-PLPs) and in combination (hCoV-RBD PLPs). Functionalized particles possess physiochemical properties compatible with pharmaceutical standards and retain antigenicity. Following primary immunization, BALB/c mice immunized with RBDSARS- or RBDMERS-PLPs display serum RBD-specific IgG endpoint and live virus neutralization titers that, in the case of SARS-CoV-2, were comparable to those detected in convalescent plasma from infected patients. Further, these antibody levels remain elevated up to 6 months post-prime. In dose-response studies, immunization with as little as one microgram of RBDSARS-PLPs elicited robust neutralizing antibody responses. Finally, animals immunized with RBDSARS-PLPs, RBDMERS-PLPs, and hCoV-RBD PLPs were protected against SARS-CoV-2 and/or MERS-CoV lung infection and disease. Collectively, these data suggest that the designer PLP system provides a platform for facile and rapid generation of single and multi-target vaccines. 

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3. Biomaterials and Oxygen Join Forces to Shape the Immune Response and Boost COVID‐19 Vaccines

   https://doi.org/10.1002/advs.202100316  

   Colombani, Thibault; Eggermont, Loek_J; Rogers, Zachary_J; McKay, Lindsay_G_A; Avena, Laura_E; Johnson, Rebecca_I; Storm, Nadia; Griffiths, Anthony; Bencherif, Sidi_A (July 2021, Advanced Science)

   Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has led to an unprecedented global health crisis, resulting in a critical need for effective vaccines that generate protective antibodies. Protein subunit vaccines represent a promising approach but often lack the immunogenicity required for strong immune stimulation. To overcome this challenge, it is first demonstrated that advanced biomaterials can be leveraged to boost the effectiveness of SARS‐CoV‐2 protein subunit vaccines. Additionally, it is reported that oxygen is a powerful immunological co‐adjuvant and has an ability to further potentiate vaccine potency. In preclinical studies, mice immunized with an oxygen‐generating coronavirus disease 2019 (COVID‐19) cryogel‐based vaccine (O₂‐Cryogel_VAX) exhibit a robust Th1 and Th2 immune response, leading to a sustained production of highly effective neutralizing antibodies against the virus. Even with a single immunization, O₂‐Cryogel_VAXachieves high antibody titers within 21 days, and both binding and neutralizing antibody levels are further increased after a second dose. Engineering a potent vaccine system that generates sufficient neutralizing antibodies after one dose is a preferred strategy amid vaccine shortage. The data suggest that this platform is a promising technology to reinforce vaccine‐driven immunostimulation and is applicable to current and emerging infectious diseases. 

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4. Second-Generation Phage Lambda Platform Employing SARS-CoV-2 Fusion Proteins as a Vaccine Candidate

   https://doi.org/10.3390/vaccines12111201  

   Catala, Alexis; Davenport, Bennett J; Morrison, Thomas E; Catalano, Carlos E (November 2024, Vaccines)

   The recent SARS-CoV-2 (COVID-19) pandemic exemplifies how newly emerging and reemerging viruses can quickly overwhelm and cripple global infrastructures. Coupled with synergistic factors such as increasing population densities, the constant and massive mobility of people across geographical areas and substantial changes to ecosystems worldwide, these pathogens pose serious health concerns on a global scale. Vaccines form an indispensable defense, serving to control and mitigate the impact of devastating outbreaks and pandemics. Towards these efforts, we developed a tunable vaccine platform that can be engineered to simultaneously display multiple viral antigens. Here, we describe a second-generation version wherein chimeric proteins derived from SARS-CoV-2 and bacteriophage lambda are engineered and used to decorate phage-like particles with defined surface densities and retention of antigenicity. This streamlines the engineering of particle decoration, thus improving the overall manufacturing potential of the system. In a prime-boost regimen, mice immunized with particles containing as little as 42 copies of the chimeric protein on their surface develop potent neutralizing antibody responses, and immunization protects mice against virulent SARS-CoV-2 challenge. The platform is highly versatile, making it a promising strategy to rapidly develop vaccines against a potentially broad range of infectious diseases. 

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

   https://doi.org/10.1073/pnas.2105739118  

   Staquicini, Daniela I.; Tang, Fenny H.; Markosian, Christopher; Yao, Virginia J.; Staquicini, Fernanda I.; Dodero-Rojas, Esteban; Contessoto, Vinícius G.; Davis, Deodate; O’Brien, Paul; Habib, Nazia; et al (July 2021, Proceedings of the National Academy of Sciences)

   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. 

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