Physical-based gene delivery via biolistic methods (such as the Helios gene gun) involve precipitation of nucleic acids onto microparticles and direct transfection through cell membranes of exposed tissue (e.g. skin) by high velocity acceleration. The glycosaminoglycan (GAG)-binding enhanced transduction (GET) system exploits novel fusion peptides consisting of cell-binding, nucleic acid condensing, and cell-penetrating domains, which enable enhanced transfection across multiple cell types. In this study, we combined chemical (GET) and physical (gene gun) DNA delivery systems, and hypothesized the combination would generate enhanced distribution and effective uptake in cells not initially transfected by biolistic penetration. Physicochemical characterization, optimization of bullet contents and transfection experiments in vitro in cell monolayers and engineered tissue demonstrated these formulations transfected efficiently, including DC2.4 dendritic cells. We incorporated these formulations into a biolistic format for gene gun by forming fireable dry bullets obtained via lyophilization (freeze drying). This system is simple and with enhanced scalability compared to conventional methods to generate bullets. Flushed GET bullet contents retained their ability to mediate transfection (17-fold greater and 13-fold greater reporter gene expression than standard spermidine bullets in the absence and presence of serum, respectively). Fired GET bullets in vitro (in cells and collagen gels) and in vivo (mice) showed increased reporter gene transfection compared to untreated controls, whilst maintaining cell viability in vitro and having no obvious toxicity in vivo. Lastly, a SARS-CoV-2 plasmid DNA vaccine with spike (S) protein-receptor binding domain (S-RBD) was delivered by gene gun using GET bullets. Specific T cell and antibody responses comparable to the conventional system were generated. The non-physical and physical combination of GET‑gold-DNA carriers using gene gun shows potential as an alternative DNA delivery method that is scalable for mass deployable vaccination and intradermal gene delivery.

01 Jul 2022·Vaccine

Safety and immunogenicity of anti-SARS CoV-2 vaccine SOBERANA 02 in homologous or heterologous scheme: Open label phase I and phase IIa clinical trials

Article

Author: Valera-Fernández, Rodrigo ; Orosa-Vázquez, Ivette ; Rodríguez-Noda, Laura ; Pérez-Massón, Beatriz ; Teresa Pérez-Guevara, María ; Rojas, Gertrudis ; Ontivero-Pino, Ivis ; Vérez-Bencomo, Vicente ; Muñoz-Morejon, Yaima ; García-López, Elena ; Valdés-Balbín, Yury ; González-Mugica, Raul ; Sánchez-Ramírez, Belinda ; Cruz-Sui, Otto ; Boggiano-Ayo, Tammy ; Mendoza-Hernández, Ivis ; Espi Ávila, Jennifer ; Hernández-García, Tays ; Quintero Moreno, Lauren ; Manuel Coviella-Artime, José ; García-Vega, Yanelda ; Bergado-Baez, Gretchen ; Verdecia-Sánchez, Leslyhana ; Castillo-Quintana, Ismavy ; García-Montero, Majela ; Cardoso-SanJorge, Félix ; Tundidor, Yaima ; Martínez-Pérez, Marisel ; Rodríguez-González, Meiby ; Pérez-Nicado, Rocmira ; Rodríguez-Alvarez, Julián ; Morales-García, Marilin ; Martínez-Bedoya, Dayle ; Gómez-Maceo, Yanet ; Medina Nápoles, Maite ; Ramírez Gonzalez, Ubel ; Arteaga, Amaylid ; Santana-Mederos, Darielys ; Fernandez-Castillo, Sonsire ; Rivera, Daniel G ; Fontanies Fernández, Marcos ; Ojito-Magaz, Eduardo ; García-Rivera, Dagmar ; Valenzuela-Silva, Carmen ; Reyes-Matienzo, Radamet ; Climent-Ruiz, Yanet ; Díaz-Hernández, Marianniz ; Galano-Frutos, Evelyn ; Garrido-Arteaga, Raine ; Morffi-Cinta, Irania ; Baró-Román, Gerardo ; Fraga-Quintero, Anitza ; Noa-Romero, Enrique ; Palenzuela-Díaz, Ariel ; Paredes-Moreno, Beatriz ; Pi-Estopiñán, Franciscary ; Eugenia-Toledo-Romaní, María ; Garcés-Hechavarría, Aniurka ; Guang-Wu-Chen

BACKGROUNDSOBERANA 02 is a COVID-19 vaccine based on SARS-CoV-2 recombinant RBD conjugated to tetanus toxoid (TT). SOBERANA Plus antigen is dimeric-RBD. Here we report safety and immunogenicity from phase I and IIa clinical trials using two-doses of SOBERANA 02 and three-doses (homologous) or heterologous (with SOBERANA Plus) protocols.METHODWe performed an open-label, sequential and adaptive phase I to evaluate safety and explore the immunogenicity of SOBERANA 02 in two formulations (15 or 25 μg RBD-conjugated to 20 μg of TT) in 40 subjects, 19-59-years-old. Phase IIa was open-label including 100 volunteers 19-80-years, receiving two doses of SOBERANA 02-25 μg. In both trials, half of volunteers were selected to receive a third dose of the corresponding SOBERANA 02 and half received a heterologous dose of SOBERANA Plus. Primary outcome was safety. The secondary outcome was immunogenicity evaluated by anti-RBD IgG ELISA, molecular neutralization of RBD:hACE2 interaction, live-virus-neutralization and specific T-cells response.RESULTSThe most frequent adverse event (AE) was local pain, other AEs had frequencies ≤ 5%. No serious related-AEs were reported. Phase IIa confirmed the safety in 60 to 80-years-old subjects. In phase-I SOBERANA 02-25 µg elicited higher immune response than SOBERANA 02-15 µg and progressed to phase IIa. Phase IIa results confirmed the immunogenicity of SOBERANA 02-25 µg even in 60-80-years. Two doses of SOBERANA02-25 µg elicited an immune response similar to that of the Cuban Convalescent Serum Panel and it was higher after the homologous and heterologous third doses. The heterologous scheme showed a higher immunological response. Anti-RBD IgG neutralized the delta variant in molecular assay, with a 2.5-fold reduction compared to D614G neutralization.CONCLUSIONSSOBERANA 02 was safe and immunogenic in persons aged 19-80 years, eliciting neutralizing antibodies and specific T-cell response. Highest immune responses were obtained in the heterologous three doses protocol.TRIAL REGISTRYhttps://rpcec.sld.cu/trials/RPCEC00000340, https://rpcec.sld.cu/trials/RPCEC00000347.

01 Aug 2021·VaccineQ3 · MEDICINE

One or two dose regimen of the SARS-CoV-2 synthetic DNA vaccine INO-4800 protects against respiratory tract disease burden in nonhuman primate challenge model

Q3 · MEDICINE

Article

Author: Fotheringham, Susan A ; Sharpe, Sally A ; Slack, Gillian S ; Ryan, Kathryn A ; Gooch, Karen E ; White, Andrew ; Sibley, Laura ; Charlton, Sue ; Schultheis, Katherine ; Dennis, Mike J ; Handley, Alastair ; Hall, Yper ; Humeau, Laurent M ; Carroll, Miles W ; Tipton, Tom ; Smith, Trevor R F ; Salguero, Francisco J ; Sarfas, Charlotte ; Broderick, Kate E ; Gleeson, Fergus ; Longet, Stephanie ; Rayner, Emma ; Watson, Robert J ; Humphries, Holly E ; Ramos, Stephanie J

Safe and effective vaccines will provide essential medical countermeasures to tackle the COVID-19 pandemic. Here, we assessed the safety, immunogenicity and efficacy of the intradermal delivery of INO-4800, a synthetic DNA vaccine candidate encoding the SARS-CoV-2 spike protein in the rhesus macaque model. Single and 2 dose vaccination regimens were evaluated. Vaccination induced both binding and neutralizing antibodies, along with IFN-γ-producing T cells against SARS-CoV-2. Upon administration of a high viral dose (5 × 10⁶ pfu) via the intranasal and intratracheal routes we observed significantly reduced virus load in the lung and throat, in the vaccinated animals compared to controls. 2 doses of INO-4800 was associated with more robust vaccine-induced immune responses and improved viral protection. Importantly, histopathological examination of lung tissue provided no indication of vaccine-enhanced disease following SARS-CoV-2 challenge in INO-4800 immunized animals. This vaccine candidate is currently under clinical evaluation as a 2 dose regimen.

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Indication	Highest Phase	Country/Location	Organization	Date
COVID-19	Phase 1	AU	University of Sydney Union	15 Feb 2021

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