1. Development of an IgG-Fc fusion COVID-19 subunit vaccine, AKS-452
- Author
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Andrea R Delpero, Larry Karnes, Shannon E. Ronca, Shashikant Nagre, David G. Alleva, Sarah S Webb, Hanne Andersen Elyard, Allison I Jasa, Thomas M. Lancaster, JoAnn Yee, Sylaja Murikipudi, Vidhya Rao, Frans Sollie, Nishit J Shah, Freedom M Green, Melanie M Scully, Jeffrey R Haworth, Thillainaygam Sathiyaseelan, Emma K Greaves, Ramya Ragupathy, Jeffrey Klein, and Todd C. Zion
- Subjects
medicine.medical_treatment ,PFU, plaque-forming units ,Antibodies, Viral ,Immunoglobulin G ,Neutralization ,Mice ,PRNT, plaque reduction neutralization test ,Infectious disease ,ID50, Inhibitory Dilution 50% ,SP, Spike Protein ,NHP, non-human primate ,Immunogenicity ,Titer ,Infectious Diseases ,Spike Glycoprotein, Coronavirus ,Vaccines, Subunit ,Molecular Medicine ,APCs, antigen-presenting cells ,Rabbits ,EUA, Emergency Use Authorization ,Adjuvant ,Primates ,COVID-19 Vaccines ,Recombinant Fusion Proteins ,Ag, antigen ,MFI, mean fluorescent intensity ,Biology ,Article ,Virus ,nAb, neutralizing antibody ,Neonatal Fc receptor ,PRNT50, maximum dilution with greater than 50% inhibition ,Antigen ,ACE2, angiotensin converting enzyme-2 ,medicine ,Animals ,Fc-fusion ,SP/RBD, spike protein receptor binding domain ,Pandemic ,General Veterinary ,General Immunology and Microbiology ,Prophylaxis ,ELISA, Enzyme Linked Immunosorbent Assay ,SARS-CoV-2 ,Public Health, Environmental and Occupational Health ,COVID-19 ,Antibodies, Neutralizing ,Virology ,Coronavirus ,HCS, Human convalescent serum ,OD, optical density ,P, passage ,biology.protein - Abstract
AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.
- Published
- 2021
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