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4 results on '"Thillainaygam Sathiyaseelan"'

1. Immunogenicity phase II study evaluating booster capacity of nonadjuvanted AKS-452 SARS-Cov-2 RBD Fc vaccine

Author

David G. Alleva, Eline A. Feitsma, Yester F. Janssen, Hendrikus H. Boersma, Thomas M. Lancaster, Thillainaygam Sathiyaseelan, Sylaja Murikipudi, Andrea R. Delpero, Melanie M. Scully, Ramya Ragupathy, Sravya Kotha, Jeffrey R. Haworth, Nishit J. Shah, Vidhya Rao, Shashikant Nagre, Shannon E. Ronca, Freedom M. Green, Stephen A. Shaw, Ari Aminetzah, Schelto Kruijff, Maarten Brom, Gooitzen M. van Dam, and Todd C. Zion

Subjects
Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract AKS-452, a subunit vaccine comprising an Fc fusion of the ancestral wild-type (WT) SARS-CoV-2 virus spike protein receptor binding domain (SP/RBD), was evaluated without adjuvant in a single cohort, non-randomized, open-labelled phase II study (NCT05124483) at a single site in The Netherlands for safety and immunogenicity. A single 90 µg subcutaneous booster dose of AKS-452 was administered to 71 adults previously primed with a registered mRNA- or adenovirus-based vaccine and evaluated for 273 days. All AEs were mild and no SAEs were attributable to AKS-452. While all subjects showed pre-existing SP/RBD binding and ACE2-inhibitory IgG titers, 60–68% responded to AKS-452 via ≥2-fold increase from days 28 to 90 and progressively decreased back to baseline by day 180 (days 28 and 90 mean fold-increases, 14.7 ± 6.3 and 8.0 ± 2.2). Similar response kinetics against RBD mutant proteins (including omicrons) were observed but with slightly reduced titers relative to WT. There was an expected strong inverse correlation between day-0 titers and the fold-increase in titers at day 28. AKS-452 enhanced neutralization potency against live virus, consistent with IgG titers. Nucleocapsid protein (Np) titers suggested infection occurred in 66% (46 of 70) of subjects, in which only 20 reported mild symptomatic COVID-19. These favorable safety and immunogenicity profiles support booster evaluation in a planned phase III universal booster study of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain.

Published
2024
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2. An antigen-specific immunotherapeutic, AKS-107, deletes insulin-specific B cells and prevents murine autoimmune diabetes

Author

David G. Alleva, Andrea R. Delpero, Thillainaygam Sathiyaseelan, Sylaja Murikipudi, Thomas M. Lancaster, Mark A. Atkinson, Clive H. Wasserfall, Liping Yu, Ramya Ragupathy, Rachel H. Bonami, and Todd C. Zion

Subjects
autoreactive B cell, autoimmunity, type 1 diabetes, Fc-fusion protein, antigen specific immunotherapeutic, insulin autoantigen, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionThe antigen-presenting cell function of insulin-reactive B cells promotes type 1 diabetes (T1D) in non-obese diabetic (NOD) mice by stimulating pathogenic T cells leading to destruction of insulin-producing β-cells of pancreatic islets.Methods/ResultsTo target insulin-reactive B cells, AKS-107, a human IgG1 Fc molecule fused with human insulin A and B chains, was engineered to retain conformational insulin epitopes that bound mouse and human B cell receptors but prevented binding to the insulin metabolic receptor. AKS-107 Fc-mediated deletion of insulin-reactive B cells was demonstrated via ex vivo and in vivo experiments with insulin-reactive B cell receptor transgenic mouse strains, VH125Tg/NOD and Tg125(H+L)/NOD. As an additional immune tolerance feature, the Y16A mutation of the insulin B(9-23) dominant T cell epitope was engineered into AKS-107 to suppress activation of insulin-specific T cells. In mice and non-human primates, AKS-107 was well-tolerated, non-immunogenic, did not cause hypoglycemia even at high doses, and showed an expectedly protracted pharmacokinetic profile. AKS-107 reproducibly prevented spontaneous diabetes from developing in NOD and VH125Tg/NOD mice that persisted for months after cessation of treatment, demonstrating durable immune tolerance.DiscussionThese preclinical outcomes position AKS-107 for clinical development in T1D prevention settings.

Published
2024
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3. Development of an IgG-Fc fusion COVID-19 subunit vaccine, AKS-452

Author

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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4. Phase I interim results of a phase I/II study of the IgG-Fc fusion COVID-19 subunit vaccine, AKS-452

Author

Yester F. Janssen, Eline A. Feitsma, Hendrikus H. Boersma, David G. Alleva, Thomas M. Lancaster, Thillainaygam Sathiyaseelan, Sylaja Murikipudi, Andrea R. Delpero, Melanie M. Scully, Ramya Ragupathy, Sravya Kotha, Jeffrey R. Haworth, Nishit J. Shah, Vidhya Rao, Shashikant Nagre, Shannon E. Ronca, Freedom M. Green, Ari Aminetzah, Frans Sollie, Schelto Kruijff, Maarten Brom, Gooitzen M. van Dam, Todd C. Zion, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Adult, History, COVID-19 Vaccines, Polymers and Plastics, Adolescent, HCS, human convalescent serum, Antibodies, Viral, Industrial and Manufacturing Engineering, Article, Young Adult, Clinical Trials, Phase II as Topic, Immunogenicity, Vaccine, ACE2, angiotensin converting enzyme-2, Humans, Business and International Management, Aged, Fc-fusion, SP/RBD, spike protein receptor binding domain, Infectious disease, SAE, serious adverse event, General Veterinary, General Immunology and Microbiology, Pandemic, SP, Spike Protein, Prophylaxis, SARS-CoV-2, ELISA, Enzyme Linked Immunosorbent Assay, Public Health, Environmental and Occupational Health, COVID-19, Middle Aged, AKS-452, Antibodies, Neutralizing, Coronavirus, Infectious Diseases, Immunoglobulin G, Spike Glycoprotein, Coronavirus, Vaccines, Subunit, Molecular Medicine, Vaccine, AE, adverse event
Abstract

To address the coronavirus disease 2019 (COVID-19) pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recombinant subunit vaccine, AKS-452, is being developed comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain (SP/RBD) antigen and human IgG1 Fc emulsified in the water-in-oil adjuvant, Montanide™ ISA 720. A single-center, open-label, phase I dose-finding and safety study was conducted with 60 healthy adults (18-65 years) receiving one or two doses 28 days apart of 22.5 µg, 45 µg, or 90 µg of AKS-452 (i.e., six cohorts, N = 10 subjects per cohort). Primary endpoints were safety and reactogenicity and secondary endpoints were immunogenicity assessments. No AEs ≥ 3, no SAEs attributable to AKS-452, and no SARS-CoV-2 viral infections occurred during the study. Seroconversion rates of anti-SARS-CoV-2 SP/RBD IgG titers in the 22.5, 45, and 90 µg cohorts at day 28 were 70%, 90%, and 100%, respectively, which all increased to 100% at day 56 (except 89% for the single-dose 22.5 µg cohort). All IgG titers were Th1-isotype skewed and efficiently bound mutant SP/RBD from several SARS-CoV-2 variants with strong neutralization potencies of live virus infection of cells (including alpha and delta variants). The favorable safety and immunogenicity profiles of this phase I study (ClinicalTrials.gov: NCT04681092) support phase II initiation of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain.

Published
2022

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