Recoding the SARS-CoV-2 genome - A multidisciplinary approach to generate live-attenuated coronavirus vaccines
Final Report Abstract
The development of live attenuated vaccines (LAVs) presents a promising approach, particularly in combating emerging SARS-CoV-2 variants and reducing viral transmission. Current vaccines, while effective at preventing severe illness, fall short in inducing strong mucosal immunity in the upper respiratory tract, which is crucial for preventing virus shedding and transmission. To tackle this issue, researchers have focused on creating genomemodified LAVs that can induce broader and more robust immune responses. In this project several LAV candidates have been developed by recoding the SARS-CoV-2 genome through codon pair deoptimization (CPD) or so called one-to-stop (OTS) codon recoding, which both are methods that alters the viral sequence without changing the proteins produced. This approach allowed the creation of LAVs, such as sCPD9, OTS-206, and OTS-228, that retain their immunogenic properties while being highly attenuated. These vaccines were administered intranasally, which better mimics the natural route of infection and induces mucosal immunity. In preclinical trials, these vaccines demonstrated genetic stability, safety, and efficacy, showing strong immune responses with minimal side effects. Key modifications included also the deletion of the furin cleavage site (FCS) from the spike protein, which eliminated the risk of vaccine transmission while maintaining strong protective immunity. These LAVs were tested in animal models, including Syrian and K18-hACE2-mice, known for their susceptibility to SARS-CoV-2 and COVID-19-like disease. The candidates, particularly sCPD9 and OTS-228, exhibited excellent safety profiles, with no detectable transmission between vaccinated and non-vaccinated animals, and provided broad protection against variants such as Alpha, Beta, Delta, Omicron BA.2, BA.5, and XBB.1.5. Moreover, a single intranasal dose of these vaccines induced sterilizing immunity, meaning vaccinated animals were fully protected from infection and did not transmit the virus. The research further showed that LAVs elicited rapid viral clearance, reduced tissue damage, and prompted a strong recall of memory T cells, offering not only protection from the original SARS-CoV-2 strains but also cross-neutralization of newer variants. Importantly, these LAVs hold potential as platform technologies for rapid adaptation to other emerging viruses. Given their ease of production and strong mucosal immune responses, they provide a valuable tool for future pandemic preparedness. In contrast to intramuscularly administered vaccines like mRNA and adenovirus-based vaccines, the LAVs showed superior efficacy in reducing virus transmission and inducing long-lasting immunity. In conclusion, the development of these live attenuated SARS-CoV-2 vaccines represents a significant advancement in the fight against COVID-19. By offering broad protection against variants, preventing transmission, and potentially serving as a basis for vaccines against other pathogens, LAVs could play a crucial role in controlling not only COVID-19 but also future viral threats.
Publications
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Development of safe and highly protective live-attenuated SARS-CoV-2 vaccine candidates by genome recoding. Cell Reports, 36(5), 109493.
Trimpert, Jakob; Dietert, Kristina; Firsching, Theresa C.; Ebert, Nadine; Thi Nhu Thao, Tran; Vladimirova, Daria; Kaufer, Susanne; Labroussaa, Fabien; Abdelgawad, Azza; Conradie, Andelé; Höfler, Thomas; Adler, Julia M.; Bertzbach, Luca D.; Jores, Joerg; Gruber, Achim D.; Thiel, Volker; Osterrieder, Nikolaus & Kunec, Dusan
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Live attenuated virus vaccine protects against SARS-CoV-2 variants of concern B.1.1.7 (Alpha) and B.1.351 (Beta). Science Advances, 7(49).
Trimpert, Jakob; Adler, Julia M.; Eschke, Kathrin; Abdelgawad, Azza; Firsching, Theresa C.; Ebert, Nadine; Thao, Tran Thi Nhu; Gruber, Achim D.; Thiel, Volker; Osterrieder, Nikolaus & Kunec, Dusan
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Synthetically recoded virus sCPD9 – A tool to accelerate SARS-CoV-2 research under biosafety level 2 conditions. Computational and Structural Biotechnology Journal, 20, 4376-4380.
Kunec, Dusan; Osterrieder, Nikolaus & Trimpert, Jakob
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A non-transmissible live attenuated SARS-CoV-2 vaccine. Molecular Therapy, 31(8), 2391-2407.
Adler, Julia M.; Martin Vidal, Ricardo; Voß, Anne; Kunder, Sandra; Nascimento, Mariana; Abdelgawad, Azza; Langner, Christine; Vladimirova, Daria; Osterrieder, Nikolaus; Gruber, Achim D.; Kunec, Dusan & Trimpert, Jakob
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Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters. Nature Microbiology, 8(5), 860-874.
Nouailles, Geraldine; Adler, Julia M.; Pennitz, Peter; Peidli, Stefan; Teixeira Alves, Luiz Gustavo; Baumgardt, Morris; Bushe, Judith; Voss, Anne; Langenhagen, Alina; Langner, Christine; Martin Vidal, Ricardo; Pott, Fabian; Kazmierski, Julia; Ebenig, Aileen; Lange, Mona V.; Mühlebach, Michael D.; Goekeri, Cengiz; Simmons, Szandor; Xing, Na ... & Trimpert, Jakob
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A safe, effective and adaptable live-attenuated SARS-CoV-2 vaccine to reduce disease and transmission using one-to-stop genome modifications. Nature Microbiology, 9(8), 2099-2112.
Schön, Jacob; Barut, G. Tuba; Trüeb, Bettina Salome; Halwe, Nico Joel; Berenguer Veiga, Inês; Kratzel, Annika; Ulrich, Lorenz; Kelly, Jenna N.; Brügger, Melanie; Wylezich, Claudia; Taddeo, Adriano; Aguiar Moreira, Etori; Túrós, Demeter; Grau-Roma, Llorenç; Ahrens, Ann Kathrin; Schlottau, Kore; Britzke, Tobias; Breithaupt, Angele; Corleis, Björn ... & Thiel, Volker
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An intranasal live-attenuated SARS-CoV-2 vaccine limits virus transmission. Nature Communications, 15(1).
Adler, Julia M.; Martin Vidal, Ricardo; Langner, Christine; Vladimirova, Daria; Abdelgawad, Azza; Kunecova, Daniela; Lin, Xiaoyuan; Nouailles, Geraldine; Voss, Anne; Kunder, Sandra; Gruber, Achim D.; Wu, Haibo; Osterrieder, Nikolaus; Kunec, Dusan & Trimpert, Jakob
