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First Report of a Phase 1 Randomised Trial of Molecular Clamp-Stabilised Spike Protein-Based and MF59-Adjuvanted Vaccine for SARS-CoV-2

37 Pages Posted: 1 Feb 2021

See all articles by Keith Joseph Chappell

Keith Joseph Chappell

University of Queensland - School of Chemistry and Molecular Biosciences

Francesca L. Mordant

University of Melbourne - Department of Microbiology and Immunology (DMI)

Zheyi Li

Australian National University (ANU) - Department of Immunology and Infectious Disease

Danushka K. Wijesundara

University of Queensland - School of Chemistry and Molecular Biosciences

Paula Ellenberg

Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, at The Peter Doherty Institute for Infection and Immunity

Julia Lackenby

University of Queensland - School of Chemistry and Molecular Biosciences

Stacey Cheung

University of Queensland - School of Chemistry and Molecular Biosciences

Naphak Modhiran

University of Queensland - School of Chemistry and Molecular Biosciences

Michael S. Avumegah

University of Queensland - School of Chemistry and Molecular Biosciences

Christina L. Henderson

University of Queensland

Kym Hoger

University of Queensland - Australian Institute for Bioengineering and Nanotechnology (AIBN)

Jillian Bennet

Tanawell Consulting

Luca Hensen

University of Melbourne - Department of Microbiology and Immunology (DMI)

Thi H. O. Nguyen

University of Melbourne - Department of Microbiology and Immunology (DMI)

Sara Marrero-Hernandez

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne

Kevin J. Selva

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne

Amy Chung

University of Melbourne - Department of Microbiology and Immunology (DMI)

Mai H. Tran

University of Queensland - TetraQ

Peter Tapley

University of Queensland - TetraQ

Patrick Reading

University of Melbourne - Department of Microbiology and Immunology

Suellen Nicholson

Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, at The Peter Doherty Institute for Infection and Immunity

Stavroula Corby

Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, at The Peter Doherty Institute for Infection and Immunity

Thomas Holgate

Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, at The Peter Doherty Institute for Infection and Immunity

Bruce D. Wines

Burnet Institute

P. Mark Hogarth

Burnet Institute

Katherine Kedzierska

University of Melbourne - Department of Microbiology and Immunology (DMI)

Damian Purcell

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne

Charani Ranasinghe

Australian National University (ANU) - Department of Immunology and Infectious Disease

Kanta Subbarao

University of Melbourne - Department of Microbiology and Immunology (DMI)

Daniel Watterson

University of Queensland - Institute for Molecular Bioscience; University of Queensland - Division of Chemistry and Structural Biology; University of Queensland - Australian Infectious Diseases Research Centre

Paul Young

University of Queensland - School of Chemistry and Molecular Biosciences; University of Queensland - Institute for Molecular Bioscience; University of Queensland - Australian Infectious Diseases Research Centre

Trent P. Munro

University of Queensland - School of Chemistry and Molecular Biosciences

More...

Abstract

Background: We assessed the safety and immunogenicity of an MF59-adjuvanted subunit vaccine for COVID-19 based on recombinant SARS-CoV-2 spike glycoprotein stabilised in a prefusion conformation by a novel molecular clamp (Sclamp).

Methods: Phase 1, double-blind, placebo-controlled trial conducted in Australia (July 2020–ongoing; ClinicalTrials.gov NCT04495933). Healthy adults (18-55 years) received two doses of placebo, 5-μg, 15-μg, or 45-μg SARS-CoV-2 Sclamp, or one 45-μg dose of SARS-CoV-2 Sclamp followed by placebo, 28 days apart (n=120; 24 per group). Safety, humoral immunogenicity (ELISA, microneutralisation, pseudovirus neutralisation), and cellular immunogenicity (antigen-specific CD4+/CD8+ T-cells, antibody-secreting cells) were assessed up to 56 days after the first dose.

Findings: The SARS-CoV-2 Sclamp vaccine was very well tolerated with few systemic reactions. All two-dose regimens elicited robust, broadly neutralising humoral responses. Geometric mean titres were higher than in sera from convalescent COVID-19 patients and strongly neutralised spike variants of concern, including N501Y. Moreover, humoral and cellular responses were highly correlated. However, antibodies elicited to a peptide sequence used in the molecular clamp derived from human immunodeficiency virus-1 (HIV-1) gp41 cross-reacted weakly with some HIV diagnostic screening tests.

Interpretation: These first-in-human results demonstrate that a subunit vaccine comprising mammalian cell culture-derived, molecular clamp-stabilised recombinant spike protein formulated in a squalene-in-oil adjuvant elicits strong immune responses with an excellent safety profile. However, the gp41 peptide induced diagnostic interference, creates a likely barrier to widespread use and highlights the criticality of potential off-target immunogenicity during vaccine development. Studies are ongoing with alternative molecular clamp trimerisation domains to ameliorate this response.

Clinical Trial Registration: ClinicalTrials.gov (NCT04495933).

Funding: Coalition for Epidemic Preparedness Innovations; National Health and Medical Research Council, Queensland Government, and philanthropic sources.

Declaration of Interests: KJC and DW report grants from the Coalition for Epidemic Preparedness Innovations, the National Health and Medical Research Council of Australia, and the Queensland Government, during the conduct of the study; other from ViceBio Limited, outside the submitted work; and has patents pending (AU 2018241252; BR112019019813.0; CA 3057171; CH 201880022016.9; EP 18775234.0; IN 201917038666; ID P00201909145; IL 269534; JP 2019-553883; MX/a/2019/011599; NZ 757178; KR 0-2019-7031415; SG 11201908280S; US 16/498865). JB reports personal fees from CSL Limited, during the conduct of the study, and other from CSL Limited, outside the submitted work. WZ reports grants from the National Health and Medical Research Council of Australia, the Research Grants Council of the Hong Kong Special Administrative Region, China, and the Jack Ma Foundation, during the conduct of the study. SM-H reports grants from Canarian Foundation Doctor Manuel Morales, during the conduct of the study. KJS reports grants from the the Australian Medical Research Future Fund, during the conduct of the study. AWC reports grants from the Australian Medical Research Future Fund and a National Health and Medical Research Council of Australia Career Development Fellowship, during the conduct of the study. BDW reports grants from the National Health and Medical Research Council of Australia, the Australian Medical Research Future Fund, and the Victorian State Government, during the conduct of the study. PMH reports grants from the Australian Medical Research Future Fund, during the conduct of the study. DP reports grants from the National Health and Medical Research Council of Australia, the A2 Milk Foundation, and the Jack Ma Foundation, during the conduct of the study. CR reports grants from the Coalition for Epidemic Preparedness Innovations, during the conduct of the study. PRY reports grants from the Coalition for Epidemic Preparedness Innovations, the National Health and Medical Research Council of Australia, and the Queensland Government, during the conduct of the study; grants from ViceBio Limited, outside the submitted work; and a patent issued (US 2020/0040042). FLM, Zl, DKW, PE, JAL, STMC, NM, SA, CLH, KH, PG, LH, THON, MHT, PT, JB, PCR, SN, SC, TH, KK, KS, and TPM have nothing to disclose.

Ethics Approval Statement: The protocol was approved by the Alfred Health Human Research Ethics Committee (2020001376/334/20).

Suggested Citation

Chappell, Keith Joseph and Mordant, Francesca L. and Li, Zheyi and Wijesundara, Danushka K. and Ellenberg, Paula and Lackenby, Julia and Cheung, Stacey and Modhiran, Naphak and Avumegah, Michael S. and Henderson, Christina L. and Hoger, Kym and Bennet, Jillian and Hensen, Luca and Nguyen, Thi H. O. and Marrero-Hernandez, Sara and Selva, Kevin J. and Chung, Amy and Tran, Mai H. and Tapley, Peter and Reading, Patrick and Nicholson, Suellen and Corby, Stavroula and Holgate, Thomas and Wines, Bruce D. and Hogarth, P. Mark and Kedzierska, Katherine and Purcell, Damian and Ranasinghe, Charani and Subbarao, Kanta and Watterson, Daniel and Young, Paul and Munro, Trent P., First Report of a Phase 1 Randomised Trial of Molecular Clamp-Stabilised Spike Protein-Based and MF59-Adjuvanted Vaccine for SARS-CoV-2. Available at SSRN: https://ssrn.com/abstract=3769210

Keith Joseph Chappell (Contact Author)

University of Queensland - School of Chemistry and Molecular Biosciences ( email )

St. Lucia
Brisbane
Australia

Francesca L. Mordant

University of Melbourne - Department of Microbiology and Immunology (DMI) ( email )

Melbourne, 3000
Australia

Zheyi Li

Australian National University (ANU) - Department of Immunology and Infectious Disease ( email )

Canberra, Australian Capital Territory 2601
Australia

Danushka K. Wijesundara

University of Queensland - School of Chemistry and Molecular Biosciences ( email )

St. Lucia
Brisbane
Australia

Paula Ellenberg

Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, at The Peter Doherty Institute for Infection and Immunity ( email )

Julia Lackenby

University of Queensland - School of Chemistry and Molecular Biosciences ( email )

St. Lucia
Brisbane
Australia

Stacey Cheung

University of Queensland - School of Chemistry and Molecular Biosciences ( email )

St. Lucia
Brisbane
Australia

Naphak Modhiran

University of Queensland - School of Chemistry and Molecular Biosciences ( email )

St. Lucia
Brisbane
Australia

Michael S. Avumegah

University of Queensland - School of Chemistry and Molecular Biosciences ( email )

St. Lucia
Brisbane
Australia

Christina L. Henderson

University of Queensland

St Lucia
Brisbane, 4072
Australia

Kym Hoger

University of Queensland - Australian Institute for Bioengineering and Nanotechnology (AIBN) ( email )

Brisbane, 4072
Australia

Jillian Bennet

Tanawell Consulting ( email )

Luca Hensen

University of Melbourne - Department of Microbiology and Immunology (DMI) ( email )

Melbourne, 3000
Australia

Thi H. O. Nguyen

University of Melbourne - Department of Microbiology and Immunology (DMI) ( email )

Melbourne, 3000
Australia

Sara Marrero-Hernandez

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne ( email )

Kevin J. Selva

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne ( email )

Amy Chung

University of Melbourne - Department of Microbiology and Immunology (DMI) ( email )

Melbourne, 3000
Australia

Mai H. Tran

University of Queensland - TetraQ ( email )

St Lucia
Brisbane, Queensland 4072
Australia

Peter Tapley

University of Queensland - TetraQ ( email )

St Lucia
Brisbane, Queensland 4072
Australia

Patrick Reading

University of Melbourne - Department of Microbiology and Immunology ( email )

185 Pelham Street
Carlton, Victoria 3053
Australia

Suellen Nicholson

Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, at The Peter Doherty Institute for Infection and Immunity ( email )

Stavroula Corby

Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, at The Peter Doherty Institute for Infection and Immunity ( email )

Thomas Holgate

Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, at The Peter Doherty Institute for Infection and Immunity ( email )

Bruce D. Wines

Burnet Institute

85 Commercial Road
Melbourne, VIC, 3004
Australia

P. Mark Hogarth

Burnet Institute

85 Commercial Road
Melbourne, VIC, 3004
Australia

Katherine Kedzierska

University of Melbourne - Department of Microbiology and Immunology (DMI)

Melbourne, 3000
Australia

Damian Purcell

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne ( email )

Charani Ranasinghe

Australian National University (ANU) - Department of Immunology and Infectious Disease ( email )

Canberra, Australian Capital Territory 2601
Australia

Kanta Subbarao

University of Melbourne - Department of Microbiology and Immunology (DMI) ( email )

Melbourne, 3000
Australia

Daniel Watterson

University of Queensland - Institute for Molecular Bioscience ( email )

St. Lucia
Brisbane
Australia

University of Queensland - Division of Chemistry and Structural Biology ( email )

St. Lucia
Brisbane
Australia

University of Queensland - Australian Infectious Diseases Research Centre ( email )

St. Lucia
Brisbane
Australia

Paul Young

University of Queensland - School of Chemistry and Molecular Biosciences ( email )

St. Lucia
Brisbane
Australia

University of Queensland - Institute for Molecular Bioscience ( email )

St. Lucia
Brisbane
Australia

University of Queensland - Australian Infectious Diseases Research Centre ( email )

St. Lucia
Brisbane
Australia

Trent P. Munro

University of Queensland - School of Chemistry and Molecular Biosciences ( email )

St. Lucia
Brisbane
Australia

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