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Interim Results from a Phase I Trial of Novel SARS-CoV-2 Beta Variant Receptor-Binding Domain Recombinant Protein and mRNA Vaccines as a 4 th Dose Booster

43 Pages Posted: 29 Jun 2023

See all articles by Terry Nolan

Terry Nolan

University of Melbourne - Peter Doherty Institute for Infection and Immunity

Georgia Deliyannis

University of Melbourne

Maryanne Griffith

University of Melbourne

Sabine Braat

University of Melbourne - Departments of Medicine and Infectious Diseases at the Doherty Institute

Lilith F. Allen

University of Melbourne - Department of Microbiology and Immunology

Jennifer Audsley

University of Melbourne - Peter Doherty Institute for Infection and Immunity

Amy Chung

University of Melbourne - Peter Doherty Institute for Infection and Immunity

Marcin Ciula

University of Melbourne

Nicholas Gherardin

University of Melbourne

Michelle Giles

University of Melbourne

Tom Gordon

Flinders University

Samantha Grimley

University of Melbourne

Lana Horng

University of Melbourne

David Jackson

University of Melbourne

Jennifer A. Juno

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

Katherine Kedzierska

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

Stephen J. Kent

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

Sharon R. Lewin

University of Melbourne - Peter Doherty Institute for Infection and Immunity

Mason Littlejohn

University of Melbourne

Hayley A. McQuilten

University of Melbourne - Department of Microbiology and Immunology

Francesca L. Mordant

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

Thi H. O. Nguyen

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

Vanessa Pac Soo

University of Melbourne - Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health; University of Melbourne - MISCH (Methods and Implementation Support for Clinical Health) Research Hub, Faculty of Medicine, Dentistry and Health Sciences

Briony Price

University of Melbourne

Damian Purcell

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

Pradhipa Ramanathan

University of Melbourne

Samuel Redmond

University of Melbourne

Steven Rockman

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

Zheng Ruan

University of Melbourne

Joseph Sasadeusz

University of Melbourne - Royal Melbourne Hospital

Julie A. Simpson

University of Melbourne - Centre for Epidemiology and Biostatistics

Kanta Subbarao

University of Melbourne

Stewart Fabb

Monash University - Monash Institute of Pharmaceutical Sciences

Thomas Payne

Monash University - Monash Institute of Pharmaceutical Sciences

Asuka Takanashi

Monash University - Monash Institute of Pharmaceutical Sciences

Chee Wah Tan

SingHealth Duke-NUS Global Health Institute

Joseph Torresi

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

Jing Jing Wang

Flinders University

Lin Fa Wang

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

Harry al Wassiti

Monash University - Monash Institute of Pharmaceutical Sciences

Chinn Yi Wong

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

Sophie Zaloumis

University of Melbourne - Centre for Epidemiology and Biostatistics

Colin Pouton

Monash University - Monash Institute of Pharmaceutical Sciences

Dale Godfrey

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

More...

Abstract

Background: SARS-CoV-2 booster vaccination should ideally enhance protection against variants and minimise immune imprinting. This Phase I trial evaluated two vaccines targeting SARS-CoV-2 beta-variant receptor-binding domain (RBD): a recombinant dimeric RBD-human IgG1 Fc-fusion protein, and an mRNA encoding a membrane-anchored RBD. 

Methods: 76 healthy adults aged 18–64y, previously triple vaccinated with licensed SARS-CoV-2 vaccines, were randomised to receive a 4th dose of either an adjuvanted (MF59®, CSL Seqirus) protein vaccine (5, 15 or 45µg, N=32), mRNA vaccine (10, 20, or 50µg,  N=32), or placebo (saline, N=12) at least 90 days after a 3rd boost vaccination or SARS-CoV-2 infection.  Bleeds occurred on days 1 (prior to vaccination), 8, and 29. ClinicalTrials.gov NCT05272605.

Findings: No vaccine-related serious or medically attended adverse events occurred. The protein vaccine reactogenicity was mild, whereas the mRNA vaccine was moderately reactogenic at higher dose levels. Best anti-RBD antibody responses resulted from the higher doses of each vaccine. A similar pattern was seen with live virus neutralisation and surrogate, and pseudovirus neutralisation assays. Breadth of immune response was demonstrated against BA.5 and more recent omicron subvariants (XBB, XBB.1.5 and BQ.1.1). Binding antibody titres for both vaccines were comparable to those of a licensed bivalent mRNA vaccine. Both vaccines enhanced CD4+ and CD8+ T cell activation.

Interpretation: There were no safety concerns and the reactogenicity profile was mild and similar to licensed SARS-CoV-2 vaccines. Both vaccines showed strong immune boosting against beta, ancestral and omicron strains.

Trial Registration: The study is registered at www.clinicaltrials.gov (NCT05272605).

Funding: Medical Research Future Fund, and philanthropies Jack Ma Foundation and IFM investors.

Declaration of Interest: The vaccines evaluated in this Phase I study were the result of independent University of Melbourne and Monash University research and development, with funding provided by the Australian Government’s Medical Research Future Fund (MRFF), the National Health and Medical Research Council (NHMRC) and philanthropic funders. The MF59 for the protein-RBD candidate was donated by CSL Seqirus. One author (SR) is an employee of CSL Seqirus and he also has an adjunct (honorary) appointment to the University of Melbourne. Several authors have received research or consulting funding from various commercial entities, but none is judged to be in conflict with the work presented.

Ethical Approval: The study was reviewed and approved by the Royal Melbourne Hospital Human Research Ethics Committee and was conducted under the Clinical Trial Notification (CTN) Scheme (CTN ID: 04968-1) administered by the Australian Therapeutic Goods Administration. All participants provided written informed consent prior to enrolment.

Keywords: SARS-CoV-2, vaccine, receptor binding domain, recombinant protein, mRNA, beta variant, phase I trial.

Suggested Citation

Nolan, Terry and Deliyannis, Georgia and Griffith, Maryanne and Braat, Sabine and Allen, Lilith F. and Audsley, Jennifer and Chung, Amy and Ciula, Marcin and Gherardin, Nicholas and Giles, Michelle and Gordon, Tom and Grimley, Samantha and Horng, Lana and Jackson, David and Juno, Jennifer A. and Kedzierska, Katherine and Kent, Stephen J. and Lewin, Sharon R. and Littlejohn, Mason and McQuilten, Hayley A. and Mordant, Francesca L. and Nguyen, Thi H. O. and Pac Soo, Vanessa and Price, Briony and Purcell, Damian and Ramanathan, Pradhipa and Redmond, Samuel and Rockman, Steven and Ruan, Zheng and Sasadeusz, Joseph and Simpson, Julie A. and Subbarao, Kanta and Fabb, Stewart and Payne, Thomas and Takanashi, Asuka and Tan, Chee Wah and Torresi, Joseph and Wang, Jing Jing and Wang, Lin Fa and al Wassiti, Harry and Wong, Chinn Yi and Zaloumis, Sophie and Pouton, Colin and Godfrey, Dale, Interim Results from a Phase I Trial of Novel SARS-CoV-2 Beta Variant Receptor-Binding Domain Recombinant Protein and mRNA Vaccines as a 4 th Dose Booster. Available at SSRN: https://ssrn.com/abstract=4485603 or http://dx.doi.org/10.2139/ssrn.4485603

Terry Nolan (Contact Author)

University of Melbourne - Peter Doherty Institute for Infection and Immunity ( email )

Georgia Deliyannis

University of Melbourne ( email )

Parkville, 3010
Australia

Maryanne Griffith

University of Melbourne ( email )

Parkville, 3010
Australia

Sabine Braat

University of Melbourne - Departments of Medicine and Infectious Diseases at the Doherty Institute

Lilith F. Allen

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

185 Pelham Street
Carlton, 3053
Australia

Jennifer Audsley

University of Melbourne - Peter Doherty Institute for Infection and Immunity ( email )

792 Elizabeth Street
Melbourne, 3000
Australia

Amy Chung

University of Melbourne - Peter Doherty Institute for Infection and Immunity ( email )

Marcin Ciula

University of Melbourne ( email )

Parkville, 3010
Australia

Nicholas Gherardin

University of Melbourne ( email )

Parkville, 3010
Australia

Michelle Giles

University of Melbourne ( email )

Parkville, 3010
Australia

Tom Gordon

Flinders University ( email )

GPO Box 2100
Adelaide S.A. 5001, 5063
Australia

Samantha Grimley

University of Melbourne ( email )

Parkville, 3010
Australia

Lana Horng

University of Melbourne ( email )

Parkville, 3010
Australia

David Jackson

University of Melbourne ( email )

Parkville, 3010
Australia

Jennifer A. Juno

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

Melbourne, 3000
Australia

Katherine Kedzierska

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

Melbourne, 3000
Australia

Stephen J. Kent

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

Sharon R. Lewin

University of Melbourne - Peter Doherty Institute for Infection and Immunity ( email )

792 Elizabeth Street
Melbourne, 3000
Australia

Mason Littlejohn

University of Melbourne ( email )

Parkville, 3010
Australia

Hayley A. McQuilten

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

185 Pelham Street
Carlton, 3053
Australia

Francesca L. Mordant

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

Vanessa Pac Soo

University of Melbourne - Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health ( email )

University of Melbourne - MISCH (Methods and Implementation Support for Clinical Health) Research Hub, Faculty of Medicine, Dentistry and Health Sciences ( email )

Melbourne
Australia

Briony Price

University of Melbourne ( email )

Parkville, 3010
Australia

Damian Purcell

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

Pradhipa Ramanathan

University of Melbourne ( email )

Samuel Redmond

University of Melbourne ( email )

Parkville, 3010
Australia

Steven Rockman

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

Zheng Ruan

University of Melbourne ( email )

Parkville, 3010
Australia

Joseph Sasadeusz

University of Melbourne - Royal Melbourne Hospital ( email )

Julie A. Simpson

University of Melbourne - Centre for Epidemiology and Biostatistics ( email )

Level 3, 207 Bouverie Street
Melbourne, VIC 3010
Australia

Kanta Subbarao

University of Melbourne ( email )

Parkville, 3010
Australia

Stewart Fabb

Monash University - Monash Institute of Pharmaceutical Sciences ( email )

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Thomas Payne

Monash University - Monash Institute of Pharmaceutical Sciences ( email )

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Asuka Takanashi

Monash University - Monash Institute of Pharmaceutical Sciences ( email )

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Chee Wah Tan

SingHealth Duke-NUS Global Health Institute ( email )

Joseph Torresi

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

Melbourne, 3000
Australia

Jing Jing Wang

Flinders University ( email )

GPO Box 2100
Adelaide S.A. 5001, 5063
Australia

Lin Fa Wang

Duke-NUS Medical School - Programme in Emerging Infectious Diseases ( email )

Harry Al Wassiti

Monash University - Monash Institute of Pharmaceutical Sciences ( email )

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Chinn Yi Wong

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

Melbourne, 3000
Australia

Sophie Zaloumis

University of Melbourne - Centre for Epidemiology and Biostatistics ( email )

Colin Pouton

Monash University - Monash Institute of Pharmaceutical Sciences ( email )

23 Innovation Walk
Wellington Road
Clayton, 3800
Australia

Dale Godfrey

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

Melbourne, 3000
Australia

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