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Safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2: a randomised, double-blind, placebo-controlled, phase 1 trial.
Chappell, Keith J; Mordant, Francesca L; Li, Zheyi; Wijesundara, Danushka K; Ellenberg, Paula; Lackenby, Julia A; Cheung, Stacey T M; Modhiran, Naphak; Avumegah, Michael S; Henderson, Christina L; Hoger, Kym; Griffin, Paul; Bennet, Jillian; Hensen, Luca; Zhang, Wuji; Nguyen, Thi H O; Marrero-Hernandez, Sara; Selva, Kevin J; Chung, Amy W; Tran, Mai H; Tapley, Peter; Barnes, James; Reading, Patrick C; Nicholson, Suellen; Corby, Stavroula; Holgate, Thomas; Wines, Bruce D; Hogarth, P Mark; Kedzierska, Katherine; Purcell, Damian F J; Ranasinghe, Charani; Subbarao, Kanta; Watterson, Daniel; Young, Paul R; Munro, Trent P.
  • Chappell KJ; School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia; The Australian Institute for Biotechnology and Nanotechnology, The University of Queensland, St Lucia, QLD, Australia; Australian Infectious Disease Research Centre, The University of Queensland, S
  • Mordant FL; Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Li Z; Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
  • Wijesundara DK; School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia; The Australian Institute for Biotechnology and Nanotechnology, The University of Queensland, St Lucia, QLD, Australia.
  • Ellenberg P; Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Lackenby JA; School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia; The Australian Institute for Biotechnology and Nanotechnology, The University of Queensland, St Lucia, QLD, Australia.
  • Cheung STM; School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia.
  • Modhiran N; School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia.
  • Avumegah MS; School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia; The Australian Institute for Biotechnology and Nanotechnology, The University of Queensland, St Lucia, QLD, Australia.
  • Henderson CL; School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia; The Australian Institute for Biotechnology and Nanotechnology, The University of Queensland, St Lucia, QLD, Australia.
  • Hoger K; The Australian Institute for Biotechnology and Nanotechnology, The University of Queensland, St Lucia, QLD, Australia.
  • Griffin P; School of Medicine, The University of Queensland, St Lucia, QLD, Australia; Nucleus Network Brisbane Clinic, Herston, QLD, Australia; Department of Infectious Diseases, Mater Health, QLD, Australia.
  • Bennet J; Tanawell Nominees, Melbourne, VIC, Australia.
  • Hensen L; Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Zhang W; Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Nguyen THO; Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Marrero-Hernandez S; Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Selva KJ; Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Chung AW; Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Tran MH; TetraQ, The University of Queensland, Herston, QLD, Australia.
  • Tapley P; TetraQ, The University of Queensland, Herston, QLD, Australia.
  • Barnes J; WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Reading PC; Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Nicholson S; Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Corby S; Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Holgate T; Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Wines BD; Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia.
  • Hogarth PM; Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia; Department of Immunology and Pathology, Monash University, Alfred Health, Melbourne, VIC, Australia.
  • Kedzierska K; Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Purcell DFJ; Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Ranasinghe C; Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
  • Subbarao K; Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; WHO Collaborating Centre for Reference and Research on Influenza, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Watterson D; School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia; The Australian Institute for Biotechnology and Nanotechnology, The University of Queensland, St Lucia, QLD, Australia; Australian Infectious Disease Research Centre, The University of Queensland, S
  • Young PR; School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia; The Australian Institute for Biotechnology and Nanotechnology, The University of Queensland, St Lucia, QLD, Australia; Australian Infectious Disease Research Centre, The University of Queensland, S
  • Munro TP; School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia; The Australian Institute for Biotechnology and Nanotechnology, The University of Queensland, St Lucia, QLD, Australia.
Lancet Infect Dis ; 21(10): 1383-1394, 2021 10.
Article in English | MEDLINE | ID: covidwho-1621119
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ABSTRACT

BACKGROUND:

Given the scale of the ongoing COVID-19 pandemic, the development of vaccines based on different platforms is essential, particularly in light of emerging viral variants, the absence of information on vaccine-induced immune durability, and potential paediatric use. We aimed to assess the safety and immunogenicity of an MF59-adjuvanted subunit vaccine for COVID-19 based on recombinant SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a novel molecular clamp (spike glycoprotein-clamp [sclamp]).

METHODS:

We did a phase 1, double-blind, placebo-controlled, block-randomised trial of the sclamp subunit vaccine in a single clinical trial site in Brisbane, QLD, Australia. Healthy adults (aged ≥18 to ≤55 years) who had tested negative for SARS-CoV-2, reported no close contact with anyone with active or previous SARS-CoV-2 infection, and tested negative for pre-existing SARS-CoV-2 immunity were included. Participants were randomly assigned to one of five treatment groups and received two doses via intramuscular injection 28 days apart of either placebo, sclamp vaccine at 5 µg, 15 µg, or 45 µg, or one dose of sclamp vaccine at 45 µg followed by placebo. Participants and study personnel, except the dose administration personnel, were masked to treatment. The primary safety endpoints included solicited local and systemic adverse events in the 7 days after each dose and unsolicited adverse events up to 12 months after dosing. Here, data are reported up until day 57. Primary immunogenicity endpoints were antigen-specific IgG ELISA and SARS-CoV-2 microneutralisation assays assessed at 28 days after each dose. The study is ongoing and registered with ClinicalTrials.gov, NCT04495933.

FINDINGS:

Between June 23, 2020, and Aug 17, 2020, of 314 healthy volunteers screened, 120 were randomly assigned (n=24 per group), and 114 (95%) completed the study up to day 57 (mean age 32·5 years [SD 10·4], 65 [54%] male, 55 [46%] female). Severe solicited reactions were infrequent and occurred at similar rates in participants receiving placebo (two [8%] of 24) and the SARS-CoV-2 sclamp vaccine at any dose (three [3%] of 96). Both solicited reactions and unsolicited adverse events occurred at a similar frequency in participants receiving placebo and the SARS-CoV-2 sclamp vaccine. Solicited reactions occurred in 19 (79%) of 24 participants receiving placebo and 86 (90%) of 96 receiving the SARS-CoV-2 sclamp vaccine at any dose. Unsolicited adverse events occurred in seven (29%) of 24 participants receiving placebo and 35 (36%) of 96 participants receiving the SARS-CoV-2 sclamp vaccine at any dose. Vaccination with SARS-CoV-2 sclamp elicited a similar antigen-specific response irrespective of dose 4 weeks after the initial dose (day 29) with 5 µg dose (geometric mean titre [GMT] 6400, 95% CI 3683-11 122), with 15 µg dose (7492, 4959-11 319), and the two 45 µg dose cohorts (8770, 5526-13 920 in the two-dose 45 µg cohort; 8793, 5570-13 881 in the single-dose 45 µg cohort); 4 weeks after the second dose (day 57) with two 5 µg doses (102 400, 64 857-161 676), with two 15 µg doses (74 725, 51 300-108 847), with two 45 µg doses (79 586, 55 430-114 268), only a single 45 µg dose (4795, 2858-8043). At day 57, 67 (99%) of 68 participants who received two doses of sclamp vaccine at any concentration produced a neutralising immune response, compared with six (25%) of 24 who received a single 45 µg dose and none of 22 who received placebo. Participants receiving two doses of sclamp vaccine elicited similar neutralisation titres, irrespective of dose two 5 µg doses (GMT 228, 95% CI 146-356), two 15 µg doses (230, 170-312), and two 45 µg doses (239, 187-307).

INTERPRETATION:

This first-in-human trial shows that a subunit vaccine comprising mammalian cell culture-derived, MF59-adjuvanted, molecular clamp-stabilised recombinant spike protein elicits strong immune responses with a promising safety profile. However, the glycoprotein 41 peptide present in the clamp created HIV diagnostic assay interference, a possible barrier to widespread use highlighting the criticality of potential non-spike directed immunogenicity during vaccine development. Studies are ongoing with alternative molecular clamp trimerisation domains to ameliorate this response.

FUNDING:

Coalition for Epidemic Preparedness Innovations, National Health and Medical Research Council, Queensland Government, and further philanthropic sources listed in the acknowledgments.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Squalene / Adjuvants, Immunologic / Spike Glycoprotein, Coronavirus / COVID-19 Vaccines / COVID-19 Type of study: Controlled clinical trial / Randomized controlled trials Topics: Vaccines / Variants Limits: Adult / Female / Humans / Male / Young adult Country/Region as subject: Oceania Language: English Journal: Lancet Infect Dis Journal subject: Communicable Diseases Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Squalene / Adjuvants, Immunologic / Spike Glycoprotein, Coronavirus / COVID-19 Vaccines / COVID-19 Type of study: Controlled clinical trial / Randomized controlled trials Topics: Vaccines / Variants Limits: Adult / Female / Humans / Male / Young adult Country/Region as subject: Oceania Language: English Journal: Lancet Infect Dis Journal subject: Communicable Diseases Year: 2021 Document Type: Article