Safety and immunogenicity of a SARS-CoV-2 spike, subunit vaccine stabilised in the prefusion conformation by second generation Molecular Clamp evaluated in adults aged 18-55 years: a randomised, double-blind, active comparator, Phase I trial

Keith J Chappell; Francesca L Mordant; Alberto A Amarilla; Naphak Modhiran; Benjamin Liang; Zheyi Li; Julia A Lackenby; Noushin Jaberolansar; Jake O'Donnell; Vivian Kienzle; Varsha Kommajosyula; Nicolas Tardiota; Jillian K Bennet; Christina L Henderson; Rhiannon L Dalrymple; Justin Goh; Kym Hoger; Marianne Gillard; Martina L Jones; Karen Hughes; Ben Hughes; James Barnes; Patrick C Reading; Charani Ranasinghe; Kanta Subbarao; Trent P Munro; Paul R Young; Daniel Watterson

doi:10.1093/infdis/jiaf568

Safety and immunogenicity of a SARS-CoV-2 spike, subunit vaccine stabilised in the prefusion conformation by second generation Molecular Clamp evaluated in adults aged 18-55 years: a randomised, double-blind, active comparator, Phase I trial

J Infect Dis. 2025 Nov 25:jiaf568. doi: 10.1093/infdis/jiaf568. Online ahead of print.

Authors

Keith J Chappell^{1

2

3}, Francesca L Mordant⁴, Alberto A Amarilla¹, Naphak Modhiran¹, Benjamin Liang¹, Zheyi Li⁵, Julia A Lackenby^{1

2}, Noushin Jaberolansar², Jake O'Donnell^{1

2}, Vivian Kienzle^{1

2}, Varsha Kommajosyula², Nicolas Tardiota², Jillian K Bennet⁶, Christina L Henderson^{1

2}, Rhiannon L Dalrymple^{1

2}, Justin Goh², Kym Hoger², Marianne Gillard², Martina L Jones², Karen Hughes², Ben Hughes², James Barnes⁷, Patrick C Reading^{4

7}, Charani Ranasinghe⁵, Kanta Subbarao^{4

7}, Trent P Munro^{1

2}, Paul R Young^{1

2

3}, Daniel Watterson^{1

2

3}

Affiliations

¹ School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia.
² The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD, Australia.
³ Australian Infectious Diseases Research Centre, The University of Queensland, St Lucia, QLD, Australia.
⁴ Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, Australia.
⁵ Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
⁶ Independent Consultant, Melbourne, VIC, Australia.
⁷ WHO Collaborating Centre for Reference and Research on Influenza, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.

PMID: 41285172
DOI: 10.1093/infdis/jiaf568

Abstract

Background: A COVID-19 subunit vaccine developed with the Molecular Clamp platform was among the first to enter clinical trials in 2020. While the vaccine was well suited to large-scale manufacture and demonstrated a favourable safety and immunogenicity profile, it did not progress into further clinical testing due to the HIV-derived sequence in the Molecular Clamp interfering with certain point-of-care HIV diagnostic tests.A second-generation Molecular Clamp (MC2) has since been developed. Here, we describe a Phase I clinical trial of a MC2 stabilised SARS-CoV-2 Spike subunit vaccine, UQSC2.

Methods: A Phase I, double-blind, active comparator-controlled trial was conducted in Australia (ClinicalTrials.gov NCT05775887; ). Healthy adults (18-50 years), who had previously received three or more doses of approved mRNA SARS-CoV-2 vaccines, received a single booster dose of either UQSC2 or approved comparator NVX-CoV2373 (NuvaxovidTM; Novavax) (n=70; 35 per group). Safety, humoral immunogenicity (including against virus variants), and cellular immunogenicity were assessed to Day 183. Cases of confirmed COVID-19 infection during the study were also examined.

Results: Both vaccines were equally well tolerated and elicited comparable increases in neutralising humoral responses against vaccine matched prototypic, Wuhan strain of SARS-CoV-2.

Findings: UQSC2 was equally well tolerated to the authorised comparator vaccine and produced an equally robust boost in neutralising immune response. These findings support the effectiveness of the MC2 platform in producing vaccines against newly emerging variants of SARS-CoV-2, and other respiratory viruses, as well as the platform's potential use in emergency response to novel viruses.

Keywords: COVID-19 vaccine; Clinical trial; Molecular Clamp; Phase I; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Spike protein; Vaccine platform.

Associated data

ClinicalTrials.gov/NCT05775887