Long-Term Safety and Immunogenicity of an MF59-Adjuvanted Spike Glycoprotein-Clamp Vaccine for SARS-CoV-2 in Adults Aged 18–55 Years or ≥56 Years: 12-Month Results from a Randomised, Double-Blind, Placebo-Controlled, Phase 1 Trial

Abstract

Background: We previously demonstrated the safety and immunogenicity of an MF59-adjuvanted COVID-19 vaccine based on the SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a molecular clamp using HIV-1 glycoprotein 41 sequences. Here, we describe 12-month results in adults aged 18–55 years and ≥56 years.

Methods: Phase 1, double-blind, placebo-controlled trial conducted in Australia (July 2020–December 2021; ClinicalTrials.gov NCT04495933; active, not recruiting). Healthy adults (Part 1: 18–55 years; Part 2: ≥56 years) received two doses of placebo, 5 μg, 15 μg, or 45 μg vaccine, or one 45 μg dose of vaccine followed by placebo (Part 1 only), 28 days apart (n=216; 24 per group). Safety, humoral immunogenicity (including against virus variants), and cellular immunogenicity were assessed to day 394 (12 months after second dose). Effects of subsequent COVID-19 vaccination on humoral responses were examined.

Findings: All two-dose vaccine regimens were well tolerated and elicited strong antigen-specific and neutralising humoral responses, and CD4+ T-cell responses, by day 43 in younger and older adults, although cellular responses were lower in older adults. Humoral responses waned by day 209 but were boosted in those receiving authorised vaccines. Neutralising activity against Delta and Omicron variants was present but lower than against the Wuhan strain. Cross-reactivity in HIV diagnostic tests declined over time but remained detectable in most participants.

Interpretation: The SARS-CoV-2 molecular clamp vaccine is well tolerated and evokes robust immune responses in adults of all ages. Although the HIV glycoprotein 41-based molecular clamp is not being progressed, the clamp concept represents a viable platform for vaccine development.

Trial Registration: The trial was registered at ClinicalTrials.gov (NCT04495933).

Funding: This study was funded by the Coalition for Epidemic Preparedness Innovations, the National Health and Medical Research Council of Australia, and the Queensland Government. KK was supported by the National Health and Medical Research Council Leadership Investigator Grant (1173871). LH and WZ were supported by the Melbourne International Research Scholarship and the Melbourne International Fee Remission Scholarship from The University of Melbourne. The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. Further philanthropic funding sources included Royal Automobile Club of Queensland, The Golden Casket Foundation, The Bryan Foundation, The a2 Milk Company (Australia), Liming International, The Bowness Family Foundation, Glencore Australia Holdings, BHP Foundation, NewCrest Mining, Dr Jian Zhou Foundation, Paul Ramsay Foundation, Aurizon Operations, and The University of Queensland in America. Medical writing assistance was provided by Rebecca Lew, PhD, CMPP, and Serina Stretton, PhD, CMPP, of ProScribe – Envision Pharma Group, and was funded by philanthropic donations made to The University of Queensland.

Declaration of Interest: KJC, DW, and PRY report grants from the Medical Research Future Fund of the Australian Government, the Coalition for Epidemic Preparedness Innovations, the Queensland Government, the Paul Ramsay Foundation, the Lott, and the a2 Milk Company; contract research funding and/or consulting fees from ViceBio Pty Ltd; and a patent (PAT-02207-WO-01); KJC and DW report two additional patents (PAT- 02387-WO-01, PAT-02432-EP-01). FLM reports owning shares in CSL. JKB reports consultancy fees from The University of Queensland. PT reports grants from The University of Queensland paid to his employer. KS reports grants from the Jack Ma Foundation paid to his institution; travel support from the World Health Organisation; and membership of the WHO Technical Advisory Group on COVID-19 Vaccines (chair) and the Data Safety Monitoring Board for a COVID-19 booster vaccine study in Thailand. TPM reports grants from the Medical Research Future Fund of the Australian Government and the Coalition for Epidemic Preparedness Innovations; honoraria from The University of Melbourne; and travel support from Moderna. All other authors declare no competing interests.

Ethical Approval: The protocol was approved by the Alfred Health Human Research Ethics Committee (2020001376/334/20), and the study was conducted at Nucleus Network, Brisbane, QLD, Australia. The trial conducted in accordance with the protocol, Good Clinical Practice, the Declaration of Helsinki, and all local regulations. All participants provided written informed consent before any study procedures.

Keywords: Clinical trial, phase 1, COVID-19 vaccine, Severe acute respiratory syndrome coronavirus 2, Spike protein, SARS-CoV-2, Molecular clamp