Safety and immunogenicity of S-Trimer (SCB-2019), a protein subunit vaccine candidate for COVID-19 in healthy adults: a phase 1, randomised, double-blind, placebo-controlled trial

Peter Richmond, Lara Hatchuel, Min Dong, Brenda Ma, Branda Hu, Igor Smolenov, Ping Li, Peng Liang, Htay Htay Han, Joshua Liang, Ralf Clemens, Peter Richmond, Lara Hatchuel, Min Dong, Brenda Ma, Branda Hu, Igor Smolenov, Ping Li, Peng Liang, Htay Htay Han, Joshua Liang, Ralf Clemens

Abstract

Background: As part of the accelerated development of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we report a dose-finding and adjuvant justification study of SCB-2019, a protein subunit vaccine candidate containing a stabilised trimeric form of the spike (S)-protein (S-Trimer) combined with two different adjuvants.

Methods: Our study is a phase 1, randomised, double-blind placebo-controlled trial at a specialised clinical trials centre in Australia. We enrolled healthy adult volunteers in two age groups: younger adults (aged 18-54 years) and older adults (aged 55-75 years). Participants were randomly allocated either vaccine or placebo using a list prepared by the study funder. Participants were to receive two doses of SCB-2019 (either 3 μg, 9 μg, or 30 μg) or a placebo (0·9% NaCl) 21 days apart. SCB-2019 either had no adjuvant (S-Trimer protein alone) or was adjuvanted with AS03 or CpG/Alum. The assigned treatment was administered in opaque syringes to maintain masking of assignments. Reactogenicity was assessed for 7 days after each vaccination. Humoral responses were measured as SCB-2019 binding IgG antibodies and ACE2-competitive blocking IgG antibodies by ELISA and as neutralising antibodies by wild-type SARS-CoV-2 microneutralisation assay. Cellular responses to pooled S-protein peptides were measured by flow-cytometric intracellular cytokine staining. This trial is registered with ClinicalTrials.gov, NCT04405908; this is an interim analysis and the study is continuing.

Findings: Between June 19 and Sept 23, 2020, 151 volunteers were enrolled; three people withdrew, two for personal reasons and one with an unrelated serious adverse event (pituitary adenoma). 148 participants had at least 4 weeks of follow-up after dose two and were included in this analysis (database lock, Oct 23, 2020). Vaccination was well tolerated, with two grade 3 solicited adverse events (pain in 9 μg AS03-adjuvanted and 9 μg CpG/Alum-adjuvanted groups). Most local adverse events were mild injection-site pain, and local events were more frequent with SCB-2019 formulations containing AS03 adjuvant (44-69%) than with those containing CpG/Alum adjuvant (6-44%) or no adjuvant (3-13%). Systemic adverse events were more frequent in younger adults (38%) than in older adults (17%) after the first dose but increased to similar levels in both age groups after the second dose (30% in older and 34% in younger adults). SCB-2019 with no adjuvant elicited minimal immune responses (three seroconversions by day 50), but SCB-2019 with fixed doses of either AS03 or CpG/Alum adjuvants induced high titres and seroconversion rates of binding and neutralising antibodies in both younger and older adults (anti-SCB-2019 IgG antibody geometric mean titres at day 36 were 1567-4452 with AS03 and 174-2440 with CpG/Alum). Titres in all AS03 dose groups and the CpG/Alum 30 μg group were higher than were those recorded in a panel of convalescent serum samples from patients with COVID-19. Both adjuvanted SCB-2019 formulations elicited T-helper-1-biased CD4+ T-cell responses.

Interpretation: The SCB-2019 vaccine, comprising S-Trimer protein formulated with either AS03 or CpG/Alum adjuvants, elicited robust humoral and cellular immune responses against SARS-CoV-2, with high viral neutralising activity. Both adjuvanted vaccine formulations were well tolerated and are suitable for further clinical development.

Funding: Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile (all ages combined)
Figure 2
Figure 2
Incidence and severity of solicited local and systemic adverse events (all ages combined) Upper panel shows local events and lower panel shows systemic events. No grade 4 adverse events were reported.
Figure 3
Figure 3
SCB-2019 binding antibody IgG titres Titres are shown in the different study groups and human convalescent serum samples from patients with COVID-19 measured by ELISA (EC50). Bars show GMTs per group with 95% CIs at days 1, 22, 36, and 50. Circles represent values for individual participants. Small arrows indicate study vaccinations at day 1 (dose 1) and day 22 (dose 2). GMT=geometric mean titre. D=day. HCS=human convalescent serum samples. NIBSC=National Institute for Biological Standards and Control.
Figure 4
Figure 4
ACE2-competitive blocking antibody IgG titres Titres are shown in the different study groups and human convalescent serum samples from patients with COVID-19 measured by ELISA (EC50). Bars show GMTs per group with 95% CIs at days 1, 22, 36, and 50. Circles represent values for individual participants. Small arrows indicate study vaccinations at day 1 (dose 1) and day 22 (dose 2). GMT=geometric mean titre. D=day. HCS=human convalescent serum samples. NIBSC=National Institute for Biological Standards and Control.
Figure 5
Figure 5
Wild-type SARS-CoV-2 neutralisation titres Titres are shown in the different study groups and human convalescent serum samples from patients with COVID-19 measured by microneutralisation based on cytopathic effect (MN50). Bars show GMTs per group with 95% CIs at days 1, 22, 36, and 50. Circles represent values for individual participants. Small arrows indicate study vaccinations at day 1 (dose 1) and day 22 (dose 2). GMT=geometric mean titre. D=day. HCS=human convalescent serum samples. NIBSC=National Institute for Biological Standards and Control. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.

References

    1. Johns Hopkins University of Medicine Coronavirus Resource Center COVID-19 dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU) Jan 23, 2021.
    1. Tan E, Song J, Deane AM, Plummer MP. Global impact of coronavirus disease 2019 infection requiring admission to the ICU: a systematic review and meta-analysis. Chest. 2020 doi: 10.1016/j.chest.2020.10.014. published online Oct 15.
    1. WHO Draft landscape of COVID-19 candidate vaccines. Jan 22, 2021.
    1. Huang Y, Yang C, Xu X-F, Xu W, Liu S-W. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol Sin. 2020;41:1141–1149.
    1. Shang J, Wan Y, Luo C, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A. 2020;117:11727–11734.
    1. Belouzard S, Millet JK, Licitra BN, Whittaker GR. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses. 2012;4:1011–1033.
    1. Florindo HE, Kleiner R, Vaskovich-Koubi D, et al. Immune-mediated approaches against COVID-19. Nat Nanotechnol. 2020;15:630–645.
    1. Poland GA, Ovsyannikova IG, Kennedy RB. SARS-CoV-2 immunity: review and applications to phase 3 vaccine candidates. Lancet. 2020;396:1595–1606.
    1. Liu H, Su D, Zhang J, et al. Improvement of pharmacokinetic profile of TRAIL via Trimer-Tag enhances its antitumor activity in vivo. Sci Rep. 2017;7
    1. Liang JG, Su D, Song T-Z, et al. S-Trimer, a COVID-19 subunit vaccine candidate, induces protective immunity in nonhuman primates. bioRxiv. 2020 doi: 10.1101/2020.09.24.311027. published online Sept 24.
    1. Shi S, Zhu H, Xia X, et al. Vaccine adjuvants: understanding the structure and mechanism of adjuvanticity. Vaccine. 2019;37:3167–3178.
    1. Zogheri A, Di Mambro A, Mannelli M, Di Serio MG. Hyponatremia and pituitary adenoma: think twice about the etiopathogenesis. J Endocrinol Invest. 2006;29:750–753.
    1. Rajput R, Jain D, Pathak V. Recurrent hyponatremia as presenting manifestation of pituitary macroadenoma. Acta Med Bulg. 2017;44:46–49.
    1. Bopeththa BVKM, Niyaz SMM, Medagedara C. Pituitary macroadenoma presenting as severe hyponatremia: a case report. J Med Case Rep. 2019;13:40.
    1. Cohet C, Van der Most R, Bauchau V, et al. Safety of AS03-adjuvanted influenza vaccines: a review of the evidence. Vaccine. 2019;37:3003–3021.
    1. Langley JM, Risi G, Caldwell M, et al. Dose-sparing H5N1 A/Indonesia/05/2005 prepandemic influenza vaccine in adults and elderly adults: a phase III, placebo-controlled, randomized study. J Infect Dis. 2011;203:1729–1738.
    1. Mulligan MJ, Lyke KE, Kitchin N, et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature. 2020;586:589–593.
    1. Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA vaccine against SARS-CoV-2 — preliminary report. N Engl J Med. 2020;383:1920–1931.
    1. Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet. 2020;396:467–478.
    1. Barry M, Cooper C. Review of hepatitis B surface antigen-1018 ISS adjuvant-containing vaccine safety and efficacy. Exp Opin Biol Ther. 2007;11:1731–1737.
    1. Halperin SA, Ward B, Cooper C, et al. Comparison of safety and immunogenicity of two doses of investigational hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligodeoxyribonucleotide and three doses of a licensed hepatitis B vaccine in healthy adults 18–55 years of age. Vaccine. 2012;30:2556–2563.
    1. Moderbacher CR, Ramirez SI, Dan JM, et al. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell. 2020;183:996–1012.
    1. Okba NMA, Müller MA, Li W, et al. Severe acute respiratory syndrome coronavirus 2-specific antibody responses in coronavirus disease patients. Emerg Infect Dis. 2020;26:1478–1488.
    1. Keech C, Albert G, Cho I, et al. Phase 1–2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine. N Engl J Med. 2020;383:2320–2332.
    1. Walsh EE, Frenck RW, Jr, Falsey AR, et al. Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N Engl J Med. 2020;383:2439–2450.
    1. Voysey M, Costa Clemens SA, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2020;397:99–111.
    1. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383:2603–2615.
    1. Luo G, Ambati A, Lin L, et al. Autoimmunity hypocretin and molecular mimicry to flu in type 1 narcolepsy. Proc Natl Acad Sci USA. 2018;115:E12323–E12332.
    1. European Medicines Agency Assessment report: Pandemrix ((EMA/CHMP/566359/2015) April 28, 2016.

Source: PubMed

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