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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.
Lancet. 2021 02 20; 397(10275):682-694.Lct

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.

Authors+Show Affiliations

Division of Paediatrics, University of Western Australia, Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute and Perth Children's Hospital, Perth, WA, Australia.Linear Clinical Research, Perth, WA, Australia.Clover Biopharmaceuticals, Chengdu, China.Clover Biopharmaceuticals, Chengdu, China.Clover Biopharmaceuticals, Chengdu, China.Clover Biopharmaceuticals, Chengdu, China.Clover Biopharmaceuticals, Chengdu, China.Clover Biopharmaceuticals, Chengdu, China.Clover Biopharmaceuticals, Chengdu, China.Clover Biopharmaceuticals, Chengdu, China.Global Research in Infectious Diseases, Rio de Janeiro, Brazil. Electronic address: clemens.ralf@outlook.com.

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33524311

Citation

Richmond, Peter, et al. "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." Lancet (London, England), vol. 397, no. 10275, 2021, pp. 682-694.
Richmond P, Hatchuel L, Dong M, et al. 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. Lancet. 2021;397(10275):682-694.
Richmond, P., Hatchuel, L., Dong, M., Ma, B., Hu, B., Smolenov, I., Li, P., Liang, P., Han, H. H., Liang, J., & Clemens, R. (2021). 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. Lancet (London, England), 397(10275), 682-694. https://doi.org/10.1016/S0140-6736(21)00241-5
Richmond P, et al. 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. Lancet. 2021 02 20;397(10275):682-694. PubMed PMID: 33524311.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Richmond,Peter, AU - Hatchuel,Lara, AU - Dong,Min, AU - Ma,Brenda, AU - Hu,Branda, AU - Smolenov,Igor, AU - Li,Ping, AU - Liang,Peng, AU - Han,Htay Htay, AU - Liang,Joshua, AU - Clemens,Ralf, Y1 - 2021/01/29/ PY - 2020/12/11/received PY - 2021/01/12/revised PY - 2021/01/18/accepted PY - 2021/2/2/pubmed PY - 2021/2/27/medline PY - 2021/2/1/entrez SP - 682 EP - 694 JF - Lancet (London, England) JO - Lancet VL - 397 IS - 10275 N2 - 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. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/33524311/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(21)00241-5 DB - PRIME DP - Unbound Medicine ER -