Safety and immunogenicity of a SARS-CoV-2 recombinant protein nanoparticle vaccine (GBP510) adjuvanted with AS03: A randomised, placebo-controlled, observer-blinded phase 1/2 trial

Joon Young Song, Won Suk Choi, Jung Yeon Heo, Jin Soo Lee, Dong Sik Jung, Shin-Woo Kim, Kyung-Hwa Park, Joong Sik Eom, Su Jin Jeong, Jacob Lee, Ki Tae Kwon, Hee Jung Choi, Jang Wook Sohn, Young Keun Kim, Ji Yun Noh, Woo Joo Kim, François Roman, Maria Angeles Ceregido, Francesca Solmi, Agathe Philippot, Alexandra C Walls, Lauren Carter, David Veesler, Neil P King, Hun Kim, Ji Hwa Ryu, Su Jeen Lee, Yong Wook Park, Ho Keun Park, Hee Jin Cheong, Joon Young Song, Won Suk Choi, Jung Yeon Heo, Jin Soo Lee, Dong Sik Jung, Shin-Woo Kim, Kyung-Hwa Park, Joong Sik Eom, Su Jin Jeong, Jacob Lee, Ki Tae Kwon, Hee Jung Choi, Jang Wook Sohn, Young Keun Kim, Ji Yun Noh, Woo Joo Kim, François Roman, Maria Angeles Ceregido, Francesca Solmi, Agathe Philippot, Alexandra C Walls, Lauren Carter, David Veesler, Neil P King, Hun Kim, Ji Hwa Ryu, Su Jeen Lee, Yong Wook Park, Ho Keun Park, Hee Jin Cheong

Abstract

Background: Vaccination has helped to mitigate the COVID-19 pandemic. Ten traditional and novel vaccines have been listed by the World Health Organization for emergency use. Additional alternative approaches may better address ongoing vaccination globally, where there remains an inequity in vaccine distribution. GBP510 is a recombinant protein vaccine, which consists of self-assembling, two-component nanoparticles, displaying the receptor-binding domain (RBD) in a highly immunogenic array.

Methods: This randomised, placebo-controlled, observer-blinded phase 1/2 study was conducted to evaluate the safety and immunogenicity of GBP510 (2-doses at a 28-day interval) adjuvanted with or without AS03 in adults aged 19-85 years at 14 hospital sites in Korea. This study was consisted of two stages (stage I, healthy adults aged 19-55 years; stage II, 240 healthy adults aged 19-85 years). Healthy participants who did not previously receive any vaccine within 4 weeks (2 weeks for flu vaccine) prior to the study, no history of COVID-19 vaccination/medication, and were naïve to SARS-CoV-2 infection at screening were eligible for the study enrollment. Participants were block-randomized in a 2:2:1 ratio to receive 2 doses of 10 µg GBP510 adjuvanted with AS03 (group 1), 10 µg unadjuvanted GBP510 (group 2) or placebo intramuscularly in stage I, while they were block-randomized in a 2:2:1:1 ratio to receive 10 µg GBP510 adjuvanted with AS03 (group 1), 25 µg GBP510 adjuvanted with AS03 (group 3), 25 µg unadjuvanted GBP510 (group 4) or placebo in stage II. The primary safety outcomes were solicited and unsolicited adverse events, while primary immunogenicity outcomes included anti-SARS-CoV-2 RBD IgG antibodies; neutralizing antibody responses; and T-cell immune responses. Safety assessment included all participants who received at least 1 dose of study intervention (safety set). Immunogenicity assessment included all participants who completed the vaccination schedule and had valid immunogenicity assessment results without any major protocol deviations (per-protocol set). This study was registered with ClinicalTrials.gov (NCT04750343).

Findings: Of 328 participants who were enrolled between February 1 and May 28, 2021, 327 participants received at least 1 dose of vaccine. Each received either 10 µg GBP510 adjuvanted with AS03 (Group 1, n = 101), 10 µg unadjuvanted GBP510 (Group 2, n = 10), 25 µg GBP510 adjuvanted with AS03 (Group 3, n = 104), 25 µg unadjuvanted GBP510 (Group 4, n = 51), or placebo (n = 61). Higher reactogenicity was observed in the GBP510 adjuvanted with AS03 groups compared to the non-adjuvanted and placebo groups. The most frequently reported solicited local adverse event (AE) was injection site pain after any vaccination: (88·1% in group 1; 50·0% in group 2; 92·3% in group 3; 66·7% in group 4). Fatigue and myalgia were two most frequently reported systemic AEs and more frequently reported in GBP510 adjuvanted with AS03 recipients (79·2% and 78·2% in group 1; 75·0% and 79·8% in group 3, respectively) than in the unadjuvanted vaccine recipients (40·0% and of 40·0% in group 2; 60·8% and 47·1% in group 4) after any vaccination. Reactogenicity was higher post-dose 2 compared to post-dose 1, particularly for systemic AEs. The geometric mean concentrations of anti-SARS-CoV-2-RBD IgG antibody reached 2163·6/2599·2 BAU/mL in GBP510 adjuvanted with AS03 recipients (10 µg/25 µg) by 14 days after the second dose. Two-dose vaccination of 10 µg or 25 µg GBP510 adjuvanted with AS03 induced high titres of neutralizing antibody via pseudovirus (1369·0/1431·5 IU/mL) and wild-type virus (949·8/861·0 IU/mL) assay.

Interpretation: GBP510 adjuvanted with AS03 was well tolerated and highly immunogenic. These results support further development of the vaccine candidate, which is currently being evaluated in Phase 3.

Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investment ID OPP1148601. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.

Keywords: COVID-19; Cellular immunity; Humoral immunity; Nanoparticle vaccine; Recombinant protein vaccine; SARS-CoV-2.

Conflict of interest statement

WSC received funding from SK Bioscience, and payment for lectures on adult immunization to Korean physicians. MA, FS, FR, and AP are employees of the GSK group of companies. MA, FR, and AP hold restricted shares in the GSK group of companies. DV received a grant and consulting fees from Vir Biotechnology. NPK is a co-founder, shareholder, paid consultant, and chair of the scientific advisory board of Icosavax, Inc. DV and NPK received a grant of University of Washington supported by Bill & Melinda Gates Foundation. NPK also received grants of University of Washington supported by GSK and Pfizer; those were unrelated to the present manuscript. NPK received royalties from licensed technology unrelated to the present manuscript. NPK received Honoraria for lectures for Pfizer, Amgen, Washington University St. Louis, University of New Mexico, Children's Hospital Seattle and Lawrence Berkeley National Lab. NPK, ACW, and DV are named as inventors on patent applications filed by the University of Washington for SARS-CoV-2 and sarbecovirus nanoparticle vaccines. HK, JHR, SJL, YWP, and HKP are full-time employees of SK Bioscience. HK, YWP, and HKP own SK Bioscience stock as employees. HKP participated in the blinded session of data safety monitoring board as an observer (NCT04750343). All other authors declare no competing interests.

© 2022 Published by Elsevier Ltd.

Figures

Figure 1
Figure 1
Trial flowchart.
Figure 2
Figure 2
Solicited local (A) and systemic (B) adverse events within 7 days after first-dose and second-dose vaccination. Data on adverse events were recorded in a paper or an electronic diary for 7 days after each injection. Group 1, 10 µg GBP510 adjuvanted with AS03; group 2, 10 µg unadjuvanted GBP510; group 3, 25 µg GBP510 adjuvanted with AS03; group 4, 25 µg unadjuvanted GBP510. Each adverse event was graded as mild (grade 1, does not interfere with activity), moderate (grade 2, interferes with activity), severe (grade 3, prevents daily activity), or potentially life-threatening (grade 4, led to an emergency department visit or hospitalization). Redness and swelling were graded as mild (2·0 to 5·0 cm in diameter), moderate (>5·0 to 10·0 cm in diameter), severe (>10·0 cm in diameter), or potentially life-threatening (necrosis or exfoliative dermatitis for redness and necrosis for swelling). Fever was graded as mild (38·0–38·4°C), moderate (38·5–38·9°C), severe (39·0–40·0°C), or potentially life-threatening (>40·0°C).
Figure 3
Figure 3
Anti-SARS-CoV-2 receptor-binding domain (RBD) IgG antibody response. Geometric mean concentrations of anti-SARS-CoV-2 RBD IgG were compared from baseline (day 0) to day 56 (28 days after the second dose). BAU, binding antibody unit; GMC, Geometric mean concentration; SD, standard deviation; SCR, seroconversion rate; NIBSC, National Institute for Biological Standards and Control; HCS, human convalescent serum.
Figure 4
Figure 4
Neutralising antibody response measured by pseudovirus-based neutralisation assay (PBNA). Geometric mean neutralising antibody titres were compared from baseline (day 0) to day 56 (28 days after the second dose). The serum neutralisation titres were defined as the 50% maximal inhibitory concentration (IC50). The titres of neutralisation assay were converted to international unit (IU)/mL using WHO international standard (NIBSC 20/136) and compared with the HCS of WHO representative panel. GMT, Geometric mean titre; SD, standard deviation; SCR, seroconversion rate; NIBSC, National Institute for Biological Standards and Control; HCS, human convalescent serum.
Figure 5
Figure 5
Neutralising antibody response measured by plaque reduction neutralisation test (PRNT). Geometric mean neutralising antibody titres were compared from baseline (day 0) to day 42 (14 days after the second dose). The serum neutralisation titres were defined as the median neutralising titre (ND50). The titres of neutralisation assay were converted to international unit (IU)/mL using WHO international standard (NIBSC 20/136). GMT, Geometric mean titre; SD, standard deviation; SCR, seroconversion rate.

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Source: PubMed

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