safety and immunogenicity of a recombinant tandem repeat dimeric rbd protein vaccine CORD-Papers-2021-10-25 (Version 1)

Title: Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD protein vaccine against COVID-19 in adults: pooled analysis of two randomized, double-blind, placebo-controlled, phase 1 and 2 trials
Abstract: Background A safe and effective coronavirus disease 2019 (COVID-19) vaccine is urgently needed to control the ongoing pandemic. Although progress has been made recently with several candidates reporting positive efficacy results, COVID-19 vaccines developed so far cannot meet the global vaccine demand. We developed a protein subunit vaccine against COVID-19, using dimeric form of receptor-binding domain (RBD) as the antigen. We aimed to assess the safety and immunogenicity of this vaccine in humans and determine the appropriate dose and schedule for an efficacy study. Methods We did two randomized, double-blind, placebo-controlled, phase 1 and 2 trials for an RBD-based protein subunit vaccine, ZF2001. In phase 1 study, 50 healthy adults aged 18-59 years were enrolled and randomly allocated to three groups to receive three doses of vaccine (25 g or 50 g RBD-dimer, with adjuvant) or placebo (adjuvant-only) intramuscularly, 30 days apart. In phase 2 study, 900 healthy adults aged 18-59 years were enrolled and randomly allocated to six groups to receive vaccine (25 g or 50 g RBD-dimer, with adjuvant) or placebo (adjuvant-only) intramuscularly, with the former 3 groups given two doses and the latter 3 groups given three doses, 30 days apart. For phase 1 trial, the primary outcome was safety, as measured by the occurrence of adverse events and serious adverse events. The secondary outcome was immunogenicity as measured by the seroconversion rate and magnitude of antigen-binding antibodies, neutralizing antibodies and T-cell cytokine production. For phase 2 trial, the primary outcome included both safety and immunogenicity. These trials are registered with ClinicaTrials.gov, NCT04445194 and NCT04466085. Findings Between June 22 and September 15, 2020, 50 participants were enrolled to the phase 1 study (mean age 32.6 years) and 900 participants were enrolled to phase 2 study (mean age 43.5 years), to receive vaccine or placebo with a two-dose or three-dose schedule. For both trials, local and systemic adverse reactions were absent or mild in most participants. There were no serious adverse events related to vaccine in either trial. After three doses, neutralizing antibodies were detected in all participants receiving either 25 g or 50 g dose of vaccine in phase 1 study, and in 97% (the 25 g group) and 93% (the 50 g group) of participants, respectively, in phase 2 study. The SARS-CoV-2-neutralizing geometric mean titres (GMTs) were 94.5 for the 25 g group and 117.8 for the 50 g group in phase 1, and 102.5 for the 25 g group and 69.1 for the 50 g group in phase 2, exceeding the level of a panel of COVID-19 convalescent samples (GMT, 51). Vaccine induced balanced TH1 and TH2 responses. The 50 g group did not show enhanced immunogenicity compared with the 25 g group. Interpretation The protein subunit vaccine ZF2001 is well-tolerated and immunogenic. The safety and immunogenicity data from phase 1 and 2 trials for ZF2001 support the use of 25 g vaccine dose with three-dose schedule to an ongoing phase 3 large-scale evaluation for safety and efficacy. Funding National Program on Key Research Project of China, National Science and Technology Major Projects of Drug Discovery, Strategic Priority Research Program of the Chinese Academy of Sciences, and Anhui Zhifei Longcom Biopharmaceutical.
Published: 12/22/2020
DOI: 10.1101/2020.12.20.20248602
DOI_URL: http://doi.org/10.1101/2020.12.20.20248602
Author Name: Yang, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/yang_s
Author Name: Li, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/li_y
Author Name: Dai, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/dai_l
Author Name: Wang, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wang_j
Author Name: He, P
Author link: https://covid19-data.nist.gov/pid/rest/local/author/he_p
Author Name: Li, C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/li_c
Author Name: Fang, X
Author link: https://covid19-data.nist.gov/pid/rest/local/author/fang_x
Author Name: Wang, C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wang_c
Author Name: Zhao, X
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhao_x
Author Name: Huang, E
Author link: https://covid19-data.nist.gov/pid/rest/local/author/huang_e
Author Name: Wu, C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wu_c
Author Name: Zhong, Z
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhong_z
Author Name: Wang, F
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wang_f
Author Name: Duan, X
Author link: https://covid19-data.nist.gov/pid/rest/local/author/duan_x
Author Name: Tian, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tian_s
Author Name: Wu, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wu_l
Author Name: Liu, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/liu_y
Author Name: Luo, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/luo_y
Author Name: Chen, Z
Author link: https://covid19-data.nist.gov/pid/rest/local/author/chen_z
Author Name: Li, F
Author link: https://covid19-data.nist.gov/pid/rest/local/author/li_f
Author Name: Li, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/li_j
Author Name: Yu, X
Author link: https://covid19-data.nist.gov/pid/rest/local/author/yu_x
Author Name: Ren, H
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ren_h
Author Name: Liu, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/liu_l
Author Name: Meng, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/meng_s
Author Name: Yan, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/yan_j
Author Name: Hu, Z
Author link: https://covid19-data.nist.gov/pid/rest/local/author/hu_z
Author Name: Gao, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/gao_l
Author Name: Gao, G F
Author link: https://covid19-data.nist.gov/pid/rest/local/author/gao_g_f
sha: 337ee8ec9e159a8e0c7b36937067e3cb7b23433d
license: medrxiv
source_x: MedRxiv; WHO
source_x_url: https://www.who.int/
url: https://doi.org/10.1101/2020.12.20.20248602 http://medrxiv.org/cgi/content/short/2020.12.20.20248602v1?rss=1
has_full_text: TRUE
Keywords Extracted from Text Content: Chao-Yang blood medRxiv preprint antibody RBD-375 ClinicaTrials.gov humans placebo-parallel-193 RBD-574 participants F redness SARS-424 CoV-2 NCT04445194 human 401 convalescent samples GMT NCT04466085 https://doi.org/10.1101/2020.12.20.20248602 doi B and appendix 4 GMTs IgG medRxiv preprint 667 RBD-dimer serum appendix medRxiv volunteers T-cell COVID-19 2:2:1 antigen appendix 7 medRxiv preprint TH2 persons participants redness Three-dose IL-4 SARS-CoV-2 three-460 convalescent IFN-γ IL-5 injection-pain IL-2 convalescent samples https://doi.org/10.1101/2020.12.20.20248602 doi COVID-508 GMTs T-cell cytokines medRxiv preprint 24 19 medRxiv medRxiv preprint 21 TH1 medRxiv preprint
Extracted Text Content in Record: First 5000 Characters:(RBD) as the antigen. We aimed to assess the safety and immunogenicity of this 87 vaccine in humans and determine the appropriate dose and schedule for an efficacy 88 study. 89 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in We did two randomized, double-blind, placebo-controlled, phase 1 and 2 trials for 92 an RBD-based protein subunit vaccine, ZF2001. In phase 1 study, 50 healthy adults 93 aged 18-59 years were enrolled and randomly allocated to three groups to receive 94 three doses of vaccine (25 μg or 50 μg RBD-dimer, with adjuvant) or placebo (adjuvant-95 only) intramuscularly, 30 days apart. In phase 2 study, 900 healthy adults aged 18-59 96 years were enrolled and randomly allocated to six groups to receive vaccine (25 μg or 97 50 μg RBD-dimer, with adjuvant) or placebo (adjuvant-only) intramuscularly, with the 98 former 3 groups given two doses and the latter 3 groups given three doses, 30 days 99 apart. For phase 1 trial, the primary outcome was safety, as measured by the 100 occurrence of adverse events and serious adverse events. The secondary outcome 101 was immunogenicity as measured by the seroconversion rate and magnitude of 102 antigen-binding antibodies, neutralizing antibodies and T-cell cytokine production. For 103 phase 2 trial, the primary outcome included both safety and immunogenicity. These 104 trials are registered with ClinicaTrials.gov, NCT04445194 and NCT04466085. Between June 22 and September 15, 2020, 50 participants were enrolled to the 108 phase 1 study (mean age 32.6 years) and 900 participants were enrolled to phase 2 109 study (mean age 43.5 years), to receive vaccine or placebo with a two-dose or three-110 dose schedule. For both trials, local and systemic adverse reactions were absent or 111 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in To response the pandemic, we launched a vaccine development program against 155 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The phase 1 trial was conducted at two hospitals in China: The Second Affiliated 176 Hospital of Chongqing Medical University (Chongqing) and Beijing Chao-Yang 177 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The trial was designed with double-blind, randomized and placebo-parallel-193 controlled. Participants in phase 1 were divided into 3 groups at a ratio of 2:2:1 and 194 allocated to receive three doses of vaccine (25 μg or 50 μg antigen dose) or placebo 195 on day 0, 30 and 60. Participants in phase 2 were divided into six groups at a 196 1:1:1:1:1:1 ratio, with the former three groups receiving two doses of vaccine (25 μg or 197 50 μg antigen dose) or placebo, 30 days apart, while the latter three groups receiving 198 three doses of vaccine (25 μg or 50 μg antigen dose) or placebo, 30 days apart. 199 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in and not allowed to disclose the blind code to any personnel participating in this clinical 214 trial. The participants were randomly assigned to the experimental vaccine group or 215 the placebo group according to the block randomisation method, with the block and 216 block size of 5 and 5, respectively, in phase 1 trial, and of 75 and 12, respectively, in 217 phase 2 trial. Investigators at trial site assign study numbers strictly according to the 218 order of screening sequence of eligible subjects, and experimental vaccines were 219 obtained and administered according to the numbers. The participants, field 220 investigators and laboratory team were always blinded to group allocation during the 221 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Laboratory safety tests including routine blood, and serum chemistry and routine urine 244 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The funders of the study had no role in data collection, data analysis, data 303 interpretation, or writing of the Article. All authors had full access to all the data in the 304 study and had final responsibility
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