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

SummaryBackgroundA 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.MethodsWe 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 μg or 50 μg 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 μg or 50 μg 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.FindingsBetween 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 μg or 50 μg dose of vaccine in phase 1 study, and in 97% (the 25 μg group) and 93% (the 50 μg group) of participants, respectively, in phase 2 study. The SARS-CoV-2-neutralizing geometric mean titres (GMTs) were 94.5 for the 25 μg group and 117.8 for the 50 μg group in phase 1, and 102.5 for the 25 μg group and 69.1 for the 50 μg 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 μg group did not show enhanced immunogenicity compared with the 25 μg group.InterpretationThe 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 μg vaccine dose with three-dose schedule to an ongoing phase 3 large-scale evaluation for safety and efficacy.FundingNational 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.

COVID-19 Vaccines: Current Understanding on Immunogenicity, Safety, and Further Considerations

“…The AR rate of Novavax recombinant vaccine with Matrix M adjuvant (69.2% local; 46.1% systemic) was comparable with that of the Clover vaccine with GSK AS03 adjuvant (68.8% local and 56.3% systemic). The ARs of those two vaccines aforementioned are higher than that of Zhifei vaccine adjuvanted with alum (total ARs <48%) (76,77,84).…”

SARS-CoV-2–Specific Vaccine Candidates; the Contribution of Structural Vaccinology

“…Additionally, 407VRQIAP412 shared cryptic epitopes between SARS-CoV-1 and SARS-CoV-2. Anhui Zhifei Longcom Biopharmaceutical Co., Ltd., is currently designing a SARS-CoV-2 vaccine antigen based on an RBD dimer produced in mammalian cells [67]. The scientists demonstrated that this dimerisation increases the stability of the vaccine antigen for SARS-CoV-2, SARS-CoV-1 and MERS-CoV constructs.…”

“…Strategies to heighten vaccine-induced immune responses by increasing the antigen size are under investigation. For instance, the Anhui Zhifei Longcom Biopharmaceutical Co., Ltd. (Hefei, China) developed a 60 kDa RBD homodimer by cloning 2 copies of RBD-encoding gene fragments into the tandem RBD monomer, which has a molecular mass of approximately 29 kDa [67]. Meanwhile, Wang et al successfully designed a chimeric MERS-CoV vaccine by fusing the canine provirus VP2 structural protein gene with the MERS-CoV RBD [69].…”

Die Corona-Pandemie und Multiple Sklerose: Impfungen und deren Implikationen für Patienten – Teil 2: Impfstofftechnologien

“…Des Weiteren wurden die nichtreplizierenden Vektorvirusimpfstoffe Sputnik‑V (bereits in Phase II am 11.08.2020) in Russland, Covaxin (BBV152) in Indien (am 02.01.2021 ohne veröffentlichte Wirksamkeitsdaten), „Serum Institute of India – Covishield“ in Indien (gleiche Formulierung wie AstraZeneca) sowie „CanSino: Ad5-nCoV“ in China zugelassen [ 38 , 51 , 75 , 88 ]. An Protein-Subunit-Impfstoffen wurden „Anhui Zhifei Longcom – RBD-Dimer“ in China und „FBRI: EpiVacCorona“ in Russland zugelassen [ 52 , 82 ]. Schließlich wurden 3 inaktivierte Totimpfstoffe („Sinopharm [Beijing] BBIBP-CorV“, „Sinopharm [Wuhan] Inactivated [Vero Cells]“ und „Sinovac CoronaVac“) in China, 1 („Bharat Biotech Covaxin“) in Indien und 1 (Chumakov Center: KoviVac) in Russland zugelassen [ 81 , 84 , 87 , 89 ].…”