Recombinant vaccine containing an RBD-Fc fusion induced protection against SARS-CoV-2 in nonhuman primates and mice

Sun, Shihui; He, Lihua; Zhao, Zhongpeng; Gu, Huiying; Fang, Xin; Wang, Tiecheng; Yang, Xiaolan; Chen, Shaolong; Deng, Yong-Qiang; Li, Jiangfan; Zhao, Jian; Li, Liang; Li, Xinwang; He, Peng; Li, Ge; Li, Hao; Zhao, Yuee; Gao, Chunrun; Lang, Xiaoling; Wang, Xin; Fei, Guoqiang; Li, Yan; Geng, Shusheng; Gao, Yuwei; Wan, Wei; Hu, Zhongliang; Han, Gencheng; Sun, Yansong

doi:10.1038/s41423-021-00658-z

Cited by 58 publications

(71 citation statements)

References 10 publications

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“… 6 One solution to address these limitations is to fuse the C-terminus of RBD with the Fc fragment of human IgG, generating RBD-Fc with improved in vivo stability and immunoglobulin-mediated effector function. 11 − 13 Importantly, the RBD-Fc-based vaccine can provide protection against SARS-CoV-2 with several natural mutations in RBD, 4 , 14 , 15 including the N501Y and D614G mutations. These findings are valuable concerning the emergence of SARS-CoV-2 variants globally.…”

Section: Introductionmentioning

confidence: 99%

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Potent Neutralizing Antibodies Elicited by RBD-Fc-Based COVID-19 Vaccine Candidate Adjuvanted by the Th2-Skewing iNKT Cell Agonist

Wang

Zhang

et al. 2021

J. Med. Chem.

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The development of a safe and effective COVID-19 vaccine is of paramount importance to terminate the current pandemic. An adjuvant is crucial for improving the efficacy of the subunit COVID19 vaccine. α-Galactosylceramide (αGC) is a classical iNKT cell agonist which causes the rapid production of Th1- and Th2-associated cytokines; we, therefore, expect that the Th1- or Th2-skewing analogues of αGC can better enhance the immunogenicity of the receptor-binding domain in the spike protein of SARS-CoV-2 fused with the Fc region of human IgG (RBD-Fc). Herein, we developed a universal synthetic route to the Th1-biasing (α-C-GC) and Th2-biasing (OCH and C20:2) analogues. Immunization of mice demonstrated that αGC-adjuvanted RBD-Fc elicited a more potent humoral response than that observed with Alum and enabled the sparing of antigens. Remarkably, at a low dose of the RBD-Fc protein (2 μg), the Th2-biasing agonist C20:2 induced a significantly higher titer of the neutralizing antibody than that of Alum.

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Section: Introductionmentioning

confidence: 99%

“…A recombinant vaccine containing an RBD-Fc fusion (RBD-Fc Vacc) is currently being assessed in phase I/II human clinical trials. 4 …”

Section: Introductionmentioning

confidence: 99%

Potent Neutralizing Antibodies Elicited by RBD-Fc-Based COVID-19 Vaccine Candidate Adjuvanted by the Th2-Skewing iNKT Cell Agonist

Wang

Zhang

et al. 2021

J. Med. Chem.

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“…Additionally, RBD fused with the Fc domain could be a better choice than a simple RBD or S protein. 7 – 9 At equimolar levels, both I-R-F and I-P-R-F induced stronger humoral immunity than RBD dimer and RBD-Fc. In general, protein vaccines do not have enough protective immunogenicity without the use of additional potent adjuvants.…”

Section: Discussionmentioning

confidence: 99%

“… 5 , 6 Additionally, RBD fused with the Fc domain showed potentially greater immune effects than RBD. 7 – 9 Alum adjuvant is used in most of these viral antigen vaccines to induce stronger humoral immunity preferentially, but does not promote T cell responses, especially type 1 T helper (Th1) cell and cytotoxic T lymphocyte (CTL) responses. 2 – 4 Although novel adjuvants may be more potent, they are challenging to prepare and increase the risk of severe side effects, resulting in limited usage.…”

Section: Introductionmentioning

confidence: 99%

Interferon-armed RBD dimer enhances the immunogenicity of RBD for sterilizing immunity against SARS-CoV-2

et al. 2021

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. A major challenge is that the receptor-binding domain (RBD)-only vaccine fails to trigger long-lasting protective immunity if used alone for vaccination. To enhance antigen processing and cross-presentation in draining lymph nodes (DLNs), we developed an interferon (IFN)-armed RBD dimerized by an immunoglobulin fragment (I-R-F). I-R-F efficiently directs immunity against RBD to DLNs. A low dose of I-R-F induces not only high titers of long-lasting neutralizing antibodies (NAbs) but also more comprehensive T cell responses than RBD. Notably, I-R-F provides comprehensive protection in the form of a one-dose vaccine without an adjuvant. Our study shows that the pan-epitope modified human I-R-F (I-P-R-F) vaccine provides rapid and complete protection throughout the upper and lower respiratory tracts against a high-dose SARS-CoV-2 challenge in rhesus macaques. Based on these promising results, we have initiated a randomized, placebo-controlled, phase I/II trial of the human I-P-R-F vaccine (V-01) in 180 healthy adults, and the vaccine appears safe and elicits strong antiviral immune responses. Due to its potency and safety, this engineered vaccine may become a next-generation vaccine candidate in the global effort to overcome COVID-19.

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“…The stringent requirements for the manufacturing, storage, transportation, and delivery of mRNA vaccines further limits its broader applicability, especially in developing countries [2,[10][11][12], where COVID-19 vaccines are desperately required. Recombinant protein vaccines based on SARS-CoV-2 S-trimer, RBD-dimer, and RBD-nanoparticles have been developed to generate higher levels of neutralizing antibodies than monomeric proteins [13][14][15][16]. In spite of this, an adjuvant is critical for the protein-based vaccine to induce robust immune responses.…”

Section: Introductionmentioning

confidence: 99%

Safety and immunogenicity of a recombinant interferon-armed RBD dimer vaccine (V-01) for COVID-19 in healthy adults: a randomized, double-blind, placebo-controlled, Phase I trial

Zhang

et al. 2021

Emerging Microbes & Infections

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Safe and effective vaccines are still urgently needed to cope with the ongoing COVID-19 pandemic. Recently, we developed a recombinant COVID-19 vaccine (V-01) containing fusion protein (IFN-PADRE-RBD-Fc dimer) as antigen verified to induce protective immunity against SARS-CoV-2 challenge in preclinical study, which supported progression to Phase Ⅰ clinical trials in humans.A Randomized, double-blind, placebo-controlled phase I clinical trial was initiated at the Guangdong Provincial Center for Disease Control and Prevention (Gaozhou, China) in February, 2021. Healthy adults aged between 18 and 59 years and over 60 years were sequentially enrolled and randomly allocated into three subgroups (1:1:1) either to receive vaccine (10, 25, and 50μg) or placebo (V-01: Placebo=4:1) intramuscularly with a 21-day interval by a sentinel and dose escalation design. The data showed promising safety profile with approximately 25% vaccine related overall adverse events within 30 days and no grade 3 or worse adverse events. Besides, V-01 provoked rapid and strong immune responses, elicited substantially high-titre neutralizing antibodies and anti-RBD IgG peaked at day 35 or 49 after first dose, presented with encouraging immunogenicity at low dose (10μg) subgroup and elderly participants, which showed great promise to be used as all-aged (18 and above) vaccine against COVID-19. Taken together, our preliminary findings indicate that V-01 is safe and well tolerated, capable of inducing rapid and strong immune responses, and warrants further testing in phase Ⅱ/Ⅲ clinical trials.

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Recombinant vaccine containing an RBD-Fc fusion induced protection against SARS-CoV-2 in nonhuman primates and mice

Cited by 58 publications

References 10 publications

Potent Neutralizing Antibodies Elicited by RBD-Fc-Based COVID-19 Vaccine Candidate Adjuvanted by the Th2-Skewing iNKT Cell Agonist

Potent Neutralizing Antibodies Elicited by RBD-Fc-Based COVID-19 Vaccine Candidate Adjuvanted by the Th2-Skewing iNKT Cell Agonist

Interferon-armed RBD dimer enhances the immunogenicity of RBD for sterilizing immunity against SARS-CoV-2

Safety and immunogenicity of a recombinant interferon-armed RBD dimer vaccine (V-01) for COVID-19 in healthy adults: a randomized, double-blind, placebo-controlled, Phase I trial

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