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

Abstract

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.

Scientific rationale for developing potent RBD-based vaccines targeting COVID-19

“…Preclinical studies have evaluated the protective efficacy of several RBD-specific monoclonals, as well as RBD as a protective immunogen. Investigators evaluating RBD as a vaccine candidate have delivered the antigen either as DNA 81 , mRNA 7,74,[82][83][84][85] , viral vector 86 , soluble monomer or dimer 6,22,[87][88][89][90][91][92][93] , a fusion protein nanoparticle 16,26,[94][95][96][97][98] , or as a virus-like particle (VLP) 91,[99][100][101][102] . Additional RBD-based vaccine candidates in clinical trials (Table 2)…”

Sequential immunization with SARS-CoV-2 RBD vaccine induces potent and broad neutralization against variants in mice

“…Previously, Sun et al constructed an interferon-armed RBD dimer vaccine inducing the production of high titers of long-lasting nAbs in mice and rhesus macaques [ 6 ]. Here, we acquired three kinds of RBD dimer vaccines carrying WT, Beta, and Delta RBD proteins from the Peng group (Fig.…”

“…1 Potent and broad neutralization against SARS-CoV-2 variants elicited by sequential immunization with a wild-type inactivated vaccine and a mutant RBD subunit vaccine in mice. a Schematic diagram of the RBD dimer vaccine named I-P-R-F [ 6 ]. The structural elements show IFNα, Pan-DR epitope (PADRE), RBD, and immunoglobulin Fc fragment.…”

A novel bacterial protease inhibitor adjuvant in RBD-based COVID-19 vaccine formulations increases neutralizing antibodies, specific germinal center B cells and confers protection against SARS-CoV-2 infection

“…While RBD+Alum induces significant immune responses, it has been suggested that its immunogenicity should be increased. Different approaches have been proposed to increase its immunogenicity, such as i) expression as dimer 42,48,65,67 or trimers 44 , ii) fusion to carrier proteins like human IgG Fc moiety 43,67 , tetanus toxoid 11 , interferon-α 67 , iii) addition of pan HLA-DR-binding epitope to enhance helper T cell responses 67 , iv) using nanoparticles as delivery system 41,45,47,52,59 or v) addition of immunopotentiators as CpG 41,42,46,59 , MPLA 43 , 3M-052 or a TLR-7/8 agonist 44,59 .…”