SARS-CoV-2 RBD trimer protein adjuvanted with Alum-3M-052 protects from SARS-CoV-2 infection and immune pathology in the lung

Abstract

There is a great need for the development of vaccines that induce potent and long-lasting protective immunity against SARS-CoV-2. Multimeric display of the antigen combined with potent adjuvant can enhance the potency and longevity of the antibody response. The receptor binding domain (RBD) of the spike protein is a primary target of neutralizing antibodies. Here, we developed a trimeric form of the RBD and show that it induces a potent neutralizing antibody response against live virus with diverse effector functions and provides protection against SARS-CoV-2 challenge in mice and rhesus macaques. The trimeric form induces higher neutralizing antibody titer compared to monomer with as low as 1μg antigen dose. In mice, adjuvanting the protein with a TLR7/8 agonist formulation alum-3M-052 induces 100-fold higher neutralizing antibody titer and superior protection from infection compared to alum. SARS-CoV-2 infection causes significant loss of innate cells and pathology in the lung, and vaccination protects from changes in innate cells and lung pathology. These results demonstrate RBD trimer protein as a suitable candidate for vaccine against SARS-CoV-2.

A modified porous silicon microparticle promotes mucosal delivery of SARS-CoV-2 antigen and induction of potent and durable systemic and mucosal T helper 1 skewed protective immunity

“…A single dose vaccination with alum-formulated S protein induced a more Th2 prone response in mice 29 . Optimized vaccine strategies include adding T helper epitope with RBD antigen or combing a TLR7/8 agonist with alum have been shown to effectively trigger strong humoral immunity supplemented with cellular immunity in mice and enhance NAb titers in various animal models 30,31 . Here, we found that mPSM serves as a better adjuvant than alum for SARS-CoV-2 RBD subunit vaccines to elicit stronger and more durable Nabs, plus memory B cell and Th1 skewed immune responses in mice following parenteral and mucosal vaccination.…”

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

“…The copyright holder for this preprint this version posted December 9, 2021. ; https://doi.org/10.1101/2021.12.07.471590 doi: bioRxiv preprint Different cell types have been used to produce RBD antigens, such as yeast, plant and insect cells 32,[40][41][42][43] . However, production in mammalian cells 11,[44][45][46][47][48] may produce a RBD antigenic domain that more closely resembles that generated during virus infection in human cells (including post-translational modifications such as glycosylation and correct folding) 49 . Our results showing binding to hACE2 expressing cells and the induction of neutralizing antibody titers confirm the preservation of the RBD structure and the suitable exposition of the receptor binding motif (RBM).…”

“…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 .…”

Role of the renin-angiotensin system in NETosis in the coronavirus disease 2019 (COVID-19)

“…It is reported that numerous viruses have been detected in neutrophils and even activate neutrophils to produce NETs [33] . As a single-stranded RNA virus, SARS-CoV-2 is quickly recognized by endosomal toll-like receptors (TLR) 7/8 after entering the cell, which activates the TLR-MyD88 signaling pathway, oxidative burst, NETs formation, and pro-inflammatory cytokines release [19] , [34] , [35] , [36] ( Fig. 1 ).…”