The receptor‐binding domain (RBD) of the SARS‐CoV‐2 spike protein is a candidate vaccine antigen that binds angiotensin‐converting enzyme 2 (ACE2), leading to virus entry. Here, it is shown that rapid conversion of recombinant RBD into particulate form via admixing with liposomes containing cobalt‐porphyrin‐phospholipid (CoPoP) potently enhances the functional antibody response. Antigen binding via His‐tag insertion into the CoPoP bilayer results in a serum‐stable and conformationally intact display of the RBD on the liposome surface. Compared to other vaccine formulations, immunization using CoPoP liposomes admixed with recombinant RBD induces multiple orders of magnitude higher levels of antibody titers in mice that neutralize pseudovirus cell entry, block RBD interaction with ACE2, and inhibit live virus replication. Enhanced immunogenicity can be accounted for by greater RBD uptake into antigen‐presenting cells in particulate form and improved immune cell infiltration in draining lymph nodes. QS‐21 inclusion in the liposomes results in an enhanced antigen‐specific polyfunctional T cell response. In mice, high dose immunization results in minimal local reactogenicity, is well‐tolerated, and does not elevate serum cobalt levels. Taken together, these results confirm that particulate presentation strategies for the RBD immunogen should be considered for inducing strongly neutralizing antibody responses against SARS‐CoV‐2.
Short
major histocompatibility complex (MHC) class I (MHC-I)-restricted
peptides contain the minimal biochemical information to induce antigen
(Ag)-specific CD8+ cytotoxic T cell responses but are generally
ineffective in doing so. To address this, we developed a cobalt–porphyrin
(CoPoP) liposome vaccine adjuvant system that induces rapid particleization
of conventional, short synthetic MHC-I epitopes, leading to strong
cellular immune responses at nanogram dosing. Along with CoPoP (to
induce particle formation of peptides), synthetic monophosphoryl lipid
A (PHAD) and QS-21 immunostimulatory molecules were included in the
liposome bilayer to generate the “CPQ” adjuvant system.
In mice, immunization with a short MHC-I-restricted peptide, derived
from glycoprotein 70 (gp70), admixed with CPQ safely generated functional,
Ag-specific CD8+ T cells, resulting in the rejection of
multiple tumor cell lines, with durable immunity. When cobalt was
omitted, the otherwise identical peptide and adjuvant components did
not result in peptide binding and were incapable of inducing immune
responses, demonstrating the importance of stable particle formation.
Immunization with the liposomal vaccine was well-tolerated and could
control local and metastatic disease in a therapeutic setting. Mechanistic
studies showed that particle-based peptides were better taken up by
antigen-presenting cells, where they were putatively released within
endosomes and phagosomes for display on MHC-I surfaces. On the basis
of the potency of the approach, the platform was demonstrated as a
tool for in vivo epitope screening of peptide microlibraries
comprising a hundred peptides.
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