A triple-RBD-based mucosal vaccine provides broad protection against SARS-CoV-2 variants of concern

Abstract

The rapid mutation and spread of SARS-CoV-2 variants urge the development of effective mucosal vaccines to provide broad-spectrum protection against the initial infection and thereby curb the transmission potential. Here, we designed a chimeric triple-RBD immunogen, 3Ro-NC, harboring one Delta RBD and two Omicron RBDs within a novel protein scaffold. 3Ro-NC elicits potent and broad RBD-specific neutralizing immunity against SARS-CoV-2 variants of concern. Notably, intranasal immunization with 3Ro-NC plus the mucosal adjuvant KFD (3Ro-NC + KFDi.n) elicits coordinated mucosal IgA and higher neutralizing antibody specificity (closer antigenic distance) against the Omicron variant. In Omicron-challenged human ACE2 transgenic mice, 3Ro-NC + KFDi.n immunization significantly reduces the tissue pathology in the lung and lowers the viral RNA copy numbers in both the lung (85.7-fold) and the nasal turbinate (13.6-fold). Nasal virologic control is highly correlated with RBD-specific secretory IgA antibodies. Our data show that 3Ro-NC plus KFD is a promising mucosal vaccine candidate for protection against SARS-CoV-2 Omicron infection, pathology and transmission potential.

Nasal vaccination of triple-RBD scaffold protein with flagellin elicits long-term protection against SARS-CoV-2 variants including JN.1

“…2e ). 26 , 28 Consistent with the defective of the TLR5 agonist, intranasal immunization of 4 µg 3R-NC without mucosal adjuvant could hardly induce RBD-specific serum IgG and salivary IgA (Fig. 1e ).…”

“…In this study, we employed a highly stable triple-RBD scaffold protein platform capable of accommodating various combinations of three RBDs. 26 Two novel triple-RBD scaffold proteins, namely 3R-NC and 3R AEW -NC, were designed as immunogens for SARS-CoV-2 mucosal vaccines to address the persistent challenge of frequently emerging variants. Nasal vaccination of 3R-NC with an optimized flagellin adjuvant KFD ( 3R-NC + KFDi.n ), triggered high-level, long-lasting, and broad cross-reactive RBD-specific neutralizing antibodies, in both serum and mucosal sites.…”

Mucosal immune response after the booster dose of the BNT162b2 COVID-19 vaccine

“…These findings suggest that the administration of a mucosal vaccine in addition to the approved intramuscular protocol could provide the sterilizing immunity required to efficiently block viral circulation and the emergence of new VOC efficiently. 48 , 49 …”

The protective nasal boosting of a triple-RBD subunit vaccine against SARS-CoV-2 following inactivated virus vaccination

“… 7 Recently, an inhaled COVID vaccine named Convidecia Air has been approved for emergency use as a booster in China. 8 We have designed a bivalent chimeric triple-RBD immunogen containing one Delta RBD and two Omicron RBDs (3Ro-NC) 9 (Supplementary Fig. 1 ) and demonstrated that intranasal (i.n) immunization with 3Ro-NC plus recombinant flagellin KFD adjuvant could induce robust systemic and mucosal immunity against SARR-CoV-2 VOCs.…”