Breadth of SARS-CoV-2 Neutralization and Protection Induced by a Nanoparticle Vaccine

Abstract

Coronavirus vaccines that are highly effective against SARS-CoV-2 variants are needed to control the current pandemic. We previously reported a receptor-binding domain (RBD) sortase A-conjugated ferritin nanoparticle (RBD-scNP) vaccine that induced neutralizing antibodies against SARS-CoV-2 and pre-emergent sarbecoviruses and protected monkeys from SARS-CoV-2 WA-1 infection. Here, we demonstrate SARS-CoV-2 RBD-scNP immunization induces potent neutralizing antibodies against all eight SARS-CoV-2 variants tested including the Beta, Delta, and Omicron variants in non-human primates (NHPs). The Omicron variant was neutralized by RBD-scNP-induced serum antibodies with a mean of 4.3-fold reduction of ID50 titers compared to SARS-CoV-2 D614G. Immunization with RBD-scNPs protected NHPs from SARS-CoV-2 WA-1, Beta, and Delta variant challenge, and protected mice from challenges of SARS-CoV-2 Beta variant and two other heterologous sarbecoviruses. These results demonstrate the ability of RBD-scNPs to induce broad neutralization of SARS-CoV-2 variants and to protect NHPs and mice from multiple different SARS-related viruses. Such a vaccine could provide the needed immunity to slow the spread of and reduce disease caused by SARS-CoV-2 variants such as Delta and Omicron.

Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models

“…Homotypic SARS-2 RBD or S trimer nanoparticles elicit potent neutralizing antibody responses that exhibit some degree of cross-reactivity across SARS-2 variants and sarbecoviruses ( 34 , 36 , 66 – 75 ). Here, we reproduced results for homotypic nanoparticles and extended them in challenge studies comparing protection against SARS-2 and SARS-1 conferred by a mosaic-8 RBD nanoparticle versus a homotypic SARS-2 RBD nanoparticle.…”

“…Thus, only one of four animals had detectable viral loads in the lungs compared to four of four in the control group, demonstrating that some level of protection was achieved. Interestingly, a similar outcome was reported upon vaccination of aged mice with RBD-scNP, a homotypic SARS-2 RBD-conjugated ferritin nanoparticle that induced neutralizing antibodies against SARS-2 and pre-emergent sarbecoviruses: upon subsequent challenge with mouse-adapted SARS-1, viral loads were significantly reduced, but not absent, in lung tissue (four of five vaccinated animals exhibited reduced, but detectable SARS-1 virus, as compared with five of five with higher viral loads in the control group) ( 75 ).…”

“…T helper: GM-CSF [44], IFN gamma [43], IL-1 beta [18], IL-2 [19], IL-4 [20], IL-5 [21], IL-6 [25], IL-8 (CXCL8) [27], IL-10 [28], IL-12p70 [34], IL-13 [35], IL-17A (CTLA-8) [36], IL-18 [66], IL-23 [63], TNF alpha [45] Cytokines: CD40L [74], G-CSF (CSF-3) [42], IFN alpha [48], IL-1RA [38], IL-7 [26], IL-15 [65] Chemokines: BLC (CXCL13) [15], Eotaxin (CCL11) [33], IP-10 (CXCL10) [22], I-TAC (CXCL11) [46], MCP-1 (CCL2) [51], MIG (CXCL9) [54], MIP-1 alpha (CCL3) [12], MIP-1 beta (CCL4) [47], SDF-1 alpha [13] Growth Factors: BDNF [57], FGF-2 [75], NGF beta [55], PDGF-BB [77], SCF [39], VEGF-A [78], VEGF-D [53] BAL samples were thawed at room temperature, quickly vortexed for 10s, and then centrifuged to pellet and remove debris. Samples were analyzed in duplicate using the above panel according to the manufacturer's protocol.…”

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

“…Understanding antibody responses elicited by and directed toward Omicron sublineages is as the result of key to informing public health policies and the design of SARS-CoV-2 and sarbecovirus vaccines ( 70 , 71 , 83 – 85 ). Our data show that Omicron breakthrough infections do not elicit high titers of pan-sarbecovirus–neutralizing antibodies (e.g., directed against SARS-CoV), in agreement with recent data ( 86 ).…”

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

“…Understanding antibody responses elicited by and directed towards Omicron sublineages is key to inform public health policies and the design of SARS-CoV-2 and sarbecovirus vaccines ( 63, 64, 70–72 ). Our data show that Omicron breakthrough infections did not elicit high titers of pan-sarbecovirus neutralizing antibodies (e.g., directed against SARS-CoV), in agreement with recent data ( 73 ).…”