SARS‐CoV‐2 Spike Stem Protein Nanoparticles Elicited Broad ADCC and Robust Neutralization against Variants in Mice

Abstract

first detected in September 2020 in southeast England and has shown enhanced transmissibility and increased mortality compared with the original lineage. [4,5] Moreover, B.1.351 (Beta, β) and P.1 (Gamma, γ) variants were first identified in South Africa and Brazil, respectively, and partially circumvented postinfection or vaccination immunity. [6][7][8][9][10][11][12][13][14][15] Subsequently, the novel B.1.617.2 (Delta, δ) variant that emerged in India spread quickly across the globe, [16][17][18][19] as it displayed increased transmissibility beyond B.1.1.7 and enhanced vaccine evasion like B.1.351. [20][21][22][23][24][25][26] The most heavily mutated variant so far identified in Botswana and named as B.1.1.529 (Omicron, ο), is rapidly becoming the dominant SARS-CoV-2 virus circulating globally and joins the World Health Organization (WHO) list of variants of concern with Delta, Alpha, Beta, and Gamma. [27,28] Such variants with striking antibody evasion and rapid transmission even in fully vaccinated individuals present a critical threat to pandemic control and disease treatment. [29][30][31][32][33][34][35] The spike protein (S) is the preferred target antigen for vaccine development, based on its essential function and abundant neutralizing epitopes. [36] S is a class I virus fusion protein including S1 and S2 subunits connected by a furin-like cleavage site. [37,38] With the receptor-binding domain (RBD), S1 recognizes and anchors the angiotensin-converting enzyme 2 (ACE2) on the host cellular membrane during viral infection. The fusion peptide (FP) in the S2 subunit mediates the fusion of the viral membrane with the cell membrane. [39][40][41][42] Based on the RBD and FP functions, S is transformed from the metastable prefusion conformation to the stable postfusion conformation during the S-protein-mediated viral cell entry through structural rearrangement. [43] Due to its integral role in infection, current messenger RNA (mRNA) and nonreplicating viral vector vaccines have used the stabilized prefusion conformation of S protein (Pre) as the major antigen to induce potent humoral and cellular immune responses. [39,[44][45][46][47][48] However, S-based vaccines face challenges as mutations continue to emerge. Most mutations occur on the relatively variable S1 subunit, the main target of vaccineinduced neutralizing antibodies. For instance, the D614G mutation exhibits enhanced replication and transmission during viral spread and has supplanted the ancestral virus and appears Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global pandemic. The virus is rapidly evolving, characterized by the emergence of several major variants. Stable prefusion spike protein (Pre) is the immunogen in current vaccines but is limited in protecting against different variants. Here, the immune responses induced by the relatively conserved stem subunit (S2) of spike protein versus Pre are investigated. Pre generates the most robust neutralization responses against SARS-CoV-2 variants in vesicular stoma...

Enhanced protective efficacy of a novel, thermostable, RBD-S2 vaccine formulation against SARS-CoV-2 and its variants

“…However, yields were low and there are manufacturing challenges associated with this complex immunogen. In another report, double layered nanoparticles incorporating both prefusion Spike and S2 elicited significant neutralizing antibody titers, ADCC activity and cellular immune responses against pre-Omicron VOCs in mice but protective efficacy was not assessed ( 56 ). In the present work the novel RS2 and S2R immunogens were expressed and purified from Expi293F cells at remarkably high yields.…”

“…While promising, such nanoparticle vaccine designs elicit titers against the nanoparticle scaffolds, and employ a large number of antigens, which adds to manufacturing complexity. Alternatively, vaccine candidates based on conserved antigens like S2 are also reported [51][52][53] .…”

Enhanced protective efficacy of a thermostable RBD-S2 vaccine formulation against SARS-CoV-2 and its variants

“…While promising, such nanoparticle vaccine designs elicit titers against the nanoparticle scaffolds, and employ a large number of antigens, which adds to manufacturing complexity. Alternatively, vaccine candidates based on conserved antigens like S2 are also reported 50 – 52 .…”

Application of nanomaterials against SARS-CoV-2: An emphasis on their usefulness against emerging variants of concern

“…The immunogenicity of S2 and Pre has been shown to improve by incorporating them into double-layered protein nanoparticles. The resulting protein nanoparticles Pre/S2 elicit higher neutralizing antibodies than Pre alone and stronger ADCC than S2 alone (Ma et al, 2022).…”