A novel linear and broadly neutralizing peptide in the SARS-CoV-2 S2 protein for universal vaccine development

Li, Tuofan; Kan, Qiuqi; Ge, Jinying; Wan, Zhimin; Yuan, Mengqi; Huang, Yao; Xie, Quan; Yang, Yi; Shao, Hongxia; Li, Xiangdong; Ye, Lilin; Qin, Aijian; Bu, Zhigao; Liu, Pinghuang; Ye, Jianqiang

doi:10.1038/s41423-021-00778-6

Cited by 19 publications

(26 citation statements)

References 11 publications

(11 reference statements)

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“…However, boosting with RBD-based immunogens may be advantageous if directing memory response towards RBD epitopes is preferred. Many potently neutralizing SARS-2 therapeutic antibodies target RBD epitopes, including antibodies that can neutralize other sarbecoviruses and SARS-2 variants ( 33 , 54 – 57 ); additionally, spike contains several highly conserved epitopes outside the RBD, including neutralizing epitopes in the stem helix and fusion peptide regions ( 58 – 60 ). Preferred epitopes targeted by future sarbecovirus vaccines should take into consideration whether to boost with RBD or spike-based immunogens.…”

Section: Discussionmentioning

confidence: 99%

Humoral responses to the SARS-CoV-2 spike and receptor binding domain in context of pre-existing immunity confer broad sarbecovirus neutralization

Hauser

Sangesland²,

Lam³

et al. 2022

Front. Immunol.

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Since the emergence of SARS-CoV-2 (SARS-2), multiple vaccine candidates were developed and studied both preclinically and clinically. Nearly all are based on the SARS-2 spike glycoprotein or its receptor binding domain (RBD). Studies of these vaccine candidates have largely been in a SARS-2 naïve context. However, pre-existing immunity to SARS-2 acquired through infection or vaccination continues to increase. Evaluating future vaccine candidates in context of this pre-existing immunity is necessary to understand how immune responses are subsequently influenced. Here, we evaluated the serum and IgG+ B cell responses to the SARS-2 RBD in context of pre-existing immunity elicited by the full SARS-2 spike, and we compared this to boosting with the full SARS-2 spike. Boosting with the SARS-2 RBD resulted in increased reactivity to RBD epitopes, but both immunization regimens resulted in similarly broad neutralization across diverse sarbecoviruses. These findings may inform comparison among SARS-2 RBD-based vaccine candidates to currently approved spike-based candidates.

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Section: Discussionmentioning

confidence: 99%

Humoral responses to the SARS-CoV-2 spike and receptor binding domain in context of pre-existing immunity confer broad sarbecovirus neutralization

Hauser

Sangesland²,

Lam³

et al. 2022

Front. Immunol.

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“…RBD monomer is depicted as a ribbon diagram with stabilizing substitutions [ 19 , 20 ] highlighted as spheres. RBD dimer, RBD trimer, stem helix trimer [ 58 ] and S2-only antigen are shown as molecular surfaces. For the RBD dimer [ 23 ], ACE2-binding sites (or receptor-binding motifs) are colored dark blue.…”

Section: Introductionmentioning

confidence: 99%

“…deleted even more residues from the C-terminus of the ectodomain, leaving no stem helix (residues 1144–1213) at the base of S2 [ 54 ]. Removing these flexible regions seems to generate a more homogenous spike, but at the expense of losing important epitopes that have been shown to elicit neutralizing antibodies in mice and humans [ 36 , 37 , 55 , 56 , 57 , 58 ]. Instead of using foldon or the GCN4 trimerization motif, Watterson et al.…”

Section: Introductionmentioning

confidence: 99%

“…While several antigen designs such as chimeric spikes and mosaic RBD nanoparticles have provided broader protection against SARS-CoV-2 VOCs and Sarbecoviruses, a major goal is to design a pan-coronavirus vaccine that protects against all existing human coronaviruses as well as coronaviruses that may emerge in the future. Identification of a conserved stem helix at the base of the S2 subunit may provide a new direction for epitope-focused designs ( Figure 1 ) [ 36 , 37 , 55 , 56 , 57 , 58 ], which are likely to extend host immunity to all major betacoronaviruses. Moreover, a handful of comprehensive studies profiling the antibody response to the full spike using peptide-binding assays have discovered a few neutralization-sensitive epitopes in close proximity to the fusion peptide in the S2 subunit [ 78∗ , 79 , 80 , 81 ].…”

Section: Introductionmentioning

confidence: 99%

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Protein engineering responses to the COVID-19 pandemic

Hsieh

McLellan

2022

Current Opinion in Structural Biology

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“…[60][61][62][63] Previous research has identified a linear peptide in S2 as a potential vaccine candidate for comprehensive protection against SARS-CoV-2 and variants. [64] Therefore, S2 is a promising target for a SARS-CoV-2 universal vaccine, resembling the influenza hemagglutinin stem subunit, which elicits broad immune protection against different influenza viruses. [65][66][67][68] In light of the ongoing pandemic, the rapid accumulation of mutations in S1, and the proliferation of variant strains, the immunogenicity of conserved S2 was investigated and compared to the wild-type S (Wt) and Pre in mice.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Dong

et al. 2022

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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...

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A novel linear and broadly neutralizing peptide in the SARS-CoV-2 S2 protein for universal vaccine development

Cited by 19 publications

References 11 publications

Humoral responses to the SARS-CoV-2 spike and receptor binding domain in context of pre-existing immunity confer broad sarbecovirus neutralization

Humoral responses to the SARS-CoV-2 spike and receptor binding domain in context of pre-existing immunity confer broad sarbecovirus neutralization

Protein engineering responses to the COVID-19 pandemic

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

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