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Broadly neutralizing antibodies are the blueprint for a variant-proof pansarvecovirus vaccine

Broadly neutralizing antibodies are the blueprint for a variant-proof pansarvecovirus vaccine

 


Recent nature review immunology research summarized efficacy of Neutralizing antibody Targeting four major regions of the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): the receptor-binding domain (RBD) of the S1 subunit and the fusion peptide region of the S2 subunit. , the stem-helical region, and the N-terminal domain.

Review: Broadly neutralizing antibodies against SARS-CoV-2 and other human coronaviruses. Image Credit: Huen Structure Bio / ShutterstockReview: Broadly neutralizes antibodies against SARS-CoV-2 and other human coronavirusesImage Credit: Huen Structure Bio / Shutterstock

different types of coronavirus

During the past decades, several pathogenic human coronavirus (HCoV) has emerged and is causing epidemics and pandemics worldwide. Severe acute respiratory syndrome coronavirus (SARS-CoV) first appeared in 2003, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, and SARS-CoV-2 in 2019, and soon Spreading around the world, the coronavirus disease of 2019 (COVID19 pandemic.

The ancestral SARS-CoV-2 strain has evolved substantially into many variants classified as variants of interest (VOCs) and variants of interest (VOIs). Unfortunately, several variants of SARS-CoV-2 reduced the efficacy of his COVID-19 vaccine, so it is important to develop broadly neutralizing antibodies for prophylactic and therapeutic purposes.

SARS-CoV-2 is less lethal than SARS-CoV and MERS-CoV, but more infectious.coronavirus belongs to the family coronavirus It is classified into four major genera, including alphacoronaviruses (alpha-CoVs), betacoronaviruses (beta-CoVs), gammacoronaviruses (gamma-CoVs), and deltacoronaviruses (delta-CoVs). increase.

Alpha-CoV and beta-CoV typically infect mammals, while gamma-CoV and delta-CoV primarily infect birds. SARS-CoV-2, SARS-CoV, MERS-CoV, and HCoV (HCoV-HKU1 and HCoV-OC43) belong to betacoronaviruses.

Major Factors Associated with Viral Infection

HCoV is a single-stranded RNA virus containing a phosphorylated nucleocapsid (N) protein, with a core encapsulated by a phospholipid bilayer to form spherical particles characterized by the presence of an outer surface S protein. The S protein contains S1 and S2 domains that play important roles in viral infection.

The receptor-binding domain (RBD) of the S1 domain recognizes host cell surface receptors, the first step in viral entry. The S2 domain is responsible for membrane fusion, allowing the viral genome to enter host cells. Her two other factors associated with viral infection are furin and transmembrane serine protease 2 (TMPRSS2).

SARS-CoV and SARS-CoV-2 utilize the host angiotensin-converting enzyme 2 (ACE2) receptor, whereas MERS-CoV uses dipeptidyl peptidase 4 (DPP4) to enter host cells.

Pathogens are recognized by neutralizing antibodies (nAbs) or non-neutralizing antibodies (non-nAbs). In general, nAbs can more effectively reduce virulence titers and protect host cells from infection. As mentioned above, this study mainly focused on the N-terminal domain (NTD), the stem helix (SH), the RBD of the S1 subunit, and the fusion peptide (FP) region of the S2 subunit.

NTDs

4A8 is recognized as one of the earliest nAbs to target NTDs. NTD has five structural loops, N1-N5, of which N3 and N5 mediate the interaction with 4A. Other NTD-targeting mAbs include COV2-2676, 5-24, and COV2-2489, which identify epitopes composed of N1, N3, and N5 loops.

Many SARS-CoV-2 variants contain mutations within the NTD supersite, making mAbs that recognize the NTD supersite less neutralizing. For example, the SARS-CoV-2 beta strain contains deletions of NTD amino acid residues 242–244, disabling 4A8, 4-8, and 5-24.

RBDMore

Most anti-SARS-CoV-2 antibodies target RBDs, which are divided into different classes based on their target epitopes. Classification of Barnes et al. The most commonly referenced grouping of RBD-targeting antibodies into four classes is based on their mode of binding to the S protein.

Class 1 and class 2 RBD-targeted antibodies tend to lose their neutralizing ability with the emergence of SARS-CoV-2 VOCs with novel mutations in the RBM. Therefore, their neutralizing respiration is limited. In contrast, class 3 and class 4 antibodies that bind highly conserved epitopes are more effective in neutralizing SARS-CoV-2 variants and other SARS-like coronaviruses.

In the future, developing COVID-19 vaccines targeting conserved epitopes may induce potent broad-spectrum antibodies effective against current and emerging SARS-CoV-2 variants there is.

S2 SH region

As previously mentioned, the S protein of SARS-CoV-2 contains S1 and S2 subunits. The majority of SARS-CoV-2 nAbs target neutralizing epitopes on the RBD of the S1 subunit and NTD. However, these epitopes are prone to mutation, increasing the potential for immune escape by viral mutants.

Compared to the S1 domain, the neutralizing epitopes of the S2 subunit are more conserved. Therefore, nAbs targeting the S2 epitope are more likely to induce broad-spectrum nAbs against SARS-CoV-2 and other HCoVs. For example, S2P6 broadly neutralizes all beta-CoV by targeting the S2 subunit.

S2FP

The S2 FP domain is highly conserved among all coronavirus genera, indicating the potential to induce broad-spectrum antibodies. Some of the antibodies generated targeting this epitope showed excellent neutralizing activity against alpha-CoV, beta-CoV, gamma-CoV, and delta-CoV.

COV44-62 and COV44-79 antibodies isolated from convalescent COVID-19 patients may bind to the S2 FP region. COV44-62 interacted with her S2 domain of SARS-CoV-2 and neutralized beta-CoV and MERS-CoV.

Sources

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2/ https://www.news-medical.net/news/20221002/Broadly-neutralizing-antibodies-are-the-blueprint-for-variant-proof-pansarbecovirus-vaccines.aspx

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