Nat Rev Immunol(IF=109) Pengfei Wang/Shibo Jiang published a review of a wide range of antibodies to the new crown virus and other human coronaviruses

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerging pathogenic human coronavirus that belongs to the sarbecavirus lineage of the genus β coronavirus
.
Ancestral strains have evolved into many varieties
of concern.
The COVID-19 pandemic caused by SARS-CoV-2 has caused serious damage to public health and the global economy, and one strategy to combat COVID-19 is to develop broadly neutralizing antibodies for prevention and treatment
.
Many drugs are in the preclinical and clinical development phases, and a few have been approved for emergency use
.

On September 27, 2022, Fudan University Pengfei Wang and Jiang Shibo published a review article entitled "Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses" online at Nature Reviews Immunology (IF=109), which summarized the response to SARS-CoV-2 spike(S).
Neutralizing antibodies to four key regions of the protein, namely the N-terminal domain and the receptor-binding domain in the S1 subunit and the stem helix region and the fusion peptide region
in the S2 subunit.
Understanding the properties of these broadly neutralizing antibodies will accelerate the development of new antibody therapies and provide guidance for the proper design of the next generation of vaccines
.

Following the emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, a new pathogenic human coronavirus (HCoV) emerged in 2019 and quickly spread worldwide, leading to the COVID-19 pandemic
。 Due to its close sequence homology (~79.
6%) with SARS-CoV, the new virus is named "SARS-CoV-2"
.
SARS-CoV-2 has a much
lower case fatality rate compared to SARS-CoV and MERS-CoV.
However, the high proportion of asymptomatic or mild symptomatic infections caused by the original strain of SARS-CoV-2 and its subsequent variants results in higher and faster transmission of the virus, which poses serious complications
for all populations worldwide.

Coronaviruses belong to the coronavirus subfamily of the Coronavirus Family, which are genotypically and serological into four main genera: α Coronavirus (α-CoV), β Coronavirus (β-CoV), γ Coronavirus (γ-CoV) and δ Coronavirus (δ-CoV).

HCoVs are those coronaviruses
that can infect humans.
Taxonomically, the historically occurring HCoV-229E and HCoV-NL63 are classified as α-CoV, while HCoV-HKU1, HCoV-OC43, SARS-CoV, SARS-CoV-2, and MERS-CoV are β-CoV
.
α-CoV and β-CoV primarily infect mammals, while γ-CoV and δ-CoV primarily infect birds
.
Both SARS-CoV-2 and SARS-CoV belong to Sarbecovirus, a subgenus of β-CoV
.
In contrast, MERS-CoV belongs to Merbecovirus, another subgenus of β-CoV
.
Two other notable HCoV, HCoV-HKU1 and HCoV-OC43, which cause common cold-like diseases, belong to the Embecovirus subgenus β-CoV
.

HCoV contains phosphorylated nucleocapsid (N) proteins with single-stranded genomic RNA as the core
.
The core of the virus is encased in a phospholipid bilayer to form spherical or polymorphic particles of 80 to 120 nanometers in size, characterized by the presence of an external surface spike(S) protein
.
S protein consists of two subunits,
S1 and S2.
S1 contains an important receptor-binding domain (RBD) that is responsible for identifying host cell surface receptors that enable viruses to enter
.
Both SARS-CoV and SARS-CoV-2 have angiotensin-converting enzyme 2 (ACE2) as the primary entry receptor, which is widely expressed
in a variety of human cells.
Dipeptidyl peptidase 4 (DPP4; Also known as CD26) is the corresponding entry receptor of MERS-CoV
.
The S2 subunit is primarily responsible for subsequent viral fusion with host cells and entry into host cells
.

The junction of S1 and S2 contains a specific furin protease cleavage site that is cleaved by the host cell furin protease to facilitate viral entry into the cell
.
The virus binds to ACE2 to expose the S2' cleavage site, where S2 is further cut into two parts by transmembrane serine protease 2 (TMPRSS2) on the cell membrane surface, facilitating the membrane fusion process
between the host cell and the virus.
ACE2-bound viruses can also be internalized by endocytosis, in which case cleavage of the S2' site is mediated by histoproteinase, especially histone protease L
in endosomes.

Neutralizing antibody against SARS-CoV-2 spike protein (Figure from Nature Reviews Immunology)

Antibodies that recognize pathogens can be classified as neutralizing antibodies (nAb) or non-neutralizing antibodies (non-nAb
).
The difference between the two generally depends on whether an antibody bound to a particular pathogen can block cell invasion or inhibit membrane fusion after recognition (using nAbs as an example) or not block cell invasion or inhibit membrane fusion after recognition (in the case of non-nAb).

In general, nAb is effective in neutralizing pathogens, reducing pathogen titers, and protecting tissues or cells from infection
.
The neutralizing activity of non-nAbs is usually undetectable, but they can exert their protective effects through Fc-mediated effector functions such as antibody-dependent cell-mediated cytotoxicity, antibody-dependent cytophagy, and complement-dependent cytotoxicity
.
In this review, only regions targeting neutralizing epitopes (bnAbs) in N-terminal domains (NTDs) and S1 subunits RBD are looked at, and regions
in antibody (FP) S2 subunits targeting stem helix (SH) and peptide-fused antibody (FP) S2 subunits.
Understanding the properties of these broadly neutralizing antibodies will accelerate the development of new antibody therapies and provide guidance for the proper design of the next generation of vaccines
.

Informational message:

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