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In Depth Characterization of Immune Response Against the Spike Protein of SARS-CoV-2 in Response to Infection and mRNA Vaccination.

Record Type:	Electronic resources : Monograph/item
Title/Author:	In Depth Characterization of Immune Response Against the Spike Protein of SARS-CoV-2 in Response to Infection and mRNA Vaccination./
Author:	Amanat, Fatima.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	769 p.
Notes:	Source: Dissertations Abstracts International, Volume: 83-03, Section: B.
Contained By:	Dissertations Abstracts International83-03B.
Subject:	Virology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28716268
ISBN:	9798535571577

In Depth Characterization of Immune Response Against the Spike Protein of SARS-CoV-2 in Response to Infection and mRNA Vaccination.
Amanat, Fatima.

In Depth Characterization of Immune Response Against the Spike Protein of SARS-CoV-2 in Response to Infection and mRNA Vaccination. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 769 p.

Source: Dissertations Abstracts International, Volume: 83-03, Section: B.

Thesis (Ph.D.)--Icahn School of Medicine at Mount Sinai, 2021.

This item must not be sold to any third party vendors.

Severe acute respiratory syndrome 2 (SARS-CoV-2) first emerged in the city of Wuhan in the province of Hubei in China in late 2019. Infection with SARS-CoV-2 leads to coronavirus disease 2019 (COVID-19), which can be fatal in some cases and the virus is the causative agent of the ongoing pandemic. Since then, SARS-CoV-2 has caused millions of deaths across the globe and led to even more infections. As of April 2021, three vaccines have received an emergency use authorization (EUA) by the Food and Drug Administration (FDA) in the United States. All three vaccines target the spike protein expressed on the surface of the virus, which is responsible for entry and attachment into host cells. Research over the past year has demonstrated that antibodies against the spike protein are highly neutralizing, post infection as well as post vaccination. The receptor binding domain (RBD), a small region of the spike protein, binds human angiotensin converting enzyme 2 (hACE2) for entry and attachment into cells. Antibodies against the RBD have been shown to be highly potent at blocking virus and hence, neutralize live virus in vitro as well as and protect from infection in vivo in various animal models. Here, we have characterized the immune response against the spike protein in depth, both in individuals who were infected with the virus as well as in individuals vaccinated with the mRNA vaccine that encodes the spike protein of SARS-CoV-2. Infected individuals mounted a robust immune response against the RBD and the spike protein post infection and this response was recapitulated in vaccinated individuals as well. We also studied, in a mouse model, whether the spike protein used for vaccination had to be stabilized by mutation of K986 and V987 to consecutive prolines in order to induce a high titer of binding as well as neutralizing antibodies and found that stabilized spike with deletion of the S1/S2 cleavage site is an optimal antigen for vaccination. In the second part, we generated monoclonal antibodies (mAbs) in mice against the RBD and found that reduction of virus in vivo was largely dependent on neutralizing capability of each mAb. Additionally, we generated plasmablast-derived mAbs from three individuals who received the mRNA vaccine and characterized them for binding and neutralization activity. Our work shows that the antibody response post vaccination targets diverse regions of the spike protein such as the N terminal domain (NTD), the S2 domain as well as the RBD. Overall, we have demonstrated that the spike protein is an excellent antigen and antibody responses against this protein in both infected individuals as well as vaccinated individuals are functional, and these antibodies likely protect from future infection. Our work can also be used as a guide to design vaccines and diagnostics for similar coronaviruses that may emerge in the future.

ISBN: 9798535571577Subjects--Topical Terms:

642304
Virology.
Subjects--Index Terms:

Coronavirus

In Depth Characterization of Immune Response Against the Spike Protein of SARS-CoV-2 in Response to Infection and mRNA Vaccination.
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520 $a Severe acute respiratory syndrome 2 (SARS-CoV-2) first emerged in the city of Wuhan in the province of Hubei in China in late 2019. Infection with SARS-CoV-2 leads to coronavirus disease 2019 (COVID-19), which can be fatal in some cases and the virus is the causative agent of the ongoing pandemic. Since then, SARS-CoV-2 has caused millions of deaths across the globe and led to even more infections. As of April 2021, three vaccines have received an emergency use authorization (EUA) by the Food and Drug Administration (FDA) in the United States. All three vaccines target the spike protein expressed on the surface of the virus, which is responsible for entry and attachment into host cells. Research over the past year has demonstrated that antibodies against the spike protein are highly neutralizing, post infection as well as post vaccination. The receptor binding domain (RBD), a small region of the spike protein, binds human angiotensin converting enzyme 2 (hACE2) for entry and attachment into cells. Antibodies against the RBD have been shown to be highly potent at blocking virus and hence, neutralize live virus in vitro as well as and protect from infection in vivo in various animal models. Here, we have characterized the immune response against the spike protein in depth, both in individuals who were infected with the virus as well as in individuals vaccinated with the mRNA vaccine that encodes the spike protein of SARS-CoV-2. Infected individuals mounted a robust immune response against the RBD and the spike protein post infection and this response was recapitulated in vaccinated individuals as well. We also studied, in a mouse model, whether the spike protein used for vaccination had to be stabilized by mutation of K986 and V987 to consecutive prolines in order to induce a high titer of binding as well as neutralizing antibodies and found that stabilized spike with deletion of the S1/S2 cleavage site is an optimal antigen for vaccination. In the second part, we generated monoclonal antibodies (mAbs) in mice against the RBD and found that reduction of virus in vivo was largely dependent on neutralizing capability of each mAb. Additionally, we generated plasmablast-derived mAbs from three individuals who received the mRNA vaccine and characterized them for binding and neutralization activity. Our work shows that the antibody response post vaccination targets diverse regions of the spike protein such as the N terminal domain (NTD), the S2 domain as well as the RBD. Overall, we have demonstrated that the spike protein is an excellent antigen and antibody responses against this protein in both infected individuals as well as vaccinated individuals are functional, and these antibodies likely protect from future infection. Our work can also be used as a guide to design vaccines and diagnostics for similar coronaviruses that may emerge in the future.
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