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Antibody-Mediated Immunity to Zika Virus.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Antibody-Mediated Immunity to Zika Virus./
Author:	Bailey, Mark J.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	172 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-09, Section: B.
Contained By:	Dissertations Abstracts International80-09B.
Subject:	Microbiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13809359
ISBN:	9781392006481

Antibody-Mediated Immunity to Zika Virus.
Bailey, Mark J.

Antibody-Mediated Immunity to Zika Virus. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 172 p.

Source: Dissertations Abstracts International, Volume: 80-09, Section: B.

Thesis (Ph.D.)--Icahn School of Medicine at Mount Sinai, 2019.

This item must not be added to any third party search indexes.

Zika virus is an emerging viral pathogen that can cause severe illnesses in humans including birth defects in newborns and neurological damage in adults. Currently, there are no approved vaccines or antivirals for Zika virus. The major objective of this thesis is to identify the fundamental requirements of antibody-mediated protection against Zika virus infection. Towards this goal, we obtained peripheral blood mononuclear cells from a patient infected with Zika virus and were able to isolate virus-specific antibodies from B cells. First, we isolated and characterized NS1-specific antibodies from this patient. We showed that while these antibodies are unable to neutralize virus in vitro, they elicited protective Fc-mediated effector functions such as antibody dependent cell-mediated cytotoxicity (ADCC) as measured by both an in vitro reporter assay and activation of primary natural killer cells. Additionally, these NS1-specific antibodies were unable to elicit the harmful antibody dependent enhancement (ADE) of viral replication. We also found an NS1-specific antibody protected mice against lethal challenges of African and Asian lineage strains of ZIKV while a mutated antibody unable to elicit Fc-mediated effector functions did not. Next, we designed an NS1 vaccine regimen that elicited high titers of NS1-specific antibodies which was able to protect mice against a similar challenge. By testing sera samples from human patients ranging from acutely ill to fully recovered, we showed the NS1-response in humans to be long lasting and functionally active as measured by an ADCC reporter assay. Finally, we characterized neutralizing antibodies elicited by acute infection. We showed that these potently neutralizing antibodies elicited the detrimental effects of ADE but not ADCC in vitro suggesting the Fc region of these antibodies may be more harmful than beneficial. Finally, by escape mutagenesis, we identified an amino acid at site 368 of the envelope protein to be critical for neutralization by a subset of our antibodies. We demonstrated that this lateral ridge region of the envelope protein is likely an immunodominant epitope that elicited protective neutralizing antibodies. Taken together, these studies have broad implications for vaccine design. A successful ZIKV vaccine would do best to induce a durable adaptive immune response allowing for Fc-mediated clearance of virally infected cells while minimizing negative effects including ADE. Inclusion of the ZIKV NS1 protein may help in the development of a safe and effective vaccine.

ISBN: 9781392006481Subjects--Topical Terms:

536250
Microbiology.
Subjects--Index Terms:

Antibody

Antibody-Mediated Immunity to Zika Virus.
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520 $a Zika virus is an emerging viral pathogen that can cause severe illnesses in humans including birth defects in newborns and neurological damage in adults. Currently, there are no approved vaccines or antivirals for Zika virus. The major objective of this thesis is to identify the fundamental requirements of antibody-mediated protection against Zika virus infection. Towards this goal, we obtained peripheral blood mononuclear cells from a patient infected with Zika virus and were able to isolate virus-specific antibodies from B cells. First, we isolated and characterized NS1-specific antibodies from this patient. We showed that while these antibodies are unable to neutralize virus in vitro, they elicited protective Fc-mediated effector functions such as antibody dependent cell-mediated cytotoxicity (ADCC) as measured by both an in vitro reporter assay and activation of primary natural killer cells. Additionally, these NS1-specific antibodies were unable to elicit the harmful antibody dependent enhancement (ADE) of viral replication. We also found an NS1-specific antibody protected mice against lethal challenges of African and Asian lineage strains of ZIKV while a mutated antibody unable to elicit Fc-mediated effector functions did not. Next, we designed an NS1 vaccine regimen that elicited high titers of NS1-specific antibodies which was able to protect mice against a similar challenge. By testing sera samples from human patients ranging from acutely ill to fully recovered, we showed the NS1-response in humans to be long lasting and functionally active as measured by an ADCC reporter assay. Finally, we characterized neutralizing antibodies elicited by acute infection. We showed that these potently neutralizing antibodies elicited the detrimental effects of ADE but not ADCC in vitro suggesting the Fc region of these antibodies may be more harmful than beneficial. Finally, by escape mutagenesis, we identified an amino acid at site 368 of the envelope protein to be critical for neutralization by a subset of our antibodies. We demonstrated that this lateral ridge region of the envelope protein is likely an immunodominant epitope that elicited protective neutralizing antibodies. Taken together, these studies have broad implications for vaccine design. A successful ZIKV vaccine would do best to induce a durable adaptive immune response allowing for Fc-mediated clearance of virally infected cells while minimizing negative effects including ADE. Inclusion of the ZIKV NS1 protein may help in the development of a safe and effective vaccine.
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