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Influenza Virus Vaccines: Enhancing Immunogenicity of the Viral Neuraminidase.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Influenza Virus Vaccines: Enhancing Immunogenicity of the Viral Neuraminidase./
作者:	Zheng, Allen.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	205 p.
附註:	Source: Dissertations Abstracts International, Volume: 82-12, Section: B.
Contained By:	Dissertations Abstracts International82-12B.
標題:	Virology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28542091
ISBN:	9798505546635

Influenza Virus Vaccines: Enhancing Immunogenicity of the Viral Neuraminidase.
Zheng, Allen.

Influenza Virus Vaccines: Enhancing Immunogenicity of the Viral Neuraminidase. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 205 p.

Source: Dissertations Abstracts International, Volume: 82-12, Section: B.

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

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

Influenza virus infections are consistently a major source of morbidity and mortality globally. Seasonal vaccination is protective, but annual vaccine effectiveness is highly variable and dependent on the degree of antigenic similarity between vaccine strains and circulating viruses. Antigenic drift necessitates annual reconsideration of seasonal vaccine composition, and antigenic shift still poses a major threat. Existing vaccination strategies rely heavily on induction of a neutralizing humoral immune response against the viral hemagglutinin (HA) for protection. Influenza virus neuraminidase (NA) is a historically underappreciated antigen given its immunosubdominance to the HA and inability to induce sterilizing immunity. Still, there is a robust collection of data from both humans and experimental animal models demonstrating that NA-based immunity is protective. Antivirals targeting the neuraminidase active site have been used in the clinic to mitigate disease severity for the last two decades. Numerous studies have demonstrated that NA-based immunization can provide heterologous protection. Monoclonal antibodies that bind to and inhibit nearly all known NA strains have recently been identified. Importantly, preexisting immunity to NA provided protection during the pandemic of 1968, when an avian HA reassorted into a circulating seasonal influenza virus. This work seeks to develop novel platforms for enhancing immunogenicity of influenza virus neuraminidase by increasing NA antigenic visibility in the context of whole viruses. In chapters two and three, I demonstrate that elongation of the hypervariable stalk of both influenza A and B viruses can increase the anti-NA immune response without compromising the anti-HA immune response relative to wild-type stalk in the mouse model. In chapter four, I demonstrate that rewiring the packaging signals of the viral genomic segments coding for HA and NA can reverse the relative abundance of these two proteins on the viral surface. Immunization of mice with rewired viruses induces a stronger humoral response against the NA and a weaker humoral response against the HA compared to immunization with wild-type virus. Additionally, combining these strategies allows me to further investigate the determinants of HA immunodominance. Taken together, this thesis demonstrates the viability of NA stalk elongation and packaging signal rewiring as methods for increasing antigenic visibility and enhancing immunogenicity of the influenza virus neuraminidase in a setting where the hemagglutinin is also present. It also provides evidence that both relative abundance and stalk length are determinants of NA immunosubdominance. This work is part of a larger body of recent literature that seeks to coax the influenza virus neuraminidase from out of the shadow of hemagglutinin as a vaccine antigen.

ISBN: 9798505546635Subjects--Topical Terms:

642304
Virology.
Subjects--Index Terms:

Immunogenicity

Influenza Virus Vaccines: Enhancing Immunogenicity of the Viral Neuraminidase.
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