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Influenza Virus Vaccination: Analysis of IgA Antibody Repertoires and Development of a Broadly Protective mRNA-Based Approach.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Influenza Virus Vaccination: Analysis of IgA Antibody Repertoires and Development of a Broadly Protective mRNA-Based Approach./
作者:	Freyn, Alec Wilson.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	191 p.
附註:	Source: Dissertations Abstracts International, Volume: 82-07, Section: B.
Contained By:	Dissertations Abstracts International82-07B.
標題:	Virology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28262601
ISBN:	9798557041805

Influenza Virus Vaccination: Analysis of IgA Antibody Repertoires and Development of a Broadly Protective mRNA-Based Approach.
Freyn, Alec Wilson.

Influenza Virus Vaccination: Analysis of IgA Antibody Repertoires and Development of a Broadly Protective mRNA-Based Approach. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 191 p.

Source: Dissertations Abstracts International, Volume: 82-07, Section: B.

Thesis (Ph.D.)--Icahn School of Medicine at Mount Sinai, 2020.

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

Influenza viruses cause substantial loss of life annually, with up to 650,000 deaths occurring across the world. Seasonal influenza virus vaccines are utilized to mitigate the incurred mortality, but are suboptimal in the protection conferred. This incomplete vaccine effectiveness is due to multiple factors including viral antigenic drift, strain mismatches between circulating viruses and vaccine strains, and socioeconomic factors such as vaccine availability and hesitancy. To overcome these obstacles, an effort to develop universal influenza virus vaccines which provide broad and long-lasting protection is currently being pursued. Chapter one is an introduction to the topic of influenza viruses.Understanding immune mechanisms which correlate with protection from influenza virus infection is crucial to the rational design of next-generation influenza virus vaccines. Chapter two of this thesis presents results of the analysis of a panel of human IgA monoclonal antibodies elicited after seasonal influenza virus vaccination. Examining the functional properties of these antibodies followed by uncovering their binding footprints with cryo-electron microscopy led to the discovery of a novel epitope on the H1 subtype influenza hemagglutinin at the head-stalk interface. The ability of a monoclonal antibody targeting this epitope to elicit strong Fc-mediated effector functions may support the development of this target for novel influenza virus vaccines. Also, comparative analyses of Fc-mediated effector functions through in vitro reporter- and primary cell-based assays led to the discovery that Fc-receptor affinity plays a role in activation of antibody-dependent cell-mediated cytotoxicity. Low affinity Fc-receptors were found to require an additional point of contact between the hemagglutinin and a cognate sialic-acid binding receptor to stimulate activation, while high affinity Fc-receptors could be activated in the absence of this second contact. Due to the lack of a cognate high affinity receptor for IgA antibodies, Fc-mediated functionality was restricted to stalk-binding antibodies which could participate in two-contact binding to elicit Fc-mediated effector functions.New vaccine technologies have allowed progress towards development of universal influenza virus vaccines. Recently, nucleoside-modified messenger RNA lipid nanoparticle vaccines have emerged as promising vectors for the effective delivery of vaccine antigens. Chapter three of this thesis discusses the harnessing of this technology to effectively deliver multiple conserved influenza virus antigens in a single combined immunization. It was found that vaccination by this method could protect mice from lethal challenge with a large dose of currently circulating H1N1 influenza virus and a subsequent dose de-escalation found that a dose in the nanogram range could protect from lethal challenge with H1N1 influenza virus. Breadth of protection was also assessed and extended to all influenza viruses tested bearing group one hemagglutinins. Optimization of this messenger RNA-based combination broadly reactive influenza virus vaccine is described in chapter four. Modifications to functional domains of influenza virus antigens were made through mutation of the corresponding amino acid sequence for three vaccine targets: hemagglutinin, neuraminidase, and matrix-2 ion channel. It was found that anchoring of the hemagglutinin through maintenance of the trans-membrane domain increased immunogenicity. Reduction of the neuraminidase catalytic activity decreased reactogenicity upon boosting, while having no significant impact on conferred protection. Ablation of the matrix-2 ion channel activity was found to increase immunogenicity of matrix-2 antigens. A comparison of two internal protein targets which generally elicit T cell-mediated immunity (nucleoprotein and matrix-1) showed the superiority of nucleoprotein in conferring protection when delivered by an mRNA lipid nanoparticle vaccine platform. These alterations will increase the effectiveness of vaccines designed using the aforementioned antigens and also has potentially broad implications of the design of vaccine antigens for other infectious diseases.In chapter five, I discuss the discovery of immune mechanisms necessary for improving rational influenza virus vaccine design, development of a combination broadly reactive influenza virus vaccine based on conserved influenza virus antigens and mRNA lipid nanoparticle technology, as well as the optimization of mRNA vectored influenza virus antigens through modification of functional domains. Together, these discoveries aid in the pursuit of universal influenza virus vaccines that aim to provide long-lasting protection from a broad array of influenza virus variants.

ISBN: 9798557041805Subjects--Topical Terms:

642304
Virology.
Subjects--Index Terms:

Antibody

Influenza Virus Vaccination: Analysis of IgA Antibody Repertoires and Development of a Broadly Protective mRNA-Based Approach.
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