Mucosal Delivery of Influenza Vaccine Antigens
by
 
Ochsner, Susan Soo Park, author. (orcid)0000-0003-2898-530X

Title
Mucosal Delivery of Influenza Vaccine Antigens

Author
Ochsner, Susan Soo Park, author. (orcid)0000-0003-2898-530X

ISBN
9780438144262

Personal Author
Ochsner, Susan Soo Park, author.

Physical Description
1 electronic resource (242 pages)

General Note
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
 
Advisors: Xiaoping Zhu Committee members: Georgiy Belov; Jeff DeStefano; Kenneth Frauwirth; Wenxia Song.

Abstract
Most pathogens infect humans and animals at mucosal surfaces, yet few mucosal vaccines are available to provide protection at these sites. Though influenza virus initiates its infection in the respiratory mucosal epithelium, currently approved influenza vaccines are administered by parenteral routes, which do not offer effective respiratory immunity. A successful mucosal influenza vaccine should induce both local and systemic immunity, however, the respiratory epithelium is an imposing barrier that prevents vaccine antigens to effectively traverse the airway. The neonatal Fc receptor (FcRn) mediates transport of IgG across the epithelial cell monolayer lining mucosal surfaces. To exploit this antibody transfer pathway for antigen delivery, I produced a soluble fusion protein that fused the monomeric Fc portion of IgG to an influenza hemagglutinin (HA) antigen harboring the T4 fibritin trimerization domain. Intranasal innoculation of the HA-Fc protein along with CpG adjuvant induced high levels of durable mucosal and systemic adaptive immune responses and, importantly, generation of lung-resident memory T cells. FcRn-dependent antigen delivery was corroborated when substantial protection characterized by significantly increased survival and reduced pulmonary pathology was observed in the HA-Fc-immunized wild-type (wt) mice. In contrast, control groups of wt and FcRn-deficient mice immunized with HA-Fc, a mutant version of HA-Fc that lacks FcRn binding capacity, HA alone, or PBS, experienced substantial morbidity, mortality, and lung damage. As the influenza nucleoprotein (NP) is highly conserved among strains, it is an attractive vaccine target. Thus I produced soluble NP-Fc fusion proteins as potential influenza vaccines. The preliminary study demonstrated that intranasal immunization of NP-Fc with CpG resulted in FcRn-mediated delivery of NP-Fc protein across the respiratory barrier and the induction of high levels of antibody titer compared to groups of control mice. Immunization with NP-Fc may be further explored for developing a universal mucosal influenza vaccine. Taken together, for the first time, my results prove that FcRn can effectively deliver an influenza antigen across the respiratory epithelial barrier, providing substantial protection against lethal respiratory infection. This study further suggests FcRn-mediated mucosal vaccination could be used to deliver a universal influenza vaccine antigen or protective antigens from other common respiratory pathogens.

Local Note
School code: 0117

Subject Term
Immunology.
 
Virology.
 
Molecular biology.

Added Corporate Author
University of Maryland, College Park. Cell Biology & Molecular Genetics.

Electronic Access
http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:10744763


Shelf NumberItem BarcodeShelf LocationShelf LocationHolding Information
XX(688396.1)688396-1001Proquest E-Thesis CollectionProquest E-Thesis Collection