Date of Award

Fall 12-10-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Sang-Moo Kang

Second Advisor

Didier Merlin

Third Advisor

Jian Dong Li

Abstract

Human respiratory syncytial virus (RSV) is responsible for several million hospitalizations and 199,000 deaths in young children worldwide. In 1960s clinical trials, children who were vaccinated with alum-adjuvanted, formalin-inactivated whole RSV (FI-RSV) developed vaccine-enhanced respiratory disease after RSV infection, resulting in tragic vaccine failure. There is no licensed RSV vaccine. The goals of my PhD thesis studies were to better understand pulmonary inflammation in vaccinated animals and to develop safe and effective RSV vaccines.

In the first project, I investigated the vaccine efficacy of RSV fusion (F) proteins in a soluble form or on virus-like particle (F-VLP). F VLP preferentially elicited T helper type 1 (Th1) immune responses whereas alum-adjuvanted F protein induced Th2 responses. Despite lung viral clearance, F protein immune mice displayed weight loss and lung histopathology and high mucus production and eosinophils. In contrast, prime or prime-boost of F VLP prevented eosinophils’ infiltration and vaccine-associated disease. An intrinsic property of F VLP to prime Th1 type immune responses appears to prevent RSV vaccine-enhanced disease after RSV challenge. In the second project, I investigated the adjuvant effects of monophosphoryl lipid A (MPL, a TLR4 ligand) and oligodeoxynucleotide CpG (CpG, a TLR9 ligand) on vaccine-enhanced respiratory disease after F protein prime vaccination and RSV challenge in infant and adult mice. Combination CpG+MPL adjuvant in RSV F protein prime vaccination of infant and adult age mice promoted the induction of Th1 type immune responses, and lung viral clearance after challenge. Importantly, CpG+MPL adjuvant plus F protein priming of mice was effective in preventing inflammatory lung histopathology and Th2 cytokine-expressing CD4 T cell responses after RSV challenge. In the third project, I found that inactivated and detergent-split RSV vaccines exposed neutralizing epitopes at higher levels than inactivated whole virus. Split RSV vaccination of mice induced less lung histopathology compared to FI-RSV after RSV challenge. Split RSV vaccination of mice with CpG and MPL adjuvants was found to be most effective in increasing Th1 type IgG2a antibodies, neutralizing activity, and lung viral clearance as well as modulating immune responses to prevent pulmonary histopathology after RSV vaccination and challenge.

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