Date of Award

Fall 12-15-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Sang-Moo Kang

Second Advisor

Roberta Attanasio

Third Advisor

Jian-Dong Li

Abstract

Respiratory syncytial virus (RSV) is a major cause of infectious lower respiratory disease in infants and the elderly. Vaccine-enhanced respiratory disease (ERD) has been a major obstacle in developing a safe vaccine against respiratory syncytial virus (RSV). This study demonstrates efficacy and safety of virus like particle (VLP) vaccines containing RSV fusion (F) (F VLP), attachment (G) glycoproteins (G VLP), F+G (FG VLP), or FG VLP plus F DNA vaccine (FFG VLP) in mouse and cotton rat models.

FFG VLP vaccine was found to be effective in inducing long-lived IgG2a antibody responses specific for RSV F in mice. Mice immunized with FFG VLP showed long term protection against RSV without causing ERD, indicating vaccine safety, whereas mice with formalin-inactivated RSV (FI-RSV) vaccination showed severe inflammatory pulmonary pathology upon RSV challenge.

In cotton rats, FFG-VLP was found to be effective in inducing B cells that are secreting RSV F specific antibodies and likely long-lived in spleens and bone marrow. In contrast to FI-RSV, FFG-VLP immunization did not prime cellular components (IL-4 secreting cells, eosinophils) responsible for RSV disease and pulmonary inflammation. Repeated live RSV infections could induce a moderate level of pulmonary inflammation, indicating that even natural infection does not induce safe immunity. F VLP and FG VLP vaccines were immunogenic and able to confer protection without causing ERD in cotton rats. Inclusion of F VLP in the G VLP vaccination could improve vaccine safety in cotton rats.

My 4th project was to determine whether F VLP priming would modulate the outcomes of immune responses suppressing ERD to subsequent FI-RSV vaccination and RSV challenge. Induction of effector CD8 T cells expressing IFN-γ in the lung as a result of F VLP priming might be responsible for suppressing pulmonary inflammation and eosinophilia as well as Th2 cytokines in the airways and lungs. An intrinsic property of F VLP to stimulate the innate immune system at the injection site appears to be contributing to modulating a Th1 pattern of immune responses.

In conclusion, these results provide evidence that FFG VLP, FG VLP and F VLP are worthwhile for further development into a safe RSV vaccine candidate.

DOI

https://doi.org/10.57709/9413570

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