Date of Award
Doctor of Philosophy (PhD)
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.
Hwang, Hye Suk, "EFFICACY AND SAFETY OF VIRUS LIKE PARTICLE VACCINES AGAINST RESPIRATORY SYNCYTIAL VIRUS IN MOUSE AND COTTON RAT MODELS." Dissertation, Georgia State University, 2016.
Available for download on Saturday, November 24, 2018