Kosanovich, Jessica L
(2023)
The Safety and Efficacy of Early-Life RSV Vaccination Approaches:
The Double-Edged Sword of Host Immunity.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Respiratory syncytial virus (RSV) is the leading cause of childhood hospitalizations due to bronchiolitis in children under 5 years of age. Furthermore, hospitalization as a result of RSV-mediated bronchiolitis is associated with the subsequent development of wheezing and asthma. Despite the unquestionable need, development of a safe and effective RSV vaccine for young children has been met with significant barriers. Toward this goal, our lab investigated the safety and efficacy of two early-life vaccination approaches – maternal RSV vaccination and direct vaccination of RSV-experienced young mice. These vaccine candidates, which used the RSV pre-fusion F (PreF) protein, were evaluated on their ability to prevent RSV replication, overcome the type 2 immune bias of neonates, and elicit enhanced respiratory disease (ERD). We hypothesized that each vaccination approach would generate high titers of RSV-neutralizing antibody, thereby conferring protection from viral replication, while also failing to elicit ERD following natural RSV exposure.
In our model of direct vaccination, we demonstrated that RSV-experienced young mice were capable of mounting protective anti-RSV immunity following RSV re-exposure. As expected, formulation of PreF with Th1- vs Th2-skewing adjuvants altered cellular immunity, with use of a Th2-skewing adjuvant eliciting strong type 2 immunity characterized by eosinophilia, ILC2s, and Th2 cells. However, neither vaccination group were protected from the type 2 immunopathology associated with early-life RSV infection and subsequent RSV exposure.
In our model of maternal RSV vaccination, we demonstrated that passive transfer of high titers of RSV-neutralizing maternal antibody (matAb) was associated with complete protection from neonatal RSV infection. Unexpectedly, primary RSV exposure in the presence of matAb led to type 2 innate immune cell skewing and Th2 cell activation with associated immunopathology. Moreover, we also demonstrated that RSV re-exposure of maternally vaccinated offspring led to considerable type 2 inflammation, characterized by hyperresponsive ILC2s, eosinophilia, and a Th2 cell phenotype that orchestrated the associated type 2 immunopathology.
Collectively, the unfavorable safety outcomes elicited following RSV re-exposure in both models of early-life RSV vaccination further underscores the importance of assessing immunity beyond antibody-mediated viral neutralization and highlights the difficulty in properly balancing early-life immune responses to RSV.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
7 July 2023 |
| Date Type: |
Publication |
| Defense Date: |
10 May 2023 |
| Approval Date: |
7 July 2023 |
| Submission Date: |
7 July 2023 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
184 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Immunization, RSV, ILC2s, Maternal Antibody, Type 2 Inflammation |
| Date Deposited: |
07 Jul 2023 16:37 |
| Last Modified: |
07 Jul 2024 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45072 |
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