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The Safety and Efficacy of Early-Life RSV Vaccination Approaches: The Double-Edged Sword of Host Immunity

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 (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Kosanovich, Jessica Ljlk190@pitt.edujlk190
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorEmpey, Kerrykme33@pitt.edukme33
Committee ChairNolin, Thomasnolin@pitt.edunolin
Committee MemberLi, Songsol4@pitt.edusol4
Committee MemberFernandez, Christianchf63@pitt.educhf6
Committee MemberOury, Timtdoury@pitt.edutdoury
Committee MemberDiPaolo,
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 2023 16:37


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