Activating the localized immune response in respiratory syncytial virus and cancer
Creators: name: Pietrok, Laura M.S.
Publisher: name: University of Iowa
Year: 2025
Subjects: cancer
respiratory syncytial virus
T cell
vaccine
public abstract
Antibodies

description: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in both young children and older adults resulting in high morbidity and mortality. Despite the immense health impact and economic burden caused by RSV worldwide, no licensed vaccine is currently available. I utilized an inbred mouse model to test the efficacy of a polyanhydride-based nanoparticle vaccine containing a prefusion-stabilized conformation of the fusion (F) protein and a CpG oligodeoxynucleotide adjuvant (RSVNanoVax). Prime-boost intranasal vaccination with RSVNanoVax protected mice from weight loss and airway dysfunction following an RSV challenge. Vaccination also mediated rapid viral clearance from the lungs and maintained a high efficacy up to 1-year post-vaccination. RSV F-directed IgG antibodies specific for sites Ø and II on the F protein were generated in the serum and exhibited high neutralizing capacity against RSV A and B virus strains. Vaccination also induced RSV-specific tissue-resident memory CD4 and CD8 T cells in the lungs capable of producing IFN-γ. Overall, this vaccine provides robust efficacy in an inbred mouse model.
description: Because humans are a genetically diverse population, it is critically important to test vaccine candidates in genetically diverse animal models. I utilized outbred Swiss Webster mice to determine the efficacy of RSVNanoVax in a more genetically diverse animal model. Intranasal vaccination induced robust titers of RSV F-directed antibodies in the serum as well as in the lungs and nasal passages. These antibodies were maintained at high titers out to at least one-year post-vaccination. Serum antibodies exhibited high neutralizing activity against RSV A and B virus strains for up to 1-year. Following RSV challenge, vaccinated mice exhibited rapid viral clearance in the lungs. In collaboration with Sigmovir Biosystems, Inc. and with financial support from the NIH, the efficacy of RSVNanoVax was tested in outbred cotton rats. Prime-boost vaccination induced RSV F-directed antibodies and reduced viral replication in the lower airways following challenge. Overall, RSVNanoVax represents a promising vaccine candidate capable of activating long-term immunity locally within the respiratory tract.
description: The activation of local immunity is also critical for the clearance of solid tissue cancers. Conventional standard of care cancer treatment options including chemotherapy and radiation provide variable efficacy and can be associated with debilitating side effects. High-dose intravenous ascorbate administration is emerging as a promising addition to standard of care therapies for several cancers. The impact of high-dose ascorbate treatment on the local anti-tumor immune response is poorly understood. I utilized human samples as well as syngeneic mouse models to examine immunological changes following high-dose ascorbate treatment in multiple cancers. Daily high-dose intravenous ascorbate administered concurrently with standard of care treatment reduced the overall burden of Lewis lung carcinoma and CMT-167 tumors compared to standard of care treatment alone. In mice, high-dose ascorbate increased the infiltration of tumor-specific CD8 T cells and enhanced their capacity to produce effector molecules including IFN-γ, TNF, and granzyme B. The efficacy of ascorbate was due in part to both CD4 and CD8 T cells, as well as IFN-γ and TNF production. These data suggest that high-dose ascorbate synergizes with standard of care treatments to promote a local anti-tumor immune response. Overall, my thesis work demonstrates that local activation of beneficial immune populations is critical for the clearance of both invading pathogens and tumor cells.