Human papillomavirus (HPV) infections will continue to be ubiquitous and frequent in patient populations despite the recent development of protective virus-like particle (VLP) vaccines. Currently, the vaccine targets 4 of the 15+ HPV types that are associated with epithelial malignancies, and provides protection only to the vaccine-related types with minimal cross-protection to related types. HPV-associated malignancies include cancers of the cervix, anogenital mucosa, oral mucosa and skin, with cervical cancer predominating at 500,000 deaths per year world-wide. Post-infection therapeutic vaccines that activate T-cell-mediated immunity therefore will be a key adjunct method to control existing HPV-associated disease. However, critical questions regarding the mechanism of immunological clearance of HPV infections remain unanswered. For example, we do not yet know: (i) which viral antigens can induce the most effective immune-mediated clearance of HPV infections;(ii) which viral epitopes produce the most potent protective and therapeutic immunity to papillomavirus infections and associated cancer;(iii) what role CD8+ T-cells play in control and clearance of HPV infections, and (iv) why naturally developing CMI responses to persistent papillomavirus infections fail to clear these viral-associated tumors and cancers. The long range goal of our research program is directed at answering these questions. To better understand host immune responses to papillomaviruses (PVs), we need effective preclinical models of natural papillomavirus (PV) infection with subsequent progression to PV-associated malignancies. Unfortunately, no small inbred rodent animal model of PV infections exists for immunological and virological studies. In the absence of mouse and rat PV model systems, the most effective small laboratory animal model is the domestic rabbit which is susceptible to infection by the cutaneous-tropic cottontail rabbit PV (CRPV) and the mucosotropic rabbit oral PV (ROPV). We have recently developed a novel HLA-A2.1 transgenic rabbit model to assist our studies on key HPV and CRPV epitopes that trigger CD8 T-cell-mediated immunity. We will pursue 3 critical aims in this renewal application as follows: 1) Assess the role of therapeutic and protective CMI-induced immunity to papillomaviral tumor antigens in a rabbit papillomavirus tumor model. 2) Determine the role of HLA-A2.1 restricted papillomaviral antigen epitopes that trigger CD8 T-cell protective and therapeutic anti-tumor immunity, and 3) Determine the mechanism of immunological responses to viral tumor antigens that lead to therapeutic resolution and/or enhancement of papillomaviral tumors and cancers. Upon conclusion of these experiments, it is our expectation that the combination of work proposed in aims 1, 2 and 3 will translate directly into the design of improved therapeutic vaccines for HPV infections in patient populations.

Public Health Relevance

Persistent Human papillomavirus (HPV) infections can lead to cervical cancer and up to 500,000 deaths in women each year world-wide. Current vaccines will provide protection, but not cures for women with these persistent infections. The goal of this research project is to optimize approaches to induce immunotherapeutic T-cell immune responses that can eliminate existing HPV infections and associated cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Pennsylvania State University
Schools of Medicine
United States
Zip Code
Esteves, Pedro J; Abrantes, Joana; Baldauf, Hanna-Mari et al. (2018) The wide utility of rabbits as models of human diseases. Exp Mol Med 50:66
Cooper, T K; Griffith, J W; Chroneos, Z C et al. (2017) Spontaneous Lung Lesions in Aging Laboratory Rabbits ( Oryctolagus cuniculus). Vet Pathol 54:178-187
Christensen, Neil D; Budgeon, Lynn R; Cladel, Nancy M et al. (2017) Recent advances in preclinical model systems for papillomaviruses. Virus Res 231:108-118
Christensen, Neil D (2016) HPV disease transmission protection and control. Microb Cell 3:476-490
Cladel, Nancy M; Budgeon, Lynn R; Balogh, Karla K et al. (2016) Mouse papillomavirus MmuPV1 infects oral mucosa and preferentially targets the base of the tongue. Virology 488:73-80
Hu, Jiafen; Budgeon, Lynn R; Cladel, Nancy M et al. (2015) Tracking vaginal, anal and oral infection in a mouse papillomavirus infection model. J Gen Virol 96:3554-65
Peng, Xuwen; Roshwalb, Sara; Cooper, Timothy K et al. (2015) High incidence of spontaneous cataracts in aging laboratory rabbits of an inbred strain. Vet Ophthalmol 18:186-90
Hu, Jiafen; Budgeon, Lynn R; Balogh, Karla K et al. (2014) Long-peptide therapeutic vaccination against CRPV-induced papillomas in HLA-A2.1 transgenic rabbits. Trials Vaccinol 3:134-142
Hu, Jiafen; Brendle, Sarah; Balogh, Karla et al. (2014) Antibody detection in tear samples as a surrogate to monitor host immunity against papillomavirus infections in vaccinated and naturally infected hosts. J Gen Virol 95:2030-7
Cladel, Nancy M; Budgeon, Lynn R; Hu, Jiafen et al. (2013) Synonymous codon changes in the oncogenes of the cottontail rabbit papillomavirus lead to increased oncogenicity and immunogenicity of the virus. Virology 438:70-83

Showing the most recent 10 out of 79 publications