The recent development of prophylactic vaccines protective against ?high risk? human papillomaviruses (HPV) is a landmark in medicine. The current vaccines are composed of recombinant virus-like particles (VLPs) of the major capsid protein, L1, including the high-risk HPV types 16 and 18. Phase II/III clinical trials have shown >95% efficacy of these VLP preparations in preventing HPV 16, 18 infection, and thus hopefully preventing the eventual development of about 70% of cervical cancers associated with these types. Despite this success the VLP vaccines have the adverse attributes of high cost ($360 for the initial three immunizations in the USA) and a requirement for refrigeration (i.e., cold chain). We have previously characterized the immunogenic properties of VLP subunits, pentameric L1 capsomeres. Capsomeres can be purified after recombinant expression of L1 in E. coli as untagged native proteins, at levels suggesting a significant reduction in manufacturing expense. The purified protein can be freeze-dried, resuspended, and stored at room temperature without loss of immunogenicity. Capsomeres have been suggested as a ?next generation? HPV vaccine that might be ideally suited for production and use in underdeveloped countries of the world where cervical cancer is particularly prevalent. We propose to use an HPV16 L1 capsomere protein that has been GMP produced (BioSidus, S.A.), vialed, and toxicology screened for study in a phase I human trial.
In Aims 1 and 2 we propose a dose escalation scheme of 15 subjects at each of three dose levels (10, 50, 250 micrograms), repeated three times, with concomitant analysis of toxicity, development of neutralizing antibodies, and cytotoxic T-cell responses. In the third aim, laboratory and animal experiments will test new vaccine formulation strategies, and evaluate the possibility that capsomere vaccines may be prepared as powders with adjuvants, which are thermostable

Public Health Relevance

The results of this project will determine whether capsomere vaccine preparations can proceed to further testing in a quadrivalent heat-stable formulation, under the auspices of the NCI PREVENT program. The goal is the development of a next generation HPV vaccine that is economically feasible for production and use in the underdeveloped world where the impact of cervical cancer on women?s health is greatest.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA098252-15
Application #
9554801
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
15
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Boitano, Teresa K L; Smith, Haller J; Rushton, Tullia et al. (2018) Impact of enhanced recovery after surgery (ERAS) protocol on gastrointestinal function in gynecologic oncology patients undergoing laparotomy. Gynecol Oncol 151:282-286
Anchoori, Ravi K; Jiang, Rosie; Peng, Shiwen et al. (2018) Covalent Rpn13-Binding Inhibitors for the Treatment of Ovarian Cancer. ACS Omega 3:11917-11929
Ooki, Akira; Dinalankara, Wikum; Marchionni, Luigi et al. (2018) Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma. Oncogene 37:5967-5981
Ahn, Julie; Bishop, Justin A; Roden, Richard B S et al. (2018) The PD-1 and PD-L1 pathway in recurrent respiratory papillomatosis. Laryngoscope 128:E27-E32
Silver, Michelle I; Rositch, Anne F; Phelan-Emrick, Darcy F et al. (2018) Uptake of HPV testing and extended cervical cancer screening intervals following cytology alone and Pap/HPV cotesting in women aged 30-65 years. Cancer Causes Control 29:43-50
Yang, J-Ming; Bhattacharya, Sayak; West-Foyle, Hoku et al. (2018) Integrating chemical and mechanical signals through dynamic coupling between cellular protrusions and pulsed ERK activation. Nat Commun 9:4673
Xing, Deyin; Zheng, Gang; Schoolmeester, John Kenneth et al. (2018) Next-generation Sequencing Reveals Recurrent Somatic Mutations in Small Cell Neuroendocrine Carcinoma of the Uterine Cervix. Am J Surg Pathol 42:750-760
Qiu, Jin; Peng, Shiwen; Ma, Ying et al. (2018) Epithelial boost enhances antigen expression by vaccinia virus for the generation of potent CD8+ T cell-mediated antitumor immunity following DNA priming vaccination. Virology 525:205-215
Ooki, Akira; Begum, Asma; Marchionni, Luigi et al. (2018) Arsenic promotes the COX2/PGE2-SOX2 axis to increase the malignant stemness properties of urothelial cells. Int J Cancer 143:113-126
Leath 3rd, Charles A; Monk, Bradley J (2018) Twenty-first century cervical cancer management: A historical perspective of the gynecologic oncology group/NRG oncology over the past twenty years. Gynecol Oncol 150:391-397

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