Abstract

HPVisanecessarycauseof10%ofallcancersofwomenglobally,including 99% of cervical cancers. Rates of cervical cancer vary markedly by geographic region and level of economic development,with>85%occurringindevelopingcountries.SuccessfulprophylacticvaccinationagainsthrHPV typescanpreventdysplasiaandthuscervicalcancer.GlobalestimatesofHPVvaccinationdeliveryandcervical screeningbyregionandincomelevelshowvirtuallynosignificantdeliverytomanypoorerpopulationsofwomen worldwide.Thereare13hrHPVtypesplusagroupof11possiblycarcinogenictypes.LicensedHPVvaccines alltargetHPV16andHPV18,andonealsotargetsthenextfivemostcommontypesincervicalcancer.Since theydonottargetallcancer-associatedHPVtypes,screeningmustbemaintainedeveninvaccinatedwomen, adding to medical costs. In addition, the stringent cold-chain requirements of HPV vaccines provide a serious impedimenttotheirdeliveryindevelopingcountries.OuroverallgoalistodevelopanaffordableHPVvaccine that both extends the breadth of protection to all cancer-associated HPV types, and is stable at ambient temperature.Hereweaddressthisgoalwithtwoinnovations:1)displayinganL2-basedprotectiveepitope(RG1) thatisconservedforHPVsinauniquepositiononthesurfaceofHPV16L1VLPs,producingasingleantigen, broadlyprotectiveHPVvaccinetechnology,RG1-VLP,and2)theRG1-VLPvaccineisformulatedonalumand embeddedinglassyorganicmatricesformedbyadjustinglyophilizationandformulationparametersinorderto control ice crystal nucleation rates, glass transition temperatures, and other material properties and thereby protectagainstdegradationduringprocessing,shippingandstorage. HYPOTHESIS1:ColdchainstoragepropertiesareasignificantbarriertothedistributionofcurrentHPVvaccines, andthedevelopmentofapowderedRG1-VLPvaccineincludingadjuvantthatisthermostablewilladdressthis need.
Specific Aim 1 : Develop a GLP freeze-dry protocol for a powder formulation of RG1-VLPs in alum and study its in vitro temperature stability, and in murine models its immunogenicity and protective efficacy in comparisontoGardasil9. HYPOTHESIS2:RG1-VLPvaccinationissafeandwelltolerated.
SpecificAim2 :ToperformaDoseEscalation PhaseITrialoftheSafetyandImmunogenicityofthermostableRG1-VLPin36healthyfemalevolunteerswith theinclusionofacontrolGardasil9arminthestudy. HYPOTHESIS3:RG1-VLPvaccinationofhealthywomeninducesbroadlyprotectiveserumantibody.
Specific Aim3 :ToanalyzethelevelsofprotectiveantibodiesintheserumofpatientsfromthephaseIstudyinducedby RG1-VLPvaccinationorGardasil9.Wewillutilizethepassivetransferassaytomeasureprotectiveresponses, as well as L2 and L1 VLP ELISA and in vitro neutralization assays to quantify antigen-specific neutralizing antibodytitersinserum.

Public Health Relevance

Oncogenichumanpapillomavirus(HPV)infectionisanecessarycauseof10%ofallcancersofwomenglobally, including99%ofcervicalcancers.Tohelpovercomedisparitiesinprimarypreventionofcervicalcancer,here weseektodevelopanaffordableHPVvaccinethatbothextendsthebreadthofprotectiontocoverallcancer- associatedHPVtypesandisstableatambienttemperature.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA098252-17
Application #
10005175
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2003-09-30
Project End
2024-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
17
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205

  Publications

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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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