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dc.contributor.authorKaranam, Balasubramanyam
dc.contributor.authorGambhira, Ratish
dc.contributor.authorPeng, Shiwen
dc.contributor.authorJagu, Subhashini
dc.contributor.authorKim, Dae-Jin
dc.contributor.authorKetner, Gary W
dc.contributor.authorStern, Peter L
dc.contributor.authorAdams, Robert J
dc.contributor.authorRoden, Richard B S
dc.date.accessioned2009-06-05T10:30:20Z
dc.date.available2009-06-05T10:30:20Z
dc.date.issued2009-02-11
dc.identifier.citationVaccination with HPV16 L2E6E7 fusion protein in GPI-0100 adjuvant elicits protective humoral and cell-mediated immunity. 2009, 27 (7):1040-9 Vaccineen
dc.identifier.issn0264-410X
dc.identifier.pmid19095032
dc.identifier.doi10.1016/j.vaccine.2008.11.099
dc.identifier.urihttp://hdl.handle.net/10541/69793
dc.description.abstractA vaccine comprising human papillomavirus type 16 (HPV16) L2, E6 and E7 in a single tandem fusion protein (termed TA-CIN) has the potential advantages of both broad cross-protection against HPV transmission through induction of L2 antibodies able to cross neutralize different HPV types and of therapy by stimulating T cell responses targeting HPV16 early proteins. However, patients vaccinated with TA-CIN alone develop weak HPV neutralizing antibody and E6/E7-specific T cell responses. Here we test TA-CIN formulated along with the adjuvant GPI-0100, a semi-synthetic quillaja saponin analog that was developed to promote both humoral and cellular immune responses. Subcutaneous administration to mice of TA-CIN (20 microg) with 50microg GPI-0100, three times at biweekly intervals, elicited high titer HPV16 neutralizing serum antibody, robust neutralizing titers for other HPV16-related types, including HPV31 and HPV58, and neutralized to a lesser extent other genital mucosatropic papillomaviruses like HPV18, HPV45, HPV6 and HPV11. Notably, vaccination with TA-CIN in GPI-0100 protected mice from cutaneous HPV16 challenge as effectively as HPV16 L1 VLP without adjuvant. Formulation of TA-CIN with GPI-0100 enhanced the production of E7-specific, interferon gamma producing CD8(+) T cell precursors by 20-fold. Vaccination with TA-CIN in GPI-0100 also completely prevented tumor growth after challenge with 5x10(4) HPV16-transformed TC-1 tumor cells, whereas vaccination with TA-CIN alone delayed tumor growth. Furthermore, three monthly vaccinations with 125 microg of TA-CIN and 1000 microg GPI-0100 were well tolerated by pigtail macaques and induced both HPV16 E6/E7-specific T cell responses and serum antibodies that neutralized all HPV types tested.
dc.language.isoenen
dc.subject.meshAdjuvants, Immunologic
dc.subject.meshAnimals
dc.subject.meshAntibodies, Viral
dc.subject.meshCD8-Positive T-Lymphocytes
dc.subject.meshCapsid Proteins
dc.subject.meshCytokines
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshImmunization, Secondary
dc.subject.meshInjections, Subcutaneous
dc.subject.meshMacaca
dc.subject.meshMice
dc.subject.meshMice, Inbred BALB C
dc.subject.meshNeutralization Tests
dc.subject.meshOncogene Proteins, Viral
dc.subject.meshPapillomavirus Infections
dc.subject.meshPapillomavirus Vaccines
dc.subject.meshRecombinant Fusion Proteins
dc.subject.meshRepressor Proteins
dc.subject.meshSaponins
dc.titleVaccination with HPV16 L2E6E7 fusion protein in GPI-0100 adjuvant elicits protective humoral and cell-mediated immunity.en
dc.typeArticleen
dc.contributor.departmentDepartment of Pathology, The Johns Hopkins University, Baltimore, MD 21231, USA.en
dc.identifier.journalVaccineen
html.description.abstractA vaccine comprising human papillomavirus type 16 (HPV16) L2, E6 and E7 in a single tandem fusion protein (termed TA-CIN) has the potential advantages of both broad cross-protection against HPV transmission through induction of L2 antibodies able to cross neutralize different HPV types and of therapy by stimulating T cell responses targeting HPV16 early proteins. However, patients vaccinated with TA-CIN alone develop weak HPV neutralizing antibody and E6/E7-specific T cell responses. Here we test TA-CIN formulated along with the adjuvant GPI-0100, a semi-synthetic quillaja saponin analog that was developed to promote both humoral and cellular immune responses. Subcutaneous administration to mice of TA-CIN (20 microg) with 50microg GPI-0100, three times at biweekly intervals, elicited high titer HPV16 neutralizing serum antibody, robust neutralizing titers for other HPV16-related types, including HPV31 and HPV58, and neutralized to a lesser extent other genital mucosatropic papillomaviruses like HPV18, HPV45, HPV6 and HPV11. Notably, vaccination with TA-CIN in GPI-0100 protected mice from cutaneous HPV16 challenge as effectively as HPV16 L1 VLP without adjuvant. Formulation of TA-CIN with GPI-0100 enhanced the production of E7-specific, interferon gamma producing CD8(+) T cell precursors by 20-fold. Vaccination with TA-CIN in GPI-0100 also completely prevented tumor growth after challenge with 5x10(4) HPV16-transformed TC-1 tumor cells, whereas vaccination with TA-CIN alone delayed tumor growth. Furthermore, three monthly vaccinations with 125 microg of TA-CIN and 1000 microg GPI-0100 were well tolerated by pigtail macaques and induced both HPV16 E6/E7-specific T cell responses and serum antibodies that neutralized all HPV types tested.


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