title: Local HPV Recombinant Vaccinia Boost Following Priming with an HPV DNA Vaccine Enhances Local HPV-Specific CD8+ T-cell-Mediated Tumor Control in the Genital Tract.
abstract: OBJECTIVE
  Two viral oncoproteins, E6 and E7, are expressed in all human papillomavirus (HPV)-infected cells, from initial infection in the genital tract to metastatic cervical cancer. Intramuscular vaccination of women with high-grade cervical intraepithelial neoplasia (CIN2/3) twice with a naked DNA vaccine, pNGVL4a-sig/E7(detox)/HSP70, and a single boost with HPVE6/E7 recombinant vaccinia vaccine (TA-HPV) elicited systemic HPV-specific CD8 T-cell responses that could traffic to the lesion and was associated with regression in some patients (NCT00788164).
  
  
  METHODS
  Here, we examine whether alteration of this vaccination regimen by administration of TA-HPV vaccination in the cervicovaginal tract, rather than intramuscular (IM) delivery, can more effectively recruit antigen-specific T cells in an orthotopic syngeneic mouse model of HPV16(+) cervical cancer (TC-1 luc).
  
  
  RESULTS
  We found that pNGVL4a-sig/E7(detox)/HSP70 vaccination followed by cervicovaginal vaccination with TA-HPV increased accumulation of total and E7-specific CD8(+) T cells in the cervicovaginal tract and better controlled E7-expressing cervicovaginal TC-1 luc tumor than IM administration of TA-HPV. Furthermore, the E7-specific CD8(+) T cells in the cervicovaginal tract generated through the cervicovaginal route of vaccination expressed the α4β7 integrin and CCR9, which are necessary for the homing of the E7-specific CD8(+) T cells to the cervicovaginal tract. Finally, we show that cervicovaginal vaccination with TA-HPV can induce potent local HPV-16 E7 antigen-specific CD8(+) T-cell immune responses regardless of whether an HPV DNA vaccine priming vaccination was administered IM or within the cervicovaginal tract.
  
  
  CONCLUSIONS
  Our results support future clinical translation using cervicovaginal TA-HPV vaccination.
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Yun-Yan
authors.initials: YY
authors.lastname: Sun
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Peng
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Liwen
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Yachea
authors.initials: Y
authors.lastname: Tsai
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Richard B S
authors.initials: RB
authors.lastname: Roden
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Cornelia L
authors.initials: CL
authors.lastname: Trimble
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, Maryland. wutc@jhmi.edu.
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005833:Genital Neoplasms, Female / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D006801:Humans; D007114:Immunization; D007117:Immunization, Secondary; D016130:Immunophenotyping; D051379:Mice; D018345:Mice, Knockout; D027383:Papillomaviridae / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins / Q000276:immunology; D030361:Papillomavirus Infections / Q000150:complications / Q000517:prevention & control*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000276:immunology*; D010641:Phenotype; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D015415:Biomarkers; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D019444:Vaccines, DNA; C100344:human papillomavirus vaccine, TA