title: Epitope specificity and longevity of a vaccine-induced human T cell response against HPV18.
abstract: Persistent human papillomavirus (HPV) type 16 and 18 infection can lead to pre-malignant and malignant diseases of the lower genital tract. Several lines of evidence suggest that T cell responses can control HPV infection. However, relative to other human viruses, strong effector memory T cell responses against HPV have been difficult to detect. We used an in vitro stimulation step prior to enzyme-linked immunospot assays to identify IFN-gamma-secreting T cells specific for HPV16 and 18 E6/E7 peptides. This allowed the detection of HPV-specific CD4+ T cells that were not evident in direct ex vivo assays. T cell responses against HPV16 or 18 peptides were detected in healthy volunteers (7/9) and patients with lower genital tract neoplasia (10/20). Importantly, this assay allowed tracking of vaccine-induced T cell responses in nine patients, following inoculation with a live recombinant vaccinia virus (HPV16 and 18 E6/E7, TA-HPV). Novel vaccine-induced T cell responses were demonstrated in five patients, but no clinical responses (lesion regressions) were seen. For one vaccinated patient, the T cell response was mapped to a single dominant HPV18 E7 epitope and this response was sustained for >3 years. Our data suggest that systemic memory T cells against HPV16 and 18, induced naturally or by TA-HPV vaccination, are relatively rare. Nevertheless, the assay system developed allowed estimation of magnitude, epitope specificity, and longevity of vaccine-induced CD4+ T cell responses. This will be useful for vaccine design and measurement of immunological endpoints in clinical trials.
authors.affiliation: Section of Infection and Immunity, Wales College of Medicine, Cardiff University, Henry Wellcome Research Building, Heath Park, Cardiff CF14 4XX, UK.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Smith
authors.forename: Amanda
authors.initials: A
authors.lastname: Tristram
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gallagher
authors.forename: Alison N
authors.initials: AN
authors.lastname: Fiander
authors.forename: Stephen
authors.initials: S
authors.lastname: Man
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000032:analysis*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007156:Immunologic Memory; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D027383:Papillomaviridae / Q000276:immunology; D030361:Papillomavirus Infections / Q000276:immunology*; D053918:Papillomavirus Vaccines; D010455:Peptides / Q000276:immunology; D002578:Uterine Cervical Dysplasia / Q000276:immunology / Q000821:virology; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; D014846:Vulvar Neoplasms / Q000276:immunology / Q000821:virology
chemical_list: D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D018984:Epitopes, T-Lymphocyte; D009856:Oncogene Proteins, Viral; D053918:Papillomavirus Vaccines; D010455:Peptides; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; C100344:human papillomavirus vaccine, TA