title: Immunological responses in women with human papillomavirus type 16 (HPV-16)-associated anogenital intraepithelial neoplasia induced by heterologous prime-boost HPV-16 oncogene vaccination.
abstract: OBJECTIVE
  The purpose is to study the immunogenicity of heterologous prime-boost human papillomavirus (HPV) oncogene vaccination in patients with anogenital intraepithelial neoplasia (AGIN).
  
  
  METHODS
  Twenty-nine women with high-grade AGIN received three i.m. doses of TA-CIN (HPV-16 L2/E6/E7 protein) at four weekly intervals followed by a single dermal scarification of vaccinia HPV-16/18 E6/E7 and were followed up for 12 weeks. Immunity to HPV-16 was assessed by lymphoproliferation, IFN-gamma enzyme-linked immunospot (ELISPOT), and ELISA.
  
  
  RESULTS
  The patient group significantly responded to TA-CIN and not to the control antigen HPV-6 L2/E7 at all postvaccination time points when compared with baseline responses (P < or = 0.05). Ten of the patients showed at least a 3-fold increase in TA-CIN-specific proliferation at one or more time points after vaccination. Comparison of stimulation with HPV-16 E6- or E7-GST fusion proteins showed that proliferative responses were biased to HPV-16 E6. This bias was also seen by IFN-gamma ELISPOT using overlapping peptides, with HPV-16 E6- or E7-specific T cells being detected in 9 and 2 patients, respectively. In addition, vaccination resulted in the induction of antibodies against the HPV-16 oncoproteins. Of the 6 clinical responders, 2 patients showed both a proliferative TA-CIN-specific response and an E6-specific IFN-gamma response, whereas 3 other patients displayed E6-specific reactivity only. Stable disease was recorded in 19 patients, 8 of whom showed a concomitant TA-CIN-specific proliferative and/or E6-specific T-cell response. Of the 4 progressors, 2 failed to make a T-cell response and 2 responded by either proliferation or E6 ELISPOT alone.
  
  
  CONCLUSIONS
  The prime-boost regimen is immunogenic in AGIN patients (humoral and cellular immunity), but there is no simple relationship between induction of systemic HPV-16-specific immunity and clinical outcome. Other factors that may play a role in the eradication of long-term established AGIN lesions need to be determined to identify the patient group that would benefit from immunotherapy with the vaccines used in this study.
authors.affiliation: Cancer Research UK Immunology Group, Paterson Institute for Cancer Research, Christie Hospital, Manchester, United Kingdom.
authors.forename: Lucy J C
authors.initials: LJ
authors.lastname: Smyth
authors.forename: Mariëtte I E
authors.initials: MI
authors.lastname: Van Poelgeest
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Davidson
authors.forename: Kitty M C
authors.initials: KM
authors.lastname: Kwappenberg
authors.forename: Debbie
authors.initials: D
authors.lastname: Burt
authors.forename: Peter
authors.initials: P
authors.lastname: Sehr
authors.forename: Michael
authors.initials: M
authors.lastname: Pawlita
authors.forename: Stephen
authors.initials: S
authors.lastname: Man
authors.forename: Julian K
authors.initials: JK
authors.lastname: Hickling
authors.forename: Alison N
authors.initials: AN
authors.lastname: Fiander
authors.forename: Amanda
authors.initials: A
authors.lastname: Tristram
authors.forename: Henry C
authors.initials: HC
authors.lastname: Kitchener
authors.forename: Rienk
authors.initials: R
authors.lastname: Offringa
authors.forename: Peter L
authors.initials: PL
authors.lastname: Stern
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: Van Der Burg
mesh_terms: D000914:Antibodies, Viral / Q000097:blood; D001005:Anus Neoplasms / Q000276:immunology* / Q000517:prevention & control; D002455:Cell Division / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005833:Genital Neoplasms, Female / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D009856:Oncogene Proteins, Viral / Q000276:immunology; D027383:Papillomaviridae / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000276:immunology* / Q000517:prevention & control; D012097:Repressor Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D014765:Viral Vaccines; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma