PURPOSE Anogenital intraepithelial neoplasia is a chronic disorder associated with infection by high-risk human papillomavirus (HPV) types. It is frequently multifocal and recurrence after conventional treatment is high. Boosting HPV-specific cell-mediated immune responses may reduce progression to carcinoma and could lead to disease clearance. We have tested the safety, immunogenicity, and efficacy of a recombinant vaccinia candidate vaccine (TA-HPV) in women with anogenital intraepithelial neoplasia. EXPERIMENTAL DESIGN Twelve women, aged 42-54 years with high-grade HPV-positive vulval or vaginal intraepithelial neoplasia of up to 15 years duration, completed a Phase II study of TA-HPV, a live recombinant vaccinia virus, expressing modified versions of the E6 and E7 open reading frames from HPV-16 and HPV-18. RESULTS The vaccine was well tolerated. Five of 12 (42%) patients showed at least a 50% reduction in total lesion diameter over 24 weeks with 1 patient showing complete regression of her lesion. Overall, 83% of women showed some improvement with an average decrease in lesion size of 40%. All cases showed an increased IgG titer and T-cell response to the vaccinia virus. An IFN-gamma enzyme-linked immunospot assay using pooled 22-mer peptides spanning HPV-16 E6 and E7 showed an increased specific T-cell response after vaccination in 6 of the 10 cases available for testing. There was no increase in specific cytotoxic response to selected individual HLA class I-restricted HPV-16 E6/7 peptides. CONCLUSIONS The results suggest that the vaccine may have an effect on HPV-positive vulval intraepithelial neoplasia/vaginal intraepithelial neoplasia and that additional studies are warranted to develop an effective therapeutic vaccine.

This study assessed the immunological and clinical responses of women with human papillomavirus (HPV) 16-associated high-grade vulval intra-epithelial neoplasia (VIN) vaccinated with TA-HPV, a recombinant vaccinia virus encoding modified HPV 16 and 18 E6 and E7. Eighteen women with HPV 16-positive high-grade VIN were vaccinated with TA-HPV. The extent of their baseline disease was compared after 24 weeks by lesion measurements and histological analysis. Viral load was assessed pre- and postvaccination by real time PCR. Cell-mediated immunity to HPV 16 E6 and/or E7 peptides (HLA-A2 epitopes) or vaccinia-infected cell lysates was determined by IFN-gamma enzyme-linked immunospot (ELISPOT) and T cell proliferation using an HPV 16 L2E6E7 fusion protein. Antibodies were measured by ELISA using vaccinia-infected cell lysates or HPV 16 and 18 E6 and E7 glutathione S-transferase-fusion proteins. Lesion-infiltrating CD4(+), CD8(+), CD1a(+), and CD68(+) immune cells were assessed by immunohistochemistry. The single vaccination with TA-HPV was well tolerated, and all patients showed an increased ELISPOT and/or antibody response to vaccinia. There were significant differences in HPV-16 E7-specific ELISPOT and L2E6E7 proliferative responses in the patients at one or more time points postvaccination as compared with the prevaccination status; two patients showed transient increased antibody responses. Overall, 13 women showed an increased HPV 16-specific immune response by one or more methodologies after immunization. Eight patients demonstrated a reduction in lesion diameter of at least 50% and a further four patients showed significant symptom relief. Viral load was reduced or cleared in six of eight lesion responders but also in six of ten nonresponders. Before vaccination, clinical responders had significantly higher levels of lesion-associated CD4(+), CD8(+), and CD1a(+)-immune cells than nonresponders. There were no differences in CD68 (macrophages) between responders and nonresponders before or after vaccination. Nonresponders did show a significant increase in CD4(+)- and CD8(+)- but not CD1a(+)-immune cells postvaccination but at lower levels overall than responder patients. Local immune infiltration may be a critical factor in potential responsiveness to vaccine therapy in HPV-associated neoplasia and should be carefully monitored in future placebo-controlled trials of immunotherapy for VIN.

PURPOSE:Cervical cancer, the second most common malignancy in women worldwide, is almost invariably associated with infection by human papillomavirus (HPV). HPV-16 or -18 is commonly present in 70% of cervical cancers. HPV-positive tumor cells present antigens of the viral protein in the context of human leukocyte antigen (HLA) class I that can be recognized by CTLs. We have conducted a study in patients with early-stage cervical cancer to assess the safety and immunological effects of vaccination with TA-HPV, a live recombinant vaccinia virus expressing modified forms of the HPV-16 and -18 E6 and E7 proteins.EXPERIMENTAL DESIGN:Twenty-nine patients with clinical International Federation of Gynecologists and Obstetricians (FIGO) stage Ib or IIa cervical cancer were given two vaccinations with TA-HPV at least 4 weeks apart, starting 2 weeks before radical hysterectomy. Patients were monitored closely for side effects of the vaccination. Serial blood samples were examined for HPV-specific CTLs or changes in levels of antibodies to HPV-16 or -18 E6 and E7 proteins and to vaccinia virus.RESULTS:Vaccination with recombinant vaccinia was well tolerated in all patients with only mild to moderate local toxicity, and no serious adverse events were attributable to the vaccine. After a single vaccination, HPV-specific CTLs were found in four patients (HLA A1, A3, three patients; HLA A1, A24, one patient). Eight patients developed HPV-specific serological responses.CONCLUSIONS:This study confirmed the safety and immunogenicity of the vaccine in a proportion of those patients vaccinated. Additional clinical studies using TA-HPV in combination with an additional experimental vaccine for HPV-16 are currently under way.

Conference Article| May 01 1997 Herpes virus-specific immune responses in individuals experiencing recurrent genital herpes Christopher M. Boswell; Christopher M. Boswell 1Cantab Pharmaceuticals Research Ltd, Cambridge Science Park, Cambridge CB4 4GN Search for other works by this author on: This Site PubMed Google Scholar Imogen A. Duncan; Imogen A. Duncan 1Cantab Pharmaceuticals Research Ltd, Cambridge Science Park, Cambridge CB4 4GN Search for other works by this author on: This Site PubMed Google Scholar Julie Uttridge; Julie Uttridge 1Cantab Pharmaceuticals Research Ltd, Cambridge Science Park, Cambridge CB4 4GN Search for other works by this author on: This Site PubMed Google Scholar Christopher Sonnex; Christopher Sonnex 2Department of GUM, Addenbrookes Hospital, Cambridge CB2 2QQ Search for other works by this author on: This Site PubMed Google Scholar Julian K. Hickling Julian K. Hickling 1Cantab Pharmaceuticals Research Ltd, Cambridge Science Park, Cambridge CB4 4GN Search for other works by this author on: This Site PubMed Google Scholar Author and article information Publisher: Portland Press Ltd Online ISSN: 1470-8752 Print ISSN: 0300-5127 © 1997 Biochemical Society1997 Biochem Soc Trans (1997) 25 (2): 278S. https://doi.org/10.1042/bst025278s Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation Christopher M. Boswell, Imogen A. Duncan, Julie Uttridge, Christopher Sonnex, Julian K. Hickling; Herpes virus-specific immune responses in individuals experiencing recurrent genital herpes. Biochem Soc Trans 1 May 1997; 25 (2): 278S. doi: https://doi.org/10.1042/bst025278s Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1997 Biochemical Society1997 Article PDF first page preview Close Modal You do not currently have access to this content.