Enhancement of human papillomavirus (HPV) type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-CIN, an HPV16 L2E7E6 fusion protein vaccine

Jong, Annemieke de; O'Neill, Terence W; Khan, A Y; Kwappenberg, Kitty M. C.; Chisholm, Susan E.; Whittle, Nigel; Dobson, Jennifer; Jack, L C; Roberts, J. M.; Offringa, Rienk; Burg, Sjoerd H. van der; Hickling, Julian

doi:10.1016/s0264-410x(02)00350-x

Cited by 147 publications

(121 citation statements)

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“…at four weekly intervals (Ͼ70% of healthy volunteers gave IFN-␥ ELISPOT responses at this dose; Ref. 7), followed 4 weeks later by a boost vaccination comprising a single dose (2.5 ϫ 10 5 plaque-forming units) of TA-HPV by dermal scarification. Women were followed up for 12 weeks after completion of the vaccination schedule.…”

Section: Methodsmentioning

confidence: 99%

“…It was well tolerated when administered to healthy volunteers and induced antibody and proliferative responses against TA-CIN, as well as IFN-␥ ELISPOT responses to the HPV-16 oncoproteins (7). A small study of VIN patients who received three booster vaccinations with TA-CIN between 7 and 15 months after the TA-HPV vaccination (5) demonstrated HPV-16-specific proliferative T-cell and/or serological activity, but there was no direct correlation between immunological and clinical responses (8).…”

Section: Introductionmentioning

confidence: 99%

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Immunological Responses in Women with Human Papillomavirus Type 16 (HPV-16)-Associated Anogenital Intraepithelial Neoplasia Induced by Heterologous Prime-Boost HPV-16 Oncogene Vaccination

Smyth

Poelgeest

Davidson

et al. 2004

Clinical Cancer Research

125

101

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Purpose:The purpose is to study the immunogenicity of heterologous prime-boost human papillomavirus (HPV) oncogene vaccination in patients with anogenital intraepithelial neoplasia (AGIN).Experimental Design: Twenty-nine women with highgrade 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-␥ 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 < 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-␥ 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-␥ 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.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunological Responses in Women with Human Papillomavirus Type 16 (HPV-16)-Associated Anogenital Intraepithelial Neoplasia Induced by Heterologous Prime-Boost HPV-16 Oncogene Vaccination

Smyth

Poelgeest

Davidson

et al. 2004

Clinical Cancer Research

125

101

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“…25 Analysis of HPV16 L1, E2 and E6-specific T-cell reactivity by IFNc ELISPOT Interferon-g (IFNg) producing HPV-specific T cells (CD41 and/or CD81) were quantified using ELISPOT that was performed as described previously. 26,27 Briefly, PBMC were thawed, washed and seeded at a density of 1-2 3 10 6 cells per well of a 24-well plate (Costar, Cambridge, MA) in 1 ml of IMDM (Bio Whittaker, Verviers, Belgium) enriched with 10% human AB serum, in the presence or absence of indicated HPV 16 L1, E2, E6 and E7 peptide pools. As a positive control, PBMC were cultured in the presence of a memory recall mix (MRM), consisting of a mixture of tetanus toxoid (0.75 limus flocculentius/ml final concentration; National Institute of Public Health and Environment, Bilthoven, The Netherlands), Mycobacterium tuberculosis sonicate (2.5 lg/ml, generously donated by Dr. P. Klatser, Royal Tropical Institute, Amsterdam, The Netherlands) and Candida albicans (0.005%, HAL Allergenen Lab, Haarlem, The Netherlands).…”

Section: Antigensmentioning

confidence: 99%

Distinct regulation and impact of type 1 T‐cell immunity against HPV16 L1, E2 and E6 antigens during HPV16‐induced cervical infection and neoplasia

Poelgeest

Nijhuis

Kwappenberg

et al. 2005

Intl Journal of Cancer

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Cervical cancer is the possible outcome of a genital infection with high-risk human papillomavirus type 16 (HPV16) and is preceded by a phase of persistent HPV infection during which the host immune system fails to eliminate the virus. Our previous work showed that failure is reflected by the absence of type 1 T-cell immunity against HPV16 early antigens E2 and E6 in patients with HPV161 cervical lesions. We now show that a majority of both patients with cervical lesions and healthy subjects display HPV16 L1 peptide-specific type 1 T-cell responses with similar magnitude. The T-cell response in patients was directed at a broad range of peptides within L1, suggesting that during persistent or repeated exposure to HPV16 L1, the immune system maximizes its efforts to counter the viral challenge. Unlike the type 1 T-cell responses against HPV16 early antigens E2 and E6, type 1 T-cell immunity against L1 does not correlate with health or disease. This argues that T-cell responses against early and late HPV16 antigens essentially differ in the manner in which they are induced and regulated, as well as in their impact on the subsequent stages of HPV16-induced cervical disease. ' 2005 Wiley-Liss, Inc.Key words: HPV16; T cell; L1; VLP; cervical cancer; healthy individuals Infection of both men and women with oncogenic human papillomavirus (HPV) types, such as HPV type 16 (HPV16), is quite common 1-3 and leads to progressive disease in only a minor fraction of infected subjects. [4][5][6] The majority of the infections and HPV-induced epithelial lesions spontaneously resolve, most likely through intervention by the adaptive immune response. [7][8][9] In a majority of healthy subjects (approximately 60%) strong type 1 Tcell reactivity directed at the nonstructural proteins HPV16 E2 and E6 can be detected, [10][11][12] suggesting that these proteins are important target antigens for a protective immune response in humans, similar to what was found in animal models. [13][14][15] These animal models also revealed that L1-specific immunity can protect against infection with the cottontail rabbit papilloma virus 16 or the canine oral papilloma virus. [17][18][19] A large HPV16 L1-VLP vaccination trial in humans revealed that vaccine-induced immunity could prevent persistent HPV16 infections. 20 Although the immunologic evaluation of this trial was focused on the role of neutralizing antibodies in preventing viral infection, VLP vaccination must also have affected the underlying CD41 Th responses and possibly Th-dependent cell-mediated effector functions.Previous work has shown that patients diagnosed with HPV16 1 CIN display proliferative responses against HPV16 L1 21,22 and that there was no difference in such proliferative responses (measured by IL-2 production) between patients who cleared their lesions or in whom lesions persisted. 23 Immunity in such subjects may differ not so much in the quantitative aspects of the immune response but more in the quality of the response, as is indicated by our studies on immunity against...

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“…In this phase II trial, we used a combination of imiquimod and vaccination with TA-CIN, which is a subunit vaccine comprising a HPV16 E6E7L2 fusion protein, proven safe and immunogenic in previous phase I and II trials (de Jong et al, 2002;Davidson et al, 2004;Smyth et al, 2004).…”

mentioning

confidence: 99%

Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia

et al. 2010

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BACKGROUND: Vulval intraepithelial neoplasia (VIN) is a premalignant condition, which is frequently associated with type HPV16 infection, and multifocal disease has high rates of surgical treatment failure. METHODS: We report a phase II clinical trial of the topical immunomodulator, imiquimod, for 8 weeks, followed by 3 doses (weeks 10, 14 and 18) of therapeutic human papillomavirus (HPV) vaccination (TA-CIN, fusion protein HPV16 E6E7L2) in 19 women with VIN grades 2 and 3. Histology and HPV testing of biopsies were performed at weeks 0, 10, 20 and 52. Intralesional infiltration of T-cell subsets and lymphocyte proliferation for HPV systemic immune responses were also assessed. RESULTS: Lesion response (complete regression of VIN on histology) was observed in 32% (6 out of 19) of women at week 10, increasing to 58% (11 out of 19) at week 20 and 63% (12 out of 19) at week 52. At this time, 36% (5 out of 14) of lesions showed HPV16 clearance and 79% (15 out of 19) of women were symptom free. At week 20, after treatment with imiquimod and vaccination, there was significantly increased local infiltration of CD8 and CD4 T cells in lesion responders; in contrast, nonresponders (persistent VIN by histology) showed an increased density of T regulatory cells. After vaccination, only lesion responders had significantly increased lympho-proliferation to the HPV vaccine antigens. CONCLUSION: The therapeutic effect of treatment depends on the differential immune response of responders and non-responders with affect locally and systemically.

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Enhancement of human papillomavirus (HPV) type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-CIN, an HPV16 L2E7E6 fusion protein vaccine

Cited by 147 publications

References 20 publications

Immunological Responses in Women with Human Papillomavirus Type 16 (HPV-16)-Associated Anogenital Intraepithelial Neoplasia Induced by Heterologous Prime-Boost HPV-16 Oncogene Vaccination

Immunological Responses in Women with Human Papillomavirus Type 16 (HPV-16)-Associated Anogenital Intraepithelial Neoplasia Induced by Heterologous Prime-Boost HPV-16 Oncogene Vaccination

Distinct regulation and impact of type 1 T‐cell immunity against HPV16 L1, E2 and E6 antigens during HPV16‐induced cervical infection and neoplasia

Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia

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