Phase I/II trial of immunogenicity of a human papillomavirus (HPV) type 16 E7 protein-based vaccine in women with oncogenic HPV-positive cervical intraepithelial neoplasia.
OBJECTIVE
Infection with oncogenic human papillomavirus (HPV) and HPV-16 in particular is a leading cause of anogenital neoplasia. High-grade intraepithelial lesions require treatment because of their potential to progress to invasive cancer. Numerous preclinical studies have demonstrated the therapeutic potential of E7-directed vaccination strategies in mice tumour models. In the present study, we tested the immunogenicity of a fusion protein (PD-E7) comprising a mutated HPV-16 E7 linked to the first 108 amino acids of Haemophilus influenzae protein D, formulated in the GlaxoSmithKline Biologicals adjuvant AS02B, in patients bearing oncogenic HPV-positive cervical intraepithelial neoplasia (CIN).


METHODS
Seven patients, five with a CIN3 and two with a CIN1, received three intramuscular injections of adjuvanted PD-E7 at 2-week intervals. Three additional CIN1 patients received a placebo. CIN3 patients underwent conization 8 weeks postvaccination. Cytokine flow cytometry and ELISA were used to monitor antigen-specific cellular and antibody responses from blood taken before and after vaccine or placebo injection.


RESULTS
Some patients had preexisting systemic IFN-gamma CD4+ (1/10) and CD8+ (5/10) responses to PD-E7. Vaccination, not placebo injection, elicited systemic specific immune responses in the majority of the patients. Five vaccinated patients (71%) showed significantly increased IFN-gamma CD8+ cell responses upon PD-E7 stimulation. Two responding patients generated long-term T-cell immunity toward the vaccine antigen and E7 as well as a weak H. influenzae protein D (PD)-directed CD4+ response. All the vaccinated patients, but not the placebo, made significant E7- and PD-specific IgG.


CONCLUSIONS
The encouraging results obtained from this study performed on a limited number of subjects justify further analysis of the efficacy of the PD-E7/AS02B vaccine in CIN patients.
Hallez
Sophie
S
Chimie Biologique, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, 12 rue des Professeurs Jeener et Brachet, 6041 Gosselies, Belgium. shallez@ulb.ac.be
Simon
Philippe
P
Maudoux
Frédéric
F
Doyen
Jean
J
Noël
Jean-Christophe
JC
Beliard
Aude
A
Capelle
Xavier
X
Buxant
Frédéric
F
Fayt
Isabelle
I
Lagrost
Anne-Cécile
AC
Hubert
Pascale
P
Gerday
Colette
C
Burny
Arsène
A
Boniver
Jacques
J
Foidart
Jean-Michel
JM
Delvenne
Philippe
P
Jacobs
Nathalie
N
D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology; D000917:Antibody Formation; D001426:Bacterial Proteins / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D002352:Carrier Proteins / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007072:Immunoglobulin D / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D008074:Lipoproteins / Q000276:immunology; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D027383:Papillomaviridae / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000276:immunology / Q000628:therapy* / Q000821:virology; D053918:Papillomavirus Vaccines; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D014611:Vaccination; D002578:Uterine Cervical Dysplasia / Q000276:immunology / Q000628:therapy* / Q000821:virology
D000914:Antibodies, Viral; D001426:Bacterial Proteins; D019496:Cancer Vaccines; D002352:Carrier Proteins; D007072:Immunoglobulin D; D008074:Lipoproteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D011993:Recombinant Fusion Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma; C067989:glpQ protein, Haemophilus influenzae