Progress in the Development of a Cervical Cancer Vaccine

Figures & data

Table 1 Contentious issues surrounding prophylactic vaccines

Prophylactic vaccines
Implementation issues
Age at wish to vaccinate
Vaccination of men
Duration of infection/need for booster doses
Coordination with screening programmes
Public education
Technology issues
Expense of manufacturing
Expense of distribution – cold chain
Type specificity
Combined therapeutic effect

Table 2 Published clinical trials of therapeutic HPV vaccines

Delivery system		Antigen	Participants	Key findings	Phase
Viral vector	Smith et al 2005	TA-HPV, Xenova E6-E7 fusion protein	11 patients CIN3, VIN3, VAIN	5 patients made novel HPV specific T cell responses after vaccination. No clinical responses	Phase I/II
	Corona-Guiterrez et al 2004	MVA E2 recombinant vaccinia	36 women CIN1,2 and 3	34/36 complete responses	Phase I/II
	Hallez et al 2004	Fusion protein PD-E7.	7 patients with CIN1 and 3.	5/7 CTL responses	Phase I/II
		E7 linked to Hemophilus influenza		7/7 antibody responses
	Davidson et al 2003	TA-HPV, Xenova, E6-E7 fusion protein	18 women with high grade VIN	8 women had partial clinical responses,13 women had HPV specific immune responses after vaccination	Phase II
				Correlation between response and pre-vaccination local immune status
	Kaufmann et al 2002	TA-HPV, Xenova, E6-E7 fusion protein	29 women stage 1b or 2a cervical cancer prior to radical hysterectomy	HPV specific CTL in 4 women Serological response in 8 women	Phase I/II
				Serological response in 8 women
Peptide	Ressing et al 2000	HPV 16 E7 peptides	15 women with advanced cervical cancer	T helper responses in 4 patients, No specific CTL responses	Phase I/II
	Muderspach et al 2000	E7 Peptide + IFA	18 women with high grade CIN or VIN	10/16 CTL responses 9/17 clinical responses	Phase I
				9/17 clinical responses
Protein	Einstein et al 2005	HSP-E7 fusion protein, Stressgen SGN-00101	32 women with CIN3 prior to LEEP	Ongoing study10/21 complete responses, 4/21 partial responses	Phase II
	Frazer 2004	Protein/Iscomatrix adjuvant E6E7-IMX, CSL	31 women with CIN randomized to vaccine or placebo	Most developed antibody responses	Phase I
				Approx half developed new CTL responses
	de Jong et al 2002	TA-CIN L2, E6, E7 Fusion protein, Xenova	40 healthy volunteers randomized to vaccine or placebo	TA-CIN specific IgG antibody and T cell proliferative responses in majority	Phase I
Prime boost	Smyth et al 2004	TA-HPV+TA-CIN, Xenova	29 women with high grade VIN	Antibody and CTL responses, no simple correlation with the clinical responses	Phase I/II
DNA	Garcia et al 2004	Plasmid DNA encoding fragments derived from E6 and E7 proteins in microparticles	161 women with CIN2/3 randomized to vaccine/placebo prior to cone	43% of vaccinated women cleared disease versus 27% of placebo recipients (not statistically significant).	Phase I/II
				Significant disease resolution in under 25 yo
DC	Ferrara et al 2003	Autologous DC pulsed with recombinant HPV16E7 and HPV18E7	15 women stage IV cervical cancer	Specific cellular responses in 4/11	Phase I/II

Abbreviations: CIN, cervical intraepithelial neoplasia; CTL: cytotoxic T lymphocyte; DC, dendritic cell; DNA, deoxyribonucleic acid; HPV, human papilloma virus; IFA, incomplete Freund's adjuvant; LEEP, loop electrosurgical excision procedure; MVA, modified vaccinia Ankara; PD, hemophilus influenza protein D; VAIN, vaginal intraepithelial neoplasia; VIN, vulval intraepithelial neoplasia.

Table 3 Active clinical trials of HPV vaccines

Trial name	Phase	Type	Age	Sponsor	Vaccine type
Phase III randomized study of vaccine therapy comprising human papillomavirus 16/18 L1 virus-like particle/AS04 vaccine versus hepatitis A vaccine (Havrix) for the prevention of grade 2 or 3 cervical intraepithelial neoplasia, adenocarcinoma in situ of the cervix, or invasive cervical cancer in younger healthy participants.	Phase III	Prevention	18 to 25	NCI	VLP
A study to evaluate the efficacy of quadrivalent HPV (types 6,11,16 and 18) L1 VLP in reducing the incidence of HPV 6,11, 16, and 18-related external genital warts, PIN, penile, perianal or perineal cancer, and the incidence of HPV 6,11,16 and 18 related genital infections in young men	Phase III	Prevention	16 to 23	Merck	VLP
Phase I/II study of pNGVL4a-Sig/E7(detox)/HSP70 DNA vaccine in preventing cervical cancer inpatients with human papillomavirus-16-positive grade 2 or 3 cervical intraepithelial neoplasia	Phase I/II	Prevention	Over 18	NCI	DNA
Phase II study of SGN-00101 immunotherapy in patients with grade III cervical intraepithelial neoplasia	Phase II	Prevention	18 and over	NCI	HSP
Phase II randomized study of SGN-00101 vaccine in human papillomavirus-16-positive patients with atypical squamous cells of undetermined significance or low grade squamous intraepithelial lesions of the cervix.	Phase II	Prevention	18 to 50	NCI	HSP
Surviving peptide vaccination for patients with advanced melanoma, pancreatic, colon and cervical cancer.	Phase I/II	Treatment	19 to 90		Peptide
Three clinical trials in progress in patients at different stages of HPV-related disease	Phase II	Treatment		University of Leiden	Long Peptide
Phase II adjuvant study of the recombinant vaccinia virus vaccine expressing the human papilloma virus 16, 18, E6, and E7 in early cervical cancer	Phase II	Treatment	19 and above	EORTC	Viral vector
Phase II clinical trial of MVA-HPV-IL2 in women with CIN 2/3 (incomplete title)	Phase II	Treatment		Transgene	Viral vector
A pilot study for the immunotherapy of recurrent cervical cancers using DCs pulsed with human papillomavirus type 16 E7 antigen	Phase I	Treatment	18 to 75	National Taiwan University Hospital	DC

Note: Information sourced from the NCI and US NIH websites.

Abbreviations: CIN, cervical intraepithelial neoplasia; DC, dendritic cells; DNA, deoxyribonucleic acid; EORTC, European organisation for research and treatment of cancer; MVA, modified vaccinia Ankara; NCI, National Cancer Institute; NIH, National Institutes of Health; PIN, Penile intraepithelial neoplasia; VLP, virus-like particles.

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