International Journal of Gynecological Cancer:
Efficacy of Human Papillomavirus Vaccines: A Systematic Quantitative Review
Medeiros, Lidia Rosi MD, PhD*; Rosa, Daniela Dornelles MD, PhD†; da Rosa, Maria Inês MD, PhD*‡; Bozzetti, Mary Clarisse MD, PhD*†§; Zanini, Roselaine Ruviaro PhD*& par;
*Federal University of Rio Grande do Sul; and †Hospital Fêmina and Hospital Moinhos deVento, Porto Alegre; ‡University of Extremo Sul Catarinense, Criciúma; §Department of Social Medicine, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre; and ∥Department of Statistics, Federal University of Santa Maria, Santa Maria,Brazil.
Address correspondence and reprint requests to Lidia Rosi Medeiros, MD, PhD, José de Alencar 1244 apt 1009, Porto Alegre, RS, Brasil, CEP 90880-480. E-mail: email@example.com.
The authors declare no conflicts of interest.
Dr. Medeiros had full access to all data and take responsibility for the integrity and the accuracy of the analysis. Dr. Rosa, Dr. da Rosa, and Dr. Bozzetti organized the study concept and the design. Dr. Zanini acquired, analyzed, and interpreted the data. All authors drafted the manuscript. Dr. Medeiros and Dr. Zanini performed the statistical analysis.
Human papillomavirus (HPV) types cause approximately 70% of cervical cancer worldwide. Two vaccines have been recently evaluated in randomized controlled trials: the bivalent vaccine for HPV 16 and 18 (Cervarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) and the quadrivalent vaccine for HPV 6, 11, 16, and 18 (Gardasil, Merck and Co, Inc, Whitehouse Station, NJ). We have performed a systematic review of all randomized controlled trials in which vaccines against HPV were compared with placebo regarding efficacy, safety, and immunogenicity. Six studies met the inclusion criteria, which included 47,236 women. The first objective in this systematic review was to assess vaccine efficacy in the prevention of cytologically and/or histologically proven lesions. And the secondary objective was the evaluation of safety and vaccine immunogenicity. Bivalent and quadrivalent HPV vaccines significantly reduced the rate of lesions in the cervix, vulva, vagina, and anogenital region, with efficacy of 93% (95% confidence interval [CI], 87-96) and 62% (95% CI, 27-70), respectively, when compared with the control groups according to intention to treat. Regarding safety, we found more symptoms in the bivalent vaccine group (35%; 95% CI, 5-73) when compared with the control groups. In regard to vaccine immunogenicity, there was seroconversion in the group that received the vaccine when compared with the placebo group in the bivalent and quadrivalent vaccines. Prophylactic vaccination can prevent HPV infection in women aged 9 to 26 years not previously infected with the HPV subtypes covered by the vaccines. To evaluate cervical cancer incidence and mortality, a longer follow-up is necessary.
Infection by human papillomavirus (HPV) is an important cause of cervical cancer, which is the second cause of female cancer mortality worldwide with 288,000 deaths yearly.1 Molecular studies show that HPV DNA is present in almost all (99.7%) cervical cancers. Human papillomavirus type 16 causes about half of cases, and type 18, about 13% of them.2
The incidence of HPV infections is rising, with 6.2 million new cases diagnosed annually.3 A common manifestation of low-risk HPV (types 6 and 11) infection is the appearance of genital warts. Infection of the cervical epithelium with low-risk HPV types may manifest as noninvasive low-grade squamous intraepithelial lesions (Lo-SIL) also referred to as cervical intraepithelial neoplasia type 1 (CIN 1). High-grade squamous intraepithelial lesions (Hi-SIL) include CIN grades 2 and 3 and are associated with persistent infection with high-risk HPV types (16 and 18). These types are the most important risk factors for developing premalignant lesions and invasive cervical cancer.4
Two vaccines have been recently evaluated in randomized controlled trials: the bivalent vaccine for HPV 16 and 18 (Cervarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) and the quadrivalent vaccine for HPV 6, 11, 16, and 18 (Gardasil, Merck and Co, Inc, Whitehouse Station, NJ). The latter has already received approval by the US Food and Drug Administration,5 showing prevention of cervical cancer, precancerous genital lesions, and genital warts. Gardasil is routinely recommended to girls aged 9 to 26 years.6,7
We have performed a systematic review with all randomized controlled trials in which vaccines against HPV were compared with placebo regarding efficacy, safety, and immunogenicity.
Identification of Studies
A comprehensive search on MEDLINE, CANCERLIT, LILACS, and EMBASE databases was made from January 1997 to September 2007. The medical subjects heading (MeSH) and text words for the terms: "cervix neoplasm," "cervix dysplasia," "vulvar diseases," "vulvar dysplasia," "vaginal diseases," "vaginal dysplasia," "anogenital diseases," associated with "human papilloma virus," "Papillomavirus*," "papillom virus*," "Papovavirida*" and "vaccine" or "vaccination" were combined with the MeSH terms: "randomized controlled trial," "controlled clinical trial." The search was limited to human studies but had no language restrictions. In addition, the Cochrane Library 2007 (issue 2) was searched. Reference lists of all available primary studies were reviewed to identify additional relevant citations.
This review focused on randomized, placebo-controlled, double-blind trials in which the vaccines against HPV were evaluated in women aged between 9 and 26 years. We chose 3 different kinds of vaccine that used L1 virus-like particle (L1-VLP)8-13: the quadrivalent HPV 6, 11, 16, 18 vaccine (20/40/40/20 μg, Gardasil),8,9 the univalent HPV 16 vaccine (40 μg; Merck Research Laboratories, West Point, PA),10 and the bivalent HPV 16 and 18 (20 μg; Cervarix; GlaxoSmithKline Biologicals).11-13 Vaccine and placebo were visually distinguishable. The trials did not exclude subjects with prior or ongoing HPV infection of any type. Thus, women who were seropositive for HPV antibodies (ie, had developed immune responses to HPV infection) and women who were HPV DNA positive (ie, had evidence of ongoing HPV infection) were enrolled.
For data extraction, we classified CIN grades II and III as Hi-SIL and CIN I as Lo-SIL. In addition, subjects with vulval intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VAIN), and anal intraepithelial neoplasia (AIN) associated with HPV infection (grades I, II, and III, according to the International Federation of Gynecology and Obstetrics) were included.14 For inclusion in the systematic review, it was necessary to have a final histological or cytological diagnosis of normal or benign cervical lesion, Lo-SIL, Hi-SIL, adenocarcinoma in situ, invasive carcinoma of the cervix, VIN, VAIN, and AIN associated with HPV infection by enzyme-linked immunosorbent assay or polymerase chain reaction. We excluded studies that did not describe final histological or cytological diagnosis, as well as cohort or case-control studies.
The first objective of this systematic review was to assess vaccine efficacy in the prevention of cytologically and/or histologically proven lesions (Lo-SIL, Hi-SIL, VIN, VAIN, AIN, adenocarcinoma in situ of the cervix, or cancer of the cervix associated with HPV infection). The secondary objective was to evaluate safety and vaccine immunogenicity. To evaluate tolerance, a detailed analysis was performed with classification of adverse events as local, systemic, and severe effects. Vaccine immunogenicity was evaluated in participants who were initially shown to be seronegative to HPV by enzyme-linked immunosorbent assay or by polymerase chain reaction (incident HPV) and who had persistent HPV infection with seroconversion (ie, had developed an immune response to HPV infection).
The studies were identified independently by 4 investigators (M.I.R, L.R.M, D.D.R, R.R.Z). Final eligibility criteria were defined by using a checklist. Disagreements about these criteria were initially solved by consensus, and when this was not possible, they were arbitrarily solved by a fifth reviewer (M.C.B). Two reviewers (L.R.M and R.R.Z) performed the statistical analysis. The agreement among reviewers was statistically computed. Only 1 author of the published clinical trials was contacted.13
All articles meeting the eligibility criteria were assessed for their methodological quality. This assessment involved scrutinizing the study designs and the relevant characteristics of the study participants. The quality of allocation concealment was graded as adequate (A), unclear (B), or inadequate (C) according to the Cochrane Gynaecological Cancer Group.15-19 Other aspects of study quality were assessed using a standard checklist: extent of blinding (if appropriate), whether groups were comparable at baseline, extent of losses from follow-up, noncompliance, whether the outcome assessment was standardized, and whether an intention-to-treat (ITT) analysis was undertaken.16-21 These data were presented in Table 1. Studies were also assessed for methodological quality with reference to the Oxford Centre for Evidence-Based Medicine Level of Evidences Classification rubric. Only studies with Oxford Evidence Level 1 were considered.17 The QUORUM (Quality Reporting of Meta-analysis) statement was used to guide the content and reporting of the review.18
Dr da Rosa and Dr Medeiros assessed the efficacy of HPV vaccines in the prevention of lesions as well as their safety. Two other reviewers (D.D.R. and R.R.Z) assessed the incidence of vaccine immunogenicity and the prevention of persistent infection with HPV (ie, those who had a diagnosis of infection before entering the trial). We found only articles published in the English language.
Data Synthesis and Statistical Analysis
Statistical analysis was performed in accordance to guidelines for the comparison of different treatments.19-21 For categorical outcomes (vaccine efficacy in the prevention of lesions, safety, and vaccine immunogenicity), the numbers reporting each outcome in each group were extracted. Results for each study were expressed as odds ratios (ORs) with 95% confidence intervals (CIs) and were combined for meta-analysis with the RevMan software using a random-effects model.20-22
Statistical heterogeneity between results of different studies was examined by χ2 tests.18-20 A P value for a χ2 test of less than 0.10 was used to indicate heterogeneity. An alternative approach that quantifies the effect of heterogeneity is the inconsistency (I2), which provides a measure of the degree of inconsistency among the results of the studies with 95% uncertainty intervals.22 A value of 0% indicates no observed heterogeneity and a value greater than 50% may indicate the presence of substantial heterogeneity.22
A sensitivity analysis was planned a priori to compare the results of the studies and the study design and to report quality. A random-effects meta-analysis was undertaken to assess the robustness of the results.19-21 We chose the random-effects model to show the results because there was heterogeneity caused by different types of HPV included in the studies and because all studies were multicentric and developed in different countries. The random-effects method assumes that the variance between studies is known, when in fact it is estimated from the data.20
Vaccine efficacy was estimated by an ITT analysis of the population, including all subjects who had undergone randomization, regardless of their baseline HPV status or evidence of HPV-associated infection.22-24 The analysis evaluated the efficacy of HPV vaccines against diseases or HPV infection. The overall effect of vaccination was calculated based on the number of prevalent and of incident cases. Data analysis was performed using the RevMan Analysis 4.2.10 (software).25
Descriptions of Studies
Study Identification and Eligibility
The process of study selection is summarized in Figure 1. Our initial search identified 59 potentially relevant articles. Twenty published articles were excluded after a review of their titles and abstracts. Thirty-nine full-text articles were retrieved. Thirty-three were excluded after further scrutiny: 11 were not randomized,26-36 6 were narrative reviews but not systematic reviews,37-42 and 16 had different end points (Fig. 1).43-58 Six primary studies, including 47,236 women, met the criteria for inclusion and were analyzed (Table 1). There were 22,827 women in the vaccine group and 22,807 in the placebo group.8-13 The agreement for study eligibility and methodological quality was 100% (κ = 1) (Table 1).58
Details of participants and outcomes as well as quality assessment of the studies selected for the meta-analysis are summarized in Table 1. Four trials were classified as allocation concealment A,8-11,13 and 2 trials were classified as Oxford Evidence Level 1b.10,12 All trials used computer-generated randomization systems in conjunction with numbered sealed envelopes.8-13 Patient numbers ranged from 560 to 9325 per arm. The studies used an explicit statement of the expected treatment effect, power, and significance level to justify the sample size. All studies reported losses, and subjects were followed for 4 years. Statistical analyses were conducted in an ITT basis according to HPV status and lesions (Table 1).
Efficacy in the Prevention of Cytologically and/or Histologically Detected Lesions
Bivalent Vaccine (HPV 16, 18 With 20 µg L1 VLPs)
Only Lo-SIL and Hi-SIL were diagnosed. Pooled estimates of prevention of these lesions in the group that received the vaccine in 2 studies showed a significant difference in favor of the vaccine group when compared with the control group (OR, 0.07; 95% CI, 0.04-0.14).11,12 No heterogeneity (χ2 = 1.53, P = 0.68) nor inconsistency (I2 = 0%) were present. None of the studies reported malignant diagnosis (carcinoma of the cervix, vagina, vulva, or anogenital region), but the length of follow-up was generally short for the analysis of these outcomes (Fig. 2)
Quadrivalent (HPV 6, 11, 16, 18 With 20/40/40/20 µg L VLPs) and Univalent (HPV 16 With 40 µg L1 VLPs) Vaccines
These studies compared if quadrivalent vaccine (HPV 6, 11, 16, 18 With 20/40/40/20 µg L VLPs)8,9 reduces the incidence of anogenital warts, VIN or VAIN grades 1 to 3, or associated cancer, and if quadrivalent vaccine reduces the combined incidence of cervical intraepithelial neoplasia grades 1 to 3 and adenocarcinoma in situ or cancer associated with the vaccine. Pooled estimates for prevention of lesions in the group that received the quadrivalent vaccine in 3 studies showed a significant difference in favor of the vaccine group when compared with the control group (OR, 0.38; 95% CI, 0.26-0.57).8-10 However, heterogeneity (χ2 = 39.97, P < 0.001) and substantial inconsistency (I2 = 77%) were present among the trials (Fig. 3). Two studies reported malignant diagnosis (adenocarcinoma in situ) in both the vaccine and the control groups.8,9
Safety of the Vaccines
After administration of bivalent and quadrivalent vaccines, the following local adverse events occurred: pain, redness, and swelling.8,11 Systemic events were described as arthralgia, fatigue, fever, gastrointestinal symptoms, headache, myalgia, rash, and urticaria.8,11 Serious adverse events were described as vaccine-related event (new-onset chronic disease, new-onset autoimmune disease) and spontaneous abortion.8,11,12 There were no deaths in the group that received the bivalent vaccine. For the adverse events, the OR from pooled estimates for the group that received the bivalent and the quadrivalent vaccines were, respectively, 1.35 (95% CI, 1.05-1.73) and 1.16 (95% CI, 0.94-1.43) when compared with placebo (Fig. 4). There was heterogeneity in the bivalent and quadrivalent vaccine groups. In one of the studies, there were 7 deaths in the group that received the quadrivalent vaccine (pneumonia, sepsis, overdose, 3 traffic accidents, pulmonary embolism).9 In the placebo group, the causes of death were suicide, asphyxia, and traffic accident.9 In a second study with the quadrivalent vaccine, there were 2 deaths in the vaccine group caused by a car accident and to a suicide.10 In the placebo group, there were 2 deaths caused by thrombosis, renal insufficiency, and pulmonary insufficiency.
Regarding the bivalent vaccine, 3 studies described vaccine immunogenicity including incidence (follow-up analysis at a mean of 42 months after completion of the vaccination schedule).11 Vaccine efficacy was assessed against 12 months' persistence of infection and seroconversion to HPV 16/18.11-13 In these trials, the vaccination protected against new cases of HPV infection and also against persistence of infection. There was seroconversion in the group that received the vaccine when compared with the placebo group (OR, 0.19; 95% CI, 0.05-0.75). There no were heterogeneity (χ2 = 73.6, P < 0.001) and inconsistency (95.9%) among the trials. There were differences in both clinical and immunologic aspects because the results came from only 3 studies that evaluated different populations (Fig. 5).22 Regarding the quadrivalent vaccine, only 1 study described persistence of HPV 16/18 infection. The trials showed that vaccination protected against persistence of infection when compared with the placebo group (OR, 0.16; 95% CI, 0.10-0.26).10
A sensitivity analysis was performed to test the robustness of the findings.19-21 Pooled estimates of treatment effect was similar for studies with adequate allocation concealment. The results of the univalent trial were added to the results of the quadrivalent trials for analysis. When we excluded the univalent trial from the analysis, the results were the same. Therefore, the univariate vaccine trial was left together with the quadrivalent ones.10
We concluded that women who received the bivalent HPV vaccine had less lesions in the cervix, vulva, vagina, and anogenital region, with efficacy of 93% and a follow-up between 14 and 44 months.11,12 For quadrivalent vaccine, the efficacy in the prevention of lesions was 62%. However, there were important inconsistency and heterogeneity probably because there were 4 different types of HPV inside the quadrivalent vaccine. Potentially important sources of heterogeneity were the duration of treatment, the number of included trials, and the number of outcomes in each trial. Quantification of heterogeneity is only 1 component of a wider investigation of variability across studies, the most important being diversity in clinical and methodological aspects.
Despite finding an efficacy of 81% in the immunogenicity of the bivalent vaccine, there were heterogeneity and inconsistency among the trials probably because there were only 2 studies analyzed where the number of women included in each group (vaccine vs placebo) was different. Moreover, the studies were performed in different countries, which could be a source of heterogeneity. We could not evaluate heterogeneity in the results of immunogenicity for the quadrivalent vaccine because the results were obtained from only 1 trial.10 The HPV vaccination has been shown to induce cell-mediated immune responses traditionally involved in the eradication of infections. These cell-mediated responses could be of benefit among subjects already infected with the HPV, providing a specific measure of immunogenicity that is clinically related to protection against HPV infection.41,59
In June 2006, the US Food and Drug Administration approved the quadrivalent vaccine against HPV types 6, 11, 16, 18 (Gardasil) for the vaccination of females from 9 to 26 years. The aim of this vaccine is the prevention of the following diseases caused by HPV: cervical cancer, genital warts, precancerous or dysplastic lesions of the cervix (adenocarcinoma in situ, cervical intraepithelial neoplasia grades 2 and 3, VIN grades 2 and 3, and VAIN grades 2 and 3). The vaccine should not be used to treat cervical cancer, CIN, VIN, VAIN, or genital wards and do not substitute routine cervical cancer screening.7
The HPV vaccines are expected to significantly reduce HPV-associated morbidity and mortality.60 Therefore, teenagers and their parents should acquire better knowledge about HPV infection and prevention. Hitherto, all studies on HPV vaccination enrolled only women, but it seems important also to include men in trials because genital HPV infections are mainly sexually transmitted.50,61
The effect of HPV vaccination in the incidence of cervical cancer will not be felt until about 20 to 30 years after a worldwide vaccination program is introduced. The introduction of such programs will probably require the involvement of the World Health Organization and the Pan-American Health Organization and other foundations and nongovernmental organizations to make vaccination available and affordable. We believe that a logical prevention strategy in regions with scarce resources is to begin vaccination before the start of sexual relationships.62,63
Our results were different from those found in another recently published systematic review by Rambout et al.64 They used Peto Odds Ratio and a fixed-effects model to analyzed per-protocol and ITT results. When we used an ITT analysis for all results from their study, we found inconsistency and heterogeneity among the trials. In our systematic review, results were analyzed in an ITT basis using OR with random-effects models.20-22
This meta-analysis complied with the criteria for performing a rigorous systematic review planned a priori.15-24 This included the use of study quality assessment and investigation of results by random-effects models to test the robustness of the results.15-24 The potential limitations of this systematic review were the small num ber of studies. An overall measure of effects could be biased because of confounding factors introducing heterogeneity between studies from different countries and also because the vaccines are against different types of HPV.
In conclusion, we showed that prophylactic HPV vaccines are promising. Although prophylactic vaccination is likely to provide important gains in the health system, cervical screening will need to be continued for the whole generation of women that is already infected with HPV.65 There are very few randomized trials in this field. Further studies should be carefully addressed for inclusion of specific subgroups of patients who would benefit from the vaccine (women older than 26 years, boys, and men). Additional outcomes should also be included such as vaccine efficacy in recurrent lesions, population satisfaction, quality of life, and costs.66
2. Munox N, Bosh FX, de Samposé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med
3. Weinstock H, Berman S, Cales W. Sexually transmitted diseases among American youth: incidence and prevalence estimates. Perspect Sex Reprod Health
4. Cox JT. The development of cervical cancer and its precursors: what is the role of human papillomavirus infection? Curr Opin Obstet Gynecol
. 2006;18(suppl 1)(suppl. 1):5-13.
5. Zimmerman RK. HPV vaccine and its recommendations, 2007. J Fam Pract
. 2007;56(suppl 2)(suppl. 2):1-5.
6. Kuehn BM. CDC panel backs routine HPV vaccination. JAMA
7. CDC. FDA licenses quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine (Gardasil) for the prevention of cervical cancer and other diseases in females caused by human papillomavirus. Office of Oncology
Available at: http://www.fda.gov/cder/Offices/OODP/whatsnew/gardasil
. Accessed March 13, 2007.
8. Garland SM, Avila MH, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases (The FUTURE I Group). N Engl J Med
9. The FUTURE II (The Females United to Unilaterally Reduce Endo/Ectocervical Disease) Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med
10. Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia. Obstet Gynecol
11. Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet
12. Paavonen J, Jenkins D, Boush FX, et alHPV PATRICIA Study Group. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomized controlled. Lancet
13. Hildesheim A, Herrero R, Wacholder S, et al. Effects of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection. JAMA
14. Benedet JL, Pecorelly S, Ngan HYS, et al. FIGO staging classifications and clinical practice guidelines of gynaecologic cancers. FIGO committed on Gynecologic Oncology. Int J Gynaecol Obstet
15. Jadad A, Moore M, Carrol D. Assessing the quality of reports of randomised clinical trials: is blinding necessary? Control Clin Trials
16. Jüni P, Altman DG, Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ
17. Phillips B, Ball C, Sackett D, et al. Oxford Centre for Evidence-Based Medicine Level of Evidence Grades of Recommendations (May 2001). Available at http://www.cebm.net/index.asp?0=1025
. Accessed October 31, 2007.
18. Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of meta-analysis of randomized controlled trial: the QUORUM statement. Lancet
19. Jüni P, Altman DG, Egger M. Systematic reviews in health care. Assessing the quality of randomized controlled trials. In: Systematic Reviews in Health Care: Meta-Analysis in Contex
. 2th ed. Egger M, ed. London, England: BMJ
20. Sutton AJ, Abrams KR, Jones DR, et al. Random effects methods for combining study estimates. In: Methods for Meta Analysis in Medical Research
. 1st ed. Sutton AJ, ed. Chichester, England: John Wiley; 2000:73-86.
21. Sterne JA, Egger M, Smith GD. Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis. BMJ
22. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ
23. Grady D, Cummings SR, Hulley S. Designing and experiment: clinical trial II. In: Designing Clinical Research and Epidemiologic Approach
. 2nd ed. Hulley S, ed. Philadelphia, PA: Lippincott Willians & Wilkins; 2001:157-174.
24. Lefebvre C, Clarke MJ. Identifying randomized trials. In: Systematic Reviews in Health Care: Meta-analysis in Context
. 2nd ed. Egger M, ed. London, England: BMJ Publishing; 2001:69-108.
25. RevMan Analysis [computer program]. Version 1.0 for Windows. In Review Manager (RevMan). Version 4.2 for Windows. Copenhagen: The Nordic Cochrane Centre. The Cochrane Colaborattion, 2003.
26. Pedersen C, Petaja T, Strauss G, et al. Immunization for early adolescent females with human papillomavirus type 16 and 18 L1 virus-like particle vaccine containing AS04 adjuvant. J Adolesc Health
27. Corona Gutierrez CM, Tinoco A, Navarro T, et al. Therapeutic vaccination MVA E2 can eliminate precancerous lesions (CIN 1, CIN 2, CIN 3) associated with infection by oncogenic human papillomavirus. Hum Gen Ther
28. Gudmundsdóttir T, Tryggvadóttir L, Mast AM, et al. Eligibility and willingness of young Icelandic women to participate in a HPV vaccination trial. Acta Obstet Gynecol Scand
29. Hallez S, Simon P, Maudoux F, et al. 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. Cancer Immunol Immunother
30. Steller MA, Gurski KJ, Murakami M, et al. Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type 16 E7. Clin Can Res
31. García-Hernández E, González-Sánchez JL, Andrade-Manzano A, et al. Regression of papillomavirus high-grade lesions (CIN 2 and CIN 3) is stimulated by therapeutic vaccination with MVA E2 recombinant vaccine. Cancer Gene Ther
32. Nardelli-Haefliger D, Lurati F, Wirthner D, et al. Immune responses induced by lower airway mucosal immunization with a human papillomavirus type 16 virus-like particle vaccine. Vaccine
33. Palefsky MJ, Berry M, Naomi J, et al. A trial of SGN-00101 (HspE7) to treat high-grade anal intraepithelial neoplasia in HIV-positive individuals. AIDS
34. Simon P, Buxant F, Hallez S, et al. Cervical response to vaccination against HPV 16 E7 in case of severe dysplasia. Eur J Obstet Gynecol Reprod Biol
35. Fiander AN, Tristram AJ, Davidson EJ, et al. Prime-boost vaccination strategy in women with high-grade, noncervical anogenital intraepithelial neoplasia: clinical results from a multicenter phase II trial. Int J Gynecol Cancer
36. Brown DR, Bryan JT, Schroeder JM, et al. Neutralization of human papillomavirus type 11 (HPV 11) by serum from women vaccinated with yeast-derived HPV-11 L1 virus-like particles: correlations with competitive radioimmunoassay titer. J Infect Dis
37. Villa LL, Costa RLR, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo controlled multicentre phase II efficacy trial. Lancet
38. Ault KA, Future II Study Group. Effects of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomized clinical trials. Lancet
39. Joura EA, Leodolter S, Hernandez-Avilla M, et al. Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16 and 18) L1 virus-like particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomized clinical trials. Lancet
40. Koutski LA, Ault KA, Wheeler CM, et al. A controlled trial of human a papillomavirus type 16 vaccine. N Engl J Med
41. Villa LL, Costa RLP, Petta CA, et al. High sustained efficacy of prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer
42. Harper DM, Wheeler C, Ferris DG, et al. Efficacy of a bivalent L1 virus- like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomizes controlled trial. Lancet
43. Siddiqui MA, Perry CM. Human papillomavirus quadrivalent (types 6, 11, 16, 18) recombinant vaccine (Gardasil). Drugs
44. Villa LL, Ault KA, Giuliano AR, et al. Immunologic responses following administration of a vaccine targeting human papillomavirus types 6, 11, 16 and 18. Vaccine
45. Reisinger K, Block SL, Lazcano-Ponce E, et al. Safety persistence immunogenicity of a quadrivalent human papillomavirus types 6,11,16, 18 L1 virus-like particle vaccine in preadolescents and adolescents. Pediatr Infect Dis J
46. Pinto LA, Edwards J, Castle PE, et al. Cellular immune responses to human papillomavirus (HPV)-16 L1 in healthy volunteers immunized with recombinant HPV-16 virus-like particles. J Infect Dis
47. Lehtinen M, Paavonen J. Vaccination against human papillomaviruses shows great promise. Lancet
48. Kahn J, Burk RD. Papillomavirus vaccines in perspective. Lancet
49. Pinto LA, Viscidi R, Harro C, et al. Cellular immune responses to HPV-8, 31, and 53 in healthy volunteers immunized with recombinant HPV-16 L1 virus-like particles. Virology
50. Stanley M. The end for genital human papillomavirus infections? Lancet Oncol
51. Sawaya GF, Smith-McCune K. HPV vaccination-more answer, more questions. N Engl J Med
52. Daldwin PJ, van der Burg S, Boswell M, et al. Vaccinia-expressed human papillomavirus 16 and 18 E6 and E7 as a therapeutic vaccination for vulva and vaginal intra-epithelial neoplasia. Clin Cancer Res
53. Duggirala MK, Cuddihy MT. A human papillomavirus type 16 vaccine. N Engl J Med
54. Crum CP. The beginning of the end for cervical cancer? N Engl J Med
55. Lehtinen M, Apter D, Dubin G, et al. Enrolment of 22,000 adolescent women to cancer registry follow-up for long term human papillomavirus vaccine efficacy: guarding against guessing. Int J STD AIDS
56. Dempsey AM, Koutsky LA, Golden M. Potential impact of human papillomavirus vaccines on public STD clinical workloads and on opportunities to diagnose and treat other sexually transmitted diseases. Sex Transm Dis
57. Insinga RP, Dasbach EJ, Elbascha EH, et al. Incidence and duration of cervical human papillomavirus 6, 11, 16 and 18 infections in young women: an evaluation from multiple analytic perspectives. Cancer Epidemiol Biomarkers Prev
58. Altman D. Practical Statistics for Medical Research
. 9th ed. London, England: Chapman & Hall; 1999.
59. Giannini SL, Hanon E, Moris P, et al. Enhanced humoral and memory B cellular immunity using HPV 16/18 L1 VLP vaccine formulated with MPL/aluminium salt combinations (AS04) compared to aluminium salt only. Vaccine
60. Zimet GD. Understanding and overcoming barriers to human papillomavirus vaccine acceptance. Curr Opin Obstet Gynecol
. 2006;18(suppl. 1):(suppl 1)23-28.
61. Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med
62. Yang BH, Bray FI, Parkin DM, et al. Cervical cancer as a priority for prevention in different world region: an evaluation using years of life lost. Int J Cancer
63. Schiffman M, Castle PE, Jeronimo J, et al. Human papillomavirus and cervical cancer. Lancet
64. Rambout L, Hoppkins L, Hutton B, et al. Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized control trials. CMAJ
65. Arbyn M, Dillner J. Review of current knowledge of HPV vaccination: an appendix to the European guidelines for quality assurance in cervical cancer screening. J Clin Virol
66. Vergote I, Van der Zee A, Kesic V, et al. ESGO stamen on cervical cancer vaccination. Int J Gynecol Cancer
This article has been cited 8 time(s).
Plos OneCausal Inference Regarding Infectious Aetiology of Chronic Conditions: A Systematic ReviewPlos One
Clinical Microbiology and InfectionMapping ongoing European research activities examining the infectious aetiology of chronic conditionsClinical Microbiology and Infection
Medicina Oral Patologia Oral Y Cirugia BucalOral cancer, HPV infection and evidence of sexual transmissionMedicina Oral Patologia Oral Y Cirugia Bucal
Journal of Cellular PhysiologyHPV Vaccines: State of the ArtJournal of Cellular Physiology
Gynecologic OncologyThe two faces of human papillomavirusGynecologic Oncology
Journal of Advanced NursingHuman papilloma virus vaccination: perceptions of young Korean womenJournal of Advanced Nursing
Bmc Infectious DiseasesInclusion of the benefits of enhanced cross-protection against cervical cancer and prevention of genital warts in the cost-effectiveness analysis of human papillomavirus vaccination in the NetherlandsBmc Infectious Diseases
Current Opinion in RheumatologyThe new H1N1 and HPV vaccines and old fearsCurrent Opinion in Rheumatology
HPV; Vaccine; Cervical intraepithelial neoplasia; Meta-analysis; Systematic review
Copyright © 2009 by IGCS and ESGO
Highlight selected keywords in the article text.