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Human papillomavirus vaccine efficacy: Aligning expectations with reality
Available online at www.sciencedirect.com
Gynecologic Oncology 111 (2008) 1 – 2 www.elsevier.com/locate/ygyno
Editorial
Human papillomavirus vaccine efficacy: Aligning expectations with reality The discovery of human papillomavirus (HPV) as the etiological agent of human genital tract cancers and, more recently, the development of a vaccine to prevent infection with some of the cancer-associated HPV types, represent a dramatic success of molecular medicine and herald a new era in cancer prevention and control. Two HPV types, 16 and 18, account for 60–70% of cervical cancers worldwide [1], and have been selected as the targets for the current generation of HPV vaccines. The quadrivalent vaccine currently available in the United States, marketed by Merck with the trade name of Gardasil, targets HPV 6 and 11 (associated with the majority of genital warts) as well as HPV 16 and 18. A bivalent vaccine under consideration for approval by the Food and Drug Administration, developed by GlaxoSmithKlein with the trade name of Cervarix, targets HPV 16 and 18 only. Given that cervical cancer is a rare outcome in populations screened for cervical cancer, such as those participating in the vaccine trials, the trial outcomes reported to date are surrogates for the outcome of HPV-associated cancers. Published results have reported on vaccine efficacy against infection with HPV 16 and 18 and on rates of precancerous lesions known as cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS). Final results from Phase II trials and interim results from Phase III trials demonstrated 100% or close to 100% efficacy against infection with vaccine HPV types as well as HPV 16 and 18-associated CIN and AIS in women naïve to these types at the time of vaccination [2–7]. Vaccines rarely achieve such high efficacy, hence these stunning results generated worldwide excitement about the unprecedented potential to prevent cancer through vaccination. The observed efficacy of 100% against CIN lesions associated with HPV 16 and 18 in a subset of trial participants (women naïve to vaccine HPV types throughout the period of vaccination) has resulted in a misconception: that vaccination provides 100% protection against cervical cancer. In fact, there have as yet been no reported cases of cervical cancer in the trial populations. The actual effectiveness of vaccination against cervical cancer will be determined over the next several decades through surveillance and longitudinal population studies such as the Nordic cohort, which will provide information about rates of CIN 3 and cancer in vaccinated and unvaccinated women beginning in the year 2020 [8]. Given that HPV 16 and 18 are associated with 60–70% of cervical cancers [1], vaccination is expected to prevent approximately two-thirds of cervical cancer 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.09.001
cases, a laudable achievement. Protection against 100% of cervical cancers will not be possible until a vaccine that targets ALL cancer-associated HPV types has been developed, tested and disseminated. In the meantime, it is neither safe nor accurate to assume that vaccination against HPV 16 and 18 will provide 100% protection against HPV-associated anogenital cancers. With regards to cancer outcomes, it is worth noting that interim Phase III trial results of the quadrivalent vaccine did report one case of cancer: a vulvar cancer in a 22-year old vaccinated woman [7]. Vulvar cancer is an HPV-associated cancer targeted by the vaccine, and is extremely rare in young women. Its occurrence in a vaccine-recipient may be an unfortunate one-off event or may reflect unanticipated adverse effects of vaccination; final Phase III trial results and long-term surveillance will determine the significance of this result. The observed vaccine efficacy of 100% against CIN lesions associated with HPV 16 and 18 in a subset of trial participants (women naïve to vaccine HPV types throughout the period of vaccination) has resulted in another misconception: that vaccination will result in 100% protection against all CIN lesions in all women. There are no FDA-approved tests to determine who is naïve to HPV 16 or 18 at the time of vaccination. Current guidelines in the United States recommend universal vaccination of girls 11–12 years of age, a population that is predominantly sexually naïve and hence expected to derive the maximal protection from vaccination [9,10]. However, current guidelines in the United States also recommend routine vaccination of sexually active women up to the ages of 18 years [9] or 26 years [10]. Phase III trials of the quadrivalent vaccine enrolled women 15–26 years of age with a very small proportion of virgins; interim results from these trials indicate that overall reduction of CIN lesions (regardless of associated HPV type or HPV exposure status) is 17% for CIN 2,3/AIS lesions [6] and 22% for CIN 1–3/AIS lesions [7], clearly far less than the 100% efficacy observed for HPV 16 and 18-associated disease in women naïve to those types. What explains the finding that overall vaccine efficacy against CIN lesions falls far short of 100%? One explanation is that the inclusion of sexually active women in the trials means that many participants had already been exposed to or were infected with the vaccine HPV types upon entry into the trial and hence would not be expected to benefit from vaccination. In this issue of Gynecologic Oncology, Gonzalez-Bosquet et al
2
Editorial
address another explanation for overall modest vaccine efficacy [11]. The authors performed HPV typing of cervical swabs from 206 women in Barcelona, Spain who had histologicallyconfirmed CIN 2 or 3. They demonstrated that only 28.2% of swabs tested positive exclusively for HPV 16 and/or 18 and an additional 14.5% had infections with other HPV types in addition to HPV 16 and/or 18, resulting in a total of 42.7% of CIN 2 or 3 lesions possibly attributable to HPV 16 and/or 18. Since these results are derived from cervical swabs, not from the biopsy specimens themselves as was done in the vaccine trials, it is possible that a higher proportion of CIN 2 or 3 lesions were actually associated with HPV 16 and/or 18 than determined from swab samples. Despite this limitation, the authors highlight the result that only 28.2% of women with CIN 2 or 3 were infected exclusively with HPV 16 and/or 18. GonzalezBosquet et al conclude that their finding “places in doubt the degree of protection afforded by vaccination” [11]. The proportion of CIN 2 and 3 attributable to vaccine HPV types varies by geographic region [12], hence the degree of vaccine protection against CIN 2 and 3 will also vary regionally. In the United States, data from a recent systematic review of HPV types associated with CIN 2 and 3 lesions indicated that the combined prevalence of HPV 16 and 18 was 59.5% [13]. It is possible that vaccination against HPV 16 and 18 might provide cross-protection against related non-vaccine HPV types, expanding the overall protection against CIN 2 and 3 lesions. Conversely, if the proportion of disease attributable to non-vaccine HPV types increases in vaccinated women, which is suggested by early results from the quadrivalent vaccine trials [14], protection conferred by vaccination will be attenuated. Final results from Phase III trials will be helpful in determining the proportion of CIN 2 and 3 attributable to vaccine HPV types, the overall protection against CIN 2 and 3 lesions, the extent of vaccine cross-protection against non-vaccine HPV types, and the effect of vaccination on rates of disease associated with non-vaccine HPV types. The report from Gonzalez-Bosquet et al. underscores the need for providers administering the HPV vaccine to set realistic expectations for their patients. Final Phase III trial results of vaccine efficacy have yet to be published, and actual overall vaccine effectiveness will not be known for many years. Nevertheless, the vaccine was never intended to confer 100% protection against all CIN 2 or 3 lesions or cervical cancers. Due to the diverse biological repertoire of HPV types that can cause cancer in women, only 2 of which are targeted by the vaccine, the estimated theoretical protection against cervical cancer is 70%, and against CIN 2 and 3 is lower. Therefore vaccinated women must continue to undergo cervical cancer screening per current guidelines. Patients and providers need to recognize that the diagnosis of an abnormal Pap test or a CIN lesion in a vaccinated woman does not necessarily represent a vaccine failure. A false sense of security based on unrealistic expectations and misconceptions about vaccine effectiveness could result in failure to comply with screening recommendations and/or distrust in the face of a CIN diagnosis. It is time for the medical community to reconcile messaging about 100%
vaccine efficacy with explicit and realistic expectations about the extent of vaccine protection for individual women. References [1] Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518–27. [2] Villa LL, Costa RL, Petta CA, Andrade RP, Paavonen J, Iversen OE, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer 2006;95:1459–66. [3] Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, 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 Oncol 2005;6:271–8. [4] Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli-Martins CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006;367:1247–55. [5] Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, 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 randomised controlled trial. Lancet 2004;364:1757–65. [6] Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915–27. [7] Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:1928–43. [8] Lehtinen M, Apter D, Dubin G, Kosunen E, Isaksson R, Korpivaara EL, 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 2006;17:517–21. [9] Saslow D, Castle PE, Cox JT, Davey DD, Einstein MH, Ferris DG, et al. American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin 2007;57:7–28. [10] Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER. Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56:1–24. [11] Gonzalez-Bosquet E, Esteva C, Munoz-Almgro C, Ferrer P, Perez M, Lailla JM. Identification of vaccine human papillomavirus genotypes in squamous intraepithelial lesions (CIN2-3). Gynecol Oncol 2008;111:9–12. [12] Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, Winer R, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer 2007;121:621–32. [13] Insinga RP, Liaw KL, Johnson LG, Madeleine MM. A systematic review of the prevalence and attribution of human papillomavirus types among cervical, vaginal, and vulvar precancers and cancers in the United States. Cancer Epidemiol Biomarkers Prev 2008;17:1611–22. [14] www.fda.gov/cber/review/hpvmer060806r.pdf.
Karen K. Smith-McCune Department of Obstetrics, Gynecology and Reproductive Sciences, The UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco E-mail address: [email protected]. Fax: +1 415 502 7062
Gynecologic Oncology 111 (2008) 1 – 2 www.elsevier.com/locate/ygyno
Editorial
Human papillomavirus vaccine efficacy: Aligning expectations with reality The discovery of human papillomavirus (HPV) as the etiological agent of human genital tract cancers and, more recently, the development of a vaccine to prevent infection with some of the cancer-associated HPV types, represent a dramatic success of molecular medicine and herald a new era in cancer prevention and control. Two HPV types, 16 and 18, account for 60–70% of cervical cancers worldwide [1], and have been selected as the targets for the current generation of HPV vaccines. The quadrivalent vaccine currently available in the United States, marketed by Merck with the trade name of Gardasil, targets HPV 6 and 11 (associated with the majority of genital warts) as well as HPV 16 and 18. A bivalent vaccine under consideration for approval by the Food and Drug Administration, developed by GlaxoSmithKlein with the trade name of Cervarix, targets HPV 16 and 18 only. Given that cervical cancer is a rare outcome in populations screened for cervical cancer, such as those participating in the vaccine trials, the trial outcomes reported to date are surrogates for the outcome of HPV-associated cancers. Published results have reported on vaccine efficacy against infection with HPV 16 and 18 and on rates of precancerous lesions known as cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS). Final results from Phase II trials and interim results from Phase III trials demonstrated 100% or close to 100% efficacy against infection with vaccine HPV types as well as HPV 16 and 18-associated CIN and AIS in women naïve to these types at the time of vaccination [2–7]. Vaccines rarely achieve such high efficacy, hence these stunning results generated worldwide excitement about the unprecedented potential to prevent cancer through vaccination. The observed efficacy of 100% against CIN lesions associated with HPV 16 and 18 in a subset of trial participants (women naïve to vaccine HPV types throughout the period of vaccination) has resulted in a misconception: that vaccination provides 100% protection against cervical cancer. In fact, there have as yet been no reported cases of cervical cancer in the trial populations. The actual effectiveness of vaccination against cervical cancer will be determined over the next several decades through surveillance and longitudinal population studies such as the Nordic cohort, which will provide information about rates of CIN 3 and cancer in vaccinated and unvaccinated women beginning in the year 2020 [8]. Given that HPV 16 and 18 are associated with 60–70% of cervical cancers [1], vaccination is expected to prevent approximately two-thirds of cervical cancer 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.09.001
cases, a laudable achievement. Protection against 100% of cervical cancers will not be possible until a vaccine that targets ALL cancer-associated HPV types has been developed, tested and disseminated. In the meantime, it is neither safe nor accurate to assume that vaccination against HPV 16 and 18 will provide 100% protection against HPV-associated anogenital cancers. With regards to cancer outcomes, it is worth noting that interim Phase III trial results of the quadrivalent vaccine did report one case of cancer: a vulvar cancer in a 22-year old vaccinated woman [7]. Vulvar cancer is an HPV-associated cancer targeted by the vaccine, and is extremely rare in young women. Its occurrence in a vaccine-recipient may be an unfortunate one-off event or may reflect unanticipated adverse effects of vaccination; final Phase III trial results and long-term surveillance will determine the significance of this result. The observed vaccine efficacy of 100% against CIN lesions associated with HPV 16 and 18 in a subset of trial participants (women naïve to vaccine HPV types throughout the period of vaccination) has resulted in another misconception: that vaccination will result in 100% protection against all CIN lesions in all women. There are no FDA-approved tests to determine who is naïve to HPV 16 or 18 at the time of vaccination. Current guidelines in the United States recommend universal vaccination of girls 11–12 years of age, a population that is predominantly sexually naïve and hence expected to derive the maximal protection from vaccination [9,10]. However, current guidelines in the United States also recommend routine vaccination of sexually active women up to the ages of 18 years [9] or 26 years [10]. Phase III trials of the quadrivalent vaccine enrolled women 15–26 years of age with a very small proportion of virgins; interim results from these trials indicate that overall reduction of CIN lesions (regardless of associated HPV type or HPV exposure status) is 17% for CIN 2,3/AIS lesions [6] and 22% for CIN 1–3/AIS lesions [7], clearly far less than the 100% efficacy observed for HPV 16 and 18-associated disease in women naïve to those types. What explains the finding that overall vaccine efficacy against CIN lesions falls far short of 100%? One explanation is that the inclusion of sexually active women in the trials means that many participants had already been exposed to or were infected with the vaccine HPV types upon entry into the trial and hence would not be expected to benefit from vaccination. In this issue of Gynecologic Oncology, Gonzalez-Bosquet et al
2
Editorial
address another explanation for overall modest vaccine efficacy [11]. The authors performed HPV typing of cervical swabs from 206 women in Barcelona, Spain who had histologicallyconfirmed CIN 2 or 3. They demonstrated that only 28.2% of swabs tested positive exclusively for HPV 16 and/or 18 and an additional 14.5% had infections with other HPV types in addition to HPV 16 and/or 18, resulting in a total of 42.7% of CIN 2 or 3 lesions possibly attributable to HPV 16 and/or 18. Since these results are derived from cervical swabs, not from the biopsy specimens themselves as was done in the vaccine trials, it is possible that a higher proportion of CIN 2 or 3 lesions were actually associated with HPV 16 and/or 18 than determined from swab samples. Despite this limitation, the authors highlight the result that only 28.2% of women with CIN 2 or 3 were infected exclusively with HPV 16 and/or 18. GonzalezBosquet et al conclude that their finding “places in doubt the degree of protection afforded by vaccination” [11]. The proportion of CIN 2 and 3 attributable to vaccine HPV types varies by geographic region [12], hence the degree of vaccine protection against CIN 2 and 3 will also vary regionally. In the United States, data from a recent systematic review of HPV types associated with CIN 2 and 3 lesions indicated that the combined prevalence of HPV 16 and 18 was 59.5% [13]. It is possible that vaccination against HPV 16 and 18 might provide cross-protection against related non-vaccine HPV types, expanding the overall protection against CIN 2 and 3 lesions. Conversely, if the proportion of disease attributable to non-vaccine HPV types increases in vaccinated women, which is suggested by early results from the quadrivalent vaccine trials [14], protection conferred by vaccination will be attenuated. Final results from Phase III trials will be helpful in determining the proportion of CIN 2 and 3 attributable to vaccine HPV types, the overall protection against CIN 2 and 3 lesions, the extent of vaccine cross-protection against non-vaccine HPV types, and the effect of vaccination on rates of disease associated with non-vaccine HPV types. The report from Gonzalez-Bosquet et al. underscores the need for providers administering the HPV vaccine to set realistic expectations for their patients. Final Phase III trial results of vaccine efficacy have yet to be published, and actual overall vaccine effectiveness will not be known for many years. Nevertheless, the vaccine was never intended to confer 100% protection against all CIN 2 or 3 lesions or cervical cancers. Due to the diverse biological repertoire of HPV types that can cause cancer in women, only 2 of which are targeted by the vaccine, the estimated theoretical protection against cervical cancer is 70%, and against CIN 2 and 3 is lower. Therefore vaccinated women must continue to undergo cervical cancer screening per current guidelines. Patients and providers need to recognize that the diagnosis of an abnormal Pap test or a CIN lesion in a vaccinated woman does not necessarily represent a vaccine failure. A false sense of security based on unrealistic expectations and misconceptions about vaccine effectiveness could result in failure to comply with screening recommendations and/or distrust in the face of a CIN diagnosis. It is time for the medical community to reconcile messaging about 100%
vaccine efficacy with explicit and realistic expectations about the extent of vaccine protection for individual women. References [1] Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518–27. [2] Villa LL, Costa RL, Petta CA, Andrade RP, Paavonen J, Iversen OE, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer 2006;95:1459–66. [3] Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, 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 Oncol 2005;6:271–8. [4] Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli-Martins CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006;367:1247–55. [5] Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, 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 randomised controlled trial. Lancet 2004;364:1757–65. [6] Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915–27. [7] Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:1928–43. [8] Lehtinen M, Apter D, Dubin G, Kosunen E, Isaksson R, Korpivaara EL, 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 2006;17:517–21. [9] Saslow D, Castle PE, Cox JT, Davey DD, Einstein MH, Ferris DG, et al. American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin 2007;57:7–28. [10] Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER. Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56:1–24. [11] Gonzalez-Bosquet E, Esteva C, Munoz-Almgro C, Ferrer P, Perez M, Lailla JM. Identification of vaccine human papillomavirus genotypes in squamous intraepithelial lesions (CIN2-3). Gynecol Oncol 2008;111:9–12. [12] Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, Winer R, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer 2007;121:621–32. [13] Insinga RP, Liaw KL, Johnson LG, Madeleine MM. A systematic review of the prevalence and attribution of human papillomavirus types among cervical, vaginal, and vulvar precancers and cancers in the United States. Cancer Epidemiol Biomarkers Prev 2008;17:1611–22. [14] www.fda.gov/cber/review/hpvmer060806r.pdf.
Karen K. Smith-McCune Department of Obstetrics, Gynecology and Reproductive Sciences, The UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco E-mail address: [email protected]. Fax: +1 415 502 7062