Commentary Human Papillomavirus Vaccination: A Case Study in Translational Science Allyson K. Palmer, B.A.1, Antoneicka L. Harris, M.S.2, and Robert M. Jacobson, M.D.3 Abstract Each year 610,000 cases of anogenital and oropharyngeal cancers caused by human papillomavirus (HPV) occur worldwide. HPV vaccination represents a promising opportunity to prevent cancer on a global scale. The vaccine’s story dates back to discoveries in chickens at the beginning of the 20th century with evidence that a cell-free filtrate could transmit the propensity to grow cancers. Later, studies with similarly derived filtrates from mammalian tumors showed that hosts could develop immunity to subsequent exposures. Epidemiologic studies linked cervical cancer to members of a family of viruses that cause papillomatosis and common warts. This led to work with DNA hybridization demonstrating a causal relationship. The formation of virus-like particles from viral capsid proteins led to the development of models for safe and effective vaccines. While much work remains with the acceptance of universal vaccination, the HPV vaccines Gardasil and Cervarix thus represent a century of successful translational research. Clin Trans Sci 2014; Volume 7: 420–424
Keywords: papillomavirus vaccines, vaccination, vaccines, virus-like particle, papillomavirus infections, uterine cervical neoplasms, uterine cervical neoplasms/pc [prevention & control], translational medical research, adolescent Approximately 610,000 new cases of anogenital and oropharyngeal cancers due to human papillomavirus (HPV) occur worldwide, of which 530,000 are cervical.1 While cervical screening (e.g., Papanicolaou test or a liquid-based monolayer cytology test) has substantially reduced mortality from cervical cancer in developed countries, it has failed to succeed as a routine practice in developing countries where more than 85% of cervical cancer cases and mortality occur.2 Vaccination against HPV, thus, represents a new opportunity to prevent death and disability from cancer worldwide. Herein we review the pathway from early observations and discoveries through efforts at the bench to postlicensure clinical research (Figure 1) to discern the significant milestones in translational science concerning HPV vaccination. Discovery that HPV Can Cause Cervical Cancer
The first discoveries that viruses could transmit cancer began with work in chickens in the early 1900s. In 1908, Danish researchers Vilhelm Ellerman and Oluf Bang reported that they could transmit chicken leukemia through a filterable agent to previously healthy chickens who would then develop an aleukemic lymphomata.3,4 In 1910, Peyton Rous demonstrated that he could transplant tissue from sarcomas in chickens to cause tumorigenesis when injected into healthy chickens.4 He then demonstrated that he could transmit some agent through a cell-free filtrate to cause the same effect. At the time, Rous considered this agent either a minute parasitic organism or a chemical stimulant.5 For his work, Rous received the Nobel Prize in 1966.6 At the time of Rous’s discovery, it was well known that human warts were contagious. In 1909, Giuseppe Ciuffo demonstrated that human warts could be transmitted by a filterable agent.7 E. V. Ullmann reported the ability to transmit a warty growth from a child’s respiratory papillomatosis to human skin via a filterable virus in 1923.7 William DeMonbreun and Ernest Goodpasture identified respiratory papillomatosis in dogs similar to human lesions and demonstrated the ability to transmit this lesion via filterable virus to the mouths of other dogs, but the transmission
was limited to mucous membranes of the mouth and to dogs.7 Notably, they showed that dogs that recovered from these lesions were immune to reinfection. In 1933, Richard Shope reported the ability to transmit papilloma via a filterable virus in wild cottontail rabbits to both wild and domestic rabbits.8 Of note, while he found no rabbit naturally immune to inoculation, he did demonstrate resistance to reinfection in some of the domestic rabbits, prolongation of the period of wart development in others, and viral neutralizing capabilities of the sera obtained from infected rabbits. I. D. Rotkin reported in 1967 that age at first coitus was the strongest epidemiologic association with development of cervical cancer and supported the idea of a causal agent being passed from male to “host” female.9 In 1973 he speculated that a very promising agent would be the Herpesvirus hominis type 2.10 Harald zur Hausen and colleagues reported in 1974 that they had failed to find evidence of herpes DNA in cervical cancer biopsies and instead focused on the papillomavirus they had found persistently in such biopsy material.11,12 In 1983 and 1984 respectively, using then-novel DNA hybridization techniques, they reported strains they tentatively labeled HPV 16 and 18 that demonstrated a “startling prevalence … in malignant tumors and (a) very occasional presence in benign papillomas.”12,13 Work with these viruses led to discoveries of the molecular basis for malignant conversion of infected cells,14 such as the expression of proteins E6 and E7 that allow maintain the malignant growth of cervical cancer cells by inhibiting the tumor suppressors p53 and pRB.15 Zur Hausen’s discovery earned him the Nobel Prize in Physiology or Medicine in 2008.16 Zur Hausen’s work inspired large-scale epidemiologic studies in the 1980s and 1990s that confirmed persistent HPV 16 and 18 infections led to precancerous and cancerous cervical lesions.17,18 Invention of HPV Vaccines from Virus-Like Particles
Crucial to the successful development of the HPV vaccination was the demonstration by Jian Zhou, Xiao-Yi Sun, and Ian Frazer in 1991, and subsequently by several other groups, that
Mayo Clinic Medical Scientist Training Program, Rochester, Minnesota, USA ; 2Mayo Graduate School, Rochester, Minnesota, USA ; 3Department of Pediatric and Adolescent Medicine, Mayo Clinic , Rochester, Minnesota, USA .
1
Correspondence: Allyson K. Palmer ( [email protected]) DOI: 10.1111/cts.12166
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Figure 1. Critical events in the development of the HPV vaccines from bench to routine practice.
the surface proteins of HPV L1 and L2 would form viruslike particles (VLPs) able to induce neutralizing antibody production. 19–23 VLPs are viral structural proteins, such as envelope or capsid proteins, that self-assemble and become indistinguishable to the human body from the true, infective virus.24 VLPs do not contain viral genetic information and are noninfectious but elicit a strong immune response comprised of both B and T cells.24 HPV vaccines were the second set of vaccines in history to be created using VLPs, the first being the hepatitis B vaccines.25 Studies conducted with papillomavirusbased VLPs in dogs and rabbits showed that immunization using VLPs prevented primary infection when animals were subsequently inoculated with natural, fully potent virus.26,27 These preclinical studies led to clinical trials in humans using HPV VLPs composed of capsid protein L1. Clinical trials showed high rates of protection against HPV infection28,29 as well as protection against primary infection for up to 8 years after vaccination.30 The safety of VLPs combined with their ability to evoke a strong immune response led to remarkably positive results of clinical trials with HPV vaccines, which in turn led to their rapid approval for use in the general population. Licensure of Currently Available HPV Vaccines
Gardasil, manufactured by Merck & Co., became the first of 2 HPV vaccines to receive FDA approval.31 It is a quadrivalent vaccine containing VLPs of the 4 major capsid (L1) proteins of HPV types 6, 11, 16, and 18. Merck’s process uses fermentation of recombinant Saccharomyces cerevisiae to generate L1 proteins, which in turn self-assemble as VLPs. The VLPs are then adsorbed on preformed aluminum-containing adjuvant. The FDA licensed Gardasil in 2006 for administration as 3 doses over 6 months’ time. Merck & Co. conducted a phase II double-blind randomized trial in 2002 to evaluate the HPV 16 component of the vaccine in 2391 females 16–23 years of age. WWW.CTSJOURNAL.COM
That study showed 100% efficacy in preventing acquisition of HPV 16 infection and HPV-16-related cervical intraepithelial neoplasia (CIN).32 Trials evaluating all 4 components of the vaccine followed, including a randomized controlled trial involving over 12,000 women.33 The 3-year follow-up period after vaccination showed not only prevention of HPV infection but also protection against CIN grade 2 or 3, adenocarcinoma in situ, or HPV-16 or -18-related cervical cancer.33 In June 2006, the FDA approved administration of Gardasil to females 9 to 26 years of age for prevention of cervical cancer, genital warts, adenocarcinoma in situ, CIN grades 1–3, and vulvar and vaginal intraepithelial neoplasia grades 2–3.34 In 2008, the FDA expanded its approval of Gardasil to include prevention of vulvar and vaginal cancer caused by HPV types 16 and 18 in females.35 In October 2009, it extended its approval to include administration to males aged 9 to 26 for prevention of genital warts caused by HPV 6 and 11.36 Cervarix, manufactured by GlaxoSmithKline, became the second HPV vaccine licensed by the FDA. 37 This bivalent vaccine contains VLPs of the major capsid protein L1 representing HPV types 16 and 18. Whereas Gardasil manufacture uses fermentation products of yeast, Cervarix uses bioreaction products of a recombinant baculovirusexpression-vector system using Trichoplusia ni insect cells. The VLPs are adsorbed onto aluminum (as hydroxide salt) and combined with an aluminum adjuvant system. The FDAlicensed Cervarix is administered as 3 intramuscular doses over 6 months, similar to Gardasil. A phase III randomized, double-blinded, controlled trial in young adults showed 92.9% effectiveness for prevention of CIN grades II and III, carcinoma in situ , or cancer in women who had not been previously infected with HPV types 16 or 18.38 Cervarix was approved originally in October 2009 by the FDA for use in girls and women 10 to 25 years old.39 VOLUME 7 • ISSUE 5
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Recommendation for HPV Vaccination in the United States and around the World
Following FDA approval of Gardasil in June 2006, the Advisory Committee on Immunization Practices (ACIP) published official recommendations in Morbidity and Mortality Weekly Report (MMWR) in March 2007, recommending routine vaccination of females at ages 11–12 and catch-up vaccination for females aged 13 to 26 and permission to begin the 3-dose series in females 9 to 10 years of age.34 Following FDA licensure of Cervarix, the ACIP published recommendations for the bivalent vaccine in May 2010, harmonizing the specifics of timing with Gardasil.39 The ACIP recommendations did not recommend one vaccine over the other.39 After FDA approval of Gardasil for use in males on October 16, 2009, ACIP published a statement permitting, but not recommending, the use of Gardasil but not Cervarix in males aged 9 through 26 on October 21, 2010. Unlike recommendations for females, this initial language for use in males did not suggest an optimal age for vaccine administration but stated that “HPV4 would be most effective when given before exposure to HPV through sexual contact.”36 HPV vaccine uptake was much lower in women than anticipated by manufacturers, causing the medical and regulatory community to attempt to shift the focus of HPV vaccination to include routine vaccinations of males.40 The ACIP released an updated statement recommending Gardasil in males in 2011, citing updated data on vaccine efficacy for anal intraepithelial neoplasia (AIN) grades 2 to 3 as well as increased information on cost-effectiveness and safety. The recommendations called for routine vaccine use in males aged 11 to 12 with catch-up doses for males aged 13 through 21 for those who had not previously completed the series.40 In 2009, the World Health Organization recommended the administration of HPV vaccine to girls prior to initiation of sexual activity.41 The Global Advisory Committee on Vaccine Safety (GACVS) reported in June 2013 that over 175 million doses of HPV vaccine had been distributed and reported worldwide.42 HPV vaccine uptake rates seem to be highest in countries that deliver the HPV vaccine through school-based programs.43–45 Mixed programs incorporating both school-based and health facility-based distribution may be more effective in developing countries.46 Worldwide, 33 countries had implemented national vaccination programs by 2010, but few of these programs were in developing countries, which suffer the highest cervical cancer deaths rates.47,48 The GAVI Alliance, a public–private partnership founded in 2010 that aims to increase access to childhood immunization in the world’s poorest countries, had approved 10 countries for HPV vaccine demonstration program support as of March 2013.49 A recent analysis focusing on global vaccination suggests that reaching coverage targets for the HPV vaccine in 73 GAVI-supported countries could prevent 15.1 deaths for every 1,000 persons vaccinated, totaling 0.5 million deaths from 2011 to 2020.50 Problems with Uptake
Despite their licensure and impressive results from preclinical studies demonstrating safety and efficacy in preventing precancerous and cancerous lesions, HPV vaccine uptake in the United States has been disappointing. In 2011—4 years since universal U.S. recommendation for females—only 34.8 (95%ile CI: 33.2–36.4) percent of females 13 to 17 years of age had completed the 3-dose series recommended.51 To put this in perspective, 422
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universal recommendation for meningococcal vaccination of adolescents at the same age—11 to 12 years old—had achieved an uptake rate of 53.6 (95%ile CIL 52.4–54.9) percent 4 years later.52 When the HPV vaccine was first recommended in 2007 by the ACIP universally for females 11 to 12 years of age, public health officials and clinicians raised concerns that uptake would be thwarted by the failure of the 3-dose series to fit in the routine health maintenance schedule,34 by concerns of insurance coverage for the expense of the vaccine,53 and by the lack of awareness for the risk of cervical cancer.54,55 Following licensure, several concerns emerged regarding safety including syncope, Guillain-Barré Syndrome, and thromboembolic phenomena. Reports of postinjection syncope emerged in 2006, resulting in an HPV-specific recommendation that vaccine providers monitor HPV-vaccine recipients for 15 minutes following vaccination.34,39 Indeed, postlicensure studies did support the association of HPV vaccination with syncope, but that this adverse event was not unique to HPV vaccination but an age-related phenomenon associated with injections and phlebotomy in the adolescent age group.56,57 For this reason, the general recommendations regarding vaccinations from the CDC’s Advisory Committee on Immunization Practices holds that vaccine providers monitor adolescents and adults for 15 minutes regardless of the type of vaccine.58 Postlicensure reports also raised a concern for an association with GuillainBarré Syndrome as well as thromboembolic phenomena,59 but subsequent studies failed to find an association of either adverse event with HPV vaccinations.60,61 The apparent link between HPV vaccination and thromboembolic events likely resulted from the earliest adopters among vaccine providers administering catch-up HPV vaccination in teens and young women presenting for oral contraception, a class of therapeutics associated with a small but real increase in the risk for thromboembolic phenomena.57 In fact, a large postlicensure study of HPV4 in nearly 200,000 adolescent females found no concerning associations with the development of chronic or debilitating conditions including autoimmune phenomena.62,63 Merck & Co. is completing a similar postlicensure study in males (ClinicalTrials.gov Identifier: NCT01567813). Despite 7 years of use since Gardasil first become universally recommended in females in the United States, no more than 34% of females 13 to 17 years of age have received all 3 doses.51 Darden et al. conducted a study from 2008 to 2010 using National Immunization Survey of Teens public-use files and found that while rates of clinicians recommending HPV have increased over the 3 years—by far more than for other adolescent vaccinations— the intentions of parents to refuse the HPV vaccine increased rather than decreased from 40% to 44%.64 Leading reasons for these intentions included safety concerns, which increased from 4.5% to 16.4%. Other concerns included that the vaccine was not recommended or needed, that the patient was too young or not sexually active, and that the parent lacked information regarding the vaccine. This is despite the strong recognition across medical and public health communities of the importance of the vaccine, its remarkable safety record, the high likelihood for exposure to the infection, and the need to vaccinate long before the possibility of exposure when the patient is young and the immune system most responsive. Conclusions
FDA approval of Gardasil occurred only 23 years after zur Hausen et al.’s report of a link between HPV and cervical cancer, and only WWW.CTSJOURNAL.COM
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15 years after the creation of VLPs. The discoveries (Figure 1) that laid the foundation for HPV vaccine development built upon epidemiologic observations of the relationship between sexual history and cervical cancer. This led to the search for molecular evidence for oncoviruses and studies that determined HPV as the cause of cervical cancer. This discovery, combined with the innovation of VLPs, paved the way for HPV vaccine development. Despite the successful translation of the science surrounding HPV and cervical cancer into an effective vaccine to prevent HPV infection, HPV vaccination has failed to achieve the same uptake rates as other adolescent vaccinations. This is a multifactorial problem involving health illiteracy, unfounded suspicions, cost barriers, and deficient access. To complete the translation of HPV vaccination, we must work to improve uptake through substantive changes in how we as a society deliver both healthcare education and healthcare itself.
17. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, Schiffman MH, Moreno V, Kurman R, Shah KV, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst. 1995; 87(11): 796–802.
Acknowledgments
24. Jin XW, Lipold L, Sikon A, Rome E. Human papillomavirus vaccine: safe, effective, underused. Cleve Clin J Med. 2013; 80(1): 49–60.
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Keywords: papillomavirus vaccines, vaccination, vaccines, virus-like particle, papillomavirus infections, uterine cervical neoplasms, uterine cervical neoplasms/pc [prevention & control], translational medical research, adolescent Approximately 610,000 new cases of anogenital and oropharyngeal cancers due to human papillomavirus (HPV) occur worldwide, of which 530,000 are cervical.1 While cervical screening (e.g., Papanicolaou test or a liquid-based monolayer cytology test) has substantially reduced mortality from cervical cancer in developed countries, it has failed to succeed as a routine practice in developing countries where more than 85% of cervical cancer cases and mortality occur.2 Vaccination against HPV, thus, represents a new opportunity to prevent death and disability from cancer worldwide. Herein we review the pathway from early observations and discoveries through efforts at the bench to postlicensure clinical research (Figure 1) to discern the significant milestones in translational science concerning HPV vaccination. Discovery that HPV Can Cause Cervical Cancer
The first discoveries that viruses could transmit cancer began with work in chickens in the early 1900s. In 1908, Danish researchers Vilhelm Ellerman and Oluf Bang reported that they could transmit chicken leukemia through a filterable agent to previously healthy chickens who would then develop an aleukemic lymphomata.3,4 In 1910, Peyton Rous demonstrated that he could transplant tissue from sarcomas in chickens to cause tumorigenesis when injected into healthy chickens.4 He then demonstrated that he could transmit some agent through a cell-free filtrate to cause the same effect. At the time, Rous considered this agent either a minute parasitic organism or a chemical stimulant.5 For his work, Rous received the Nobel Prize in 1966.6 At the time of Rous’s discovery, it was well known that human warts were contagious. In 1909, Giuseppe Ciuffo demonstrated that human warts could be transmitted by a filterable agent.7 E. V. Ullmann reported the ability to transmit a warty growth from a child’s respiratory papillomatosis to human skin via a filterable virus in 1923.7 William DeMonbreun and Ernest Goodpasture identified respiratory papillomatosis in dogs similar to human lesions and demonstrated the ability to transmit this lesion via filterable virus to the mouths of other dogs, but the transmission
was limited to mucous membranes of the mouth and to dogs.7 Notably, they showed that dogs that recovered from these lesions were immune to reinfection. In 1933, Richard Shope reported the ability to transmit papilloma via a filterable virus in wild cottontail rabbits to both wild and domestic rabbits.8 Of note, while he found no rabbit naturally immune to inoculation, he did demonstrate resistance to reinfection in some of the domestic rabbits, prolongation of the period of wart development in others, and viral neutralizing capabilities of the sera obtained from infected rabbits. I. D. Rotkin reported in 1967 that age at first coitus was the strongest epidemiologic association with development of cervical cancer and supported the idea of a causal agent being passed from male to “host” female.9 In 1973 he speculated that a very promising agent would be the Herpesvirus hominis type 2.10 Harald zur Hausen and colleagues reported in 1974 that they had failed to find evidence of herpes DNA in cervical cancer biopsies and instead focused on the papillomavirus they had found persistently in such biopsy material.11,12 In 1983 and 1984 respectively, using then-novel DNA hybridization techniques, they reported strains they tentatively labeled HPV 16 and 18 that demonstrated a “startling prevalence … in malignant tumors and (a) very occasional presence in benign papillomas.”12,13 Work with these viruses led to discoveries of the molecular basis for malignant conversion of infected cells,14 such as the expression of proteins E6 and E7 that allow maintain the malignant growth of cervical cancer cells by inhibiting the tumor suppressors p53 and pRB.15 Zur Hausen’s discovery earned him the Nobel Prize in Physiology or Medicine in 2008.16 Zur Hausen’s work inspired large-scale epidemiologic studies in the 1980s and 1990s that confirmed persistent HPV 16 and 18 infections led to precancerous and cancerous cervical lesions.17,18 Invention of HPV Vaccines from Virus-Like Particles
Crucial to the successful development of the HPV vaccination was the demonstration by Jian Zhou, Xiao-Yi Sun, and Ian Frazer in 1991, and subsequently by several other groups, that
Mayo Clinic Medical Scientist Training Program, Rochester, Minnesota, USA ; 2Mayo Graduate School, Rochester, Minnesota, USA ; 3Department of Pediatric and Adolescent Medicine, Mayo Clinic , Rochester, Minnesota, USA .
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Correspondence: Allyson K. Palmer ( [email protected]) DOI: 10.1111/cts.12166
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Figure 1. Critical events in the development of the HPV vaccines from bench to routine practice.
the surface proteins of HPV L1 and L2 would form viruslike particles (VLPs) able to induce neutralizing antibody production. 19–23 VLPs are viral structural proteins, such as envelope or capsid proteins, that self-assemble and become indistinguishable to the human body from the true, infective virus.24 VLPs do not contain viral genetic information and are noninfectious but elicit a strong immune response comprised of both B and T cells.24 HPV vaccines were the second set of vaccines in history to be created using VLPs, the first being the hepatitis B vaccines.25 Studies conducted with papillomavirusbased VLPs in dogs and rabbits showed that immunization using VLPs prevented primary infection when animals were subsequently inoculated with natural, fully potent virus.26,27 These preclinical studies led to clinical trials in humans using HPV VLPs composed of capsid protein L1. Clinical trials showed high rates of protection against HPV infection28,29 as well as protection against primary infection for up to 8 years after vaccination.30 The safety of VLPs combined with their ability to evoke a strong immune response led to remarkably positive results of clinical trials with HPV vaccines, which in turn led to their rapid approval for use in the general population. Licensure of Currently Available HPV Vaccines
Gardasil, manufactured by Merck & Co., became the first of 2 HPV vaccines to receive FDA approval.31 It is a quadrivalent vaccine containing VLPs of the 4 major capsid (L1) proteins of HPV types 6, 11, 16, and 18. Merck’s process uses fermentation of recombinant Saccharomyces cerevisiae to generate L1 proteins, which in turn self-assemble as VLPs. The VLPs are then adsorbed on preformed aluminum-containing adjuvant. The FDA licensed Gardasil in 2006 for administration as 3 doses over 6 months’ time. Merck & Co. conducted a phase II double-blind randomized trial in 2002 to evaluate the HPV 16 component of the vaccine in 2391 females 16–23 years of age. WWW.CTSJOURNAL.COM
That study showed 100% efficacy in preventing acquisition of HPV 16 infection and HPV-16-related cervical intraepithelial neoplasia (CIN).32 Trials evaluating all 4 components of the vaccine followed, including a randomized controlled trial involving over 12,000 women.33 The 3-year follow-up period after vaccination showed not only prevention of HPV infection but also protection against CIN grade 2 or 3, adenocarcinoma in situ, or HPV-16 or -18-related cervical cancer.33 In June 2006, the FDA approved administration of Gardasil to females 9 to 26 years of age for prevention of cervical cancer, genital warts, adenocarcinoma in situ, CIN grades 1–3, and vulvar and vaginal intraepithelial neoplasia grades 2–3.34 In 2008, the FDA expanded its approval of Gardasil to include prevention of vulvar and vaginal cancer caused by HPV types 16 and 18 in females.35 In October 2009, it extended its approval to include administration to males aged 9 to 26 for prevention of genital warts caused by HPV 6 and 11.36 Cervarix, manufactured by GlaxoSmithKline, became the second HPV vaccine licensed by the FDA. 37 This bivalent vaccine contains VLPs of the major capsid protein L1 representing HPV types 16 and 18. Whereas Gardasil manufacture uses fermentation products of yeast, Cervarix uses bioreaction products of a recombinant baculovirusexpression-vector system using Trichoplusia ni insect cells. The VLPs are adsorbed onto aluminum (as hydroxide salt) and combined with an aluminum adjuvant system. The FDAlicensed Cervarix is administered as 3 intramuscular doses over 6 months, similar to Gardasil. A phase III randomized, double-blinded, controlled trial in young adults showed 92.9% effectiveness for prevention of CIN grades II and III, carcinoma in situ , or cancer in women who had not been previously infected with HPV types 16 or 18.38 Cervarix was approved originally in October 2009 by the FDA for use in girls and women 10 to 25 years old.39 VOLUME 7 • ISSUE 5
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Recommendation for HPV Vaccination in the United States and around the World
Following FDA approval of Gardasil in June 2006, the Advisory Committee on Immunization Practices (ACIP) published official recommendations in Morbidity and Mortality Weekly Report (MMWR) in March 2007, recommending routine vaccination of females at ages 11–12 and catch-up vaccination for females aged 13 to 26 and permission to begin the 3-dose series in females 9 to 10 years of age.34 Following FDA licensure of Cervarix, the ACIP published recommendations for the bivalent vaccine in May 2010, harmonizing the specifics of timing with Gardasil.39 The ACIP recommendations did not recommend one vaccine over the other.39 After FDA approval of Gardasil for use in males on October 16, 2009, ACIP published a statement permitting, but not recommending, the use of Gardasil but not Cervarix in males aged 9 through 26 on October 21, 2010. Unlike recommendations for females, this initial language for use in males did not suggest an optimal age for vaccine administration but stated that “HPV4 would be most effective when given before exposure to HPV through sexual contact.”36 HPV vaccine uptake was much lower in women than anticipated by manufacturers, causing the medical and regulatory community to attempt to shift the focus of HPV vaccination to include routine vaccinations of males.40 The ACIP released an updated statement recommending Gardasil in males in 2011, citing updated data on vaccine efficacy for anal intraepithelial neoplasia (AIN) grades 2 to 3 as well as increased information on cost-effectiveness and safety. The recommendations called for routine vaccine use in males aged 11 to 12 with catch-up doses for males aged 13 through 21 for those who had not previously completed the series.40 In 2009, the World Health Organization recommended the administration of HPV vaccine to girls prior to initiation of sexual activity.41 The Global Advisory Committee on Vaccine Safety (GACVS) reported in June 2013 that over 175 million doses of HPV vaccine had been distributed and reported worldwide.42 HPV vaccine uptake rates seem to be highest in countries that deliver the HPV vaccine through school-based programs.43–45 Mixed programs incorporating both school-based and health facility-based distribution may be more effective in developing countries.46 Worldwide, 33 countries had implemented national vaccination programs by 2010, but few of these programs were in developing countries, which suffer the highest cervical cancer deaths rates.47,48 The GAVI Alliance, a public–private partnership founded in 2010 that aims to increase access to childhood immunization in the world’s poorest countries, had approved 10 countries for HPV vaccine demonstration program support as of March 2013.49 A recent analysis focusing on global vaccination suggests that reaching coverage targets for the HPV vaccine in 73 GAVI-supported countries could prevent 15.1 deaths for every 1,000 persons vaccinated, totaling 0.5 million deaths from 2011 to 2020.50 Problems with Uptake
Despite their licensure and impressive results from preclinical studies demonstrating safety and efficacy in preventing precancerous and cancerous lesions, HPV vaccine uptake in the United States has been disappointing. In 2011—4 years since universal U.S. recommendation for females—only 34.8 (95%ile CI: 33.2–36.4) percent of females 13 to 17 years of age had completed the 3-dose series recommended.51 To put this in perspective, 422
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universal recommendation for meningococcal vaccination of adolescents at the same age—11 to 12 years old—had achieved an uptake rate of 53.6 (95%ile CIL 52.4–54.9) percent 4 years later.52 When the HPV vaccine was first recommended in 2007 by the ACIP universally for females 11 to 12 years of age, public health officials and clinicians raised concerns that uptake would be thwarted by the failure of the 3-dose series to fit in the routine health maintenance schedule,34 by concerns of insurance coverage for the expense of the vaccine,53 and by the lack of awareness for the risk of cervical cancer.54,55 Following licensure, several concerns emerged regarding safety including syncope, Guillain-Barré Syndrome, and thromboembolic phenomena. Reports of postinjection syncope emerged in 2006, resulting in an HPV-specific recommendation that vaccine providers monitor HPV-vaccine recipients for 15 minutes following vaccination.34,39 Indeed, postlicensure studies did support the association of HPV vaccination with syncope, but that this adverse event was not unique to HPV vaccination but an age-related phenomenon associated with injections and phlebotomy in the adolescent age group.56,57 For this reason, the general recommendations regarding vaccinations from the CDC’s Advisory Committee on Immunization Practices holds that vaccine providers monitor adolescents and adults for 15 minutes regardless of the type of vaccine.58 Postlicensure reports also raised a concern for an association with GuillainBarré Syndrome as well as thromboembolic phenomena,59 but subsequent studies failed to find an association of either adverse event with HPV vaccinations.60,61 The apparent link between HPV vaccination and thromboembolic events likely resulted from the earliest adopters among vaccine providers administering catch-up HPV vaccination in teens and young women presenting for oral contraception, a class of therapeutics associated with a small but real increase in the risk for thromboembolic phenomena.57 In fact, a large postlicensure study of HPV4 in nearly 200,000 adolescent females found no concerning associations with the development of chronic or debilitating conditions including autoimmune phenomena.62,63 Merck & Co. is completing a similar postlicensure study in males (ClinicalTrials.gov Identifier: NCT01567813). Despite 7 years of use since Gardasil first become universally recommended in females in the United States, no more than 34% of females 13 to 17 years of age have received all 3 doses.51 Darden et al. conducted a study from 2008 to 2010 using National Immunization Survey of Teens public-use files and found that while rates of clinicians recommending HPV have increased over the 3 years—by far more than for other adolescent vaccinations— the intentions of parents to refuse the HPV vaccine increased rather than decreased from 40% to 44%.64 Leading reasons for these intentions included safety concerns, which increased from 4.5% to 16.4%. Other concerns included that the vaccine was not recommended or needed, that the patient was too young or not sexually active, and that the parent lacked information regarding the vaccine. This is despite the strong recognition across medical and public health communities of the importance of the vaccine, its remarkable safety record, the high likelihood for exposure to the infection, and the need to vaccinate long before the possibility of exposure when the patient is young and the immune system most responsive. Conclusions
FDA approval of Gardasil occurred only 23 years after zur Hausen et al.’s report of a link between HPV and cervical cancer, and only WWW.CTSJOURNAL.COM
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15 years after the creation of VLPs. The discoveries (Figure 1) that laid the foundation for HPV vaccine development built upon epidemiologic observations of the relationship between sexual history and cervical cancer. This led to the search for molecular evidence for oncoviruses and studies that determined HPV as the cause of cervical cancer. This discovery, combined with the innovation of VLPs, paved the way for HPV vaccine development. Despite the successful translation of the science surrounding HPV and cervical cancer into an effective vaccine to prevent HPV infection, HPV vaccination has failed to achieve the same uptake rates as other adolescent vaccinations. This is a multifactorial problem involving health illiteracy, unfounded suspicions, cost barriers, and deficient access. To complete the translation of HPV vaccination, we must work to improve uptake through substantive changes in how we as a society deliver both healthcare education and healthcare itself.
17. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, Schiffman MH, Moreno V, Kurman R, Shah KV, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst. 1995; 87(11): 796–802.
Acknowledgments
24. Jin XW, Lipold L, Sikon A, Rome E. Human papillomavirus vaccine: safe, effective, underused. Cleve Clin J Med. 2013; 80(1): 49–60.
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