Spotlight on Quadrivalent Human Papillomavirus(Types 6, 11, 16, 18) Recombinant Vaccine(Gardasil®) in the Prevention of PremalignantGenital Lesions, Genital Cancer, and Genital Warts in Women†
Abstract
Quadrivalent human papilloma virus (HPV) [types 6, 11, 16, 18] recombinant vaccine (Gardasil®; Silgard®) is composed of virus-like particles (VLPs) formed by self-assembly of recombinant L1 capsid protein from each of HPV types 6, 11, 16, and 18. The VLPs are noninfectious, containing no DNA, and are highly immunogenic, inducing high levels of neutralizing antibodies against the particular HPV types when administered to animals or humans. Quadrivalent HPV vaccine is indicated for use from the age of 9 years for the prevention of premalignant genital lesions (cervical, vulvar, and vaginal), cervical cancer, and external genital warts (condyloma acuminata) causally related to certain oncogenic or specific HPV types.
In placebo-controlled clinical trials, quadrivalent HPV vaccine administered as three doses over 6 months provided high-level protection against infection or disease caused by the vaccine HPV types over 2–4 years of follow-up in females aged 15–45 years who were naive to the vaccine HPV types. A degree of cross-protection against certain other non-vaccine high-risk HPV types was also observed. The vaccine is not effective against current infection with a vaccine HPV type. Girls or women with current infection with one or more of the vaccine HPV types gained protection from infection or disease caused by the remaining vaccine HPV types and they were also protected against reinfection with the same HPV type after clearance of an infection caused by a vaccine HPV type. High seroconversion rates and high levels of anti-HPV antibodies were observed in all vaccinated individuals of all age ranges from 9 to 45 years. No correlation was found between antibody levels and protective efficacy of the vaccine. Rechallenge with quadrivalent HPV vaccine produced a potent anamnestic humoral immune response. The vaccine is generally well tolerated and is projected to be cost effective in most pharmacoeconomic models. Therefore, quadrivalent HPV vaccine offers an effective means, in combination with screening programs, to substantially reduce the burden of HPV-related precancerous lesions and cancer, particularly cervical cancer, as well as anogenital warts.
... In contrast, natural infection that had been cleared was not fully protective [58]. In women with previous or current infection with one or more vaccine HPV types, quadrivalent HPV vaccine provided protection against lesions caused by the remaining HPV types [59]. ...
... Clinical studies evaluating reduced dose schedules and the intervals between doses for both vaccines have demonstrated non-inferior antibody responses in girls younger than 15 years of age who received two doses, given 6 months apart, when compared with women who received the standard three doses of vaccine and had evidence of efficacy in clinical trials. These findings have led to the recommendations and approval of two-dose schedules in 9-to 14-year-old girls [14,59]. Immunogenicity data for a single vaccine dose are limited. ...
Human papillomavirus (HPV) is the most common sexually transmitted infection, with 15 HPV types related to cervical, anal, oropharyngeal, penile, vulvar, and vaginal cancers. However, cervical cancer remains one of the most common cancers in women, especially in developing countries. Three HPV vaccines have been licensed: bivalent (Cervarix, GSK, Rixensart, Belgium), quadrivalent (Merck, Sharp & Dome (Merck & Co, Whitehouse Station, NJ, USA)), and nonavalent (Merck, Sharp & Dome (Merck & Co, Whitehouse Station, NJ, USA)). The current HPV vaccine recommendations apply to 9 years old and above through the age of 26 years and adults aged 27–45 years who might be at risk of new HPV infection and benefit from vaccination. The primary target population for HPV vaccination recommended by the WHO is girls aged 9–14 years, prior to their becoming sexually active, to undergo a two-dose schedule and girls ≥ 15 years of age, to undergo a three-dose schedule. Safety data for HPV vaccines have indicated that they are safe. The most common adverse side-effect was local symptoms. HPV vaccines are highly immunogenic. The efficacy and effectiveness of vaccines has been remarkably high among young women who were HPV seronegative before vaccination. Vaccine efficacy was lower among women regardless of HPV DNA when vaccinated and among adult women. Comparisons of the efficacy of bivalent, quadrivalent, and nonavalent vaccines against HPV 16/18 showed that they are similar. However, the nonavalent vaccine can provide additional protection against HPV 31/33/45/52/58. In a real-world setting, the notable decrease of HPV 6/11/16/18 among vaccinated women compared with unvaccinated women shows the vaccine to be highly effective. Moreover, the direct effect of the nonavalent vaccine with the cross-protection of bivalent and quadrivalent vaccines results in the reduction of HPV 6/11/16/18/31/33/45/52/58. HPV vaccination has been shown to provide herd protection as well. Two-dose HPV vaccine schedules showed no difference in seroconversion from three-dose schedules. However, the use of a single-dose HPV vaccination schedule remains controversial. For males, the quadrivalent HPV vaccine possibly reduces the incidence of external genital lesions and persistent infection with HPV 6/11/16/18. Evidence regarding the efficacy and risk of HPV vaccination and HIV infection remains limited. HPV vaccination has been shown to be highly effective against oral HPV type 16/18 infection, with a significant percentage of participants developing IgG antibodies in the oral fluid post vaccination. However, the vaccines’ effectiveness in reducing the incidence of and mortality rates from HPV-related head and neck cancers should be observed in the long term. In anal infections and anal intraepithelial neoplasia, the vaccines demonstrate high efficacy. While HPV vaccines are very effective, screening for related cancers, as per guidelines, is still recommended.
... Comparison of other studies reporting on HPV prevalence in China indicates wide geographic variability in subtype distribution thus undermining the selection of the most effective vaccine. In addition to providing excellent protection against the HPV types contained in the vaccine, Gardisil has also demonstrated significant cross-protection to other oncogenic types in both naive and previously infected women 26 encourage the implementation of an HPV vaccine program in Beijing, China. 27 HPV vaccines that prevent against HPV 16 and 18 infections are now available and have the potential to reduce the incidence of cervical and other anogenital cancers. ...
... 27 HPV vaccines that prevent against HPV 16 and 18 infections are now available and have the potential to reduce the incidence of cervical and other anogenital cancers. 26 This study aimed to detect the high-risk HPV types in external genital warts from females in Erbil, Iraq from 2010 -2017, study all low risk group HPV infection and correlate with some of clinical parameters. ...
... To date, the licensed human papillomavirus (HPV) prophylactic vaccines have demonstrated robust immunogenicity and efficacy [1][2][3][4]. Although immune correlates of protection against HPV infection are unclear due to the exceptional efficacy of the vaccines, a growing body of preclinical and clinical data suggest HPV-specific neutralizing antibodies as the primary mechanism of protection [5][6][7][8]. ...
The HPV Serology Laboratory is leading a global partnership initiative aiming for standardization and harmonization of current serology assay platforms being used to assess immune responses to HPV vaccines. Serology standardization is particularly important given the increasing number of immunobridging trials relying on serology data for approval of new vaccine dosing schedules or vaccine formulations. The initiative was established in 2017 to enable comparisons of data between different vaccines and relevant studies as well as expedite the implementation of new vaccines and vaccine indications. The HPV Serology Laboratory has held or attended several meetings with partnering laboratories, including international meetings in 2017, 2018, and 2021.
... There are currently three licensed HPV prophylactic vaccines: Cervarix Ò , a bivalent HPV-16/18 product from GlaxoSmithKline; Gardasil Ò , a quadrivalent HPV-6/11/16/18 product and Gardasil Ò 9, a nonavalent HPV-6/11/16/18/31/33/45/52/58 vaccine, both from Merck & Co., Inc. [1][2][3][4]. These products were licensed following highly encouraging efficacy data from large phase III vaccine trials and have the potential (nonavalent vaccine) to prevent up to 90% of cervical cancer cases. ...
When administered as standard three-dose schedules, the licensed HPV prophylactic vaccines have demonstrated extraordinary immunogenicity and efficacy. We summarize the immunogenicity of these licensed vaccines and the most commonly used serology assays, with a focus on key considerations for one-dose vaccine schedules.
Although immune correlates of protection against infection are not entirely clear, both preclinical and clinical evidence point to neutralizing antibodies as the principal mechanism of protection. Thus, immunogenicity assessments in vaccine trials have focused on measurements of antibody responses to the vaccine. Non-inferiority of antibody responses after two doses of HPV vaccines separated by 6 months has been demonstrated and this evidence supported the recent WHO recommendations for two-dose vaccination schedules in both boys and girls 9–14 years of age. There is also some evidence suggesting that one dose of HPV vaccines may provide protection similar to the currently recommended two-dose regimens but robust data on efficacy and immunogenicity of one-dose vaccine schedules are lacking. In addition, immunogenicity has been assessed and reported using different methods, precluding direct comparison of results between different studies and vaccines. New head-to-head vaccine trials evaluating one-dose immunogenicity and efficacy have been initiated and an increase in the number of trials relying on immunobridging is anticipated. Therefore, standardized measurement and reporting of immunogenicity for the up to nine HPV types targeted by the current vaccines is now critical. Building on previous HPV serology assay standardization and harmonization efforts initiated by the WHO HPV LabNet in 2006, new secondary standards, critical reference reagents and testing guidelines will be generated as part of a new partnership to facilitate harmonization of the immunogenicity testing in new HPV vaccine trials.
... Gardisil is a quadrivalent vaccine containing four genotypes, namely 16, 18, 6 and 11; and Cervarix (GSK) is a bivalent vaccine containing 16 and 18. In addition to providing excellent protection against the HPV types contained in the vaccine, Gardisil has also demonstrated significant cross-protection to other oncogenic types in both naive and previously infected women [13]. ...
Aim: The aim of this study was to analyze the distribution of human papillomavirus (HPV) genotypes among women with genital warts in the Beijing region of China. Methods: A total of 350 women diagnosed with genital warts between 2014 and 2016 were analyzed by real-time polymerase chain reaction (PCR) to test for high-risk and low-risk HPV subtypes. Results: The results show that 52.6% (184/350) of cases were positive for HPV6+11. The three most common high-risk HPVs detected were HPV52, HPV16 and HPV58, detected in 12.0% (42/350), 10.6% (37/350) and 10.0% (35/350) of all cases, respectively. Conclusion: These results indicate that vaccines targeting HPV subtypes 6, 11, 16, 52 and 58 would have the greatest impact among sexually active women living in Beijing.
... This extended schedule corresponds with clinical trials demonstrating non-inferior immune responses with two doses compared to three doses for the quadrivalent vaccine (2). The vaccine has recorded long-term protective benefits against genital warts, cellular dysplasia, early low-grade cancers, pre-cancerous lesions, and HPVrelated cancers (3). ...
In 2014, Brazil introduced an HPV immunization program for girls 9-13 years of age as part of the Unified Health System's (SUS) National Immunization Program. The first doses were administered in March 2014; the second ones, in September 2014. In less than 3 months more than 3 million girls received the first dose of quadrivalent HPV vaccine, surpassing the target rate of 80%. This paper examines three elements that may influence the program's long-term success in Brazil: sustaining effective outreach, managing a large technology-transfer collaboration, and developing an electronic immunization registry, with a focus on the State of São Paulo. If these three factors are managed, the Government of Brazil is primed to serve as a model of success for other countries interested in implementing a national HPV vaccination program to decrease HPV-related morbidity and mortality.
... This extended schedule corresponds with clinical trials demonstrating non-inferior immune responses with two doses compared to three doses for the quadrivalent vaccine (2). The vaccine has recorded long-term protective benefits against genital warts, cellular dysplasia, early low-grade cancers, pre-cancerous lesions, and HPVrelated cancers (3). ...
In 2014, Brazil introduced an HPV immunization program
for girls 9–13 years of age as part of the Unified Health
System’s (SUS) National Immunization Program. The first
doses were administered in March 2014; the second ones, in
September 2014. In less than 3 months more than 3 million
girls received the first dose of quadrivalent HPV vaccine, surpassing
the target rate of 80%. This paper examines three elements
that may influence the program’s long-term success in
Brazil: sustaining effective outreach, managing a large technology-
transfer collaboration, and developing an electronic
immunization registry, with a focus on the State of São Paulo.
If these three factors are managed, the Government of Brazil is
primed to serve as a model of success for other countries interested
in implementing a national HPV vaccination program
to decrease HPV-related morbidity and mortality.
Objective:
Anogenital warts are caused by human papillomavirus (HPV). Globally, HPV genotypes 6 and 11 are most often associated with anogenital warts. However, the diversity of HPV genotypes found in patients with genital warts in Thailand is unknown. The aim of this study was to investigate HPV-associated anogenital warts in the Thai population and to assess whether genotypes found are represented in the bivalent and quadrivalent HPV vaccine.
Methods:
This study included 206 anogenital swab samples from patients who were diagnosed with anogenital warts. Detection of HPV DNA was performed using polymerase chain reaction to amplify the L1 gene and sequencing.
Results:
HPV was identified in 88.3% (182/206) of the samples. The majority of HPV genotypes were low-risk genotypes HPV6 (36.9%) and HPV11 (36.4%), which represented the most common infection found in genital warts in this study.
Conclusion:
Immunization with the quadrivalent vaccine (HPV6, HPV11, HPV16, and HPV18) could potentially prevent genital warts caused by HPV infection.
Background:
Persistent infection with high-risk human papillomaviruses (hrHPV) types is causally linked with the development of cervical precancer and cancer. HPV types 16 and 18 cause approximately 70% of cervical cancers worldwide.
Objectives:
To evaluate the harms and protection of prophylactic human papillomaviruses (HPV) vaccines against cervical precancer and HPV16/18 infection in adolescent girls and women.
Search methods:
We searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase (June 2017) for reports on effects from trials. We searched trial registries and company results' registers to identify unpublished data for mortality and serious adverse events.
Selection criteria:
Randomised controlled trials comparing efficacy and safety in females offered HPV vaccines with placebo (vaccine adjuvants or another control vaccine).
Data collection and analysis:
We used Cochrane methodology and GRADE to rate the certainty of evidence for protection against cervical precancer (cervical intraepithelial neoplasia grade 2 and above [CIN2+], CIN grade 3 and above [CIN3+], and adenocarcinoma-in-situ [AIS]), and for harms. We distinguished between the effects of vaccines by participants' baseline HPV DNA status. The outcomes were precancer associated with vaccine HPV types and precancer irrespective of HPV type. Results are presented as risks in control and vaccination groups and risk ratios (RR) with 95% confidence intervals in brackets.
Main results:
We included 26 trials (73,428 participants). Ten trials, with follow-up of 1.3 to 8 years, addressed protection against CIN/AIS. Vaccine safety was evaluated over a period of 6 months to 7 years in 23 studies. Studies were not large enough or of sufficient duration to evaluate cervical cancer outcomes. All but one of the trials was funded by the vaccine manufacturers. We judged most included trials to be at low risk of bias. Studies involved monovalent (N = 1), bivalent (N = 18), and quadrivalent vaccines (N = 7). Most women were under 26 years of age. Three trials recruited women aged 25 and over. We summarize the effects of vaccines in participants who had at least one immunisation.Efficacy endpoints by initial HPV DNA statushrHPV negativeHPV vaccines reduce CIN2+, CIN3+, AIS associated with HPV16/18 compared with placebo in adolescent girls and women aged 15 to 26. There is high-certainty evidence that vaccines lower CIN2+ from 164 to 2/10,000 (RR 0.01 (0 to 0.05)) and CIN3+ from 70 to 0/10,000 (RR 0.01 (0.00 to 0.10). There is moderate-certainty evidence that vaccines reduce the risk of AIS from 9 to 0/10,000 (RR 0.10 (0.01 to 0.82).HPV vaccines reduce the risk of any CIN2+ from 287 to 106/10,000 (RR 0.37 (0.25 to 0.55), high certainty) and probably reduce any AIS lesions from 10 to 0/10,000 (RR 0.1 (0.01 to 0.76), moderate certainty). The size of reduction in CIN3+ with vaccines differed between bivalent and quadrivalent vaccines (bivalent: RR 0.08 (0.03 to 0.23), high certainty; quadrivalent: RR 0.54 (0.36 to 0.82), moderate certainty). Data in older women were not available for this comparison.HPV16/18 negativeIn those aged 15 to 26 years, vaccines reduce CIN2+ associated with HPV16/18 from 113 to 6 /10,000 (RR 0.05 (0.03 to 0.10). In women 24 years or older the absolute and relative reduction in the risk of these lesions is smaller (from 45 to 14/10,000, (RR 0.30 (0.11 to 0.81), moderate certainty). HPV vaccines reduce the risk of CIN3+ and AIS associated with HPV16/18 in younger women (RR 0.05 (0.02 to 0.14), high certainty and RR 0.09 (0.01 to 0.72), moderate certainty, respectively). No trials in older women have measured these outcomes.Vaccines reduce any CIN2+ from 231 to 95/10,000, (RR 0.41 (0.32 to 0.52)) in younger women. No data are reported for more severe lesions.Regardless of HPV DNA statusIn younger women HPV vaccines reduce the risk of CIN2+ associated with HPV16/18 from 341 to 157/10,000 (RR 0.46 (0.37 to 0.57), high certainty). Similar reductions in risk were observed for CIN3+ associated with HPV16/18 (high certainty). The number of women with AIS associated with HPV16/18 is reduced from 14 to 5/10,000 with HPV vaccines (high certainty).HPV vaccines reduce any CIN2+ from 559 to 391/10,000 (RR 0.70 (0.58 to 0.85, high certainty) and any AIS from 17 to 5/10,000 (RR 0.32 (0.15 to 0.67), high certainty). The reduction in any CIN3+ differed by vaccine type (bivalent vaccine: RR 0.55 (0.43 to 0.71) and quadrivalent vaccine: RR 0.81 (0.69 to 0.96)).In women vaccinated at 24 to 45 years of age, there is moderate-certainty evidence that the risks of CIN2+ associated with HPV16/18 and any CIN2+ are similar between vaccinated and unvaccinated women (RR 0.74 (0.52 to 1.05) and RR 1.04 (0.83 to 1.30) respectively). No data are reported in this age group for CIN3+ or AIS.Adverse effectsThe risk of serious adverse events is similar between control and HPV vaccines in women of all ages (669 versus 656/10,000, RR 0.98 (0.92 to 1.05), high certainty). Mortality was 11/10,000 in control groups compared with 14/10,000 (9 to 22) with HPV vaccine (RR 1.29 [0.85 to 1.98]; low certainty). The number of deaths was low overall but there is a higher number of deaths in older women. No pattern in the cause or timing of death has been established.Pregnancy outcomesAmong those who became pregnant during the studies, we did not find an increased risk of miscarriage (1618 versus 1424/10,000, RR 0.88 (0.68 to 1.14), high certainty) or termination (931 versus 838/10,000 RR 0.90 (0.80 to 1.02), high certainty). The effects on congenital abnormalities and stillbirths are uncertain (RR 1.22 (0.88 to 1.69), moderate certainty and (RR 1.12 (0.68 to 1.83), moderate certainty, respectively).
Authors' conclusions:
There is high-certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and young women aged 15 to 26. The effect is higher for lesions associated with HPV16/18 than for lesions irrespective of HPV type. The effect is greater in those who are negative for hrHPV or HPV16/18 DNA at enrolment than those unselected for HPV DNA status. There is moderate-certainty evidence that HPV vaccines reduce CIN2+ in older women who are HPV16/18 negative, but not when they are unselected by HPV DNA status.We did not find an increased risk of serious adverse effects. Although the number of deaths is low overall, there were more deaths among women older than 25 years who received the vaccine. The deaths reported in the studies have been judged not to be related to the vaccine. Increased risk of adverse pregnancy outcomes after HPV vaccination cannot be excluded, although the risk of miscarriage and termination are similar between trial arms. Long-term of follow-up is needed to monitor the impact on cervical cancer, occurrence of rare harms and pregnancy outcomes.
The field of tumor immunotherapy is evolving rapidly. Many promising areas are discussed in depth in various chapters in this book. This chapter provides a broad overview of additional approaches not covered in specific book chapters. Some areas are nonetheless quite advanced, such as the use of TLR agonists in clinical trials, and some have received FDA approvals such as BCG to treat bladder cancer and the IMiD lenalidomide to treat multiple myeloma. Other areas are of great interest but lack sufficient information to require a dedicated chapter. These miscellaneous areas hold great promise to further the development of effective cancer immunotherapies. © 2013 Springer Science+Business Media New York. All rights are reserved.
Background. A quadrivalent (types 6, 11, 16, and 18) human papillomavirus (HPV) L1 virus-like-particle (VLP) vaccine has been shown to be 95%-100% effective in preventing cervical and genital disease related to HPV-6, -11, -16, and -18 in 16-26-year-old women naive for HPV vaccine types. Because most women in the general population are sexually active, some will have already been infected with ≥1 HPV vaccine types at the time vaccination is offered. Here, we assessed whether such infected women are protected against disease caused by the remaining HPV vaccine types. Methods. Two randomized, placebo-controlled trials of the quadrivalent (types 6, 11, 16, and 18) HPV vaccine enrolled 17,622 women without consideration of baseline HPV status. Among women infected with 1-3 HPV vaccine types at enrollment, efficacy against genital disease related to the HPV vaccine type or types for which subjects were naive was assessed. Results. Vaccination was 100% effective (95% confidence interval [CI], 79%-100%) in preventing incident cervical intraepithelial neoplasia 2 or 3 or cervical adenocarcinoma in situ caused by the HPV type or types for which the women were negative at enrollment. Efficacy for preventing vulvar or vaginal HPV-related lesions was 94% (95% CI, 81%-99%). Conclusions. Among women positive for 1-3 HPV vaccine types before vaccination, the quadrivalent HPV vaccine protected against neoplasia caused by the remaining types. These results support vaccination of the general population without prescreening.
BACKGROUND: Human papillomavirus types 16 (HPV-16) and 18 (HPV-18) cause approximately 70% of cervical cancers worldwide. A phase 3 trial was conducted to evaluate a quadrivalent vaccine against HPV types 6, 11, 16, and 18 (HPV-6/11/16/18) for the prevention of high-grade cervical lesions associated with HPV-16 and HPV-18. METHODS: In this randomized, double-blind trial, we assigned 12,167 women between the ages of 15 and 26 years to receive three doses of either HPV-6/11/16/18 vaccine or placebo, administered at day 1, month 2, and month 6. The primary analysis was performed for a per-protocol susceptible population that included 5305 women in the vaccine group and 5260 in the placebo group who had no virologic evidence of infection with HPV-16 or HPV-18 through 1 month after the third dose (month 7). The primary composite end point was cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV-16 or HPV-18. RESULTS: Subjects were followed for an average of 3 years after receiving the first dose of vaccine or placebo. Vaccine efficacy for the prevention of the primary composite end point was 98% (95.89% confidence interval [CI], 86 to 100) in the per-protocol susceptible population and 44% (95% CI, 26 to 58) in an intention-to-treat population of all women who had undergone randomization (those with or without previous infection). The estimated vaccine efficacy against all high-grade cervical lesions, regardless of causal HPV type, in this intention-to-treat population was 17% (95% CI, 1 to 31). CONCLUSIONS: In young women who had not been previously infected with HPV-16 or HPV-18, those in the vaccine group had a significantly lower occurrence of high-grade cervical intraepithelial neoplasia related to HPV-16 or HPV-18 than did those in the placebo group.
Quadrivalent human papilloma virus (HPV) [types 6, 11, 16, 18] recombinant vaccine (Gardasil®; Silgard®) is composed of virus-like particles (VLPs) formed by self-assembly of recombinant L1 capsid protein from each of HPV types 6,11, 16 and 18. The VLPs are noninfectious, containing no DNA, and are highly immunogenic, inducing high levels of neutralizing antibodies against the particular HPV types when administered to animals or humans. Quadrivalent HPV vaccine is indicated for use from the age of 9 years for the prevention of premalignant genital lesions (cervical, vulvar and vaginal), cervical cancer and external genital warts (condyloma acuminata) causally related to certain oncogenic or specific HPV types.
In placebo-controlled clinical trials, quadrivalent HPV vaccine administered as three doses over 6 months provided high-level protection against infection or disease caused by the vaccine HPV types over 2–4 years of follow-up in females aged 15–45 years who were naive to the vaccine HPV types. A degree of crossprotection against certain other non-vaccine high-risk HPV types was also observed. The vaccine is not effective against current infection with a vaccine HPV type. Girls or women with current infection with one or more of the vaccine HPV types gained protection from infection or disease caused by the remaining vaccine HPV types and they were also protected against reinfection with the same HPV type after clearance of an infection caused by a vaccine HPV type. High seroconversion rates and high levels of anti-HPV antibodies were observed in all vaccinated individuals of all age ranges from 9 to 45 years. No correlation was found between antibody levels and protective efficacy of the vaccine. Rechallenge with quadrivalent HPV vaccine produced a potent anamnestic humoral immune response. The vaccine is generally well tolerated and is projected to be cost effective in most pharmacoeconomic models. Therefore, quadrivalent HPV vaccine offers an effective means, in combination with screening programmes, to substantially reduce the burden of HPV-related precancerous lesions and cancer, particularly cervical cancer, as well as anogenital warts.
To assess the cost effectiveness of routine vaccination of 12 year old schoolgirls against human papillomavirus infection in the United Kingdom.
Economic evaluation.
UK. Population Schoolgirls aged 12 or older.
Costs, quality adjusted life years (QALYs), and incremental cost effectiveness ratios for a range of vaccination options.
Vaccinating 12 year old schoolgirls with a quadrivalent vaccine at 80% coverage is likely to be cost effective at a willingness to pay threshold of pound30,000 (euro37,700; $59,163) per QALY gained, if the average duration of protection from the vaccine is more than 10 years. Implementing a catch-up campaign of girls up to age 18 is likely to be cost effective. Vaccination of boys is unlikely to be cost effective. A bivalent vaccine with the same efficacy against human papillomavirus types 16 and 18 costing pound13- pound21 less per dose (depending on the duration of vaccine protection) may be as cost effective as the quadrivalent vaccine although less effective as it does not prevent anogenital warts.
Routine vaccination of 12 year old schoolgirls combined with an initial catch-up campaign up to age 18 is likely to be cost effective in the UK. The results are robust to uncertainty in many parameters and processes. A key influential variable is the duration of vaccine protection.
Quadrivalent human papilloma virus (HPV) [types 6, 11, 16, 18] recombinant vaccine (Gardasil®; Silgard®) is composed of virus-like particles (VLPs) formed by self-assembly of recombinant L1 capsid protein from each of HPV types 6, 11, 16 and 18. The VLPs are noninfectious, containing no DNA, and are highly immunogenic, inducing high levels of neutralizing antibodies against the particular HPV types when administered to animals or humans. Quadrivalent HPV vaccine is indicated for use from the age of 9 years for the prevention of premalignant genital lesions (cervical, vulvar and vaginal), cervical cancer and external genital warts (condyloma acuminata) causally related to certain oncogenic or specific HPV types. In placebo-controlled clinical trials, quadrivalent HPV vaccine administered as three doses over 6 months provided high-level protection against infection or disease caused by the vaccine HPV types over 2-4 years of follow-up in females aged 15-45 years who were naive to the vaccine HPV types. A degree of cross-protection against certain other non-vaccine high-risk HPV types was also observed. The vaccine is not effective against current infection with a vaccine HPV type. Girls or women with current infection with one or more of the vaccine HPV types gained protection from infection or disease caused by the remaining vaccine HPV types and they were also protected against reinfection with the same HPV type after clearance of an infection caused by a vaccine HPV type. High seroconversion rates and high levels of anti-HPV antibodies were observed in all vaccinated individuals of all age ranges from 9 to 45 years. No correlation was found between antibody levels and protective efficacy of the vaccine. Rechallenge with quadrivalent HPV vaccine produced a potent anamnestic humoral immune response. The vaccine is generally well tolerated and is projected to be cost effective in most pharmacoeconomic models. Therefore, quadrivalent HPV vaccine offers an effective means, in combination with screening programmes, to substantially reduce the burden of HPV-related precancerous lesions and cancer, particularly cervical cancer, as well as anogenital warts.
OBJECTIVE: To assess the cost effectiveness of routine vaccination of 12 year old schoolgirls against human papillomavirus infection in the United Kingdom. DESIGN: Economic evaluation. SETTING: UK. Population Schoolgirls aged 12 or older. MAIN OUTCOME MEASURES: Costs, quality adjusted life years (QALYs), and incremental cost effectiveness ratios for a range of vaccination options. RESULTS: Vaccinating 12 year old schoolgirls with a quadrivalent vaccine at 80% coverage is likely to be cost effective at a willingness to pay threshold of pound30,000 (euro37,700; $59,163) per QALY gained, if the average duration of protection from the vaccine is more than 10 years. Implementing a catch-up campaign of girls up to age 18 is likely to be cost effective. Vaccination of boys is unlikely to be cost effective. A bivalent vaccine with the same efficacy against human papillomavirus types 16 and 18 costing pound13- pound21 less per dose (depending on the duration of vaccine protection) may be as cost effective as the quadrivalent vaccine although less effective as it does not prevent anogenital warts. CONCLUSIONS: Routine vaccination of 12 year old schoolgirls combined with an initial catch-up campaign up to age 18 is likely to be cost effective in the UK. The results are robust to uncertainty in many parameters and processes. A key influential variable is the duration of vaccine protection.
Background:
We describe the safety of the human papillomavirus (HPV)-6/11/16/18 vaccine using updated clinical trial data (median follow-up time of 3.6 years) and summarize up to 3 years of post-licensure surveillance.
Methods:
In 5 clinical trials, 21,480 girls/women aged 9 to 26 years and boys aged 9 to 16 years received >or=1 dose of HPV-6/11/16/18 vaccine or placebo. All serious and non-serious adverse experiences (AEs) and new medical conditions were recorded for the entire study period(s). As of June 2009, >25 million doses of HPV-6/11/16/18 vaccine had been distributed in the United States with >50 million doses globally. Post-licensure safety as summarized by the Centers for Disease Control and Prevention using the United States Vaccine Adverse Event Reporting System database is also reported.
Results:
Eight subjects experienced a treatment-related serious AE (0.05% vaccine; 0.02% placebo). Of 18 deaths (0.1% vaccine; 0.1% placebo), all were considered unrelated to study treatment. New medical conditions which were potentially consistent with autoimmune phenomena were reported in 2.4% of both vaccine and placebo recipients. Pain, the most common injection-site AE, occurred more frequently with vaccine (81% vaccine; 75% placeboaluminum; 45% placebo-saline). No differences were seen in the incidence of the most common non-serious AEs-headache and pyrexia. The Vaccine Adverse Event Reporting System has received 14,072 reports for the HPV-6/11/16/18 vaccine since licensure, with only 7% being serious AEs, about half the average reported for licensed vaccines in general.
Conclusions:
HPV-6/11/16/18 vaccination was associated with more injection-site pain than placebo but similar incidences of systemic and serious AEs and new medical conditions potentially consistent with autoimmune phenomena. Based on review of post-licensure safety information, the benefits of vaccination to prevent the majority of genital tract precancers and cancers continue to far outweigh its risks.