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Human papillomavirus vaccine—recent results and future developments
Human papillomavirus vaccine—recent results and future developments William Bonnez1,2 A subset of human papillomaviruses that infect the anogenital tract and the upper aero-digestive tract is the cause of a number of benign and malignant tumors in these locations, including cervical cancer. Since the past year, a vaccine directed at human papillomaviruses types 6 and 11, the main cause of genital warts, and types 16 and 18, the main cause of cervical cancer, has been on the international market. Another vaccine directed at types 16 and 18 alone is soon expected to be widely available. This review presents the updated, currently available clinical information that has demonstrated the efficacy and safety of these vaccines. It examines the questions remaining on their safety, true efficacy, spectrum of activity, and protection duration. The future directions of the current clinical research and its possible impact on prevention are discussed. Addresses 1 University of Rochester School of Medicine and Dentistry, Rochester, NY, USA 2 Infectious Diseases Division, Box 689, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA Corresponding author: Bonnez, William ([email protected])
Current Opinion in Pharmacology 2007, 7:470–477 This review comes from a themed issue on Anti-infectives Edited by John Rex and Frederick Hayden Available online 9th August 2007 1471-4892/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2007.07.001
Introduction Human papillomaviruses (HPV) form the genus Papillomavirus of the family Papovaviridae. They infect the stratified epithelia and the glandular epithelium of the uterine cervix of humans only. This is a large group of viruses with at least 106 different types that have been fully characterized, a number that is still expanding. Typing is based on the nucleotide sequence of the gene (L1) coding for the major capsid protein. Genotypes differ by at least 10% from one another, subtypes by 2–10%, and variants by up to 2% from the prototype isolate [1]. HPV infections are extremely common. Although most are latent and asymptomatic, they can be the source of a significant health burden by causing conditions that range from benign, such as warts, papillomas, and condylomas, Current Opinion in Pharmacology 2007, 7:470–477
to malignant, namely invasive cancers. Over 40 HPV types are able to infect the mucosal surfaces of the anogenital and upper aero-digestive tracts. A subset of those, including HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, is considered to have a highoncogenic risk because of its epidemiologic association with invasive squamous cell cancer and adenocarcinoma of the uterine cervix [2]. Another subset has a clear lowoncogenic risk and includes types 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, and 81. About 90% of genital warts are caused by HPV-6 and HPV-11 [3,4], while over 70% of cervical cancers are caused by HPV-16 and HPV-18 [5]. High-risk HPVs, especially types 16 and 18, are also associated with other cancers of the anogenital and upper aero-digestive tract, and it has been estimated that they account for 90% of anal cancers, 40% of penile, vulvar, and vaginal cancers – some histologic variants of these cancers are not associated with HPV – and up to 70% of oropharyngeal cancers [6,7]. Low-risk and high-risk HPV types are found in the intraepithelial neoplasias, lesions that are the precursors of invasive squamous cell cancers of the cervix, vulva, vagina, anus, and penis known as CIN, VIN, VAIN, AIN, and PIN, respectively. Intraepithelial neoplasias range in histologic grades from 1 to 3, 3 being the most severe, less likely to spontaneously regress, most likely to progress to invasive cancer, and most likely to be associated with a high-risk HPV, especially types 16 and 18 [6,8]. Cervical condylomas and CIN 1 lesions are also regarded in the Bethesda classification as low-grade squamous intraepithelial lesions (SIL) or LSIL, while CIN 2 and 3 make up high SIL or HSIL. The impact of cervical cancer is quite considerable. In 2000, the cervix was second after the breast as the site for new cancers in women throughout the world (471 000 cases/100 000) and as the source of malignancy-related deaths (233 000 cases/100 000) [9]. In the United States, as in many developed nations, cervical cancer has been well controlled, with an estimated incidence for 2007 of 9.1 cases/100 000, corresponding to 11 150 new cases, and with 3670 annual deaths [10]. This favorable situation is the result of the screening procedures that are in place, and which rely on cervical cytology (Pap smear) and high-risk HPV DNA detection. However, it costs $3.3 billion to provide for the more than 50 million Pap smears done every year, as well as the treatment and follow-up of those patients with abnormal results; threefourths of this expenditure being in 15–24-year-old females [11]. www.sciencedirect.com
Human papillomavirus vaccine—recent results and future developments Bonnez 471
The availability in more than 80 countries since June 2006 of a quadrivalent vaccine made in yeast cells (Gardasil, Merck), against HPV types 6, 11, 16, and 18, has been a major addition to the control of genital HPV diseases. It is the first vaccine specifically targeted against cancer. A second, slightly different, bivalent vaccine directed against HPV-16 and HPV-18 and made in insect cells (Cervarix, GSK) was approved on May 21, 2007, to be used in Australia in females aged 10–45. It is likely to become available by the end of 2007 in Europe and in the first quarter of 2008 in the United States. This article will describe the vaccines, review the recently expanded safety and efficacy data, address the issue of type crossprotection, and discuss some of the future directions for the application of HPV prophylactic vaccines.
The HPV prophylactic vaccines The principle
Infective HPV virions have a naked icosahedral capsid made of a major (L1) and a minor (L2) capsid protein. The fundamental principle underlying the current vaccines is that the expression of the L1 gene alone, under conditions that retain the native conformation of the protein, something typically achieved in eukaryotic expression systems, allows this protein to fold and assemble spontaneously with other L1 proteins to form viral particles devoid of viral DNA that are identical in shape, size, and immunologic properties to the native infectious particles. These empty, non-infectious particles are called virus-like particles (VLP). Like infectious virions, these HPV VLP can elicit after immunization the strong production of neutralizing antibodies that is sufficient to completely block virus infectivity and pathogenesis (see, for example [12]). The concept of VLP as a vaccine was further validated in different models of animal papillomavirus infection [13]. These experiments showed that the protective immunity could be passively transferred to naive animals by the intravenous infusion of the immunoglobulins from immunized animals. Phase 1 and 2 studies
The first human trials began in 1997, with HPV-11 and HPV-16 VLP monovalent vaccines. These phase I studies established that these vaccines were well-tolerated and immunogenic, inducing a strong neutralizing antibody response [14,15]. In 2002, the first controlled trial to demonstrate the ability of an HPV-16 VLP vaccine made by Merck to prevent cervical HPV infection was reported [16]. Two thousand three hundred ninety two women aged 16–23 years and with no more than five lifetime sexual partners were randomized to receive an intramuscular injection of 40 mg HPV-16 L1 VLP formulated in 225 mg of aluminum hydroxide adjuvant or adjuvant alone given at day 0, month 2, and month 6. Genital samples were obtained at enrollment, one month after the last immunization and every six www.sciencedirect.com
months thereafter to test for the presence of HPV DNA. Cervical cytology was monitored, and colposcopy was done according to protocol. The primary endpoint of the study was persistent HPV-16 infection; infections first noted in two or more consecutive visits after the completion of the immunization. At a median follow-up of 17.4 months, the data were analyzed after the study had reached a pre-determined number of cases of persistent infection. According to protocol, thus excluding women who were HPV-16 DNA positive or seropositive for HPV-16 on day 0, none of 768 vaccine recipients and 41 of 765 placebo recipients had developed persistent HPV-16 infection, an observed efficacy of 100% (95% confidence interval, CI, 90–100%). Ten of the cases of persistent HPV-16 infection in the placebo group were associated with the development of CIN, hence the suggestion that the vaccine prevented not only the infection but also the disease caused by HPV-16. These impressive results were obtained without any difference in adverse reactions between the two treatment groups, pain at the injection site being the most common side effect. When the results of this study were re-analyzed after 48 months of follow-up, there were 7 cases of HPV-16 persistent infection in the 755 vaccine recipients, but 111 cases among the 750 placebo recipients, a vaccine efficacy of 94% (95% CI, 88–98%) [17]. Twelve women in the placebo group developed CIN (CIN2 and CIN3 in equal numbers) but none in the vaccine group. The antiHPV-16 VLP titers to a neutralizing epitope peaked one month after the third immunization, decayed until month 18, and then reached a plateau with levels well higher than titers developed after a natural infection. Comparable results were obtained with the Cervarix vaccine, a bivalent preparation directed against HPV-16 and HPV-18 and containing 20 mg of each antigen [18]. In a phase 2 study, women between the age of 15 and 25 years and with no more than six lifetime sexual partners were equally randomized to receive either the vaccine containing an AS04 adjuvant made of 500 mg of aluminum hydroxide and 50 mg of 3-deacylated monophosporyl lipid (MPL) or the adjuvant alone, given intramuscularly on day 0, month 1, and month 6. The primary endpoint was the prevention of the acquisition of incident (transient or persistent) HPV-16 or HPV-18 infections in HPV DNA negative and HPV seronegative subjects at entry. The secondary endpoints were the prevention of persistent HPV-16 and HPV-18 infections, as well as of cytologic or histologic CIN or adenocarcinoma. At up to 18 months of follow-up, in the according-to-protocol analysis, vaccine efficacy in the 366 vaccinees and 355 placebo recipients was 91.6% (95% CI, 64.5–98.0%) for the prevention of cervical incident infections, 100% (95% CI, 47.0–100%) for persistent infections, and 92.3% (95% CI, 70.0–98.3) for CIN or adenocarcinoma, all values significant at P < 0.001. At a 4.5-year follow-up, these results largely Current Opinion in Pharmacology 2007, 7:470–477
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held up with vaccine efficacy figures of 96.9 (95% CI, 81.3–99.9%), 100% (95% CI, 33.6–100%), and 96.7% (95% CI, 83.5–99.5%), respectively [19].
efficacy of the vaccine was well demonstrated not only against the immediate precursor lesions of cervical cancer but also against several other HPV-associated lesions, including genital warts.
Phase 3 studies
Cervical HPV infection is an unsatisfactory endpoint for the prediction of invasive cancer because these infections are frequent and usually of brief duration [20]. At the same time, invasive cancer is not a desirable clinical endpoint because of the morbidity and mortality risks. These two considerations led to the selection of CIN2/3 as the proper surrogate clinical marker of the efficacy of the vaccine against cervical cancer for definitive phase 3 studies. These studies were completed for the Food and Drug Administration (FDA) approval of Gardasil on June 8, 2006. The data based on follow-up visits until month 36 were recently published, and the efficacy results are presented in Table 1 [21–23,24]. The remarkable
The comparison of the results between the per-protocol population and the intention-to-treat population (Table 1) makes very clear that the greatest protection from the vaccine is derived if the immunization is given before the subject has a chance of being exposed to HPV types 6, 11, 16, or 18. But even then, the subject who is infected or seropositive for one of the vaccine types retains the benefit of the vaccine protection against the other vaccine types. The preclinical work had indicated that vaccine immunity is provided by the development of neutralizing antibodies, the serum antibodies that develop in virtually all the adolescents and adults immunized with HPV VLP. Therefore, in order to demonstrate that the vaccine would not
Table 1 Summary of the efficacy results of Gardasil against HPV-related lesions Merck protocol #
Lesion prevented Condylomas (external and vaginal)
Per-protocol susceptible population 005, 007, 013, 015 013 007, 013, 015 013 013
VIN/VAIN 1
2/3
CIN 1
2/3 and AIS
6/11
Number of subjects a
Vaccine efficacy (95% confidence interval)
Reference
17 4 15 4 4
129 499 596 540 540
99% 100% 100% 100% 100%
(93–100%) (94–100%) (72–100%) (49–100%) (92–100%)
[23] [21] [24] [21] [21]
19 4 17 5 5
466 951 531 351 351
98% 98% 97% 82% 96%
(93–100%) (92–100%) (79–100%) (16–98%) (86–99%)
[23] [21] [24] [21] [21]
20 5 18 5 5
583 455 174 455 455
44% 55% 71% 63% 76%
(31–55%) (40–66%) (37–88%) (<0–88%) (61–86%)
[23] [21] [24] [21] [21]
20 5 18 5 5
583 455 174 455 455
18% 20% 49% 18% 51%
(7–29%) (8–31%) (18–69%) (<0–46%) (32–65%)
[23] [21] [24] [21] [21]
16/18
Others
b
Unrestricted susceptible population c 005, 007, 013, 015 013 007, 013, 015 013 013 Intention-to-treat population d 005, 007, 013, 015 013 007, 013, 015 013 013
Caused by HPV
Intention-to-treat population—any lesion regardless of type 005, 007, 013, 015 013 007, 013, 015 013 013
a
The subjects were randomized equally between the vaccine and placebo groups, and the two groups were closely balanced. This was the population used for the primary endpoint analysis. Subjects were seronegative and HPV DNA negative at day 1 for the HPV types included in the vaccine. They had a normal Pap smear and received all three immunizations, and cases were counted starting one month after the third immunization. c This population included subjects who were seronegative and HPV DNA negative at day 1 for the HPV types included in the vaccine, but it included protocol violators, individuals who had received less than three doses, who had developed HPV DNA positivity during the vaccination phase, and who had an abnormal Pap smear at day 1. Case counting began one month after the first immunization. About a quarter of the subjects were positive by HPV DNA or serology at day 1 for at least one of the vaccine types. d This population was identical to the unrestricted susceptible population, except that it included subjects who were HPV seropositive and/or HPV DNA positive for the vaccine types at day 1. b
Current Opinion in Pharmacology 2007, 7:470–477
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Human papillomavirus vaccine—recent results and future developments Bonnez 473
only be safe but also effective to administer to children who are not yet exposed to genital HPV, the presence of neutralizing antibodies was viewed as a proper surrogate of protection. Gardasil was evaluated in a comparative study of 506 10–16-year-old girls, 510 10–15-year-old boys, and 513 16–23-year-old women who were fully immunized [25]. Virtually all the subjects were seroconverted for all four HPV types. Not only were the neutralization titers in the boys and girls non-inferior to those of the women, but they were also 1.7–2.7-fold higher, thus indicating that by immunizing early in life, higher and presumably longer sustaining antibody titers can be expected. Another recent study has included boys and girls 9 to 15 years of age [16]. The results were similar and the titers held for at least 12 months [26]. Similarly, immunization with Cervarix produced in 158 10–14-year-old girls anti-HPV-16 or antiHPV-18 antibody titers that were twice as high as in 458 15–25-year-old females [27].
Tolerance and safety HPV VLPs are not infectious, as they are by design devoid of HPV DNA. Furthermore, the VLPs used in both Gardasil and Cervarix are dissociated, treated by DNase, and re-associated. About 85% of the Gardasil vaccine recipients experienced local adverse reaction, but only a 6.5–9.4% excess relative to the placebo [21,22]. These local side effects included pain at the injection site, 85%, and swelling, 26%, both about 10% more common than with the placebo. Fever was noted not only in 13.5% of the vaccine immunizations but also in 10.2% of the placebo immunizations [21]. Girls and boys were 7–15% less likely than women to experience pain at the site of injection but more likely to experience fever [25]. Serious adverse events related to the immunization and requiring its discontinuation were noted only twice (hypersensitivity reaction and hypoesthesia at injection site) in a combined population of over 17 000 subjects, and both were in the placebo group. There was otherwise no difference in adverse events. The experience with Cervarix has been qualitatively similar, though with rates of pain and swelling perhaps slightly higher, by about 8%, than that with Gardasil [18]. Redness was also as common as swelling. There was no difference in systemic adverse reactions between the vaccine and placebo groups [18,19]. As of February 2007, the post-licensure Vaccine Adverse Event Reporting System (VAERS) had recorded dizziness or fainting in 11% in each of the notifications submitted. Consequently, the Advisory Committee on Immunization Practices (ACIP) has recommended that patients should be observed for 15 min after vaccination [28,29]. During the clinical trials of Gardasil, pregnancies occurred in 1115 of 10 418 subjects in the vaccine group and in 1551 of 9120 subjects in the placebo group [26]. The rates of fetal loss were comparable in the two groups, www.sciencedirect.com
38% and 40%, respectively. The VAERS has not registered any unexpected outcomes, but the immunization remains contraindicated during pregnancy. Since the vaccine has been sold, two types of adverse reactions not encountered during the clinical trials have been reported: Guillain Barre´ syndrome and facial palsy [29]. Of the three Guillain Barre´ syndrome cases, only one occurred with the administration of Gardasil alone, the others with the co-administration of the meningococcal conjugate vaccine. There were three cases of facial palsy, all within one day of the administration of different vaccines. The small numbers preclude at the moment any reliable conclusions, but both types of events are actively and passively monitored [29]. It should be pointed out that several cases of Guillain Barre´ syndrome have been associated with the administration of the meningococcal conjugate vaccine [30]. The co-administration of the hepatitis B vaccine has been shown not to interfere with the immunogenicity and safety of the HPV vaccine [26,28]. A study is underway looking at the combination of the HPV vaccine with the combined diphtheria, tetanus, pertussis vaccine, and meningococcal conjugate vaccine in adolescents [ClinicalTrials.gov Identifier: NCT00325130], but the ACIP and the American Academy of Pediatrics endorse the administration of these vaccines at the same visit [28,31]; in that case each vaccine should each be given at a different injection site. Should the immunization series be interrupted, it is to be completed as soon as possible.
Efficacy issues In the United States, the ACIP has recommended immunization with Gardasil in 11–12-year-old girls, with catchup vaccination for 13–18-year-old girls. The vaccine can be given to girls as young as 9 years and to women as old as 26 years [28]. The American Cancer Society recommends vaccination only up to 18 years of age [32]. In a few countries, like Australia, male immunization is allowed, but not in most. The current indications for the vaccine are the prevention of cancer of the cervix, CIN1-3, AIS (adenocarcinoma in situ), VIN2/3, VAIN2/3, and genital warts. Therapeutic efficacy
The clinical trials that have taken place so far have failed to demonstrate a therapeutic effect of vaccination on the infections or lesions already present at the time of vaccination [22]. There might be, however, a benefit in seropositive women who have cleared their infection with a vaccine HPV type by having a lower chance of re-acquiring the disease [29]. Efficacy against infections and diseases caused by non-vaccine HPV types
The low efficacy of the vaccine against diseases caused by any HPV types in a population irrespective of its HPV Current Opinion in Pharmacology 2007, 7:470–477
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DNA status or seropositivity (see Table 1, the section ‘Intention-to-Treat population—Any lesion regardless of type’) has been noted as a significant weakness of the vaccine. Sawaya and Smith-McCune commenting on the 17% efficacy figure observed in Merck protocol 017 study [22] argued that ‘129 women would need to be vaccinated in order to prevent one case of CIN2/3 or AIS’ [33]. Clearly, HPV immunization should not for now change or obviate screening for cervical cancer. There are, however, several points not to be overlooked. First, most of the efficacy results that have been published on Gardasil stop at three years of follow-up. Because the placebo recipients acquire lesions at a slightly higher rate than vaccine recipients [21–23, 24], the low efficacy figures are likely to improve as long as a booster is not needed. In fact, similar outcomes measured at five years with Cervarix bear this expectation, demonstrating a 45% vaccine efficacy [19]. Second, there appear to be geographic variations of these figures, with a vaccine efficacy against vaccine type CIN13 and AIS in North America, double than that found in Asia in the Intention-to-Treat population [23]. This may reflect different HPV types geographic distribution. Third, HPV type 16, which is included in the vaccine, is substantially more oncogenic than the other high-risk types and clearly carries the highest risk of progression to CIN3 or invasive cervical carcinoma [34]. Fourth, the same HPV types that are included in the vaccine are also responsible for other cancers (vulva, vagina, anus, penis, oropharyngeal) [6,7]. Screening is typically not available for these cancers. Therefore, vaccination is likely to be effective and the best hope to prevent these tumors. New types
Another concern that has been raised is the possibility that by hopefully eradicating HPV types 6, 11, 16, and 18, the vaccine would open the way for other types to fill the vacuum. As indicated by Sawaya and Smith-McCune, the FDA when reviewing the Biologics License Application of Gardasil in May 2006, pointed out in the subjects who were seropositive and HPV DNA positive for the vaccine types a greater number of cases of CIN1/3 in the vaccine group than in the placebo group [33,35]. This difference appeared to have been due to a greater number of subjects in the vaccine group who had baseline evidence of HSIL on Pap smear than those in the placebo group. There was no evidence of lesion replacement by nonvaccine HPV types in the study of Cervarix [19]. Although this issue deserves vigilance, it should be pointed out that HPV is not part of the cervical normal flora. Therefore, there is a priori no intrinsic reason for the cervix to become colonized with non-vaccine types. Moreover, there is evidence that infections by different HPV types are not independent but synergistic and that under these conditions, epidemiologic modeling predicts Current Opinion in Pharmacology 2007, 7:470–477
that vaccination should have a favorable effect on nonvaccine types [36]. HPV cross-protection
Each genotype, in general, corresponds to its own serotype. However, it has been long recognized that there are exceptions, most notably that HPV-6 and HPV-11 share conformational, including neutralizing, epitopes [37–40]. By phylogeny, HPV types 16, 31, 33, 58 are related and belong to species 9, whereas types 18, 39, 45, and 59 belong to species 7. Cross-neutralizing epitopes have been identified that are shared more or less strongly within each species [41]. Therefore, it was not a complete surprise to see that subjects immunized with Cervarix, containing HPV-16 and HPV-18, developed cross-protection against HPV-31 (vaccine efficacy 54.5%) and HPV-45 (vaccine, efficacy of 94.2%) cervical infections [19]. These two types account for 2.9% and 6.7%, respectively, of all cervical cancers [5]. Similar results, but based on limited in vitro data, have been presented with Gardasil [42]. They are expected to be confirmed clinically given that Merck has submitted a supplemental Biologics Licensing Application to the FDA on April 18, 2007, on cross-neutralization of new types. The fact that no cross-neutralization with Cervarix was observed against HPV types 33 and 58 suggests that our understanding of neutralizing epitopes in humans is partial. Duration of protection
At this time, it is not possible to tell how long the vaccine protection lasts and when a booster might be necessary. Merck has established a registry in the Nordic countries to examine the duration of the vaccine efficacy. To date, only the results at five years of follow-up of a small cohort of 225 vaccine and placebo recipients derived from Merck protocol 07 have been published [43]. The efficacy of Gardasil was 95.1% in the per-protocol analysis of cases of infection or diseases (warts, VIN, VAIN, CIN, AIS) caused by the vaccine types. The fact that in this study the neutralization antibody titers to HPV-6 and HPV-18 in the vaccinees overlapped with those of the seropositive placebo recipients suggests that these titers, at least for these HPV types, are not a perfect predictor of protection. This possible limitation is probably linked to the incomplete blockade of all the neutralization epitopes by the monoclonal antibodies used in the competition assays that measure these titers [44]. A very recent study of Gardasil confirmed that neutralizing antibody titers to the vaccine HPV types reach a plateau at month 24 but remain stable up to 5 years after immunization, at which time a booster induces 1 month later titers higher than those measured 1 month after the third dose of the vaccine [44a]. At five years, Cervarix was also still very effective, with a vaccine efficacy of 92.6% for the prevention of HPV16/18 www.sciencedirect.com
Human papillomavirus vaccine—recent results and future developments Bonnez 475
CIN1-3 and 100% for CIN2/3 [19]. GSK investigators have shown higher titers of binding and neutralizing antibodies to HPV-16 and HPV-18 with the AS04 adjuvant compared with aluminum hydroxide alone [45]. Although higher neutralizing titers are expected to confer longer protection, this remains to be established. It should also be noted that Cervarix and Gardasil do not use the same amount or mode of preparation of their aluminum hydroxide adjuvant. GSK is now conducting a double-blind comparative study of the immunogenicity of the two vaccines (ClinicalTrials.gov Identifier: NCT00423046).
Future directions Within approximately six months, both Gardasil and Cervarix will be available in many countries. The first vaccine is quadrivalent, the second bivalent. Beyond this obvious difference, other factors, in particular, price and duration of effectiveness, will be important in guiding choices. Several cost-effective and epidemiologic modeling analyses have indicated that men will need to be immunized to achieve the greatest effectiveness of the vaccine [46–48]. A randomized, double-blind, placebo-controlled study of Gardasil is currently under way to demonstrate efficacy for the prevention of genital warts (ClinicalTrials.gov Identifier: NCT00090285). The results of this study will determine whether Gardasil receives an indication for men. Extending the indications to women beyond the age of 26 years is being sought. One randomized, double-blind, placebo-controlled trial of Cervarix is examining its immunogenicity in women aged between 18 and 45 years (ClinicalTrials.gov Identifier: NCT00423046), while another is looking at safety, immunogenicity, and efficacy in women older than 26 years (ClinicalTrials.gov Identifier: NCT00456807). Merck is currently evaluating the efficacy of Gardasil in women between the age of 24 and 45 years (ClinicalTrials.gov Identifier: NCT00090220). At the other end of the age spectrum, the National Institute of Allergy and Infectious Diseases is conducting a study on the safety and immunogenicity of Gardasil in male and female children aged 7–12 infected with HIV (ClinicalTrials.gov Identifier: NCT00339040). Trials of Gardasil are also being considered in populations at high risk for genital HPV infections and diseases, such as solid organ and bone marrow transplant patients and HIV-positive men and women [29]. HPV VLP vaccines are likely to remain relatively expensive, and this constitutes a significant barrier to the dissemination of HPV vaccination to where it is most needed, the developing world. In order to resolve this issue, alternative dosing regimens are being considered [29]. Another approach has been the development of a cheaper vaccine, one made in E. coli [49,50]. Two important questions will need to be resolved. The first one is whether HPV immunization will have an www.sciencedirect.com
impact on the rate of cervical invasive cancer. Merck has set up in Norway a surveillance study that will examine this issue. Other studies will probably be in place in the future to examine this crucial point. The second question, will be to determine the impact of the vaccine on cervical cancer screening to lead, hopefully, toward the design of less frequent, more targeted screening procedures [51]. The impact of the vaccine on other HPV-associated diseases will be worth examining as well. For example, diseases such as oropharyngeal cancer, anal cancer, and recurrent respiratory papillomatosis, an uncommon but usually severe disease caused by HPV6 or HPV-11 [52]. Finally, one can reasonably anticipate that the current vaccines will be modified to include additional HPV types.
Acknowledgements This work is supported partly by NIH contract N01-AI-15435. Bonnez reports consulting and lecture fees from Merck. He also holds intellectual property rights on HPV VLP vaccines and is to derive royalties from the sale of the vaccine from Merck and GlaxoSmithKline.
References and recommended reading Papers of particular interest, published within the period of review have been highlighted as: of special interest of outstanding interest
1.
Bernard HU: The clinical importance of the nomenclature, evolution and taxonomy of human papillomaviruses. J Clin Virol 2005, 32(Suppl 1):S1-S6.
2.
Munoz N, Castellsague X, de Gonzalez AB, Gissmann L: Chapter 1: HPV in the etiology of human cancer. Vaccine 2006, 24S3:S1-S10.
3.
Brown DR, Schroeder JM, Bryan JT, Stoler MH, Fife KH: Detection of multiple human papillomavirus types in condylomata acuminata lesions from otherwise healthy and immunosuppressed patients. J Clin Microbiol 1999, 37:3316-3322.
4.
Vandepapeliere P, Barrasso R, Meijer CJ, Walboomers JM, Wettendorff M, Stanberry LR et al.: Randomized controlled trial of an adjuvanted human papillomavirus (HPV) type 6 L2E7 vaccine: infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination. J Infect Dis 2005, 192:2099-2107.
5.
Munoz N, Bosch FX, Castellsague X, Diaz M, de Sanjose S, Hammouda D et al.: Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 2004, 111:278-285.
6.
Parkin DM, Bray F: Chapter 2: the burden of HPV-related cancers. Vaccine 2006, 24(Suppl 3):S11-S25.
7.
D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM et al.: Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007, 356:1944-1956.
8.
Clifford G, Franceschi S, Diaz M, Munoz N, Villa LL: Chapter 3: HPV type-distribution in women with and without cervical neoplastic diseases. Vaccine 2006, 24(Suppl 3):S26-S34.
9.
Parkin DM: Global cancer statistics in the year 2000. Lancet Oncol 2001, 2:533-543.
10. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer statistics, 2007. CA Cancer J Clin 2007, 57:43-66. 11. Chesson HW, Blandford JM, Gift TL, Tao G, Irwin KL: The estimated direct medical cost of sexually transmitted diseases among American youth, 2000. Perspect Sex Reprod Health 2004, 36:11-19. Current Opinion in Pharmacology 2007, 7:470–477
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12. Rose RC, Reichman RC, Bonnez W: Human papillomavirus type 11 (HPV-11) recombinant virus-like particles (VLPs) induce the formation of neutralizing antibodies and detect HPV-specific antibodies in human sera. J Gen Virol 1994, 75:2075-2079. 13. Breitburd F, Coursaget P: Human papillomavirus vaccines. Semin Cancer Biol 1999, 9:431-444. 14. Harro CD, Pang Y-YS, Roden RBS, Hildesheim A, Wang Z, Reynolds MJ et al.: Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst 2001, 93:284-292. 15. Evans TG, Bonnez W, Rose RC, Koenig S, Demeter L, Suzich JA et al.: A phase 1 study of a recombinant viruslike particle vaccine against human papillomavirus type 11 in healthy adult volunteers. J Infect Dis 2001, 183:1485-1493. As with the study by Harro et al. [14], the Evans study examined different doses of HPV VLP antigen, and both demonstrated a vigorous antibody response with both binding and neutralizing functions. Evans et al. also showed that HPV-11 VLP stimulated T cells in a way that appeared not to be type-restricted. A cytokine expression pattern consistent with T helper cell type 1 and 2 responses was also noted. 16. Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB et al.: A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002, 347:1645-1651. This phase 2 controlled study of an HPV-16 L1 VLP vaccine was a milestone in the clinical development of the HPV vaccine. It demonstrated the complete efficacy of the vaccine in preventing cervical HPV-16 infection. It served to establish the model by which these types of vaccines are to be evaluated, by targeting a population of sexually active adolescent and young adults but with a low-to-moderate risk of being already HPV-infected. As expected, the study confirmed that immunization against HPV-16 did not necessarily prevent infections by other HPV types, as an equal number of subjects developed CIN not related to HPV16. It also confirmed the low chance for transient infections to lead to CIN. None of the 6 vaccine recipients and 27 placebo recipients who were transiently positive for HPV-16 developed an HPV-16-related CIN. Although the six transient infections in the vaccine recipients might not have been true infections, and even if they were, this would give weight to the idea that below a certain viral exposure or load the body can clear an HPV infection. 17. Mao C, Koutsky LA, Ault KA, Wheeler CM, Brown DR, Wiley DJ et al.: Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol 2006, 107:18-27 [erratum appears in Obstet Gynecol. 2006 Jun;107(6):1425]. 18. 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, 364:1757-1765. 19. 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, 367:1247-1255. This publication is about an extension beyond 27 months of the study described in reference [18]. Originally, 1113 women were enrolled, and 776 were followed in the extension phase for up to 4.5 years, in the according-to-protocol cohort. Although, the primary endpoint was prevention not of disease or persistent infection but of HPV incident infection, both studies, though small in size, offer a very clear and convincing picture of the Cervarix’s efficacy. The results are comparable to those reported with Gardasil, including when protocol violators (intention-totreat analysis) were included. This study is also remarkable for showing that the vaccines also confer protection against HPV-45 (94.2% efficacy, 95% CI 63.3–99.9%) and HPV-31 (54.5%, 95% CI 11.5–77.7%) infections. The L1 gene DNA sequence of HPV-45 and HPV-31 are phylogenetically related to those of HPV-18 and HPV-16, respectively. At entry, the subjects were cytologically negative, seronegative for HPV-16 and HPV18, and HPV DNA negative for 14 high-risk types, including types 16 and 18. This allowed the investigators to measure the impact of vaccination on the prevention of cervical disease caused by high-risk HPV types, not just types 16 and 18; it was 48.2% (95% CI 27.0–63.8%). The vaccine efficacy was still substantive, 39.8% (95% CI 20.9–54.4%) against cervical disease, irrespective of HPV DNA status. Simply interpreting these results as indicating a modest impact of the vaccine on cervical HPV disease is incomplete. First, as follow-up duration increases and as long as the vaccine remains effective, these efficacy figures will increase because Current Opinion in Pharmacology 2007, 7:470–477
placebo recipients will accrue disease at a faster rate than vaccinees (the same phenomenon has been documented with Gardasil see reference [23]). Second, although it is desirable to reduce screening cost to eliminate all grades of CIN, only the high grades, CIN 2 or 3 have the highest impact on the risk of invasive cancer. Although, the number of observations is too limited at this point to draw firm conclusions on the impact of the vaccine on these lesions, this study shows a vaccine efficacy of 67.1% against high-risk HPV type CIN2/3 and 73.3% against CIN2/3 independent of HPV DNA status. 20. Kang M, Lagakos SW: Evaluating the role of human papillomavirus vaccine in cervical cancer prevention. Stat Methods Med Res 2004, 13:139-155. 21. 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, 356:1928-1943. 22. Koutsky LA: Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007, 356:1915-1927. 23. Ault KA: Effect of prophylactic human papillomavirus L1 viruslike-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet 2007, 369:1861-1868. 24. Joura EA, Leodolter S, Hernandez-Avila M, Wheeler CM, Perez G, Koutsky LA et al.: Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16 and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet 2007, 369:1693-1702. This series of publications [21–23,24] presents the updated results, at 36 month of follow-up, of the main studies that led to the licensing of the first HPV VLP vaccine (Gardasil, Merck), which is directed at HPV types 6, 11, 16, and 18. The first two publications are devoted to Merck protocols 013 and 015, respectively. The last two present the combined results of these studies as well as those of two antecedents studies (protocols 005 and 007) to provide a more precise assessment of the vaccine efficacy. The first two publications address the vaccine safety in detail by analyzing data collected from almost 18 000 subjects. 25. Block SL, Nolan T, Sattler C, Barr E, Giacoletti KE, Marchant CD et al.: Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16 and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics 2006, 118:2135-2145. 26. Reisinger KS, Block SL, Lazcano-Ponce E, Samakoses R, Esser MT, Erick J et al.: Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J 2007, 26:201209. 27. Pedersen C, Petaja T, Strauss G, Rumke HC, Poder A, Richardus JH et al.: Immunization of early adolescent females with human papillomavirus type 16 and 18 L1 virus-like particle vaccine containing AS04 adjuvant. J Adolesc Health 2007, 40:564-571. 28. Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER et al.: Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007, 56:1-24. This reference offers the finalized recommendations of the ACIP for the use of the quadrivalent HPV vaccine. Anyone who wants to use the vaccine is invited to consult this document that covers some aspects of the immunization in a greater detail than this reviews allows. The site of the American Academy of Pediatrics (http://www.cispimmunize.org/) is also an excellent resource. 29. Advisory Committee on Immunization Practices, February 21–22, 2007, Atlanta, Georgia, Record of the Proceedings. www.cdc.gov/ vaccines/recs/acip/downloads/acip_min_feb07.pdf. 30. Guillain-Barre´ syndrome (GBS) among persons who received meningococcal conjugate vaccine. In Centers for Disease Control and Prevention; 2007. http://www.cdc.gov/od/science/ iso/concerns/gbsfactsheet.htm. www.sciencedirect.com
Human papillomavirus vaccine—recent results and future developments Bonnez 477
31. Prevention of human papillomavirus infection: provisional recommendations for immunization of females with quadrivalent human papillomavirus vaccine. In American Academy of Pediatrics; 2007. http://www.cispimmunize.org/ill/ pdf/HPVprovisional.pdf.
43. 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, 95:1459-1466.
32. 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.
44. Dias D, Van Doren J, Schlottmann S, Kelly S, Puchalski D, Ruiz W et al.: Optimization and validation of a multiplexed luminex assay to quantify antibodies to neutralizing epitopes on human papillomaviruses 6, 11, 16 and 18. Clin Diagn, Lab Immunol 2005, 12:959-969.
33. Sawaya GF, Smith-McCune K: HPV vaccination—more answers, more questions. N Engl J Med 2007, 356:1991-1993. 34. Schiffman M, Herrero R, Desalle R, Hildesheim A, Wacholder S, Rodriguez AC et al.: The carcinogenicity of human papillomavirus types reflects viral evolution. Virology 2005, 337:76-84. 35. FDA Executive Summary—GARDASIL Licensing Action; 2006. www.fda.gov/cber/sba/hpvmer060806s.pdf. 36. Elbasha EH, Galvani AP: Vaccination against multiple HPV types. Math Biosci 2005, 197:88-117. 37. Bonnez W, Harvey C, Rose RC, Reichman RC: Use of HPV-11 viral particles in an ELISA to detect antibodies in humans with or without condylomata acuminata. Ninth International Papillomavirus Workshop; Heidelberg, FRG: 1990:153. 38. Bonnez W, Greer C, DaRin C, Borkhuis C, Van Nest G, Rose RC: Correlation between ELISA and neutralizing activities of antiHPV-6 L1 virus-like particles (VLP) rabbit antisera against HPV-11. 15th International Papillomavirus Workshop; Gold Coast, Queensland, Australia, December 1–5: 1996. 39. Touze A, Dupuy C, Mahe D, Sizaret PY, Coursaget P: Production of recombinant virus-like particles from human papillomavirus types 6 and 11, and study of serological reactivities between HPV 6, 11, 16 and 45 by ELISA: implications for papillomavirus prevention and detection. FEMS Microbiol Lett 1998, 160:111-118. 40. Wang XM, Cook JC, Lee JC, Jansen KU, Christensen ND, Ludmerer SW et al.: Human papillomavirus type 6 virus-like particles present overlapping yet distinct conformational epitopes. J Gen Virol 2003, 84:1493-1497. 41. Combita AL, Touze A, Bousarghin L, Christensen ND, Coursaget P: Identification of two cross-neutralizing linear epitopes within the L1 major capsid protein of human papillomaviruses. J Virol 2002, 76:6480-6486. 42. Smith JF, Brownlow MK, Brown MJ, Esser MT, Ruiz W, Brown DR: Gardasil antibodies cross-neutralize pseudovirion infection of vaccine-related HPV types. 23rd International Papillomavirus Conference & Clinical Workshop; Prague, Czech Republic, September 1–7: 2006.
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44a. Olsson SE, Villa LL, Costa RL, Petta CA, Andrade RP, Malm C et al.: Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. Vaccine 2007, 25:4931-4939. 45. Giannini SL, Hanon E, Moris P, Van Mechelen M, Morel S, Dessy F et al.: Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/ aluminium salt combination (AS04) compared to aluminium salt only. Vaccine 2006, 24:5937-5949. 46. Hughes JP, Garnett GP, Koutsky L: The theoretical populationlevel impact of a prophylactic human papilloma virus vaccine. Epidemiology 2002, 13:631-639. 47. Elbasha EH, Dasbach EJ, Insinga RP: Model for assessing human papillomavirus vaccination strategies. Emerg Infect Dis 2007, 13:28-41. 48. Dasbach EJ, Elbasha EH, Insinga RP: Mathematical models for predicting the epidemiologic and economic impact of vaccination against human papillomavirus infection and disease. Epidemiol Rev 2006, 28:88-100. 49. Li M, Cripe TP, Estes PA, Lyon MK, Rose RC, Garcea RL: Expression of the human papillomavirus type 11 L1 capsid protein in Escherichia coli: characterization of protein domains involved in DNA binding and capsid assembly. J Virol 1997, 71:2988-2995. 50. Chen XS, Casini G, Harrison SC, Garcea RL: Papillomavirus capsid protein expression in Escherichia coli: purification and assembly of HPV11 and HPV16 L1. J Mol Biol 2001, 307: 173-182. 51. Kulasingam SL, Myers ER: Potential health and economic impact of adding a human papillomavirus vaccine to screening programs. JAMA 2003, 290:781-789. 52. Freed GL, Derkay CS: Prevention of recurrent respiratory papillomatosis: role of HPV vaccination. Int J Ped Otorhinolaryngol 2006, 70:1799-1803.
Current Opinion in Pharmacology 2007, 7:470–477
Current Opinion in Pharmacology 2007, 7:470–477 This review comes from a themed issue on Anti-infectives Edited by John Rex and Frederick Hayden Available online 9th August 2007 1471-4892/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2007.07.001
Introduction Human papillomaviruses (HPV) form the genus Papillomavirus of the family Papovaviridae. They infect the stratified epithelia and the glandular epithelium of the uterine cervix of humans only. This is a large group of viruses with at least 106 different types that have been fully characterized, a number that is still expanding. Typing is based on the nucleotide sequence of the gene (L1) coding for the major capsid protein. Genotypes differ by at least 10% from one another, subtypes by 2–10%, and variants by up to 2% from the prototype isolate [1]. HPV infections are extremely common. Although most are latent and asymptomatic, they can be the source of a significant health burden by causing conditions that range from benign, such as warts, papillomas, and condylomas, Current Opinion in Pharmacology 2007, 7:470–477
to malignant, namely invasive cancers. Over 40 HPV types are able to infect the mucosal surfaces of the anogenital and upper aero-digestive tracts. A subset of those, including HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, is considered to have a highoncogenic risk because of its epidemiologic association with invasive squamous cell cancer and adenocarcinoma of the uterine cervix [2]. Another subset has a clear lowoncogenic risk and includes types 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, and 81. About 90% of genital warts are caused by HPV-6 and HPV-11 [3,4], while over 70% of cervical cancers are caused by HPV-16 and HPV-18 [5]. High-risk HPVs, especially types 16 and 18, are also associated with other cancers of the anogenital and upper aero-digestive tract, and it has been estimated that they account for 90% of anal cancers, 40% of penile, vulvar, and vaginal cancers – some histologic variants of these cancers are not associated with HPV – and up to 70% of oropharyngeal cancers [6,7]. Low-risk and high-risk HPV types are found in the intraepithelial neoplasias, lesions that are the precursors of invasive squamous cell cancers of the cervix, vulva, vagina, anus, and penis known as CIN, VIN, VAIN, AIN, and PIN, respectively. Intraepithelial neoplasias range in histologic grades from 1 to 3, 3 being the most severe, less likely to spontaneously regress, most likely to progress to invasive cancer, and most likely to be associated with a high-risk HPV, especially types 16 and 18 [6,8]. Cervical condylomas and CIN 1 lesions are also regarded in the Bethesda classification as low-grade squamous intraepithelial lesions (SIL) or LSIL, while CIN 2 and 3 make up high SIL or HSIL. The impact of cervical cancer is quite considerable. In 2000, the cervix was second after the breast as the site for new cancers in women throughout the world (471 000 cases/100 000) and as the source of malignancy-related deaths (233 000 cases/100 000) [9]. In the United States, as in many developed nations, cervical cancer has been well controlled, with an estimated incidence for 2007 of 9.1 cases/100 000, corresponding to 11 150 new cases, and with 3670 annual deaths [10]. This favorable situation is the result of the screening procedures that are in place, and which rely on cervical cytology (Pap smear) and high-risk HPV DNA detection. However, it costs $3.3 billion to provide for the more than 50 million Pap smears done every year, as well as the treatment and follow-up of those patients with abnormal results; threefourths of this expenditure being in 15–24-year-old females [11]. www.sciencedirect.com
Human papillomavirus vaccine—recent results and future developments Bonnez 471
The availability in more than 80 countries since June 2006 of a quadrivalent vaccine made in yeast cells (Gardasil, Merck), against HPV types 6, 11, 16, and 18, has been a major addition to the control of genital HPV diseases. It is the first vaccine specifically targeted against cancer. A second, slightly different, bivalent vaccine directed against HPV-16 and HPV-18 and made in insect cells (Cervarix, GSK) was approved on May 21, 2007, to be used in Australia in females aged 10–45. It is likely to become available by the end of 2007 in Europe and in the first quarter of 2008 in the United States. This article will describe the vaccines, review the recently expanded safety and efficacy data, address the issue of type crossprotection, and discuss some of the future directions for the application of HPV prophylactic vaccines.
The HPV prophylactic vaccines The principle
Infective HPV virions have a naked icosahedral capsid made of a major (L1) and a minor (L2) capsid protein. The fundamental principle underlying the current vaccines is that the expression of the L1 gene alone, under conditions that retain the native conformation of the protein, something typically achieved in eukaryotic expression systems, allows this protein to fold and assemble spontaneously with other L1 proteins to form viral particles devoid of viral DNA that are identical in shape, size, and immunologic properties to the native infectious particles. These empty, non-infectious particles are called virus-like particles (VLP). Like infectious virions, these HPV VLP can elicit after immunization the strong production of neutralizing antibodies that is sufficient to completely block virus infectivity and pathogenesis (see, for example [12]). The concept of VLP as a vaccine was further validated in different models of animal papillomavirus infection [13]. These experiments showed that the protective immunity could be passively transferred to naive animals by the intravenous infusion of the immunoglobulins from immunized animals. Phase 1 and 2 studies
The first human trials began in 1997, with HPV-11 and HPV-16 VLP monovalent vaccines. These phase I studies established that these vaccines were well-tolerated and immunogenic, inducing a strong neutralizing antibody response [14,15]. In 2002, the first controlled trial to demonstrate the ability of an HPV-16 VLP vaccine made by Merck to prevent cervical HPV infection was reported [16]. Two thousand three hundred ninety two women aged 16–23 years and with no more than five lifetime sexual partners were randomized to receive an intramuscular injection of 40 mg HPV-16 L1 VLP formulated in 225 mg of aluminum hydroxide adjuvant or adjuvant alone given at day 0, month 2, and month 6. Genital samples were obtained at enrollment, one month after the last immunization and every six www.sciencedirect.com
months thereafter to test for the presence of HPV DNA. Cervical cytology was monitored, and colposcopy was done according to protocol. The primary endpoint of the study was persistent HPV-16 infection; infections first noted in two or more consecutive visits after the completion of the immunization. At a median follow-up of 17.4 months, the data were analyzed after the study had reached a pre-determined number of cases of persistent infection. According to protocol, thus excluding women who were HPV-16 DNA positive or seropositive for HPV-16 on day 0, none of 768 vaccine recipients and 41 of 765 placebo recipients had developed persistent HPV-16 infection, an observed efficacy of 100% (95% confidence interval, CI, 90–100%). Ten of the cases of persistent HPV-16 infection in the placebo group were associated with the development of CIN, hence the suggestion that the vaccine prevented not only the infection but also the disease caused by HPV-16. These impressive results were obtained without any difference in adverse reactions between the two treatment groups, pain at the injection site being the most common side effect. When the results of this study were re-analyzed after 48 months of follow-up, there were 7 cases of HPV-16 persistent infection in the 755 vaccine recipients, but 111 cases among the 750 placebo recipients, a vaccine efficacy of 94% (95% CI, 88–98%) [17]. Twelve women in the placebo group developed CIN (CIN2 and CIN3 in equal numbers) but none in the vaccine group. The antiHPV-16 VLP titers to a neutralizing epitope peaked one month after the third immunization, decayed until month 18, and then reached a plateau with levels well higher than titers developed after a natural infection. Comparable results were obtained with the Cervarix vaccine, a bivalent preparation directed against HPV-16 and HPV-18 and containing 20 mg of each antigen [18]. In a phase 2 study, women between the age of 15 and 25 years and with no more than six lifetime sexual partners were equally randomized to receive either the vaccine containing an AS04 adjuvant made of 500 mg of aluminum hydroxide and 50 mg of 3-deacylated monophosporyl lipid (MPL) or the adjuvant alone, given intramuscularly on day 0, month 1, and month 6. The primary endpoint was the prevention of the acquisition of incident (transient or persistent) HPV-16 or HPV-18 infections in HPV DNA negative and HPV seronegative subjects at entry. The secondary endpoints were the prevention of persistent HPV-16 and HPV-18 infections, as well as of cytologic or histologic CIN or adenocarcinoma. At up to 18 months of follow-up, in the according-to-protocol analysis, vaccine efficacy in the 366 vaccinees and 355 placebo recipients was 91.6% (95% CI, 64.5–98.0%) for the prevention of cervical incident infections, 100% (95% CI, 47.0–100%) for persistent infections, and 92.3% (95% CI, 70.0–98.3) for CIN or adenocarcinoma, all values significant at P < 0.001. At a 4.5-year follow-up, these results largely Current Opinion in Pharmacology 2007, 7:470–477
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held up with vaccine efficacy figures of 96.9 (95% CI, 81.3–99.9%), 100% (95% CI, 33.6–100%), and 96.7% (95% CI, 83.5–99.5%), respectively [19].
efficacy of the vaccine was well demonstrated not only against the immediate precursor lesions of cervical cancer but also against several other HPV-associated lesions, including genital warts.
Phase 3 studies
Cervical HPV infection is an unsatisfactory endpoint for the prediction of invasive cancer because these infections are frequent and usually of brief duration [20]. At the same time, invasive cancer is not a desirable clinical endpoint because of the morbidity and mortality risks. These two considerations led to the selection of CIN2/3 as the proper surrogate clinical marker of the efficacy of the vaccine against cervical cancer for definitive phase 3 studies. These studies were completed for the Food and Drug Administration (FDA) approval of Gardasil on June 8, 2006. The data based on follow-up visits until month 36 were recently published, and the efficacy results are presented in Table 1 [21–23,24]. The remarkable
The comparison of the results between the per-protocol population and the intention-to-treat population (Table 1) makes very clear that the greatest protection from the vaccine is derived if the immunization is given before the subject has a chance of being exposed to HPV types 6, 11, 16, or 18. But even then, the subject who is infected or seropositive for one of the vaccine types retains the benefit of the vaccine protection against the other vaccine types. The preclinical work had indicated that vaccine immunity is provided by the development of neutralizing antibodies, the serum antibodies that develop in virtually all the adolescents and adults immunized with HPV VLP. Therefore, in order to demonstrate that the vaccine would not
Table 1 Summary of the efficacy results of Gardasil against HPV-related lesions Merck protocol #
Lesion prevented Condylomas (external and vaginal)
Per-protocol susceptible population 005, 007, 013, 015 013 007, 013, 015 013 013
VIN/VAIN 1
2/3
CIN 1
2/3 and AIS
6/11
Number of subjects a
Vaccine efficacy (95% confidence interval)
Reference
17 4 15 4 4
129 499 596 540 540
99% 100% 100% 100% 100%
(93–100%) (94–100%) (72–100%) (49–100%) (92–100%)
[23] [21] [24] [21] [21]
19 4 17 5 5
466 951 531 351 351
98% 98% 97% 82% 96%
(93–100%) (92–100%) (79–100%) (16–98%) (86–99%)
[23] [21] [24] [21] [21]
20 5 18 5 5
583 455 174 455 455
44% 55% 71% 63% 76%
(31–55%) (40–66%) (37–88%) (<0–88%) (61–86%)
[23] [21] [24] [21] [21]
20 5 18 5 5
583 455 174 455 455
18% 20% 49% 18% 51%
(7–29%) (8–31%) (18–69%) (<0–46%) (32–65%)
[23] [21] [24] [21] [21]
16/18
Others
b
Unrestricted susceptible population c 005, 007, 013, 015 013 007, 013, 015 013 013 Intention-to-treat population d 005, 007, 013, 015 013 007, 013, 015 013 013
Caused by HPV
Intention-to-treat population—any lesion regardless of type 005, 007, 013, 015 013 007, 013, 015 013 013
a
The subjects were randomized equally between the vaccine and placebo groups, and the two groups were closely balanced. This was the population used for the primary endpoint analysis. Subjects were seronegative and HPV DNA negative at day 1 for the HPV types included in the vaccine. They had a normal Pap smear and received all three immunizations, and cases were counted starting one month after the third immunization. c This population included subjects who were seronegative and HPV DNA negative at day 1 for the HPV types included in the vaccine, but it included protocol violators, individuals who had received less than three doses, who had developed HPV DNA positivity during the vaccination phase, and who had an abnormal Pap smear at day 1. Case counting began one month after the first immunization. About a quarter of the subjects were positive by HPV DNA or serology at day 1 for at least one of the vaccine types. d This population was identical to the unrestricted susceptible population, except that it included subjects who were HPV seropositive and/or HPV DNA positive for the vaccine types at day 1. b
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Human papillomavirus vaccine—recent results and future developments Bonnez 473
only be safe but also effective to administer to children who are not yet exposed to genital HPV, the presence of neutralizing antibodies was viewed as a proper surrogate of protection. Gardasil was evaluated in a comparative study of 506 10–16-year-old girls, 510 10–15-year-old boys, and 513 16–23-year-old women who were fully immunized [25]. Virtually all the subjects were seroconverted for all four HPV types. Not only were the neutralization titers in the boys and girls non-inferior to those of the women, but they were also 1.7–2.7-fold higher, thus indicating that by immunizing early in life, higher and presumably longer sustaining antibody titers can be expected. Another recent study has included boys and girls 9 to 15 years of age [16]. The results were similar and the titers held for at least 12 months [26]. Similarly, immunization with Cervarix produced in 158 10–14-year-old girls anti-HPV-16 or antiHPV-18 antibody titers that were twice as high as in 458 15–25-year-old females [27].
Tolerance and safety HPV VLPs are not infectious, as they are by design devoid of HPV DNA. Furthermore, the VLPs used in both Gardasil and Cervarix are dissociated, treated by DNase, and re-associated. About 85% of the Gardasil vaccine recipients experienced local adverse reaction, but only a 6.5–9.4% excess relative to the placebo [21,22]. These local side effects included pain at the injection site, 85%, and swelling, 26%, both about 10% more common than with the placebo. Fever was noted not only in 13.5% of the vaccine immunizations but also in 10.2% of the placebo immunizations [21]. Girls and boys were 7–15% less likely than women to experience pain at the site of injection but more likely to experience fever [25]. Serious adverse events related to the immunization and requiring its discontinuation were noted only twice (hypersensitivity reaction and hypoesthesia at injection site) in a combined population of over 17 000 subjects, and both were in the placebo group. There was otherwise no difference in adverse events. The experience with Cervarix has been qualitatively similar, though with rates of pain and swelling perhaps slightly higher, by about 8%, than that with Gardasil [18]. Redness was also as common as swelling. There was no difference in systemic adverse reactions between the vaccine and placebo groups [18,19]. As of February 2007, the post-licensure Vaccine Adverse Event Reporting System (VAERS) had recorded dizziness or fainting in 11% in each of the notifications submitted. Consequently, the Advisory Committee on Immunization Practices (ACIP) has recommended that patients should be observed for 15 min after vaccination [28,29]. During the clinical trials of Gardasil, pregnancies occurred in 1115 of 10 418 subjects in the vaccine group and in 1551 of 9120 subjects in the placebo group [26]. The rates of fetal loss were comparable in the two groups, www.sciencedirect.com
38% and 40%, respectively. The VAERS has not registered any unexpected outcomes, but the immunization remains contraindicated during pregnancy. Since the vaccine has been sold, two types of adverse reactions not encountered during the clinical trials have been reported: Guillain Barre´ syndrome and facial palsy [29]. Of the three Guillain Barre´ syndrome cases, only one occurred with the administration of Gardasil alone, the others with the co-administration of the meningococcal conjugate vaccine. There were three cases of facial palsy, all within one day of the administration of different vaccines. The small numbers preclude at the moment any reliable conclusions, but both types of events are actively and passively monitored [29]. It should be pointed out that several cases of Guillain Barre´ syndrome have been associated with the administration of the meningococcal conjugate vaccine [30]. The co-administration of the hepatitis B vaccine has been shown not to interfere with the immunogenicity and safety of the HPV vaccine [26,28]. A study is underway looking at the combination of the HPV vaccine with the combined diphtheria, tetanus, pertussis vaccine, and meningococcal conjugate vaccine in adolescents [ClinicalTrials.gov Identifier: NCT00325130], but the ACIP and the American Academy of Pediatrics endorse the administration of these vaccines at the same visit [28,31]; in that case each vaccine should each be given at a different injection site. Should the immunization series be interrupted, it is to be completed as soon as possible.
Efficacy issues In the United States, the ACIP has recommended immunization with Gardasil in 11–12-year-old girls, with catchup vaccination for 13–18-year-old girls. The vaccine can be given to girls as young as 9 years and to women as old as 26 years [28]. The American Cancer Society recommends vaccination only up to 18 years of age [32]. In a few countries, like Australia, male immunization is allowed, but not in most. The current indications for the vaccine are the prevention of cancer of the cervix, CIN1-3, AIS (adenocarcinoma in situ), VIN2/3, VAIN2/3, and genital warts. Therapeutic efficacy
The clinical trials that have taken place so far have failed to demonstrate a therapeutic effect of vaccination on the infections or lesions already present at the time of vaccination [22]. There might be, however, a benefit in seropositive women who have cleared their infection with a vaccine HPV type by having a lower chance of re-acquiring the disease [29]. Efficacy against infections and diseases caused by non-vaccine HPV types
The low efficacy of the vaccine against diseases caused by any HPV types in a population irrespective of its HPV Current Opinion in Pharmacology 2007, 7:470–477
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DNA status or seropositivity (see Table 1, the section ‘Intention-to-Treat population—Any lesion regardless of type’) has been noted as a significant weakness of the vaccine. Sawaya and Smith-McCune commenting on the 17% efficacy figure observed in Merck protocol 017 study [22] argued that ‘129 women would need to be vaccinated in order to prevent one case of CIN2/3 or AIS’ [33]. Clearly, HPV immunization should not for now change or obviate screening for cervical cancer. There are, however, several points not to be overlooked. First, most of the efficacy results that have been published on Gardasil stop at three years of follow-up. Because the placebo recipients acquire lesions at a slightly higher rate than vaccine recipients [21–23, 24], the low efficacy figures are likely to improve as long as a booster is not needed. In fact, similar outcomes measured at five years with Cervarix bear this expectation, demonstrating a 45% vaccine efficacy [19]. Second, there appear to be geographic variations of these figures, with a vaccine efficacy against vaccine type CIN13 and AIS in North America, double than that found in Asia in the Intention-to-Treat population [23]. This may reflect different HPV types geographic distribution. Third, HPV type 16, which is included in the vaccine, is substantially more oncogenic than the other high-risk types and clearly carries the highest risk of progression to CIN3 or invasive cervical carcinoma [34]. Fourth, the same HPV types that are included in the vaccine are also responsible for other cancers (vulva, vagina, anus, penis, oropharyngeal) [6,7]. Screening is typically not available for these cancers. Therefore, vaccination is likely to be effective and the best hope to prevent these tumors. New types
Another concern that has been raised is the possibility that by hopefully eradicating HPV types 6, 11, 16, and 18, the vaccine would open the way for other types to fill the vacuum. As indicated by Sawaya and Smith-McCune, the FDA when reviewing the Biologics License Application of Gardasil in May 2006, pointed out in the subjects who were seropositive and HPV DNA positive for the vaccine types a greater number of cases of CIN1/3 in the vaccine group than in the placebo group [33,35]. This difference appeared to have been due to a greater number of subjects in the vaccine group who had baseline evidence of HSIL on Pap smear than those in the placebo group. There was no evidence of lesion replacement by nonvaccine HPV types in the study of Cervarix [19]. Although this issue deserves vigilance, it should be pointed out that HPV is not part of the cervical normal flora. Therefore, there is a priori no intrinsic reason for the cervix to become colonized with non-vaccine types. Moreover, there is evidence that infections by different HPV types are not independent but synergistic and that under these conditions, epidemiologic modeling predicts Current Opinion in Pharmacology 2007, 7:470–477
that vaccination should have a favorable effect on nonvaccine types [36]. HPV cross-protection
Each genotype, in general, corresponds to its own serotype. However, it has been long recognized that there are exceptions, most notably that HPV-6 and HPV-11 share conformational, including neutralizing, epitopes [37–40]. By phylogeny, HPV types 16, 31, 33, 58 are related and belong to species 9, whereas types 18, 39, 45, and 59 belong to species 7. Cross-neutralizing epitopes have been identified that are shared more or less strongly within each species [41]. Therefore, it was not a complete surprise to see that subjects immunized with Cervarix, containing HPV-16 and HPV-18, developed cross-protection against HPV-31 (vaccine efficacy 54.5%) and HPV-45 (vaccine, efficacy of 94.2%) cervical infections [19]. These two types account for 2.9% and 6.7%, respectively, of all cervical cancers [5]. Similar results, but based on limited in vitro data, have been presented with Gardasil [42]. They are expected to be confirmed clinically given that Merck has submitted a supplemental Biologics Licensing Application to the FDA on April 18, 2007, on cross-neutralization of new types. The fact that no cross-neutralization with Cervarix was observed against HPV types 33 and 58 suggests that our understanding of neutralizing epitopes in humans is partial. Duration of protection
At this time, it is not possible to tell how long the vaccine protection lasts and when a booster might be necessary. Merck has established a registry in the Nordic countries to examine the duration of the vaccine efficacy. To date, only the results at five years of follow-up of a small cohort of 225 vaccine and placebo recipients derived from Merck protocol 07 have been published [43]. The efficacy of Gardasil was 95.1% in the per-protocol analysis of cases of infection or diseases (warts, VIN, VAIN, CIN, AIS) caused by the vaccine types. The fact that in this study the neutralization antibody titers to HPV-6 and HPV-18 in the vaccinees overlapped with those of the seropositive placebo recipients suggests that these titers, at least for these HPV types, are not a perfect predictor of protection. This possible limitation is probably linked to the incomplete blockade of all the neutralization epitopes by the monoclonal antibodies used in the competition assays that measure these titers [44]. A very recent study of Gardasil confirmed that neutralizing antibody titers to the vaccine HPV types reach a plateau at month 24 but remain stable up to 5 years after immunization, at which time a booster induces 1 month later titers higher than those measured 1 month after the third dose of the vaccine [44a]. At five years, Cervarix was also still very effective, with a vaccine efficacy of 92.6% for the prevention of HPV16/18 www.sciencedirect.com
Human papillomavirus vaccine—recent results and future developments Bonnez 475
CIN1-3 and 100% for CIN2/3 [19]. GSK investigators have shown higher titers of binding and neutralizing antibodies to HPV-16 and HPV-18 with the AS04 adjuvant compared with aluminum hydroxide alone [45]. Although higher neutralizing titers are expected to confer longer protection, this remains to be established. It should also be noted that Cervarix and Gardasil do not use the same amount or mode of preparation of their aluminum hydroxide adjuvant. GSK is now conducting a double-blind comparative study of the immunogenicity of the two vaccines (ClinicalTrials.gov Identifier: NCT00423046).
Future directions Within approximately six months, both Gardasil and Cervarix will be available in many countries. The first vaccine is quadrivalent, the second bivalent. Beyond this obvious difference, other factors, in particular, price and duration of effectiveness, will be important in guiding choices. Several cost-effective and epidemiologic modeling analyses have indicated that men will need to be immunized to achieve the greatest effectiveness of the vaccine [46–48]. A randomized, double-blind, placebo-controlled study of Gardasil is currently under way to demonstrate efficacy for the prevention of genital warts (ClinicalTrials.gov Identifier: NCT00090285). The results of this study will determine whether Gardasil receives an indication for men. Extending the indications to women beyond the age of 26 years is being sought. One randomized, double-blind, placebo-controlled trial of Cervarix is examining its immunogenicity in women aged between 18 and 45 years (ClinicalTrials.gov Identifier: NCT00423046), while another is looking at safety, immunogenicity, and efficacy in women older than 26 years (ClinicalTrials.gov Identifier: NCT00456807). Merck is currently evaluating the efficacy of Gardasil in women between the age of 24 and 45 years (ClinicalTrials.gov Identifier: NCT00090220). At the other end of the age spectrum, the National Institute of Allergy and Infectious Diseases is conducting a study on the safety and immunogenicity of Gardasil in male and female children aged 7–12 infected with HIV (ClinicalTrials.gov Identifier: NCT00339040). Trials of Gardasil are also being considered in populations at high risk for genital HPV infections and diseases, such as solid organ and bone marrow transplant patients and HIV-positive men and women [29]. HPV VLP vaccines are likely to remain relatively expensive, and this constitutes a significant barrier to the dissemination of HPV vaccination to where it is most needed, the developing world. In order to resolve this issue, alternative dosing regimens are being considered [29]. Another approach has been the development of a cheaper vaccine, one made in E. coli [49,50]. Two important questions will need to be resolved. The first one is whether HPV immunization will have an www.sciencedirect.com
impact on the rate of cervical invasive cancer. Merck has set up in Norway a surveillance study that will examine this issue. Other studies will probably be in place in the future to examine this crucial point. The second question, will be to determine the impact of the vaccine on cervical cancer screening to lead, hopefully, toward the design of less frequent, more targeted screening procedures [51]. The impact of the vaccine on other HPV-associated diseases will be worth examining as well. For example, diseases such as oropharyngeal cancer, anal cancer, and recurrent respiratory papillomatosis, an uncommon but usually severe disease caused by HPV6 or HPV-11 [52]. Finally, one can reasonably anticipate that the current vaccines will be modified to include additional HPV types.
Acknowledgements This work is supported partly by NIH contract N01-AI-15435. Bonnez reports consulting and lecture fees from Merck. He also holds intellectual property rights on HPV VLP vaccines and is to derive royalties from the sale of the vaccine from Merck and GlaxoSmithKline.
References and recommended reading Papers of particular interest, published within the period of review have been highlighted as: of special interest of outstanding interest
1.
Bernard HU: The clinical importance of the nomenclature, evolution and taxonomy of human papillomaviruses. J Clin Virol 2005, 32(Suppl 1):S1-S6.
2.
Munoz N, Castellsague X, de Gonzalez AB, Gissmann L: Chapter 1: HPV in the etiology of human cancer. Vaccine 2006, 24S3:S1-S10.
3.
Brown DR, Schroeder JM, Bryan JT, Stoler MH, Fife KH: Detection of multiple human papillomavirus types in condylomata acuminata lesions from otherwise healthy and immunosuppressed patients. J Clin Microbiol 1999, 37:3316-3322.
4.
Vandepapeliere P, Barrasso R, Meijer CJ, Walboomers JM, Wettendorff M, Stanberry LR et al.: Randomized controlled trial of an adjuvanted human papillomavirus (HPV) type 6 L2E7 vaccine: infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination. J Infect Dis 2005, 192:2099-2107.
5.
Munoz N, Bosch FX, Castellsague X, Diaz M, de Sanjose S, Hammouda D et al.: Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 2004, 111:278-285.
6.
Parkin DM, Bray F: Chapter 2: the burden of HPV-related cancers. Vaccine 2006, 24(Suppl 3):S11-S25.
7.
D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM et al.: Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007, 356:1944-1956.
8.
Clifford G, Franceschi S, Diaz M, Munoz N, Villa LL: Chapter 3: HPV type-distribution in women with and without cervical neoplastic diseases. Vaccine 2006, 24(Suppl 3):S26-S34.
9.
Parkin DM: Global cancer statistics in the year 2000. Lancet Oncol 2001, 2:533-543.
10. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer statistics, 2007. CA Cancer J Clin 2007, 57:43-66. 11. Chesson HW, Blandford JM, Gift TL, Tao G, Irwin KL: The estimated direct medical cost of sexually transmitted diseases among American youth, 2000. Perspect Sex Reprod Health 2004, 36:11-19. Current Opinion in Pharmacology 2007, 7:470–477
476 Anti-infectives
12. Rose RC, Reichman RC, Bonnez W: Human papillomavirus type 11 (HPV-11) recombinant virus-like particles (VLPs) induce the formation of neutralizing antibodies and detect HPV-specific antibodies in human sera. J Gen Virol 1994, 75:2075-2079. 13. Breitburd F, Coursaget P: Human papillomavirus vaccines. Semin Cancer Biol 1999, 9:431-444. 14. Harro CD, Pang Y-YS, Roden RBS, Hildesheim A, Wang Z, Reynolds MJ et al.: Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst 2001, 93:284-292. 15. Evans TG, Bonnez W, Rose RC, Koenig S, Demeter L, Suzich JA et al.: A phase 1 study of a recombinant viruslike particle vaccine against human papillomavirus type 11 in healthy adult volunteers. J Infect Dis 2001, 183:1485-1493. As with the study by Harro et al. [14], the Evans study examined different doses of HPV VLP antigen, and both demonstrated a vigorous antibody response with both binding and neutralizing functions. Evans et al. also showed that HPV-11 VLP stimulated T cells in a way that appeared not to be type-restricted. A cytokine expression pattern consistent with T helper cell type 1 and 2 responses was also noted. 16. Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB et al.: A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002, 347:1645-1651. This phase 2 controlled study of an HPV-16 L1 VLP vaccine was a milestone in the clinical development of the HPV vaccine. It demonstrated the complete efficacy of the vaccine in preventing cervical HPV-16 infection. It served to establish the model by which these types of vaccines are to be evaluated, by targeting a population of sexually active adolescent and young adults but with a low-to-moderate risk of being already HPV-infected. As expected, the study confirmed that immunization against HPV-16 did not necessarily prevent infections by other HPV types, as an equal number of subjects developed CIN not related to HPV16. It also confirmed the low chance for transient infections to lead to CIN. None of the 6 vaccine recipients and 27 placebo recipients who were transiently positive for HPV-16 developed an HPV-16-related CIN. Although the six transient infections in the vaccine recipients might not have been true infections, and even if they were, this would give weight to the idea that below a certain viral exposure or load the body can clear an HPV infection. 17. Mao C, Koutsky LA, Ault KA, Wheeler CM, Brown DR, Wiley DJ et al.: Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol 2006, 107:18-27 [erratum appears in Obstet Gynecol. 2006 Jun;107(6):1425]. 18. 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, 364:1757-1765. 19. 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, 367:1247-1255. This publication is about an extension beyond 27 months of the study described in reference [18]. Originally, 1113 women were enrolled, and 776 were followed in the extension phase for up to 4.5 years, in the according-to-protocol cohort. Although, the primary endpoint was prevention not of disease or persistent infection but of HPV incident infection, both studies, though small in size, offer a very clear and convincing picture of the Cervarix’s efficacy. The results are comparable to those reported with Gardasil, including when protocol violators (intention-totreat analysis) were included. This study is also remarkable for showing that the vaccines also confer protection against HPV-45 (94.2% efficacy, 95% CI 63.3–99.9%) and HPV-31 (54.5%, 95% CI 11.5–77.7%) infections. The L1 gene DNA sequence of HPV-45 and HPV-31 are phylogenetically related to those of HPV-18 and HPV-16, respectively. At entry, the subjects were cytologically negative, seronegative for HPV-16 and HPV18, and HPV DNA negative for 14 high-risk types, including types 16 and 18. This allowed the investigators to measure the impact of vaccination on the prevention of cervical disease caused by high-risk HPV types, not just types 16 and 18; it was 48.2% (95% CI 27.0–63.8%). The vaccine efficacy was still substantive, 39.8% (95% CI 20.9–54.4%) against cervical disease, irrespective of HPV DNA status. Simply interpreting these results as indicating a modest impact of the vaccine on cervical HPV disease is incomplete. First, as follow-up duration increases and as long as the vaccine remains effective, these efficacy figures will increase because Current Opinion in Pharmacology 2007, 7:470–477
placebo recipients will accrue disease at a faster rate than vaccinees (the same phenomenon has been documented with Gardasil see reference [23]). Second, although it is desirable to reduce screening cost to eliminate all grades of CIN, only the high grades, CIN 2 or 3 have the highest impact on the risk of invasive cancer. Although, the number of observations is too limited at this point to draw firm conclusions on the impact of the vaccine on these lesions, this study shows a vaccine efficacy of 67.1% against high-risk HPV type CIN2/3 and 73.3% against CIN2/3 independent of HPV DNA status. 20. Kang M, Lagakos SW: Evaluating the role of human papillomavirus vaccine in cervical cancer prevention. Stat Methods Med Res 2004, 13:139-155. 21. 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, 356:1928-1943. 22. Koutsky LA: Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007, 356:1915-1927. 23. Ault KA: Effect of prophylactic human papillomavirus L1 viruslike-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet 2007, 369:1861-1868. 24. Joura EA, Leodolter S, Hernandez-Avila M, Wheeler CM, Perez G, Koutsky LA et al.: Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16 and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet 2007, 369:1693-1702. This series of publications [21–23,24] presents the updated results, at 36 month of follow-up, of the main studies that led to the licensing of the first HPV VLP vaccine (Gardasil, Merck), which is directed at HPV types 6, 11, 16, and 18. The first two publications are devoted to Merck protocols 013 and 015, respectively. The last two present the combined results of these studies as well as those of two antecedents studies (protocols 005 and 007) to provide a more precise assessment of the vaccine efficacy. The first two publications address the vaccine safety in detail by analyzing data collected from almost 18 000 subjects. 25. Block SL, Nolan T, Sattler C, Barr E, Giacoletti KE, Marchant CD et al.: Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16 and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics 2006, 118:2135-2145. 26. Reisinger KS, Block SL, Lazcano-Ponce E, Samakoses R, Esser MT, Erick J et al.: Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J 2007, 26:201209. 27. Pedersen C, Petaja T, Strauss G, Rumke HC, Poder A, Richardus JH et al.: Immunization of early adolescent females with human papillomavirus type 16 and 18 L1 virus-like particle vaccine containing AS04 adjuvant. J Adolesc Health 2007, 40:564-571. 28. Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER et al.: Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007, 56:1-24. This reference offers the finalized recommendations of the ACIP for the use of the quadrivalent HPV vaccine. Anyone who wants to use the vaccine is invited to consult this document that covers some aspects of the immunization in a greater detail than this reviews allows. The site of the American Academy of Pediatrics (http://www.cispimmunize.org/) is also an excellent resource. 29. Advisory Committee on Immunization Practices, February 21–22, 2007, Atlanta, Georgia, Record of the Proceedings. www.cdc.gov/ vaccines/recs/acip/downloads/acip_min_feb07.pdf. 30. Guillain-Barre´ syndrome (GBS) among persons who received meningococcal conjugate vaccine. In Centers for Disease Control and Prevention; 2007. http://www.cdc.gov/od/science/ iso/concerns/gbsfactsheet.htm. www.sciencedirect.com
Human papillomavirus vaccine—recent results and future developments Bonnez 477
31. Prevention of human papillomavirus infection: provisional recommendations for immunization of females with quadrivalent human papillomavirus vaccine. In American Academy of Pediatrics; 2007. http://www.cispimmunize.org/ill/ pdf/HPVprovisional.pdf.
43. 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, 95:1459-1466.
32. 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.
44. Dias D, Van Doren J, Schlottmann S, Kelly S, Puchalski D, Ruiz W et al.: Optimization and validation of a multiplexed luminex assay to quantify antibodies to neutralizing epitopes on human papillomaviruses 6, 11, 16 and 18. Clin Diagn, Lab Immunol 2005, 12:959-969.
33. Sawaya GF, Smith-McCune K: HPV vaccination—more answers, more questions. N Engl J Med 2007, 356:1991-1993. 34. Schiffman M, Herrero R, Desalle R, Hildesheim A, Wacholder S, Rodriguez AC et al.: The carcinogenicity of human papillomavirus types reflects viral evolution. Virology 2005, 337:76-84. 35. FDA Executive Summary—GARDASIL Licensing Action; 2006. www.fda.gov/cber/sba/hpvmer060806s.pdf. 36. Elbasha EH, Galvani AP: Vaccination against multiple HPV types. Math Biosci 2005, 197:88-117. 37. Bonnez W, Harvey C, Rose RC, Reichman RC: Use of HPV-11 viral particles in an ELISA to detect antibodies in humans with or without condylomata acuminata. Ninth International Papillomavirus Workshop; Heidelberg, FRG: 1990:153. 38. Bonnez W, Greer C, DaRin C, Borkhuis C, Van Nest G, Rose RC: Correlation between ELISA and neutralizing activities of antiHPV-6 L1 virus-like particles (VLP) rabbit antisera against HPV-11. 15th International Papillomavirus Workshop; Gold Coast, Queensland, Australia, December 1–5: 1996. 39. Touze A, Dupuy C, Mahe D, Sizaret PY, Coursaget P: Production of recombinant virus-like particles from human papillomavirus types 6 and 11, and study of serological reactivities between HPV 6, 11, 16 and 45 by ELISA: implications for papillomavirus prevention and detection. FEMS Microbiol Lett 1998, 160:111-118. 40. Wang XM, Cook JC, Lee JC, Jansen KU, Christensen ND, Ludmerer SW et al.: Human papillomavirus type 6 virus-like particles present overlapping yet distinct conformational epitopes. J Gen Virol 2003, 84:1493-1497. 41. Combita AL, Touze A, Bousarghin L, Christensen ND, Coursaget P: Identification of two cross-neutralizing linear epitopes within the L1 major capsid protein of human papillomaviruses. J Virol 2002, 76:6480-6486. 42. Smith JF, Brownlow MK, Brown MJ, Esser MT, Ruiz W, Brown DR: Gardasil antibodies cross-neutralize pseudovirion infection of vaccine-related HPV types. 23rd International Papillomavirus Conference & Clinical Workshop; Prague, Czech Republic, September 1–7: 2006.
www.sciencedirect.com
44a. Olsson SE, Villa LL, Costa RL, Petta CA, Andrade RP, Malm C et al.: Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. Vaccine 2007, 25:4931-4939. 45. Giannini SL, Hanon E, Moris P, Van Mechelen M, Morel S, Dessy F et al.: Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/ aluminium salt combination (AS04) compared to aluminium salt only. Vaccine 2006, 24:5937-5949. 46. Hughes JP, Garnett GP, Koutsky L: The theoretical populationlevel impact of a prophylactic human papilloma virus vaccine. Epidemiology 2002, 13:631-639. 47. Elbasha EH, Dasbach EJ, Insinga RP: Model for assessing human papillomavirus vaccination strategies. Emerg Infect Dis 2007, 13:28-41. 48. Dasbach EJ, Elbasha EH, Insinga RP: Mathematical models for predicting the epidemiologic and economic impact of vaccination against human papillomavirus infection and disease. Epidemiol Rev 2006, 28:88-100. 49. Li M, Cripe TP, Estes PA, Lyon MK, Rose RC, Garcea RL: Expression of the human papillomavirus type 11 L1 capsid protein in Escherichia coli: characterization of protein domains involved in DNA binding and capsid assembly. J Virol 1997, 71:2988-2995. 50. Chen XS, Casini G, Harrison SC, Garcea RL: Papillomavirus capsid protein expression in Escherichia coli: purification and assembly of HPV11 and HPV16 L1. J Mol Biol 2001, 307: 173-182. 51. Kulasingam SL, Myers ER: Potential health and economic impact of adding a human papillomavirus vaccine to screening programs. JAMA 2003, 290:781-789. 52. Freed GL, Derkay CS: Prevention of recurrent respiratory papillomatosis: role of HPV vaccination. Int J Ped Otorhinolaryngol 2006, 70:1799-1803.
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