2 HPV vaccines, 7 questions that you need answered
The availability of two vaccines against human papillomavirus raises numerous questions about fine points of cervical cancer prevention
IN THIS ARTICLE
Not long ago (in medical years), we were still trying to discover the cause of cervical cancer. Today, not only do we know that cause to be persistent human papillomavirus (HPV) infection, but we have two vaccines at our disposal to prevent the primary oncogenic strains of the virus.
We’ve come a long way.
The availability of two vaccines raises questions, however. What kind of data do we have on the bivalent (Cervarix, GlaxoSmithKline) and quadrivalent (Gardasil, Merck) vaccines so far? Is one of them clearly superior to the other? If not, what population is each vaccine best suited for—and how do we counsel patients about their options?
To address these and other questions, OBG Management Contributing Editor Neal M. Lonky, MD, MPH, assembled a panel of physicians who have expertise in cervical disease detection and prevention and asked them to sift the data that have accumulated thus far. In the discussion that follows, they touch on long-term efficacy, the likely impact of the vaccines on cervical cancer screening, and other aspects of disease prevention in the era of HPV vaccination.
The OBG Management expert panel
Juan C. Felix, MD
Professor of Clinical Pathology and Obstetrics and Gynecology; Director of Cytopathology fellowship; and Chief of Gynecologic Pathology at the Keck School of Medicine, University of Southern California; and Chief of Cytopathology at Los Angeles County and University of Southern California Medical Center in Los Angeles.
Dr. Felix reports that he is a speaker for Merck and GlaxoSmithKline.
Diane M. Harper, MD, MS, MPH
Director of the Gynecologic Cancer Prevention Research Group and Professor of Obstetrics and Gynecology, Community and family Medicine, and Informatics and Personalized Medicine at the University of Missouri–Kansas City School of Medicine.
Dr. Harper reports that she has served as a speaker and advisor for Merck and GlaxoSmithKline, and that the institutions at which she conducted HPV vaccination trials have received funding from Merck and GlaxoSmithKline.
Warner K. Huh, MD
Associate Professor in the Department of Obstetrics and Gynecology, and Associate Scientist at the Comprehensive Cancer Center at the University of Alabama– Birmingham.
Dr. Huh reports that he receives grant or research support from and is a speaker and consultant to Merck and GlaxoSmithKline.
Karen K. Smith-McCune, MD, PhD
John Kerner Endowed Chair of Gynecologic Oncology, Director of the Dysplasia Clinic, and Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of California–San francisco.
Dr. Smith-McCune reports she has performed unpaid consulting for OncoHealth Inc. and is planning to join its Scientific Advisory Board.
1. How were the vaccines developed?
Neal M. Lonky, MD, MPH: What should clinicians know about the development, function, and mechanism of action of the two HPV vaccines?
Warner K. Huh, MD: The bivalent and quadrivalent vaccines are both excellent products, and their respective Phase-3 trials demonstrate that they provide impressive protection against HPV, particularly among women who test negative (by polymerase chain reaction) for the specific HPV types contained within the vaccines.1-3
Cervarix protects against HPV types 16 and 18, whereas Gardasil is effective against HPV types 6, 11, 16, and 18.
Dr. Lonky: Do the vaccines function similarly?
Diane M. Harper, MD, MS, MPH: Yes. Both stimulate an immediate antibody response in the woman who is not infected with the relevant virus and are effective in preventing cervical intraepithelial neoplasia grade 2 and higher (CIN 2+), as well as persistent infection, caused by vaccine-related and cross-protected HPV types. The quality of the antibody response is best for HPV 16 for both vaccines. The quality of the antibody response for HPV 6, 11, and 18 for Gardasil is much poorer than its response for HPV 16. Cervarix induces an equally high and sustained antibody response for HPV 18 as for HPV 16.
Juan C. Felix, MD: Both vaccines are based on the same virus-like particles (VLP). The functionality of the vaccines is, therefore, mainly dependent on the dosage of VLP and the adjuvant used. Gardasil uses a proprietary aluminum sulfate adjuvant, whereas Cervarix uses aluminum hydroxide and monophosphoryl lipid A.
Karen K. Smith-McCune, MD, PhD: Both adjuvants have an extensive track record of safety and efficacy in other vaccines. Because they have different structures, however, they may have varying effects on many components of the immune response elicited by the L1 antigens.
Dr. Harper: Both adjuvants contain aluminum, which has so far proved to be safe despite the newly established association between high aluminum intake and Alzheimer’s disease.
Dr. Lonky: Were there any notable challenges in developing the vaccines?
Dr. Harper: It was difficult to formulate the appropriate dosages of VLP in Gardasil. Higher dosages of HPV 11 and 16 were needed to prevent cross-inhibition by HPV 6 and 18. As a result, the antigenic protein component of Gardasil that is necessary to effect an immunologic antibody response is high, at 120 μg. In Cervarix, the antigenic VLP load is 20 μg each for HPV 16 and 18.
Dr. Lonky: What is the significance of the different VLP loads?
Dr. Harper: Side effects, such as autoimmune neurologic demyelination, albeit rare, have been associated with a higher antigenic protein load. Multiple reports of autoimmune demyelinating diseases—including paralysis, blindness, and death—have been published by neurologists in regard to Gardasil.4,5 Others have shown that young girls are more at risk than young boys for these neurologic side effects.6
Dr. Felix: Some data suggest that the two vaccine formulations interact differently with the human immune system. In a head-to-head trial funded by GlaxoSmithKline, Cervarix produced higher total and neutralizing antibody titers than Gardasil did.7
Although higher immunogenicity is generally thought to be beneficial, the ultimate determinant of a vaccine’s success is its efficacy—and duration of that efficacy—in clinical trials and follow-up of vaccinated populations. So far, Cervarix has demonstrated efficacy through 8.4 years in its follow-up cohort.8 Similarly, Gardasil has proved to be effective after 5 years of follow-up, with no incident cases of cervical cancer reported in the vaccinated arm.9
2. Does either vaccine offer “extra” immunity?
Dr. Lonky: What is the potential for overlapping immunity to other high-risk viral types with these vaccines?
Dr. Harper: It is quite clear from pivotal trials of both vaccines that Gardasil produces efficacy of 46% against persistent infection caused by HPV 31. Data from the pivotal Phase-3 trial of Gardasil also show that it offers no protection against persistent infection with HPV 45, an important cause of adenocarcinoma.10
In contrast, Cervarix demonstrates substantial efficacy against both persistent infection and CIN 2+ disease caused by HPV 31, 33, and 45.3
These findings mean that Cervarix is 91% effective against HPV types that cause adenocarcinoma and 83% effective overall against squamous cell carcinoma. Compare that with Gardasil, which is 78% effective overall against HPV types that cause adenocarcinoma and 73% effective against HPV types that cause squamous cell carcinoma.
The immune titers tell a supportive story. After vaccination with Gardasil, the antibody titer immediately declines for HPV 6, 11, and 18, reaching the baseline for natural infection within 18 months.7 HPV 18 shows continued, significant loss of seropositivity over time, and antibody titers for HPV 6 and 11 also decline. In the monovalent HPV 16 pre-Gardasil experimental vaccine, 14% of women no longer had measurable titers to HPV 16 after 8.5 years.11
After vaccination with Cervarix, antibody titers for HPV 16 and 18 remain more than seven times and more than four times higher, respectively, than natural infection titers for 8.4 years, with no loss of measurable antibody titer for either type. The antibody titers for HPV 31, 33, and 45 remain substantially higher than natural infection titers for at least 6.4 years. These titers correlate with the vaccine’s very high efficacy against CIN 2+ lesions caused by HPV 16, 18, 31, 33, and 45.
In other words, Cervarix generates an immune response (and efficacy) that indicates robust protection against five of the most common oncogenic HPV types, providing maximal protection against nearly 85% of all cervical cancers. Gardasil protects against 74% of all cervical cancers overall.12 This makes Cervarix the superior cervical cancer vaccine.
Gardasil is the superior vaccine against genital warts, although the duration of its protection is uncertain.
Dr. Huh: I’d just like to point out that there are no head-to-head trials comparing the vaccines in terms of efficacy. Antibody titers are higher with Cervarix than with Gardasil, as you noted, and it may be that, over time, the higher titers are more durable with Cervarix. However, we have yet to fully correlate clinical efficacy with antibody titers. In other words, immunogenicity does not equal clinical efficacy.
Dr. Felix: The data for Gardasil are particularly interesting because there have been no incident HPV-18 lesions detected despite the absence of detectable HPV-18 antibody titers in more than 20% of vaccinated women as soon as 2 years after immunization.9 These data strongly suggest that it is not antibody titer alone that grants protection against HPV-induced lesions of the cervix.
Dr. Harper: This speaks to the difficulty of running a trial to ensure both enough participants and a sufficient attack rate of HPV 18 to cause new lesions to be detected in vaccinated women. In the relevant trial, there were only 112 vaccinated women—not nearly enough women to overcome the very low attack rate of HPV 18 in the trial population—and they were followed for 5 years.9 We cannot be sure that the lack of incident HPV-18 lesions in the vaccinated women is the result of efficacy.
Dr. Felix: As for overlapping immunity to HPV types not included in the vaccines, it has been described for both Cervarix and Gardasil. In the case of Cervarix, the manufacturer demonstrated unexpectedly high rates of protection against all CIN 2+ and CIN 3+ lesions—70% and 87%, respectively. These rates were too high to be explained by protection against types 16, 18, 31, and 45 alone. It is possible, therefore, that Cervarix may protect against other high-risk HPV types.13
Gardasil has proved to be effective against HPV types 31, 33, 52, and others.10 When total protection against CIN 2+ and CIN 3+ lesions is examined from Phase-3 trials of the vaccine, however, the rates are only 42% and 43%, respectively. These data are difficult to interpret because HPV 16 and 18 together are thought to account for 70% of CIN 3. Some reassurance can be gained from the fact that the number of incident cases of CIN 2+ and CIN 3+ caused by HPV 16 and 18 in the vaccinated group in the Gardasil trial was identical to the number seen in the Cervarix trial.3,10 The reason for the discrepancy in total number of cases of CIN 2+ and CIN 3+ between the two trials—and, therefore, between the two vaccines—cannot be explained by cross-protection alone and is probably attributable to differences in study populations. The Gardasil trial had a higher baseline prevalence of HPV 16 and 18 (9% and 4%, respectively) than the Cervarix trial did (5% and 2%, respectively), a fact that may be explained by the different demographics of their respective populations.2,14
Ultimately, it is hazardous to compare trials, particularly when they are conducted in significantly different populations. On this issue, I concur with the World Health Organization (WHO), which recommended that such comparisons be avoided in the determination of which type of HPV vaccine to recommend.15
Dr. Huh: I agree that it would be inappropriate to make cross-trial comparisons, given differences in the way the trials were designed and conducted. To draw conclusions about clinical efficacy of these two excellent vaccines, based on a comparison of their trials, is completely unscientific. Only a true head-to-head study that has efficacy as its endpoint can tell us which vaccine is superior—and such a trial would require thousands (if not tens of thousands) of subjects and a considerable amount of time to complete. In my opinion, such a study would be counterproductive to our goal of vaccination.