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
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.
