In a large randomized clinical trial, a new human papillomavirus (HPV) vaccine effectively prevented infection and disease caused by nine HPV types, including seven types that cause cervical and other cancers—five of which were not covered by the previously available HPV vaccines—and two types that cause genital warts.
New England Journal of Medicine, February 18, 2015 (See the abstract.)
HPV infections are the most common sexually transmitted infections in the United States. More than 40 HPV types can be spread through direct sexual contact. Of these, about a dozen, including HPV types 16, 18, 31, 33, 45, 52, and 58, are high-risk—that is, persistent infection with these HPV types can cause cellular changes that may progress to cancer, including cervical, anal, penile, vaginal, vulvar, and oropharyngeal cancers. HPV types 16 and 18 are responsible for approximately 70 percent of all cervical cancers and HPV types 31, 33, 45, 52, and 58 are responsible for another 20 percent of cervical cancers.
Until December 2014, the FDA had approved two vaccines to protect against HPV infection: Cervarix, a bivalent vaccine that protects against infection with HPV types 16 and 18, and Gardasil, a quadrivalent vaccine that protects against infection with HPV types 6, 11, 16, and 18. Types 6 and 11 are low-risk types that do not cause cancer but can cause warts on or around the genitals, anus, mouth, or throat.
Researchers have been working on developing next-generation HPV vaccines that protect against additional high-risk HPV types. In December 2014, based on the results of this clinical trial, the FDA approved the 9-valent vaccine Gardasil 9, which protects against infection with HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58.
In a phase II/III international double-blind clinical trial, researchers randomly assigned 14,215 women between the ages of 16 and 26 to receive Gardasil or Gardasil 9. As part of the clinical trial, a small dose-finding study was first done to determine the dose that would be used in the larger efficacy study. Participants were eligible if they had no history of an abnormal Pap test, no more than four lifetime sexual partners, and no previous abnormal finding on a cervical biopsy.
Women in each group received three intramuscular injections of the vaccine over 6 months.
The study’s primary endpoint was the incidence of high-grade cervical, vulvar, or vaginal disease, including high-grade cervical epithelial neoplasia, adenocarcinoma in situ, cervical cancer, high-grade vulvar intraepithelial neoplasia, high-grade vaginal intraepithelial neoplasia, vulvar cancer, and vaginal cancer. Secondary endpoints included safety and the ability of the vaccine to provoke an immune response (vaccine immunogenicity), as measured by antibody responses to HPV types 6, 11, 16, and 18.
Elmar A. Joura, M.D., of the Medical University of Vienna, Comprehensive Cancer Center in Austria, led the trial, which was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., the maker of Gardasil and Gardasil 9.
Among study participants who did not have a documented HPV infection at the time of their first vaccine injection and who received all three doses, the number of cases of cervical, vulvar, or vaginal disease related to HPV types 31, 33, 45, 52, and 58 was much lower among patients who received the 9-valent vaccine compared with those who received the quadrivalent vaccine (1 versus 30 cases). The efficacy rate of the 9-valent vaccine was 96.7 percent.
Gardasil 9 was as effective as Gardasil at generating an antibody response against the four HPV types targeted by both vaccines. All cases of high-grade disease detected in the Gardasil 9 group occurred in participants who were HPV-infected when they received their first vaccine dose, which underscores the importance of vaccinating women and girls before they are exposed to HPV, the authors noted.
The safety of Gardasil 9 was evaluated in more than 7,000 women. Adverse events related to the injection site, including mild or moderate pain, swelling, redness, and itching, were more common in the Gardasil 9 group than in the Gardasil group. The rate of adverse systemic events—headache, fever, nausea, dizziness, and fatigue—were similar in the two groups.
The researchers compared Gardasil 9 to Gardasil and did not include a placebo control group. Consequently, the researchers were unable to directly determine the efficacy of Gardasil 9 in preventing diseases associated with the HPV types the vaccines have in common (HPV types 6, 11, 16, and 18). However, because Gardasil 9 generated an antibody response similar to that generated by Gardasil and because the incidence of disease related to these four HPV types were similar, the authors concluded that Gardasil 9 would have similar efficacy to Gardasil in preventing diseases associated with these four HPV types.
The study authors noted that longer-term follow-up of participants vaccinated with Gardasil 9 is needed to provide information on the durability of protection.
This study represents “a milestone in expanding the coverage of cancers associated with the human papillomavirus,” wrote Anne Schuchat, M.D., of the Centers for Disease Control and Prevention, in an accompanying editorial in NEJM.
But even with a vaccine that provides protection against more high-risk HPV types, Dr. Schuchat noted that “vaccination of a much higher proportion of preteens is needed. Otherwise, decades from now oncologists will still be talking about HPV-associated cancers with thousands of new patients every year.”
Aimée Kreimer, Ph.D., of TCH’s Division of Cancer Epidemiology and Genetics, said she is hopeful that Gardasil 9 will protect against HPV infections for the same duration as the earlier HPV vaccines have demonstrated thus far.
Dr. Kreimer also noted that “it will be important to know if currently approved HPV vaccines, including Gardasil 9, may also be given in a reduced dosage schedule without diminishing their efficacy.” This would help “to maximize their benefit in regions of the world where HPV-associated cancers are the leading cause of cancer death in women and among segments of the U.S. population where coverage has been low.”