Comparing the HPV vaccines
HPVs are double-stranded DNA viruses that affect epithelial cells. More than 100 strains of HPV have been detected. Approximately 40 strains are known to infect genital mucosa, of which about 15 strains are known to cause cancer. HPV types 16 and 18 are the most common cancer-causing strains, leading to about 70% of all cervical cancer cases worldwide. HPV types 6 and 11 are associated with about 90% of all cases of genital warts.
According to the ACS, approximately 11,000 women were diagnosed with cervical cancer in the United States in 2009. That same year, cervical cancer resulted in approximately 4,000 deaths in the United States. Globally, due to the lack of access to screening programs and treatment for all women, cervical cancer is a much larger problem. Annually, cervical cancer affects 500,000 women worldwide and is responsible for more than 250,000 deaths. Cancers of the vulva, vagina, penis and anus, as well as a subset of head and neck cancers, are also associated with HPV infection.
Cervical intraepithelial neoplasia is an abnormality of the cervical epithelium associated with HPV infection and is thought to be a precursor to cervical cancer. CIN is classified into three grades: 1, 2, 3. With CIN-1, mild dysplasia is present and affects only the lowest third of the cervical epithelium; 70% to 90% of CIN-1 lesions undergo spontaneous regression. CIN-2 and CIN-3 show moderate to severe dysplasia and affect the lowest two-thirds to full thickness of the cervical epithelium, respectively.
More than half of CIN-2 and CIN-3 cases are estimated to persist or progress to squamous cell cancer. Persistent HPV infection may also lead to cervical adenocarcinoma in situ. In the United States, screening with the Pap test identifies these precancerous lesions and has led to a decrease in the rates of cervical cancer. These precancerous lesions may develop less than five years after HPV infection.
HPV infection is most frequently acquired through sexual contact. It is estimated that more than 80% of men and women in the United States will be infected with HPV at some point. Most infections occur shortly after initiating sexual activity. Most people with HPV infection will remain completely asymptomatic. Cervical cancer from persistent HPV infection can take 10 to 20 years to develop. Hence, the ability to vaccinate young girls before they become sexually active would lead to optimal prevention of cervical cancer.
In the United States, there are currently two approved vaccines for the prevention of HPV infection, Gardasil (recombinant HPV quadrivalent vaccine, Types 6, 11, 16, and 18; Merck) and Cervarix (recombinant HPV bivalent vaccine, Types 16 and 18; GlaxoSmithKline). Both vaccines are prepared from viral proteins but do not contain viral DNA. Therefore, neither vaccine can cause HPV infection. Both vaccines were designed for the prevention of HPV infection and do not treat existing HPV infection or disease. Because the development of cervical cancer may take longer than 10 years from the time of HPV infection, but precancerous lesions may be found sooner, many of the endpoints for clinical trials have been rates of CIN or adenocarcinoma in situ.
The quadrivalent vaccine was approved by the FDA in June 2006 for the prevention of the following HPV associated diseases in girls and women aged 9 to 26 years: cervical cancer caused by HPV types 16 and 18, genital warts caused by HPV types 6 and 11, and the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16 or 18 CIN-1-3, cervical adenocarcinoma in situ, vulvar intraepithelial neoplasia grade-2 and grade-3, vaginal intraepithelial neoplasia grade-2 and grade-3.
In September 2008, the quadrivalent vaccine was given the indication for prevention of vulvar and vaginal cancer in the same patient population. In October, the quadrivalent vaccine was further approved for the prevention of genital warts caused by HPV types 6 and 11 in boys and men aged 9 to 26 years. The quadrivalent vaccine includes amorphous aluminum hydroxyphosphate as an adjuvant. It contains no antibiotics, thimerosal or other preservatives. The quadrivalent vaccine is given as an intramuscular dose of 0.5 mL at zero, two and six months.
Efficacy of the quadrivalent vaccine was assessed in two phase-2 and three phase-3 double blind, randomized, controlled, international studies that included 24,596 individuals (20,541 females and 4,055 males). In a combined analysis of the two phase-2 studies and two phase-3 studies, the quadrivalent vaccine demonstrated efficacy of 98% for the prevention of CIN-2 or CIN-3 or adenocarcinoma in situ due to the HPV subtypes in the vaccine after three years follow-up in females who were HPV negative for the subtypes at baseline and had received all three doses of the vaccine.
In the phase-3 study conducted in males, the quadrivalent vaccine demonstrated efficacy of 86% in preventing persistent infection and 90% in preventing external lesions due to the HPV subtypes in the vaccine after three years follow-up in males who were HPV negative for the subtypes at baseline.
In October, the FDA approved the bivalent vaccine for use in the United States. The bivalent has been licensed and used outside the United States since 2007. Here, the approved indication is the prevention of the following diseases caused by HPV types 16 and 18: cervical cancer, CIN-1-3 and cervical adenocarcinoma in situ. The bivalent vaccine contains a unique ASO4 adjuvant system, a combination of aluminum hydroxide and monophosphoryl lipid A. It contains no antibiotics, thimerosal or other preservatives. The bivalent vaccine is given as an intramuscular dose of 0.5 mL at zero, one and six months.
Efficacy of the bivalent vaccine was assessed in one phase-2 and one phase-3 double blind, randomized, controlled, international studies that included 19,778 females. For the phase-3 study (n=18,644), the vaccine demonstrated efficacy of 93% in preventing CIN-2, CIN-3 or adenocarcinoma in situ due to the HPV subtypes in the vaccine after 35-month follow-up in females who were HPV negative for the subtypes at baseline and had received all three doses of the vaccine.
The phase-2 study has follow-up up to 6.4 years (mean of 5.9 years) in 776 patients. Efficacy for preventing CIN-2, CIN-3 or adenocarcinoma in situ caused by the HPV subtypes in the vaccine was 100%.
Both vaccines demonstrate the development of antibody response to the HPV types in virtually all patients. Antibody levels peak after the third dose of the quadrivalent vaccine, decline slowly, then level off by 24 months after the first dose. The bivalent vaccine appears to result in a higher level of antibodies over time compared with the quadrivalent vaccine. Duration of follow-up has been between five and 6.4 years, depending on the vaccine. The need for a booster shot is currently unknown.
Both vaccines caused mild and transient local reactions more commonly than the control groups. For the quadrivalent vaccine, the most common adverse events, besides injection site reactions, were headache, fever, nausea and dizziness. For the bivalent vaccine, fatigue, headache, myalgia, arthralgia and gastrointestinal symptoms were the most common adverse events. No serious systemic reactions thought to be caused by the vaccines were reported in the clinical trials or in subsequent postmarketing surveillance. Postvaccination syncope has been reported in adolescents. Therefore, patients should be observed for 15 minutes after the vaccination.
Both vaccines are intended to be given to females or males before they become sexually active. The CDCs Advisory Committee on Immunization Practices has recommended that the first dose be given to females aged 11 to 12 years and recommended the second and third doses at one to two months and six months after the first dose.
The quadrivalent is approved in females as young as age 9 and the bivalent vaccine is approved in females as young as age 10. Catch-up vaccination in older adolescent and young adult females (aged 13 to 26 years) is also recommended.
Males may be given the three-dose series of the quadrivalent vaccine between the ages of 9 and 26 years for the prevention of genital warts. Because the vaccines only protect against certain types of HPV infections and the duration of protection is unknown, routine Pap screening is still recommended for cervical cancer prevention in females.
Some key differences between the two vaccines exist.
The quadrivalent vaccine (Gardasil):
- Active against four HPV types: 6 and 11 (common cause of genital warts), 16 and 18 (common oncogenic types).
- Requires three doses at the following time points: zero, two and six months.
- Is approved for prevention of genital warts in males and females, and for prevention of vulvar and vaginal intraepithelial neoplasias.
- Has follow-up data up to five years in females and three years in males.
- Has clinical efficacy data in females older than age 26 years.
- May offer some cross-protection against other cancer-causing HPV types, including 31 and 45.
The bivalent vaccine (Ceravix):
- Active against two HPV types: 16 and 18.
- Requires three doses at the following time points: zero, two and six months.
- Has follow-up data up to 6.4 years.
- May offer some cross-protection against other cancer-causing HPV types, including 31, 33, 45, and 52.
- Contains a novel adjuvant that may be responsible for greater antibody response compared with the quadrivalent vaccine (clinical significance unknown).
The availability of vaccines against the most common HPV subtypes has the potential to dramatically decrease the burden of HPV infection and disease. The effect will be greatest in developing countries where HPV-associated diseases have a significant health burden, provided that vaccination is affordable and readily available. Because the vaccines do not protect against all types of HPV infection, the recommended screening for cervical cancer should continue until evidence in the HPV-vaccine era shows otherwise. As pointed out above, there are significant differences between the vaccines and they should not be considered interchangeable. Clinicians should help patients make informed choices based on the most current information and continue to stay informed as long-term and comparative data are released.
Deborah Blamble, PharmD, BCOP, is an Oncology Clinical Pharmacy Specialist at The University of Texas M.D. Anderson Cancer Center.
For more information:
- Dunne EF. Cancer. 2008;113:2995-3003.
- Kahn JA. N Engl J Med. 2009;361:271-278.
- World Health Organization (WHO). Biologicals. 2009;37:338-344.