The New HPV Vaccine Preventing Cervical Cancer

By Susan J. Spencer, M.D.

Recent FDA approval of the human papillomavirus (HPV) vaccine has signaled a new era in reproductive medicine. The vaccine provides protection against four types of HPV, including two that cause approximately 70 percent of cervical cancers.

The American Cancer Society has estimated for 2006 that there will be 9700 new cases of invasive cervical cancer in the United States, with an estimated 3700 deaths caused by this disease. About half of all women diagnosed with cervical cancer are between 35 and 55 years old. Cervical Pap smear screening has led to a steady reduction in the incidence of cervical cancer over the last several decades. Cytologic recognition of cervical intraepithelial neoplasia (CIN) allows treatment of premalignant lesions before progression to invasive cancer. Unfortunately, CIN is common and affects many young women. Treatment of CIN with excision or conization procedures carries morbidity, including potential impact on future fertility. Reduction of HPV-related disease would be a tremendous improvement in women’s health.

What is the association of HPV and cervical cancer? The causative agent of cervical neoplasia remained elusive for decades. We now know that the vast majority of cervical precancers and nearly 100 percent of squamous carcinomas of the cervix are caused by HPV. Although annual cervical cancer rates are slowly declining in the United States, the data on the incidence of HPV are staggering. HPV is the most common sexually transmitted infection in the nation, with a prevalence estimated at 20 million cases (CDC, 2005). There is an 80 percent lifetime risk of acquisition of HPV. The peak incidence of HPV virus is the late teens and early ’20s and is correlated with sexual activity. In an immunocompetent female, HPV infection is usually transient. Most new infections are asymptomatic and clear naturally. However, based on virulence of the HPV type and host factors, HPV infection may persist and cervical, vaginal, and vulvar disease can occur.

There are approximately 100 types of HPV, including more than 30 that cause genital infections. Low-risk HPV types are associated with genital warts and mild CIN, a form of cervical dysplasia unlikely to progress to cancer. The high-risk HPV types are so-called because of their oncogenic potential in cervix and, less commonly, vulva and vagina. Precancers caused by high-risk HPV types are more likely to progress to invasive cancer. The recently approved HPV vaccine is Gardasil, manufactured by Merck. Gardasil is a quadrivalent vaccine that protects against four viral types: low-risk HPV types 6 and 11 and high-risk HPV types16 and 18. These four viral types account for 90 percent of genital warts and 70 percent of cervical cancers. The vaccine is preventative, meaning it causes antibody production that protects against infection with these four HPV types. The vaccine is not therapeutic, so pre-existing HPV infection is not cured.

Gardasil is the first HPV vaccine to win FDA approval, but a GlaxoSmithKline product, Cervarix, is forthcoming. Both vaccines are constructed using the L1 protein of the viral capsid. Recombinant production in a yeast vector system (Gardasil) or baculovirus vector (Cervarix) yields L1 protein spheres, which are highly immunogenic.1 The viral proteins induce type-specific neutralizing antibodies. The vaccine contains no DNA and no live virus, and therefore has no infectious potential. The FDA approved Gardasil for prevention of cervical cancer, cervical precancers (high-grade CIN and adenocarcinoma in situ), vulvar precancers, and vaginal precancers caused by HPV types 16 and 18. Gardasil is also approved for the prevention of genital warts and low-grade CIN caused by HPV types 6, 11, 16, and 18. The vaccine is given as an intramuscular injection at 0, 3, and 6 months (Gardasil) or 0, 1, and 6 months (Cervarix).

In protocol-adherent participants in phase 3 randomized controlled trials, Gardasil had 100 percent efficacy in preventing genital warts, mild CIN, and high-grade CIN or adenocarcinoma in situ associated with HPV types 6, 11, 16, and 18.2 Clinical trials of Cervarix have shown that a three-dose course of the vaccine was 92 percent effective against incident infection, 95 percent effective against persistent infection, and 93 percent effective in preventing cytologic abnormalities associated with HPV 16 and 18. 3 More than 98 percent seropositivity was maintained for HPV-16/-18 antibodies over 4.5 years of follow-up.4 Interestingly, although the vaccines target only two high-risk HPV types, there was evidence of cross protection, seen by reduction in incident infection by high-risk HPV types 41 and 45.4

It is important to note that the vaccines do not protect against all oncogenic HPV types, so routine Pap screening will still be required in vaccine recipients.

We always counsel patients about safe sex to reduce sexually transmitted infections. But how protective are condoms against acquisition of HPV? A recent study published in the New England Journal of Medicine examined male to female transmission of HPV in a cohort of university students over an eight-month period.5 Eighty-two female university students reporting their first intercourse with a male partner during the study period underwent cervical and vulvovaginal HPV DNA testing and Pap smears every four months. Testing included HPV types 6, 11, 16, and 18, which are the viral types targeted by the vaccine Gardasil. The incidence of genital HPV infection was 37.8 per 100 patient-years at risk for women whose partners used condoms consistently, compared with 89.3 per 100 patient-years for women whose partners used condoms less than 5 percent of the time. Although not a large study, the report yielded two important points. First, among newly sexually active women consistent condom use significantly reduced, but did not eliminate, the risk of HPV infection. Further, the magnitude of risk of HPV infection in condom nonusers was very high in this population. These observations serve to underscore the importance of a preventive HPV vaccine.

Parental attitudes regarding vaccinating their 11-year-old daughters to prevent a sexually transmitted infection will be important in determining the success of prevention of HPV-related disease in the United states. It may be difficult to acknowledge future sexual activity of

As with every promising advance in medicine, questions have emerged regarding the wisest use of the new vaccine. The current FDA approved candidates are females nine to 26 years of age. What is the optimal timing for administration of the HPV vaccine? For a preventive vaccine to work, it obviously has to be given prior to viral exposure; that is, prior to sexual debut. What information do we have about the age of onset of sexual activity in the United States? The statistics are sobering. The Center for Disease Control (CDC) annual "youth risk behavior surveillance summary" for 2005 reported that 46.8 percent of high school students had engaged in sex and that 37.2 percent had not used a condom with their last intercourse.6 Among kids under age 13 years, 3.7 percent of females and 8.8 percent of males reported having sex. Among 9th to 12th graders, 12 percent of females and 16.5 percent of males reported at least four sexual partners. One in four sexually active teens contract a sexually transmitted infection each year.

Additional compelling data echoing the need for early HPV vaccination come from the CDC HPV surveillance project. From 2003 to 2005, a multicenter trial examined the prevalence of high-risk HPV in more than 8,400 women in the United States, aged 14 to 65 years. The highest prevalence (at 33 percent) was in the 14-to-19-year age group.

The CDC’s Advisory Committee on Immunization Practices (ACIP) has recommended the HPV vaccine for all girls between 11 and 12 years of age and for women age 13 to 26 who have not yet received it. The 11-to-12-year age group is also the target age for tetanus, diphtheria, and pertussis vaccine and meningococcal vaccine, which could allow an opportunity for the HPV vaccine to be administered around the same time. According to the ACIP, girls as young as nine years old could be vaccinated, at the discretion of their physician. ACIP stated that Pap smear or HPV screening prior to vaccination are NOT necessary, and females with a history of abnormal Pap smears or genital warts should not be excluded.

Research is ongoing to determine the duration of protection by the HPV vaccines. The adjuvant in Gardasil and Cervarix is aluminum hydroxyphosphate. Based on previous alum-based vaccines, the duration of protection may be estimated at 7 to 10 years. If this estimate is accurate, then, if a girl is vaccinated at age 10, her immunity will be waning by age 19, which coincides with the age of peak incidence of HPV infection. Data available up to five years after vaccination indicate a high level of efficacy, about 96 percent.4 But by year 10, boosters may be needed. Are 20 year olds, who have outgrown the pediatrician’s office but haven’t yet met a gynecologist, likely to have access to a health care provider who can provide a needed HPV vaccine booster?

Parental attitudes regarding vaccinating their 11-year-old daughters to prevent a sexually transmitted infection will be extremely important in determining the success of prevention of HPV-related disease in the United States. It may be difficult to acknowledge future sexual activity of adolescents, but it should be emphasized that this is a cancer prevention vaccine. One potential concern for parents may be whether the vaccine might somehow encourage young people to be sexually active. However, this concern is not valid, according to researchers in adolescent medicine. For example, one study was conducted to examine whether providing emergency contraception to adolescents affected sexual behavior. The authors found no increase in sexual activity, unprotected coitus, or number of partners.7

In an effort to improve adolescent health care, the American College of Obstetrics & Gynecology recently lowered its recommended age for initial GYN visit to 13 to 15 years of age.8 The purpose of this first visit is to provide preventive services and education, and a pelvic exam would not be a usual component of that visit. However, parents and health care personnel need to start even earlier than this to discuss the vaccine, if HPV prevention is our goal.

What about males? What about them, I’m a gynecologist! Actually, because male Pap smear screening is not routine (penile cancer is rare in the United States) and the fact that HPV infection is usually asymptomatic, women rarely know whether their male partners carry HPV. Many young women stop using condoms with their new partners who have been screened for sexually transmitted infections because they falsely assume HPV has been checked for and excluded. HPV vaccination for men would reduce disease in women as well as anogenital disease in men. An efficacy study in males aged 16 to 26 is underway using the Gardasil vaccine; data are projected to be available in 2008.

All health care providers should be aware of the newly approved HPV vaccine and should be prepared to discuss it with patients and parents. We must educate patients that HPV is the most common sexually transmitted infection and that this infection does have oncogenic potential. The HPV vaccine is our new weapon in the fight against gynecologic cancers.

Dr. Spencer practices gynecology and reproductive endocrinology in San Mateo.