Study review indicates human papillomavirus vaccine safe, well tolerated

December 2006

The newly licensed human papillomavirus vaccine from Merck is safe and well tolerated, according to a recent review during the 19th Annual Infectious Diseases in Children New York Symposium.

Larry K. Pickering, MD, senior advisor to the director of the National Center for Immunization and Respiratory Diseases of the CDC in Atlanta, discussed the HPV vaccine as part of a discussion on adolescent immunization during the symposium held last month.

Pickering said that “although breast cancer is by far the most common type of cancer in women throughout the world, in less economically developed countries of the world, cervical cancer is second.” The reason that cervical cancer is not second in women in the United States is because women have access to Pap smears, whereas women in developing countries do not, highlighting the need for vaccination options as an adjunct to routine Pap screening.

Provisional recommendations from the CDC’s Advisory Committee on Immunization Practices call for routine vaccination with three doses of quadrivalent HPV vaccine for girls aged 11 to 12 years old. The vaccination series can be started in girls as young as 9 years old. Catch-up vaccination is recommended for young women aged 13 to 26 years old who have not been vaccinated previously or who have not completed the full vaccine series. Ideally, vaccine should be administered before potential exposure to HPV through sexual contact.

The idea behind vaccinating girls aged 11 to 12 years old, Pickering said, is based on the need to immunize them before exposure to HPV. According to the Youth Risk Behavioral Survey, the percentage of high-school students who have had sexual intercourse by 9th grade is around 30%; that number jumps to near 60% by the time those students enter 12th grade.

Merck’s quadrivalent HPV (6/11/16/18) L1 virus-like particle vaccine (Gardasil) was licensed by the FDA in June 2006. According to Pickering, the vaccine is well tolerated among children and young adults 9 to 26 years of age, regardless of age, sex, race, ethnicity and country. The studies were performed in different countries and 90 different medical centers.

Pickering said the Merck vaccine has shown 95% to 100% efficacy in all studies. The effect of a second HPV vaccine (GlaxoSmithKline), which contains types 16 and 18, is in clinical trials. A study by Harper et al, published in Lancet (2006;367:1247-55), has shown sustained efficacy out to 4.5 years.

In that trial, some 800 women from the original clinical trial were included in the follow-up. Not only did the vaccine still appear strong after four years, the women encountered no other vaccine-related diseases, Harper and colleagues noted in their study. In other studies of HPV vaccines, the duration of effect was three years but participants are being monitored to determine duration of protection.

Not only is the vaccine showing sustained efficacy, a study published in Pediatrics last month, by Stan Block, MD, an editorial board member of Infectious Diseases in Children, noted after three doses, more than 99% of women aged 16 to 23 had good immune responses. That study also evaluated boys 10 to 15 years of age, and noted “by month 7, seroconversion rates after three doses administered at birth, 1 month and 6 months were 99% or higher for all four human papillomavirus types in each group. By month 7, anti-human papillomavirus geometric mean titers in girls or boys were noninferior and were 1.7- to 2.7-fold higher than titers in adult women who also had been immunized.” The researchers also noted that most injection-site adverse events were mild to moderate in intensity. They wrote, “Significantly more boys (13.8%) and girls (12.8%) than women (7.3%) reported fevers 37.8°C or higher within five days of vaccination. Most (96.4%) fevers were mild (<39°C).”

However, Block, who also spoke at the symposium, noted that cost as well as the need for additional data in boys has been an issue in getting this population vaccinated as well. “We’re having trouble finding the funds to get our girls vaccinated at this point,” he said.

Vaccine efficacy

The FDA based its approval of the Merck vaccine on four studies of more than 21,000 women 16 to 26 years of age. Results from the studies showed the vaccine was nearly 100% effective in preventing precancerous cervical lesions, precancerous vaginal and vulvar lesions and genital warts caused by the HPV types contained in the vaccine.

Researchers also performed two studies to measure the immune response to the vaccine among girls 9 years to 15 years of age. Their immune response was comparable to the response among women 16 to 26 years of age. Researchers evaluated safety in a study of about 11,000 participants.

Merck agreed to further study the vaccine post-licensure, including general safety and long-term effectiveness. Merck will continue studies to evaluate the vaccine in men and to study the pregnancy outcomes of women who receive Gardasil while unknowingly pregnant.

GlaxoSmithKline expects to file for FDA approval of its candidate HPV vaccine containing types 16 and 18 L1 virus-like particle vaccine with adjuvant AS04 against HPV (Cervarix) before the year’s end, company officials have said.

That vaccine is being evaluated in phase-3 clinical trials that involve more than 30,000 women worldwide. Results from studies so far have demonstrated the vaccine has 100% efficacy.

Disease

HPV is the most common sexually transmitted infection in the United States. The CDC estimates that genital HPV infects about 6.2 million Americans every year, and more than half of all sexually active men and women become infected at some time in their lives.

On average, there are 9,710 new cases of cervical cancer and 3,700 deaths attributed to HPV in the United States each year. Cervical cancer is the second most common cancer in women worldwide; each year it is estimated to cause more than 470,000 new cases worldwide and 233,000 deaths.

For more information:

• Pickering LK. Adolescent immunizations: Many dilemmas. Presented at: 19th Annual Infectious Diseases in Children New York Symposium. Nov. 18-19. New York.
• Schiller JT. Development of virus-like particles for immunization against human papillomavirus. Presented at: 2006 Pediatric Academic Societies’ Annual Meeting. April 29-May 2, 2006. San Francisco.