ARCHIVED - Recommendations on a Human Papillomavirus Immunization Program

3. HPV vaccine characteristics

Two HPV vaccines have been tested in clinical studies: Gardasil^TM, by Merck Frosst, and Cervarix^TM, by GlaxoSmithKline. The quadrivalent vaccine Gardasil^TM, which contains HPV types 6, 11, 16 and 18, was authorized for sale in Canada for females between 9 and 26 years of age in 2006. The bivalent vaccine Cervarix^TM, which contains HPV types 16 and 18, has been submitted for approval. Cervarix^TM includes a new adjuvant, AS04, which contains monophosphoryl lipid A, derived from bacterial cell walls and alum.

Gardasil^TM and Cervarix^TM are subunit vaccines containing virus-like particles produced by recombinant technology. The vaccines cannot cause disease because they contain no live biologicals or DNA and are not infectious. They have been shown to be safe and generally well tolerated(11-14): in clinical trials, systemic adverse events such as headache or fatigue were reported by a similar proportion in the vaccine and placebo recipients⁽²⁾.

In clinical trials, the vaccines showed a remarkable 90%-100% efficacy against the development of high-grade cervical lesions associated with HPV 16 and 18 for periods of up to 5.5 years.

Immunogenicity data are available for women aged 9-26 and boys aged 9-15 vaccinated with Gardasil^TM and for women aged 10-45 vaccinated with Cervarix^TM(15-18). One month following the administration of the third dose, nearly all participants (= 99%) had developed antibodies against the types of HPV contained in the vaccines. The antibody levels after vaccination have been found to be 10-100 times higher than the levels produced by natural infection. Comparative studies have shown that the average anti-HPV geometric mean titres (GMTs) in preadolescents and adolescents aged 9-14 were twice those in women aged 15-25⁽¹⁶⁾. One month after the second dose of GardasilTM, GMTs against all virus types included in the vaccine in youths aged 10-15 were higher than the GMTs observed 1 month after the third dose in women aged 16-23⁽¹⁶⁾. The vaccine was well tolerated in both age groups.

The seroconversion rate 1 month after the second dose exceeded 97.5% for all types of HPV included in the vaccine⁽¹⁶⁾. Robust anti-HPV GMTs were observed at this time.

Efficacy data are not available for the 9-13 age group since most are not sexually active and pelvic examinations are not performed and that CIN does not develop at such a young age. However, immunogenicity results showing high antibody response in young girls would support no inferiority in protection as compared with older age groups.

A recent double-blind, placebo-controlled study examined the extent of immune memory in response to a primary vaccination series with a quadrivalent HPV vaccine. Serum anti-HPV levels declined after vaccination but reached a plateau at month 24 and remained stable through month 60. Administration of a challenge dose of vaccine induced a classic anamnestic response, with anti-HPV levels 1 week post-challenge reaching levels observed 1 month after completion of the three-dose primary series. At 1 month post-challenge, anti-HPV responses were higher than those observed 1 month after the third dose. The authors concluded that HPV vaccine induces high efficacy and stable anti-HPV levels for at least 5 years⁽¹⁹⁾.

The main criteria used in clinical trials to establish the efficacy of the vaccines were as follows:

• a reduction in the number of moderate and severe abnormalities (CIN 2/3) and adenocarcinoma in situ; and
• a reduction in the incidence of persistent infections with the types of virus included in the vaccine⁽²⁰⁾.

Cervical cancer has not been used as the primary criterion for measuring the efficacy of HPV vaccines in clinical trials because of the time it takes for the disease to develop and the need for appropriate clinical management of premalignant lesions to be provided immediately⁽²¹⁾.

Aside from the prevention of lesions caused by HPV 16 and 18, Cervarix^TM has been shown to be 35% to 60% effective in preventing infections caused by types 31 and 45, which are responsible for 8%-10% of cervical cancers^(15,22). Cross-protection data on Gardasil^TM are emerging. Gardasil^TM has also been shown to provide 99% protection against anogenital condylomas in women.

There is no evidence that women who have already been infected with one of the types contained in a vaccine will be protected against that type by vaccination. This is why it is preferable to vaccinate girls before the onset of sexual activity. Currently, there are no data on the efficacy of the vaccines in men or on the interchangeability of the two HPV vaccines.

Manufacturers currently recommend a schedule of three doses administered at 0, 2 and 6 months for Gardasil^TM or 0, 1 and 6 months for Cervarix^TM. A clinical trial was started in 2007 to determine the immunogenicity of a schedule of two doses of GardasilTM spaced 6 months apart in girls aged 9-13 compared with three doses given to young women aged 16-26. The study, involving 825 girls, is funded by the ministries of health of British Columbia, Quebec and Nova Scotia⁽²³⁾. A clinical trial is also planned to determine the immunogenicity of a two-dose schedule with Cervarix^TM.

HPV vaccines are safe and well tolerated. Clinical trials have found no increased number of serious adverse events in girls/women who received HPV vaccine compared with those who received placebo, and the types of serious adverse event reported were similar in the vaccine and placebo groups. There was no evidence that vaccination resulted in allergic reactions or other immune-mediated disease⁽²⁾. As of 30 June, 2007, 13 cases of possible Guillain-Barré syndrome (GBS) after vaccination with Gardasil^TM had been reported in the United States with distribution of more than 7 million doses. Expert review indicated that only two out of the 13 met the case definition of GBS. These two cases occurred within 6 weeks of vaccination with GardasilTM alone. Because GBS occurs at a rate of 1-2/100,000 person-years during the second decade of life, 13 reported cases of GBS are within the expected numbers⁽²⁴⁾.

Additional information on HPV vaccines can be found in the NACI Statement on Human Papillomavirus Vaccine⁽²⁾.