HPV vaccine efficacy remains high according to results 2.4 years later

New Mexico passed legislation requiring vaccination for sixth-grade girls; more states are introducing legislation

Issue: June 1, 2007

ATLANTA - The benefits of the quadrivalent human papillomavirus vaccine become more apparent over time, according to updated efficacy data.

The vaccine reduces overall risk of cervical, vulvar and vaginal cancer, genital warts and cervical lesions in girls and women, according to Eliav Barr, program head of HPV vaccines at Merck. Researchers also noted reductions in Pap test abnormalities and cervical procedures.

In addition, the HPV vaccine (Gardasil, Merck), demonstrated encouraging results against nonvaccine HPV types, according to preliminary data, said Barr. In June 2006, the CDC Advisory Committee on Immunization Practices (ACIP) recommended administration of the vaccine in girls and women aged 9 to 25.

Barr presented updated information on Gardasil at the Meeting of the Advisory Committee on Immunization Practices.

Updated efficacy data

Among HPV-naive women, efficacy remained high during follow-up. At licensure in 2005, efficacy was 100% for cervical intraepithelial neoplasia (CIN) 2/3 or adenocarcinoma in situ, and the researchers found 99% efficacy during follow-up 2.4 years later. For vulvar intraepithelial neoplasia 2/3 or vaginal intraepithelial neoplasia 2/3, efficacy was 100% in 2005 and at follow-up, according to Barr.

Barr presented updated data on a population that included women regardless of HPV status in a study and did not exclude those who were already infected to determine the vaccine's overall effects on the population. In 2005, 117 women in the vaccine group had CIN 2/3 or adenocarcinoma in situ compared with 178 women in the placebo group (34% efficacy). Based on updated data, women in the vaccine group (n=137) were less likely to have HPV 16/18-related CIN 2/3 or adenocarcinoma in situ compared with women in the placebo group (n=137, 41% efficacy), according to Barr.

The researchers found eight cases of vulvar intraepithelial neoplasia 2/3 or vaginal intraepithelial neoplasia 2/3 in women in the vaccine group at licensure in 2005 compared with 26 cases in the placebo group (69% efficacy). The updated data reflect greater efficacy in the vaccine group, which had nine total cases, compared with the placebo group, which had 31 new cases (71% efficacy).

The cumulative incidence of time to HPV 16/18-related CIN 2/3 or adenocarcinoma in situ is comparable, but then risk diverges, according to Barr. The researchers noticed a flattening of the line in the vaccine group, although risk still increased in the placebo group.

"What we see is the effect of the vaccine becomes more and more apparent over time," Barr said.

The incidence of HPV 6/11/16/18-related cervical, vulvar and vaginal disease was better among women who received the vaccine, as well, Barr said.

In 2005, there were 170 women with any grade of CIN or adenocarcinoma in situ in the vaccine group compared with 317 in the placebo group (46% efficacy). Updated data show 192 cases among women in the vaccine group compared with 414 cases in the placebo group (54% efficacy). The researchers found 68 cases of vulvar and vaginal lesions, including genital warts, in the vaccine group compared with 229 cases in the placebo group (70% efficacy); cases increased to 72 in the vaccine group compared with 319 in the placebo group (78% efficacy).

Barr concluded that prophylactic administration of the HPV vaccine is highly effective in reducing cervical, vulvar and vaginal cancer associated with HPV 6/11/16/18, CIN or adenocarcinoma in situ associated with HPV 16/18 and external genital lesions associated with HPV 6/11/16/18. According to previously presented data, women had long-lived immune memory and high efficacy through year five following vaccine administration.

Although evaluation is ongoing, two analyses provided encouraging results that the vaccine also affects nonvaccine HPV types, Barr said.

The combined clinical analysis of studies 013 and 015 have been encouraging, and the vaccine appears to affect cervical, vulvar and vaginal disease due to nonvaccine HPV types. Researchers conducted a substudy of 013 that analyzes persistent infection efficacy, and was needed to confirm the findings from the combined clinical analysis. Data from these analyses should be available later in the year.

Possible risks

The ACIP recommended the HPV vaccine at the June 2006 meeting, when the Vaccines for Children Fund resolution was also adopted, said Lauri Markowitz, MD, an epidemiologist at the CDC. In October 2006, the Vaccines for Children Fund established a federal contract for the vaccine; the contract price is $96.76 per dose. As of Dec. 31, 2006, the manufacturer distributed 2.1 million doses of vaccine, and public sector funds purchased about 40% of the doses, according to Markowitz.

The Vaccine Adverse Event Reporting System received 542 reports of adverse events, and about 5% of the reports were serious. The system received no reports of mortality. Most of the reports occurred in adolescents aged 13 to 18 (47%) and women aged 19 to 26 (38%). The most common events reported were injection site pain (18%), dizziness (11%), syncope (11%), fever (9%) and nausea (9%), Markowitz said.

Among the syncope cases, the reporting system received three reports of nose fractures and one skull fracture following a seizure. The ACIP HPV vaccine statement includes a precaution regarding syncope and suggests monitoring patients for 15 minutes following vaccination, Markowitz said.

The system received three reports of Guillain-Barré Syndrome postvaccination, two of which occurred in girls who also received meningococcal conjugate vaccine (MCV4; Menactra, Sanofi Pasteur), and three cases of facial palsy. Markowitz said they would continue to monitor for Guillain-Barré Syndrome. The expected rate of facial palsy is higher than that of Guillain-Barré Syndrome, she said, and is 30 cases per 100,000 people per year. The observed rate was much lower than expected. Monitoring Guillain-Barré Syndrome and facial palsy will continue.

Monitoring the impact of the HPV vaccine will include a variety of data sources. Monitoring cancers associated with HPV will continue through cancer registries. Systems are being established to monitor cervical cancer precursor lesions and HPV infection, according to Markowitz.

The ACIP HPV vaccine work group intends to continue to review data on current and future vaccines, HPV epidemiology and cost effectiveness. The work group will develop recommendations for the bivalent HPV vaccine (Cervarix, GlaxoSmithKline) if licensed by the FDA. GLaxoSmithKline applied for licensure in late March. The ACIP will revise its statement as needed, Markowitz said.

Markowitz and colleagues prepared recommendations for the vaccine, which were available in the March 12 issue Morbidity and Mortality Weekly Report and on the National Immunization Program's Web site (www.cdc.gov/nip/recs/provisional_recs/default.htm).

The Association of Immunization Managers issued a statement regarding school immunization mandates, Markowitz said. The statement said that school and child care immunization requirements must be approached cautiously and used sparingly, and considered after an appropriate implementation period. The association states that Insurance coverage, sufficient funding, physician support, public acceptance, adequate supply and safety data are necessary elements to support a school requirement, Markowitz said.

Future studies

Merck is also studying the vaccine's efficacy in women aged 24 to 45 and men aged 16 to 26, as well as in India, Peru and Vietnam. Initial data from the study in adult women will be available later this year; the data from the studies involving men will be available in 2008 and 2009; and data from the study in India, Peru and Vietnam will be available between 2008 and 2010, Barr said.

Researchers will analyze efficacy in people of all ages who had solid organ and bone transplants and men and women of all ages who have HIV in studies that will begin this year.

State mandates

In related news, New Mexico recently passed legislation requiring HPV vaccination of girls in the sixth grade. Texas became the first state to require the vaccine for sixth-grade girls, according to Gov. Rick Perry's mandate, but the legislature rejected the mandate. More than 18 states have introduced legislation requiring HPV vaccination, Markowitz said.

In Virginia, Gov. Tim Kaine indicated that he still supports vaccination for girls. His proposed budget provides more available funding for lower-income families wishing to receive immunization. If he signs the HPV legislation into law, immunization would be required in fall 2008.

Massachusetts Gov. Deval Patrick increased immunization funding by $24.8 million in his 2008 budget proposal to increase finding for newly recommended vaccines, including the HPV vaccine for girls aged 9 to 18, rotavirus vaccine for infants (RotaTeq, Merck) and MCV4. Patrick's budget proposal would provide $61.6 million for Massachusetts' Universal Immunization Program.

The increased funding will provide 72,126 girls aged 9 to 18 with the HPV vaccine, which is recommended but strictly voluntary, according to the governor's office. The funding will also provide 71,334 infants with rotavirus vaccine and 108,188 children with MCV4 vaccine.

In Florida, Rep. Anitere Flores, chairwoman of the House K-12 Committee, killed bill HB 561, which would require vaccination of sixth-grade girls by the fall of 2011, before it could reach the House for a vote. Rep. Edward Homan, MD, assistant professor of orthopedic surgery at the University of South Florida Medical School in Tampa, sponsored the bill. – by Lauren Riley

This article also appeared in Infectious Disease in Children, a SLACK Incorporated publication.

For more information:

Barr E. Updated efficacy data. Presented at: The Meeting of the Advisory Committee on Immunization Practices; Feb. 21-22, 2007; Atlanta.

Markowitz L. Quadrivalent human papillomavirus (HPV) update. Presented at: The Meeting of the Advisory Committee on Immunization Practices; Feb. 21-22, 2007; Atlanta.

CDC. Quadrivalent human papillomavirus vaccine recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2007:56(early release);1-24.

Visit the Association of Immunization Managers' website for more information on the statement on school immunization mandates at www.immunizationmanagers.org/pdfs/SchoolrequirementsFINAL.pdf.