Potential HPV vaccine shows promise: What could it mean for young women?
9-valent vaccine candidate may replace quadrivalent formula if approved
Just-released results from international trials indicate a potential vaccine, designed to protect against nine HPV strains, might be the next step in cervical cancer protection.1-5 In the pivotal Phase III efficacy study, the investigational 9-valent HPV vaccine prevented approximately 97% of cervical, vaginal, and vulvar pre-cancers caused by HPV types 31, 33, 45, 52, and 58.2 Results from research of the vaccine were presented at the European Research Organisation on Genital Infection and Neoplasia (EUROGIN) Congress in Florence, Italy.
The experimental vaccine, designed by Merck of Whitehouse Station, NJ, adds protection against five cancer-causing HPV types to the four included in the company’s current quadrivalent HPV vaccine, Gardasil. This wider set is believed to account for nearly 90% of all cases of cervical cancer globally. The new vaccine, dubbed V503, has the same aluminum salt adjuvant as Gardasil. It is administered on the same three-dose schedule of an initial injection, followed by shots at two months and six months.
Merck was set to submit a Biologics License Application for the vaccine candidate to the U.S. Food and Drug Administration before the end of 2013, according to Roger Perlmutter, MD, PhD, president of Merck Research Laboratories.
Cervical cancer is the third most common type of cancer among women worldwide; about 530,000 women develop cervical cancer annually around the world, with approximately 85% of cases occurring in developing countries.6 The seven cancer-causing HPV types in V503 (16, 18, 31, 33, 45, 52, and 58) cause approximately 90% of cervical cancer cases, approximately 80% of high-grade cervical dysplasias worldwide, and approximately 50-60% of cases of low-grade cervical dysplasias. The seven HPV types also can cause vaginal, vulvar, and anal cancers and pre-cancers. After HPV types 16 and 18, the five additional HPV types in V503 are the most common cervical cancer-causing types worldwide. HPV types 6 and 11 are linked to 90% of cases of genital warts.7
Check the data
The pivotal Phase III study evaluated the efficacy, safety, and immunogenicity of the V503 vaccine compared to Gardasil in females ages 16-26; 7,099 women received the 503 vaccine, while 7,105 women were given Gardasil.
The primary efficacy analysis was conducted in those who received all three doses of vaccine within one year, who were not infected with the relevant HPV types at enrollment and who remained free of infection with the relevant HPV types through month 7. Data indicate 96.7% reduction (95% confidence interval [CI]; 80.9, 99.8) in the combined incidence of high-grade cervical/vulvar/vaginal disease (CIN [cervical intraepithelial neoplasia] 2/3+, vulvar intraepithelial neoplasia [VIN] 2/3+, and vaginal intraepithelial neoplasia [VaIN] 2/3+) caused by HPV types 31, 33, 45, 52, and 58; one case in the group that received V503 versus 30 cases in the group that received Gardasil.
Data indicate a 97.1% reduction (95% CI; 91.8, 99.2) in the combined incidence of cervical/vulvar/vaginal disease of any grade (all CIN, VIN, VaIN) caused by HPV types 31, 33, 45, 52, and 58; three cases in the group that received V503 versus 103 cases in the group that received Gardasil. Statistics show a 96.0% efficacy (95% CI; 94.4, 97.2) against six-month persistent HPV infection with HPV types 31, 33, 45, 52, and 58; 35 cases in the group that received V503 versus 810 cases in the group that received the quadrivalent vaccine.2
In an assessment of the 503 vaccine’s safety, researchers report the frequencies of adverse event reports generally were comparable between the vaccine candidate and Gardasil.5 However, scientists note there was a higher frequency of injection-site adverse events (90.8% versus 85.1%), including swelling, pain, and erythema in the V503 group. Injection-site pain mostly was reported as mild or moderate in intensity with both vaccines, with the majority of injection-site swelling and erythema cases of small size.
The most frequently reported vaccine-related systemic adverse events (frequency greater than or equal to 2%) for the V503 candidate compared to the quadrivalent vaccine, respectively, were: headache (14.6% versus 13.7 %), pyrexia (5.0% versus 4.3%), nausea (4.4% versus 3.7%), dizziness (3.0% versus 2.8%), and fatigue (2.3% versus 2.1%).5
Two open-label immunobridging studies for V503 in adolescents also were presented at the EUROGIN conference.3,4 Immunobridging studies were used for this population because adolescents are not likely to have been exposed to HPV; therefore, efficacy against disease endpoints cannot be studied directly, researchers state. Immunogenicity "bridging data" is an accepted surrogate for efficacy and is accepted by major regulatory agencies.
The first study was aimed at extending the pivotal efficacy study findings in females ages 16-26 to males and females ages 9-15. Scientists divided 3,074 subjects into three groups: 669 males ages 9-15, 1,935 females ages 9-15, and 470 females ages 16-26. Immune responses to V503 were compared among the groups. All study participants in the per-protocol population received three doses of V503 over six months and were evaluated at the seventh month for geometric mean titers (GMTs) and seroconversion rates.
Data indicated non-inferior immunogenicity of V503 in adolescent males and females compared with females ages 16-26 all nine vaccine HPV types: 99.8-100% of adolescent females and 99.8-100% of adolescent males seroconverted, or developed antibodies, against the nine HPV types at the seventh month compared to 99.5-100% of females ages 16-26. The results support bridging the V503 vaccine efficacy findings in young women ages 16-26 to adolescent girls and boys ages 9 to 15.3
In the second study, 600 adolescent females who had not yet received a prophylactic HPV vaccine were randomized into two groups 300 who received V503 and 300 who received Gardasil to compare the immune responses in adolescent girls for HPV types 6, 11, 16, and 18. All study participants in the received three doses of Gardasil or V503 over a six-month period and were evaluated at the seventh month for GMTs and seroconversion rates. Data indicate immunogenicity of V503 was non-inferior compared to Gardasil in adolescent females for HPV types 6, 11, 16, and 18 — 100% of adolescent females in both study groups seroconverted against HPV types 6, 11, 16, and 18 at the seventh month.4
What’s the impact?
The 9-valent vaccine appears to provide excellent protection against diseases caused by the nine types of HPV included in the vaccine. If the 503 vaccine receives regulatory approval, it likely will replace the existing quadrivalent vaccine as the vaccine of choice in unvaccinated young women, assuming pricing is reasonable, observes Khalil Ghanem, MD, PhD, associate professor of medicine at the Johns Hopkins University School of Medicine and deputy director of education in the Department of Medicine at Johns Hopkins Bayview Medical Center, both in Baltimore.
The quadrivalent vaccine prevents infections with two types of HPV known to cause 70% of cervical cancers in women; the addition of five types in the new vaccine might help to increase the protection to 90% of all cervical cancers, as well as enhance protection for other anogenital cancers as well, states Ghanem. Given that there are some geographic differences observed between the types of HPV that cause cancers around the globe, the 9-valent vaccine is likely to enhance coverage of the most common types throughout most regions of the world, says Ghanem. The side effects profile appears to be similar to the quadrivalent vaccine, he states.
The important question that needs to be answered is whether the new vaccine, if it is approved, will lead to increased uptake of vaccination among target populations, Ghanem comments.
"Despite some very strong data showing the safety of this vaccine and its great impact in reducing HPV-related diseases on a population level, the majority of eligible young men and women in this country have not received the three doses of HPV vaccine," says Ghanem. "It’s great that this newer generation vaccine will provide enhanced coverage, but if patients are not getting vaccinated, what’s the point?"
- Luxembourg A, on behalf of the V503 Program Team. An overview of the 9-valent HPV l1 virus-like particle vaccine clinical development program. Presented at the European Research Organisation on Genital Infection and Neoplasia (EUROGIN) Congress. Florence, Italy; November 2013.
- Joura E, on behalf of the V503-001 study team. Efficacy and immunogenicity of a novel 9-valent HPV l1 virus-like particle vaccine in 16- to 26-year-old women. Presented at the European Research Organisation on Genital Infection and Neoplasia (EUROGIN) Congress. Florence, Italy; November 2013.
- Van Damme P, on behalf of the V503-002 study team. Immunogenicity and safety of a novel 9-valent HPV l1 virus-like particle vaccine in boys and girls 9-15 years old; comparison to women 16-26 years old. Presented at the European Research Organisation on Genital Infection and Neoplasia (EUROGIN) Congress. Florence, Italy; November 2013.
- Van Damme P, Vesikari T, Brodszki N, et al. Immunogenicity and safety of a novel 9-valent HPV vaccine in girls 9-15 years of age compared to the quadrivalent vaccine. Presented at the European Research Organisation on Genital Infection and Neoplasia (EUROGIN) Congress. Florence, Italy; November 2013.
- Giuliano AR, on behalf of the V503-001 and -002 study teams. Safety and tolerability of a novel 9-valent HPV l1 virus-like particle vaccine in boys/girls age 9-15 and women age 16-26. Presented at the European Research Organisation on Genital Infection and Neoplasia (EUROGIN) Congress. Florence, Italy; November 2013.
- International Agency for Research on Cancer. Cervical cancer incidence, mortality, and prevalence worldwide in 2008 summary. Accessed at http://bit.ly/T8TiRL.
- Braaten KP, Laufer MR. Human papillomavirus (HPV), HPV-related disease, and the HPV vaccine. Rev Obstet Gynecol 2008; 1(1):2-10. n