Gardasil 9 joins the fight against cervix cancer

Abstract

A trial of 14,215 women aged between 16 and 26 years comparing a new vaccine with nine human papilloma virus types – four from the licensed Gardasil vaccine (types 6, 11,16 and 18) and five new ones (types 31, 33, 45, 52 and 58) to Gardasil – has shown improved protection against cervical cancer precursor lesions. Antibody response for the four original Gardasil types was not inferior and a 96.3% reduction in high-grade cervical disease for the other five types not in Gardasil was seen in the per-protocol population. Six-month persistent infection was reduced by 96% for these types. There were no serious safety concerns, although injection site reactions were more common with the new vaccine.

Keywords:

• 9-valent vaccine
• cervical disease
• Gardasil
• human papilloma virus
• vaccination

Methods

In a recent report [1], results from a trial of 14,215 women aged 16 to 26 years randomised between three doses of either Gardasil (n = 7109) or the new nine-valent vaccine (n = 7106) were presented. Doses were given as 0.5 ml intramuscular injections at entry and 2 and 6 months subsequently. Women were eligible if they had no history of an abnormal Pap smear, no previous abnormal cervical biopsy and no more than four lifetime sexual partners. Gardasil was given as licensed, but in addition to the virus like particles (VLPs) for the five new types, the VLP amounts for type 16 were increased from 40 to 60 µg and from 20 to 40 µg for human papilloma virus (HPV) 18. In addition, the adjuvant (amorphous aluminum hydroxy phosphate sulfate) was more than doubled from 225 to 500 µg. Follow-up was 6 monthly up to 54 months and ThinPrep samples were collected for cytology and HPV typing for types 6, 11, 16, 18, 33, 35, 39, 45, 51, 52, 56, 58 and 59 by PCR. Women with abnormal cytology were referred for colposcopy, and a biopsy was taken if needed. Persistent infection was defined as detection of the same HPV type on swabs or biopsies on two consecutive occasions at least 6 months apart. Immunogenicity was evaluated on a 7-month serum sample in the per protocol population. Median follow-up was in excess of 42 months. The primary efficacy endpoint was the incidence of high grade cervical, vulvar and vaginal precursor lesions associated with the five new types in Gardasil 9 in the per protocol population of women who received all three doses within 1 year of entry, and were not seropositive at entry or PCR positive for the initial 7 months for the type of interest. A modified intention-to-treat (ITT) analysis was also conducted, which included all randomized patients who received at least one vaccine dose and one efficacy follow-up measurement.

Results

In the per protocol analysis, high-grade cervical, vulvar and vaginal lesions associated with HPV 31, 33, 45, 52 and 58 were reduced from 30 cases in the Gardasil arm to one case in the Gardasil 9 arm, a 96.6% reduction (95% CI: 97.5–99.8%). Cases of high-grade lesions associated with HPV 6, 11, 16 or 18 were reduced from three (Gardasil) to one. Thus, if given before infection, both vaccines offer virtually 100% protection against these types [2]. Persistent infections of duration 6 months or longer related to HPV 31, 33, 45, 52 or 58 were reduced by 96.0% (95% CI: 94.4–97.2%) from 810 to 35 cases (52.4 vs 2.1 cases per 1000 women-years of follow-up). A non-significant 26.4% (95% CI: 4.3–47.5%) reduction in persistent infection due to HPV 6, 11, 16 or 18 was also seen.

In the modified ITT analysis, no reduction in high-grade disease was seen overall. This was essentially due to women who were infected at entry. There were 314 cases in the Gardasil 9 arm and 298 cases in the Gardasil arm. However, if this analysis is restricted to women not infected on day one, a significant 42% (95% CI 7.9–65.9%) reduction for disease related to all HPV types was seen. This reflects the benefit of reduced infection from the five extra types in Gardasil 9, suggesting that an added protection of 42% above that was achieved by Gardasil, although multiple lesions due vaccine and non-vaccine types may reduce this slightly. There was no added cross-protection against non-vaccine types and the number of high-grade lesions from these types was similar in the two arms (26 [Gardasil 9] versus 33 [Gardasil]).

Immunogenicity was very strong with virtually 100% seroconversion of all per protocol patients within 1 month of the third dose. Geometric mean titers were similar between Gardasil 9 and Gardasil for the four types in common and 50-fold higher for each of the five new types.

Expert commentary

There is little doubt that Gardasil 9 represents an important advance over Gardasil. Instead of having to rely on cross-protection to control disease from the five new types, virtually 100% direct protection can now be expected against these types as well as the four types in Gardasil. Altogether the nine types in the vaccine account for about 90% of cervical cancer, so a virtual elimination of this disease in vaccinated women is likely. Similarly high rates of reduction of cervical intraepithelial neoplasia grade 3 (CIN3) have been reported for Cervarix due to cross-protection [3] but these may have been too high by chance as lower reductions in persistent infection were seen [3], and protection may not be as durable as that achievable by direct protection. Indications are that the vaccine will only be slightly more expensive than Gardasil and should replace it in the very near future. A two-dose regimen has largely replaced the three-dose schedule for both Gardasil and Cervarix for girls under the age of 16 years, and it will be important to establish if the same schedule will be effective for Gardasil 9. Efficacy in this age group will necessarily have to be based on antibody titers, and ongoing studies should provide the needed data in the very near future. In will be many decades still before we have any indication of the impact of this or other HPV vaccines on other HPV-related cancers, such as those occurring in the anus, penis, oropharynx and base of tongue [4,5]

It is unlikely that Gardasil, Gardasil 9 or Cervarix will provide much protection against the remaining high-risk HPV types not in any of these vaccines (types 35, 51, 56, 59 and 66). However, these can be considered more as intermediate risk types [6] and may play a lesser role in cancer than in high-grade CIN precursor lesions, so the protection against cervical cancer with Gardasil 9 will be of the order of 90%. At this level of protection, the role of screening in vaccinated women will need to be re-examined, and possibly can be reduced to three tests in a lifetime [7] at, say ages 30, 40 and 60 years, but this will need to be verified in large studies using an HPV screening test.

While high coverage of adolescents and young women must be the primary focus, another important area is to determine if the use of Gardasil 9 in older women – potentially up to age 45 or 50, as part of a screen and vaccinate program will be effective. As none of the vaccines currently available provide protection against an existing infection, a key issue will be the protection against types not yet seen, and the potential for boosting response to types associated with a previous infection that has now been cleared. Clearly, this needs to be done in conjunction with HPV-based screening to ensure that any disease associated with a current infection is treated. However, if effective, such an approach could substantially hasten the impact of vaccination on cervical cancer incidence.

Five-year view

A key issue will be the ability to obtain high coverage. This will depend on the type of organization of the health service, and different approaches will be needed in different countries. Probably only two doses will be required, separated by 6–24 months, but this still needs to be demonstrated and may not be so clear if women aged 16 or older are also vaccinated. Vaccinated women will not need to be screened so often, but challenges will remain to accurately identify those who have been vaccinated, as this will occur > 15 years prior to the need for screening. Vaccination of women as part of screening up to the age of 45–50 years promises to more quickly virtually eliminate cervical cancer, but effective means for delivering vaccines within screening programs remain a challenge.

Key issues

• Gardasil 9 offers 90% expected protection against cervical cancer.

• Virtually 100% protection against persistent infection for the nine types in the vaccine.

• Substantial added protection above Gardasil.

• Slightly more injection site inflammation but no other adverse effects.

• May be appropriate to screen and vaccinate older women from age 26–50 years (but not yet proven).

• Approved for three-dose regimen for girls aged 16–26 years in the USA. Approval elsewhere expected soon.

• Data on two-dose regimens awaited.

Financial & competing interest’s disclosure

J Cuzick is an employee of Queen Mary University of London; this institution has received research reagents from Hologic, Roche, Qiagen, Abbott and Becton Dickinson. J Cuzick has received honoraria for serving on the advisory boards or consulting for Merck, GSK, Hologic, Cepheid and Trovagene. He has been paid for conference travel from Merck and Cepheid. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.