Gardasil 9 (Human Papillomavirus 9-valent Vaccine, Recombinant) - 7 indications

Scroll down for information on each indication:

• for use in females ages 9 through 26 and males ages 9 through 15 for the prevention of cervical, vulvar, vaginal and anal cancers and for use in females for the prevention of genital warts and precancerous or dysplastic lesions, approved December of 2014; subsequently approved for use males and females up to 45 years of age; October 2018
• for use in males 16 through 26 years of age for the prevention of anal cancer, precancerous or dysplastic lesions and genital warts; approved December 2015
• for males and females 9 to 45 years of age for the prevention of oropharyngeal and other head and neck cancers; approved June of 2020

General Information

The FDA originally approved Gardasil in June of 2006. However, the last doses of Gardasil expired on May 1, 2017 and it is no longer available for use in the United States. Gardasil has now been replaced by Gardasil 9 (human papillomavirus 9-valent vaccine, recombinant).

Gardasil 9 (Human Papillomavirus 9-valent Vaccine, Recombinant) is a non-infectious recombinant 9-valent vaccine against HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58.

Gardasil 9 is a vaccine indicated in girls and women 9 through 45 years of age for the prevention of the following diseases:

• Cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by Human Papillomavirus (HPV) types 16, 18, 31, 33, 45, 52, and 58.
• Genital warts (condyloma acuminata) caused by HPV types 6 and 11.   

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58:

• Cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical adenocarcinoma in situ (AIS).  
• Cervical intraepithelial neoplasia (CIN) grade 1.
• Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3.
• Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3.
• Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.

Gardasil 9 is indicated in boys and men 9 through 45 years of age for the prevention of the following diseases:  

• Anal, oropharyngeal and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58

• Genital warts (condyloma acuminata) caused by HPV types 6 and 11.

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58:     

• Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3

Gardasil 9 is indicated for males and females 9 to 45 years of age for the prevention of oropharyngeal and other head and neck cancers.

Gardasil 9 is supplied as a suspension for intramuscular injection. Each dose of Gardasil 9 is 0.5-mL. Administer Gardasil 9 as follows:

Age: 9 through 14 years

Regimen and Schedule:

• 2-dose Regimen: 0, 6 to 12 months*
• 3-dose Regimen: 0, 2, 6 months

*If the second dose is administered earlier than 5 months after the first dose, administer a third dose at least 4 months after the second dose.

Age: 15 through 45 years

Regimen and Schedule:

• 3-dose Regimen: 0, 2, 6 months

Mechanism of Action

Gardasil 9 (Human Papillomavirus 9-valent Vaccine, Recombinant) is a non-infectious recombinant 9-valent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58. HPV only infects human beings. Animal studies with analogous animal papillomaviruses suggest that the efficacy of L1 VLP vaccines may involve the development of humoral immune responses. Efficacy of Gardasil 9 against anogenital diseases related to the vaccine HPV types in human beings is thought to be mediated by humoral immune responses induced by the vaccine, although the exact mechanism of protection is unknown.

Side Effects

Adverse effects associated with the use of Gardasil 9 may include, but are not limited to, the following:

In girls and women 16 through 26 years of age:

• injection-site pain
• injection-site swelling
• injection-site erythema
• headache

In girls 9 through 15 years of age:

• injection-site pain
• injection-site swelling
• injection-site erythema
• headache

In women 27 through 45 years of age:

• injection-site pain
• injection-site swelling
• injection-site erythema
• headache

In boys and men 16 through 26 years of age:

• injection-site pain
• injection-site swelling
• injection-site erythema

In boys 9 through 15 years of age:

• injection-site pain
• injection-site swelling
• injection-site erythema

Indication 1 - girls and women 9 through 45 years of age for the prevention of Cervical, vulvar, vaginal and anal cancers caused by Human Papillomavirus (HPV) types 16, 18, 31, 33, 45, 52, and 58.

approved December 2014; October 2018

Indication 2 - girls and women 9 through 45 years of age for the prevention of genital warts (condyloma acuminata) caused by HPV types 6 and 11

approved December 2014; October 2018

Indication 3 - girls and women 9 through 45 years of age for the prevention of precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58

approved December 2014; October 2018

Clinical Trial Results for indications 1-3:

The FDA approval for Gardasil 9 was based on four clinical trials, which included two Phase II trials and two Phase III trials also known as FUTURE (Females United To Unilaterally Reduce Endo/Ectocervical Disease) I and II clinical trials. All four clinical studies were placebo-controlled, double-blind, randomized trials, which enrolled a total of 20,541 women between the age of 16 and 26. 

Results of the study demonstrated no new cases of HPV-16 or 18 related cervical intraepithelial neoplasia (CIN) 2/3 or adenocarcinoma in situ (AIS) were reported in patients treated with the full treatment regimen of Gardasil 9, while 53 cases were reported in the placebo group. Four new cases of HPV-6, 11, 16, or 18 related CIN or AIS were reported in Gardasil 9-administered patients, when compared to 83 for placebo, and one case of HPV-6, 11, 16, or 18 related genital warts in Gardasil 9-group, compared to 91 for placebo.

The efficacy of Gardasil 9 was also assessed in an active comparator-controlled, double-blind, randomized clinical trial (Study 1) conducted on girls and women between the age of 16 and 26. The study enrolled 14,204 women who were vaccinated without pre-screening for the presence of HPV infection. It compared clinical efficacy of Gardasil 9 and Gardasil for five additional HPV types. 

In clinical trials, Gardasil 9 demonstrated 96.7% efficacy against the combined incidence of cervical, vaginal and vulvar cancers caused by HPV types 31, 33, 45, 52 and 58. It showed 98.6% efficacy against CIN 1, 96.3% efficacy against CIN 2 / 3 or AIS, 93.8% efficacy against vulvar or vaginal disease, 96.2% efficacy against persistent HPV infection six months or longer. It also showed 96.1% efficacy against persistent HPV infection 12 months or longer, 92.6% efficacy against abnormal pap tests, 96.9% efficacy against biopsy, and 87.5% efficacy against definitive therapy, related to HPV types 31, 33, 45, 52 and 58. 

Indication 4 - boys and men 9 through 45 years of age for the prevention of anal cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58

approved December 2015; October 2018

Indication 5 - boys and men 9 through 45 years of age for the prevention of genital warts (condyloma acuminata) caused by HPV types 6 and 11

approved December 2015; October 2018

Indication 6 - boys and men 9 through 45 years of age for the prevention of anal intraepithelial neoplasia (AIN) grades 1, 2, and 3

approved December 2015; October 2018

Clinical Trial Results for indications 4, 5 and 6:

The efficacy of Gardasil was examined in a placebo-controlled, double-blind trial in 4,065 men ages 16–26 from 18 countries. The primary endpoint of the study was protection from HPV6, 11, 16 or 18-associated incident EGLs, defined as external genital warts (condylomata acuminata) or penile, perianal or perineal intraepithelial neoplasia (PIN) of any grade, or cancer at these sites. Protection against this combined endpoint was 90.4% in the according to protocol (ATP) population and 65.8% in the intent-to-treat (ITT) population. Of the EGLs, 28 of 31 and 72 of 77 were genital warts in the ATP and ITT cohorts, respectively, and most were associated with HPV6 or HPV11 infections. Significant protection against EGLs was also observed in both populations, irrespective of the HPV type in the lesion, reflecting the large proportion of genital warts caused by the vaccine types 6 and 11.

A subset of 602 men in the above trial who reported having sex with men was concurrently enrolled in a study of anal infection and anal intraepithelial neoplasia (AIN). After 3 years, Gardasil was 78.6% effective against HPV16/18 and 77.5% effective at preventing HPV6/11/16/18-related AIN of any grade in the ATP population. It was 54.9% effective for preventing AIN of any grade caused by any HPV type . Efficacy against AIN2+ for this population was 74.9%. An efficacy of 94.9% was observed against persistent infection by the vaccine-targeted types.

Indication 7 - males and females 9 to 45 years of age for the prevention of oropharyngeal and other head and neck cancers

approved June of 2020

Clinical Trial Results

The FDA granted this indication accelerated approval based on effectiveness in preventing HPV-related anogenital disease. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The FDA relied on effectiveness data used to support approval for prevention of HPV-related anogenital infection and disease as a surrogate to predict clinical benefit in prevention of HPV-related oropharyngeal infection and disease. It also used epidemiologic evidence to support that prevention of persistent oropharyngeal HPV infection is reasonably likely to predict prevention of HPV-related head and neck cancer.

A post-approval confirmatory study is underway to evaluate the safety and efficacy of Gardasil 9 vaccination for prevention of persistent oropharyngeal HPV infection. Analyses of the randomized, blinded, placebo-controlled trial will be driven by the number of oropharyngeal HPV-positive cases identified through polymerase chain reaction testing at six-month intervals. Once complete, the FDA will evaluate the study data to determine whether to grant traditional approval for this indication or remove the indication from the label.