GRADE was used to evaluate 9vHPV for routine vaccination of females and males aged 11 or 12 years as well as catch-up vaccination of females aged 13 through 26 years and males aged 13 through 21 years who were not vaccinated previously. Evidence of benefits, harms, values and preferences, and cost-effectiveness were reviewed in accordance with GRADE methods.

1 The policy questions were:

“Should 9vHPV be recommended for routine vaccination of 11 or 12 year olds?” and “Should 9vHPV be recommended for females aged 13 through 26 years and males aged 13 through 21 years who have not been vaccinated previously?” The benefits considered critical outcomes in GRADE were the prevention of cervical intraepithelial neoplasia grade 2 or 3, or adenocarcinoma in situ (≥CIN2), cervical cancer, definitive therapies, oropharyngeal cancer, vaginal/vulvar cancer, and anal cancer in females and anal cancer and oropharyngeal cancer in males (Table 1). Anogenital warts were considered an important outcome for both females and males. The evidence profile included the most prevalent HPV-attributable outcomes for females, ≥CIN2, cervical cancer and anogenital warts, and for males, anal cancer and anogenital warts. Evidence was not available for the critical outcome, oropharyngeal cancer, in females or males; definitive therapies, vaginal/vulvar cancer, and anal cancer in females were not included in the evidence profile for GRADE. Data used for the evidence review were from 9vHPV pre-licensure clinical trials as well as the efficacy trials from the quadrivalent HPV vaccine (4vHPV) program (Table 2). The pivotal efficacy trial for 9vHPV was conducted in females aged 16 through 26 years.2 This was a randomized trial comparing 9vHPV with 4vHPV conducted among approximately 14,000 females aged 16 through 26 years. This trial provided evidence for all policy questions including vaccination of females in the catch-up age group. Evidence used to evaluate efficacy of 9vHPV for prevention of HPV 31, 33, 45, 52, 58-related outcomes was directly from this trial. Evidence used to evaluate efficacy of 9vHPV for prevention of HPV 6, 11, 16, 18-related outcomes was from randomized controlled trials (RCT) of 4vHPV3 and from immunogenicity studies comparing 9vHPV with 4vHPV;4 these data were used to infer 9vHPV efficacy for HPV 6, 11, 16, 18-related outcomes. For HPV vaccination of females in the routine age group, evidence from two immunobridging trials was also used. One trial compared 9vHPV in females aged 9 through 15 years with females aged 16 through 26 years, and another trial compared 9vHPV with 4vHPV in females aged 9 through 15 years.4 Noninferior immunogenicity of 9vHPV compared with 4vHPV in females aged 9 through 15 years and 9vHPV in females aged 9 through 15 years compared with females aged 16 through 26 years was used to infer efficacy for prevention of HPV 6, 11, 16, 18, 31, 33, 45, 52, 58-related outcomes. For HPV vaccination of males, evidence used to evaluate efficacy of 9vHPV for prevention of HPV 6, 11, 16, 18-related outcomes was from one RCT of 4vHPV among approximately 4,000 males aged 16 through 26 years, which evaluated anogenital warts; anal precancer outcomes were evaluated in a subset of approximately 600;5,6 and an immunogenicity study comparing 9vHPV in males with females aged 16 through 26 years.4 Noninferior immunogenicity of 9vHPV in males compared with females was used to infer efficacy for prevention of HPV 6, 11, 16, 18-related outcomes. For HPV vaccination of males in the routine age group, evidence was also from an immunobridging trial, which showed noninferior immunogenicity of 9vHPV in males aged 9 through 15 years compared to females aged 16 through 26 years.4 These data were used to infer efficacy for prevention of HPV 6, 11, 16, 18-related outcomes. We also compared immunogenicity of 9vHPV in males aged 9 through 15 years with males aged 16 through 26 years. The critical harms considered were serious adverse events (SAE) and anaphylaxis. Safety of 9vHPV was evaluated based on 6 Phase III studies* in the clinical development program. Immunogenicity and efficacy evidence used was from analyses of the per protocol populations. For the efficacy trials, this included individuals who received all 3 vaccinations within one year of enrollment, did not have major deviations from the study protocol, were naïve (PCR negative and seronegative) to the relevant HPV type(s) prior to dose 1, and who remained PCR negative to the relevant HPV type(s) through one month post-dose 3 (Month 7).7 Evidence type for each considered outcome was derived through a review of study design, risk of bias, inconsistency, indirectness, imprecision, and other considerations.