Recombinant human papillomavirus nonavalent vaccine in the prevention of cancers caused by human papillomavirus

Figures & data

Figure 1 Timeline of pivotal Phase III HPV vaccine trials and licensure/registration of the HPV vaccines.

Notes: ^aTwo-dose schedule separated by six months to adolescents aged <15 years. ^bData from Iversen et al.⁵⁷

Abbreviations: 4vHPV, quadrivalent HPV vaccine; 2vHPV, bivalent HPV vaccine; 9vHPV, nonavalent HPV vaccine; FDA, The U.S. Food and Drug Administration; HPV, human papillomavirus; EU, European Union; VLP, virus-like particle.

Figure 2 Countries that have introduced a national human papillomavirus immunization program using any of the three licensed vaccines (91 countries, 47%).

Source: Data from WHO.⁸⁵

Table 1 Characteristics of HPV VLP vaccines

Manufacturer	Merck™ (Gardasil^®)	GlaxoSmithKline™ (Cervarix^®)	Merck™ (Gardasil^® 9)
L1 VLP types	6, 11, 16, and 18	16 and 18	6, 11, 16, 18, 31, 33, 45, 52, and 58
Dose	20/40/40/20 µg	20/20 µg	30/40/60/40/20/20/20/20/20 µg
Producer cells	Saccharomyces cerevisiae (baker’s yeast) expressing L1	Trichoplusia ni (Hi 5) insect cell line infected with L1 recombinant baculovirus	Saccharomyces cerevisiae (baker’s yeast) expressing L1
Adjuvant	225 µg aluminium hydroxyphosphate sulfate	500 µg aluminium hydroxide, 50 µg 3-O-deacylated-4ʹ-monophosphoryl lipid A	500 µg aluminium hydroxyphosphate sulfate
Vaccination schedule	0, 2, and 6 months	0, 1, and 6 months	0, 2, and 6 months

Abbreviations: HPV, human papillomavirus; VLP, virus-like particle.

Table 2 Studies reporting efficacy of 9vHPV against HPV infection and associated diseases

Type of study	Primary endpoint	Number of participants and age	Study findings	References
Subgroup analyses of two Phase III RCTs	Efficacy, immunogenicity, and safety in Asian participants	Study 001: N=1717 (women, 16–26 years) Study 002: N=608 (boys and girls)	Per-protocol 9vHPV efficacy against HPV31, 33, 45, 52, and 58: Any grade cervical, vulva, and vaginal diseases: 100% (95% CI, 40.0–100) ≥6 months persistent infection: 95.8% (95% CI, 87.8–98.9) ≥12 months persistent infection: 93.9% (95% CI, 81.4–98.4)	^Citation44
Subgroup analyses of two Phase III RCTs	Efficacy, immunogenicity, and safety in Latin American participants	Study 001: N=4744 (women, 16–26 years) Study 002: N=568 (boys and girls)	Per-protocol 9vHPV efficacy against HPV31, 33, 45, 52, and 58 (Study 001): Any grade cervical, vulva, and vaginal diseases: 96.9% (95% CI, 89.2–99.5) ≥6 months persistent infection: 95.2% (95% CI, 92.7–97.0)	^Citation45
Phase III double-blind RCT	Vaccine efficacy against incidence of high-grade CIN, AIS, ICC, VIN, VaIN, and vaginal/vulva cancer related to HPV31, 33, 45, 52, and 58	N=14,215 (16–26 years) Follow up to 42 months for both groups, N=13,587; up to 60 months for 9vHPV group	Per-protocol 9vHPV efficacy against HPV31, 33, 45, 52, and 58: Any high-grade diseases: 96.7% (95% CI, 80.9–99.8) CIN and AIS: 96.3% (95% CI, 79.5–99.8) ≥6 months persistent infection: 96.0% (95% CI, 94.4–97.2) Per-protocol 9vHPV efficacy against HPV31, 33, 45, 52, and 58, 6 years post dose one: Any high-grade diseases: 97.4% (95% CI, 85.0–99.9) CIN and AIS: 98.2% (95% CI, 93.7–99.7) 12 months persistent infection: 96.7% (95% CI, 95.1–97.9) Similar incidence of CIN, VIN, ValN, and persistent infection related to HPV6, 11, 16, and 18 between 4vHPV and 9vHPV	^Citation42, ^Citation43

Abbreviations: 4vHPV, quadrivalent HPV vaccine; 9vHPV, nonavalent HPV vaccine; AIS, adenocarcinoma in situ; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; ICC, invasive cervical carcinoma; RCT, randomized controlled trial; VaIN, vaginal intraepithelial neoplasia; VIN, vulvar intraepithelial neoplasia.

Table 3 Studies reporting immunogenicity and reactogenicity of 9vHPV

Type of study	Immunogenicity endpoint	Study findings	References
Subgroup analyses of Asian and Latin American participants from two Phase III RCTs	Non-inferior GMTs for anti-4vHPV types in girls/boys aged 9–15 years and young women aged 16–26 years at month seven	Immunogenicity: >98% of girls, boys, and young women seroconverted for each 9vHPV type GMTs for anti-HPV6/11/16/18 at month seven were generally similar between the qHPV vaccine and 9vHPV vaccine groups for Asian participants, while for Latin American participants, GMTs for HPV types 6 and 16 were similar in both vaccine groups; GMT for HPV11 was lower in the 9vHPV vaccine group than in the qHPV vaccine group and GMT for HPV18 was higher in the 9vHPV vaccine group than in the qHPV vaccine group Month seven GMTs in girls and boys were higher than those in young women for all 9vHPV types for both populations For Latin America participants, >90% of girls/boys remained seropositive at month 36 for all 9vHPV types; no follow-up data for Asian participants Reactogenicity: For both Phase III studies, injection-site AEs were 62.4–89.6% and 77.7–83.1% for 9vHPV and 4vHPV, respectively; most common were injection-site pain, swelling, and erythema, which were mild to moderate in intensity For Asian population, vaccine-related systemic AEs (9vHPV, 4.3–18.8%; 4vHPV, 6.3–13.9%) were lower than in the overall study population (9vHPV, 21.1–29.5%; 4vHPV, 27.3%), except for Thailand (9vHPV, 26.4–42.2%; 4vHPV, 40.3%) which were higher due to higher incidence of pyrexia; no participants experienced vaccine-related serious AEs For Latin American population, vaccine-related systemic AEs were 27.2–37.5% and 29.3% for 9vHPV and 4vHPV, respectively; most were headache and pyrexia; three participants experienced vaccine-related serious AEs, which were found to be due to previous medical history; they fully recovered following treatment	^Citation44, ^Citation45
Phase III double-blind-RCT	Immunogenicity in young women aged 16–26 years at month seven	Immunogenicity: 99.6–100% seroconverted to all 9vHPV types at month seven ^aNon-inferior antibody responses for HPV6, 11, 16, and 18 when compared with 4vHPV at month seven (GMT ratio 0.8–1.19 depending on types) 77.5–100% remained seropositive at month 60 ^aNon-inferior antibody responses for HPV6, 11, 16, and 18 persist to 42 months (GMT ratio 0.80–1.26 type dependent) Reactogenicity: AEs related to injection site higher in 9vHPV than 4vHPV group (90.7% and 84.9%, respectively); most were injection-site pain Systemic AEs (headache, pyrexia, nausea, dizziness, and fatigue) are similar in both groups (55.8% and 54.9% in 9vHPV and 4vHPV, respectively). Discontinuation due to serious AE: <0.1%	^Citation42, ^Citation43
Phase III, open-label, safety and immunogenicity study	Immunogenicity, safety, and tolerability of 9vHPV to HPV types 6/11/16/18/31/33/45/52/58 in girls aged 9–15 years at month seven	Immunogenicity: 100% of participants seroconverted to 9vHPV types at month seven, and maintained for two years GMTs in girls aged 9–15 years were comparable to girls of the same age group in the V503-002 study, and at least two-fold higher than those observed in Japanese women aged 6–26 years (from V503-001) Reactogenicity: Most common injection-site AE was pain at the site of injection (93%), followed by swelling (42%) and erythema (33%) Vaccine-related systemic AEs were 14.0%; most common was pyrexia (3%). No serious AEs, deaths, or discontinuation due to an AE	^Citation46
Prospective cohort study	Persistence of HPV antibody response and immune memory at five years post 9vHPV vaccination in girls aged 9–15 years	Immunogenicity: Seropositivity rates to 9vHPV types at month 60 range from 77.5% to 100% Significant increase in GMT to all 9vHPV types at one week and one month post dose four, which were 1.25–4.10- and 1.65–4.88-fold higher, respectively, than levels observed at month seven Seropositivity rates were >99% and 100% at one week and one month post dose four, respectively Reactogenicity: A higher proportion of participants reported injection-site AEs after dose four (84.0%) than after doses one, two, or three (70.7%, 69.3%, 67.3%, respectively); most common were pain, swelling, erythema; mild to moderate in intensity Most common vaccine-related systemic AE after dose four was headache (6.7%) No participants experienced vaccine-related serious AEs following fourth dose of 9vHPV	^Citation49
Phase III, double-blind RCT	Non-inferior GMTs for anti-4vHPV types in the 9vHPV group compared with the 4vHPV group at month seven in men aged 16–26 years	^bGMTs to HPV 6/11/16/18 elicited by 9vHPV were non-inferior to those elicited by the qHPV vaccine Anti-9vHPV GMTs were higher in the younger age group (16–17 years) than the older age group (18–26 years) Anti-HPV 31/33/45/52/58 GMTs were greater by at least two-fold and up to 15-fold in 9vHPV group compared with 4vHPV group at month 7 100% seroconversion for HPV31, 33, 45, 52, and 58 in 9vHPV group Reactogenicity: One or more vaccine-related AEs and systemic AEs were similar between 9vHPV (81.5%, 23.0%, respectively) and 4vHPV (79.0%, 21.0%, respectively) No participants experienced vaccine-related serious AEs	^Citation47
Phase III double-blind RCT	Non-inferior GMTs for HPV16 and 18 antibody response between 9vHPV and 4vHPV in young girls aged 9–15 years at month seven	Immunogenicity: ^aNon-inferior antibody GMTs to HPV 6/11/16/18 induced by 9vHPV when compared with 4vHPV post dose three Robust anti-HPV 31/33/45/52/58 GMTs post dose three were elicited by 9vHPV (one- to two-fold higher than 4vHPV) Higher antibody responses to 9vHPV vaccine types in younger girls (age 9–12 years) compared with older girls (age 13–15 years) Reactogenicity: Injection-site AEs are 93.3% and 90.3% for 9vHPV and 4vHPV, respectively; most were injection-site pain Vaccine-related systemic AEs were 20.7% and 24.3% for 9vHPV and qHPV vaccine, respectively; most common vaccine-related systemic AEs were headache, pyrexia, and nausea No participants experienced vaccine-related serious AEs	^Citation48
Non-inferiority and immunogenicity substudies	(1) Non-inferiority of month seven GMTs in girls and boys versus young women (2) Immunogenicity of the lot consistency for 27 pairs of tests of equivalence for three manufacturing lots to nine HPV types at month seven in girls aged 9-15 years	Immunogencity: (1) ^aNon-inferior antibody GMT responses in girls and boys compared with young women; month seven GMTs in girls and boys were higher than those in young women for all 9vHPV types; >90% of girls/boys remained seropositive at month 36 for all 9vHPV types (2) 99.6% of participants seroconverted by month seven to all nineHPV type GMT responses in groups who received the three vaccine lots were equivalent at month seven (lower bound of two-sided 95% CI of GMT ratio for each of three pairs of lots (lot 1 vs lot 2, lot 1 vs lot 3, and lot 2 vs lot 3) for all nine vaccine types was within the interval (0.5, 2.0)) Reactogenicity: Injection-site AEs and vaccine-related systemic AEs were lower among girls (81.9% and 20.9%, respectively) and boys (72.8% and 21.8%, respectively) than among young women (85.4% and 26.0%, respectively) Most AEs were mild to moderate in intensity (ie, pain, swelling, erythema, and pruritus) Discontinuation due to vaccine-related serious AE <0.2%	^Citation49, ^Citation50
Phase II studies, immunogenicity and safety of multivalent HPV VLP vaccine dose formulation	Immunogenicity of seven vaccine candidates in comparison to 4vHPV in three Phase II studies in girls aged 16–26 years ^cStudy 1: 8vHPV vs 4vHPV ^cStudy 2: 9vHPV vs 4vHPV Study 3: 5vHPV and 4vHPV vs 4vHPV	Immunogenicity: Study 1: non-inferior antibody response between 8vHPV and 4vHPV, but lower GMTs for HPV types 6/11/16/18 in the 8vHPV recipients compared with the 4vHPV recipients Study 2: mid- and high-dose 9vHPV have similar and non-inferior antibody response for HPV types 6/11/16/18 as 4vHPV Study 3: non-inferior antibody response between 5vHPV and 4vHPV, but lower GMTs for HPV types 6/11/16/18 in the 5vHPV and 4vHPV recipients compared with the 4vHPV recipients Reactogenicity: Study 1: injection-site AEs were more common in girls who received 8vHPV (95.8–98.2%) or 9vHPV (92.4–92.8%) than 4vHPV (90.3–91.7%) Similar vaccine-related systemic AEs between vaccination groups for all three studies (Study 1: 50.6–55.0%; Study 2: 29.2–33.5%; Study 3: 23.8–25.6%) Serious AEs and discontinuations due to AE were rare (0–1.2% and 0–0.6%, respectively) No participants experienced serious vaccine-related AEs	^Citation51
Phase III, open-label, randomized, immunogenicity study	Safety and non-inferior antibody response to the 9vHPV types administered with Menactra and Adacel vaccines in girls and boys aged 11–15 years at month seven	Immunogenicity: Similar and non-inferior anti-GMT between Groups A and B (fold difference range: 0.97–1.1) Seroconversion rates were 100% for all HPV types in both groups Non-inferiority antibody response for all four Neisseria meningitidis serogroups (Menactra) and diphtheria and tetanus (Adacel) Reactogenicity: Injection-site AEs were 46.7–80.9% and 46.5–80.4% for Group A and B, respectively; most were mild to moderate in intensity Vaccine-related systemic AEs were 16.1–43.1% and 15.0–42.4% for Group A and B, respectively Higher proportion in Group A reported swelling (14.4%) following 9vHPV compared with Group B (9.4%), although not statistically significant No participants experienced vaccine-related serious AEs	^Citation63
Phase III, open-label, randomized, immunogenicity and safety study	Safety and non-inferior antibody response to the 9vHPV types administered concomitantly (Group A) and nonconcomitantly (Group B) with Tdap-IPV 4 weeks postdose in girls and boys aged 11–15 years at month seven	Immunogenicity: Anti-HPV GMTs against all HPV types were lower in Group A but non-inferior to Group B, with fold differences (ie, Group A/Group B) ranging from 0.89 to 0.97 Seroconversion rates were ≥99.8% for all HPV types in both groups Non-inferiority antibody response for diphtheria, tetanus, and all three poliovirus types Reactogenicity: Injection-site AEs were 60.7–93.9% and 60.2–90.1% for Group A and B, respectively; most were mild to moderate in intensity Vaccine-related systemic AEs were 19.2–48.6% and 18.0–48.6% for Group A and B, respectively Higher proportion of participants in Group A reported erythema (8.2%) and swelling (13.0%) at the 9vHPV injection site compared with Group B (5.7% and 8.2%); as well as for Tdap-IPV vaccination, erythema (26.9%) and swelling (39.4%) in Group A compared with Group B (21.7% and 31.3%, respectively) No participants experienced vaccine-related serious AEs	^Citation62
Phase III, randomized, double-blind, controlled, immunogenicity study	Non-inferior GMTs for anti-9vHPV types between young men and young women aged 16–26 years at month seven	Immunogenicity: >99% in all three groups seroconverted to all 9vHPV types GMTs to all 9vHPV types were higher in HM than those in women or MSM at month seven ^aNon-inferior antibody GMTs between HM and young women (range 1.09–1.27) Reactogenicity: Proportion of participants who reported at least one injection-site or systemic AE were lower among young men (67.6% and 16.0% respectively) than among young women (84.1% and 23.4%); most common for injection-site AEs were pain, swelling, erythema, and pruritus; most were mild to moderate in intensity. Most common vaccine-related systemic AEs among young men were headache (7.3%) and pyrexia (2.4%) No participants experienced vaccine-related serious AEs	^Citation53
Double-blind, placebo-controlled, safety and immunogenicity study	Comparison of immunogenicity to HPV types 31/33/45/52/58 in girls and women aged 12–26 years who previously received three doses of 4vHPV following three doses of 9vHPV or placebo	>98% seroconverted for each 9vHPV type in the 9vHPV group Significant increase in GMTs for HPV types 31/33/45/52/58 following one dose, and increased further following doses two and three in the 9vHPV group Compared to HPV vaccination-naïve women (from another study): (1) month seven GMTs for HPV 6/11/16/18 were numerically higher in prior 4vHPV recipients (2) month seven GMTs for HPV 31/33/45/52/58 were generally numerically lower in prior 4vHPV recipients Reactogenicity: Injection-site AEs more common in 9vHPV vaccine group (91.1%) compared with saline placebo group (43.9%); most common were pain, swelling, erythema, pruritus, and hematoma; mild to moderate in intensity Most common vaccine-related systemic AEs in the 9vHPV group (30.6%) were headache (19.6%), pyrexia (5.1%), nausea (3.9%), and dizziness (3%) Discontinuations from study vaccination as a result of an AE were rare (0.5%) Incidence of serious vaccine-related AEs was low (0.5%)	^Citation54

Notes: ^aNon-inferiority criterion: the lower bound of the two-sided 95% CI of the GMT ratio (9vHPV:4vHPV) was >0.67. ^bNon-inferiority criterion: the lower bound of the two-sided 95% CI for the GMT ratio (9vHPV: 4vHPV) was ⩾0.5. ^cThree-dose formulation: low, mid, and high.

Abbreviations: 4vHPV, quadrivalent HPV vaccine; 5vHPV, pentavalent HPV vaccine; 8vHPV, octavalent HPV vaccine; 9vHPV, nonavalent HPV vaccine; AE, adverse events; GMT, geometric mean titer; HPV, human papillomavirus; MSM, men who have sex with men; RCT, randomized controlled trial; Tdap-IPV, diphtheria, tetanus, pertussis, and poliomyelitis vaccines.

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