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 |
44, 45 |
| 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% |
42, 43 |
| 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 |
46 |
| 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 |
49 |
| 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 |
47 |
| 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 |
48 |
| 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% |
49, 50 |
| 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 |
51 |
| 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 |
63 |
| 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 |
62 |
| 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 |
53 |
| 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%) |
54 |
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.