MenQuadfi Mechanism of Action

Pharmacotherapeutic group: meningococcal vaccines. ATC code: J07AH08.
Pharmacology: Pharmacodynamics: Mechanism of action: Anti-capsular meningococcal antibodies protect against meningococcal diseases via complement mediated bactericidal activity.
MenQuadfi induces the production of bactericidal antibodies specific to the capsular polysaccharides of Neisseria meningitidis serogroups A, C, W, and Y.
Immunogenicity: The immunogenicity of a single dose of MenQuadfi for primary vaccination in toddlers (12-23 months of age), children and adolescents (2-17 years of age), adults (18-55 years of age) and older adults (56 years and above) was assessed in six pivotal studies and in two additional studies in toddlers (12-23 months of age ) and children and adolescents (10-17 years of age). The immunogenicity of a single dose of MenQuadfi when used as a booster vaccination was assessed in one pivotal study (subjects 15-55 years of age) and in four additional studies: two in children 3 years and 5 years after primary vaccination as toddlers 12 through 23 months of age, one in adolescents and adults 3-6 years after primary vaccination, and one in older adults 3, 5 and 6-7 years after primary vaccination at ≥56 years of age. In addition, clinical data on the persistence of antibody response from at least 3 years and up to 7 years after primary vaccination with MenQuadfi are available in these additional studies.
Primary immunogenicity analyses were conducted by measuring serum bactericidal activity (SBA) using human serum as the source of exogenous complement (hSBA). Rabbit complement (rSBA) data are available in subsets in all age groups and generally follows the trends observed with human complement (hSBA) data. In addition, all subjects were assessed for primary immunogenicity measured by hSBA and rSBA for serogroup C in MEQ00065 study [NCT03890367].
Immunogenicity in toddlers 12 to 23 month of age: Immunogenicity in subjects 12 through 23 months of age was evaluated in three clinical studies (MET51 [NCT02955797], MET57 [NCT03205371] and MEQ00065 [NCT03890367]).
MET51 was conducted in subjects who were either meningococcal vaccine naïve or had been primed with monovalent meningococcal C conjugate vaccines in their first year of life (see Table 1).

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Response in subjects previously vaccinated with MenC conjugate vaccines in their first year of life: The majority of monovalent meningococcal C conjugate vaccine primed toddlers (12 through 23 months of age) in study MET51 (NCT02955797) had hSBA titres ≥1:8 in the MenQuadfi group (N=198) (≥ 86.7%) and in MenACWY-TT group (N=99) (≥ 85.7%) at D30 post-vaccination. These toddlers received during their infancy MenC-TT or MenC-CRM vaccines. Post-vaccination seroprotection rates were comparable between MenQuadfi and MenACWY-TT for all serogroups regardless of the priming background.
In MenC-CRM primed subjects the GMTs for serogroup A were lower in the MenQuadfi group (N=49) than in the MenACWY-TT group (N=25) [12.0 (8.23; 17.5) vs 42.2 (25.9; 68.8)]. After administration of MenQuadfi seroprotection rates (hSBA titres ≥1:8) for subjects primed with MenC-CRM were lower but still comparable for serogroups A and W compared with those in the MenACWY-TT group [A: 68.8% (53.7; 81.3) vs 96.0% (79.6; 99.9); W: 68.1% (52.9; 80.9) vs 79.2% (57.8; 92.9)]. The rates for serogroup Y were higher but still comparable with those in the MenACWY-TT group [95.8% (85.7; 99.5) vs 80.0% (59.3; 93.2)]. The rates for serogroup C were comparable in both groups [95.7% (85.5; 99.5) vs 92.0% (74.0; 99.0)]. The clinical relevance of these results is unknown. This aspect might be considered for individuals at high risk for MenA infection who received MenC-CRM vaccine in their first year of life.
MET57 (NCT03205371) was conducted in meningococcal vaccine naïve toddlers 12 through 23 months of age to assess the immunogenicity of the concomitant administration of MenQuadfi with paediatric vaccines (MMR+V, DTaP-IPV-HB-Hib or PCV-13). Overall, the post-vaccination hSBA seroprotection rates in subjects who received MenQuadfi was high for all serogroups (between 88.9% and 100%). Seroresponse and seroprotection rates for serogroup A were comparable when MenQuadfi was co-administered with PCV-13 and alone (56.1%, [95% CI 48.9; 63.2] and 83.7% [95% CI 77.7; 88.6] vs 71.9% [95%CI 61.8; 80.6] and 90.6% [95%CI 82.9; 95.6]). There were differences in the hSBA GMTs for serogroup A when MenQuadfi was co-administered with PCV-13 (N=196) compared with MenQuadfi administered alone (N=96) (24.6 [95%CI 20.2; 30.1] and 49.0 [95%CI 36.8; 65.3]).) The clinical relevance of these results is unknown but this observation might be taken into consideration for individuals at high risk for MenA infection and consequently vaccinations with MenQuadfi and PCV13 might be performed separately.
MEQ00065 (NCT03890367) study was conducted in meningococcal vaccine naïve toddlers 12 through 23 months of age to assess the immunogenicity of serogroup C using hSBA and rSBA assays following administration of a single dose of MenQuadfi compared to MenACWY-TT or to MenC-TT.
Superiority of MenQuadfi was demonstrated in comparison to MenACWY-TT vaccine for the hSBA seroprotection rate and hSBA and rSBA GMTs to meningococcal serogroup C. Non-inferiority was demonstrated for the rSBA seroprotection rate to meningococcal serogroup C.
Superiority of MenQuadfi was also demonstrated in comparison to MenC-TT vaccine for the rSBA and hSBA GMTs to meningococcal serogroup C and non-inferiority was demonstrated for the rSBA and hSBA seroprotection rates to meningococcal serogroup C (see Table 2).

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Immunogenicity in children 2 through 9 years of age: Immunogenicity in subjects 2 through 9 years of age was evaluated in study MET35 (NCT03077438) (stratified by ages 2 through 5 and 6 through 9 years) comparing seroresponses following administration of either MenQuadfi or MenACWY-CRM.
Overall, for subjects 2 through 9 years of age, immune non-inferiority, based on hSBA seroresponse, was demonstrated for MenQuadfi as compared to MenACWY-CRM for all four serogroups. (See Table 3.)

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Immunogenicity in children and adolescents 10 through 17 years of age: Immunogenicity in subjects aged 10 through 17 years of age was evaluated in three studies comparing seroresponses following administration of MenQuadfi compared to either MenACWY-CRM (MET50 [NCT02199691]) or MenACWY-DT (MET43[NCT02842853]) or comparing seroprotection following administration of MenQuadfi compared to MenACWY-TT (MEQ00071) [NCT04490018]).
MET50 was conducted in meningococcal vaccine naïve subjects and seroresponse was evaluated following administration with either MenQuadfi alone, MenACWY-CRM alone, MenQuadfi co-administered with Tdap and 4vHPV or Tdap and 4vHPV alone. (See Table 4.)

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Study MET43 was performed to evaluate the immunogenicity of MenQuadfi compared to MenACWY-DT in children, adolescents and adults (10 through 55 years of age). (See Table 5.)

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MEQ00071 was conducted in subjects who were either meningococcal vaccine naïve or had been primed with MenC vaccines before two years of age. Seroprotection was evaluated 30 days following administration with either MenQuadfi alone, MenACWY-TT alone, or MenQuadfi co-administrated with Tdap-IPV and 9vHPV. (See Table 6.)

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In an exploratory analysis in a non-random subset of participants (N=60), the immune response and protection rates were measured 6 and 30 days following co-administration of MenQuadfi with Tdap-IPV and 9vHPV. The proportion of subjects with seroprotection for serogroup A did not increase within 6 days, whereas most of the subjects had seroprotection against serogroups C, W and Y (>94%). After 30 days, protection rates in this subset were comparable to the full study population reported in Table 6.
Response in subjects according to MenC vaccination status: The immunogenicity of serogroup C following administration of a single dose of MenQuadfi compared to a single dose of MenACWY-TT was assessed in both meningococcal vaccine naïve and MenC primed (before two years of age) subjects (MEQ00071). Overall, the post vaccination seroresponse and hSBA GMTs against serogroup C were higher in meningococcal vaccine naive subjects who received MenQuadfi than those who received MenACWY-TT, with seroprotection rates also trending higher. No differences in antibody response were observed in MenC primed subjects between groups.
Immunogenicity in adults 18 through 55 years of age: Immunogenicity in subjects from 18 through 55 years of age was evaluated in study MET43 (NCT02842853) comparing MenQuadfi to MenACWY-DT. (See Table 7.)

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Immunogenicity in adults 56 years of age and older: Immunogenicity in adults ≥ 56 years of age (mean 67.1 years, range 56.0 - 97.2 years) was assessed in study MET49 (NCT02842866) comparing the immunogenicity of MenQuadfi to MenACWY polysaccharide vaccine. (See Table 8.)

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Persistence of immune response and MenQuadfi booster response: Antibody persistence following primary vaccination in toddlers, adolescents and young adults, and older adults was assessed from at least 3 years and up to 7 years after primary vaccination. The immunogenicity of a MenQuadfi booster dose was also assessed.
Persistence of immune response and MenQuadfi booster response in children 4 through 5 years of age: MET62 (NCT03476135) evaluated the antibody persistence of a primary dose, immunogenicity and safety of a booster dose of MenQuadfi in children 4 through 5 years of age. These children were primed with a single dose of MenQuadfi or MenACWY-TT 3 years before as part of the phase II study MET54 when they were 12 through 23 months old. The antibody persistence prior to the MenQuadfi booster dose and the booster immune response were assessed according to the vaccine (MenQuadfi or MenACWY-TT) children had received 3 years ago (see Table 9).
For all serogroups, hSBA GMTs were higher at D30 post-primary dose than at 3 years (3Y) post-primary dose (D0 pre-booster) for MenQuadfi or MenACWY-TT. The 3Y post-primary (D0 pre-booster) GMTs were higher than the pre-primary GMTs, indicative of long-term persistence of immune response.
After the booster dose, seroprotection rates were nearly 100% for all serogroups in children primed with MenQuadfi. (See Table 9.)

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Persistence of immune response and MenQuadfi booster response in children 6 through 7 years of age: MEQ00073 (NCT04936685) evaluated the antibody persistence of a primary dose, immunogenicity and safety of a booster dose of MenQuadfi in children 6 through 7 years of age who had previously received a primary dose of MenQuadfi 5 years earlier as part of study MET51 when they were 12 through 23 months of age (see Table 10).
For all serogroups, the 5Y post-primary (pre-booster) GMTs were higher than the pre-primary GMTs, indicative of persistence of immune response.
After the booster dose, seroprotection rates were nearly 100% for all serogroups in children primed with MenQuadfi (98.9%, 97.7%, 100%, and 100% for serogroups A, C, W, and Y, respectively). (See Table 10.)

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Response in subjects according to MenC vaccination status before priming with MenQuadfi in MET51: The antibody responses against serogroup C following administration of a booster dose of MenQuadfi were comparable regardless of MenC vaccination status during their first year of life before priming with MenQuadfi 5 years earlier in MET51.
Persistence of immune response and MenQuadfi booster response in adolescents and adults 13 through 26 years of age: MET59 (NCT04084769) evaluated the antibody persistence of a primary dose, immunogenicity and safety of a booster dose of MenQuadfi in adolescents and adults 13 through 26 years of age who had received a single dose of MenQuadfi in study MET50 or MET43 or MenACWY-CRM in study MET50 or outside of Sanofi Pasteur trials 3-6 years prior. The antibody persistence prior to the MenQuadfi booster dose and the booster immune response were assessed according to the vaccine (MenQuadfi or MenACWY-CRM) subjects had received 3-6 years previously (see Table 11).
For all serogroups, hSBA GMTs were higher at D30 post-primary dose than at 3-6 Years (3-6Y) post-primary dose (D0 pre-booster) for MenQuadfi and MenACWY-CRM primed subjects. The 3-6Y post-primary dose (D0 pre-booster) GMTs were higher than the pre-primary GMTs, indicative of long-term persistence of immune response.
After the booster dose, seroprotection rates were nearly 100% for all serogroups in adolescents and adults primed with MenQuadfi. (See Table 11.)

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Persistence of immune response and MenQuadfi booster response in adults 59 years of age and older: MEQ00066 (NCT04142242) evaluated the antibody persistence of a primary dose, immunogenicity, and safety of a booster dose of MenQuadfi in adults ≥59 years of age who had received a single dose of MenQuadfi or MenACWY-PS ≥3 years previously in study MET49 or MET44.
3 year persistence: The antibody persistence prior to the MenQuadfi booster dose and the booster immune response were assessed according to the vaccine (MenQuadfi or MenACWY-PS) subjects had received 3 years previously in MET49 (Table 12).
For all serogroups, hSBA GMTs were higher at D30 post-primary dose than at 3 Year (3Y) post-primary dose (D0 pre-booster) for both MenQuadfi-primed and MenACWY-PS-primed adults. In addition, for both primed groups, the 3 Year (3Y) post-primary dose (pre-booster) GMTs were higher than the pre-primary GMTs for serogroups C, W and Y (indicative of long-term persistence of immune response for these serogroups) and were comparable for serogroup A. (See Table 12.)

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5 years persistence: A subset of subjects (N=52) who were assessed for antibody persistence at 3 years and did not receive the booster dose were re-assessed for antibody persistence at 5 years at which time they received a booster dose of MenQuadfi. In MenQuadfi-primed subjects, hSBA GMTs for serogroups C, W and Y 5Y post-primary dose trended higher than the pre-priming GMTs (and were comparable for serogroup A). Following the MenQuadfi booster dose, seroprotection rates were 100% for serogroups A, C, and Y, and 95.0% for serogroup W in subjects primed with MenQuadfi and 87.5%, 62.5%, 87.5% and 68.8% for serogroups A, C, W and Y, respectively, for those primed with MenACWY-PS. Additionally, hSBA GMTs were higher and seroresponse rates were higher or trended higher for all serogroups in subjects primed with MenQuadfi compared to those primed with MenACWY-PS.
6-7 year persistence: The antibody persistence was assessed according to the vaccine (MenQuadfi or MenACWY-PS) subjects had received 6-7 years previously in study MET44 (Table 11).
For all serogroups, hSBA GMTs were higher at D30 post-primary dose than at 6-7 Year (6-7Y) post-primary dose for MenQuadfi-primed adults. The 6-7Y post-primary GMTs were higher than the pre-primary GMTs for serogroup C, W, and Y in MenQuadfi-primed adults, indicative of long-term persistence of immune response for these serogroups, and were comparable for serogroup A. (See Table 13.)

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Booster response in adolescents and adults at least 15 years of age primed with other MenACWY vaccines: Study MET56 (NCT02752906) compared the immunogenicity of a booster dose of MenQuadfi with a booster dose of MenACWY-DT in subjects at least 15 years of age. These subjects were primed with a quadrivalent meningococcal conjugate vaccine (MenACWY-CRM (11.3%) or with MenACWY-DT (86.3%)) 4 to 10 years earlier.
At baseline, hSBA seroprotection and GMT were similar for serogroups A, C, W, and Y. (See Table 14.)

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Pharmacokinetics: No pharmacokinetic studies have been performed.
Toxicology: Preclinical safety data: Non-clinical safety data revealed no special risks for humans based on a developmental and reproductive toxicity study in female rabbits.
The administration of MenQuadfi to female rabbits at a full human dose showed no effects on mating performance, female fertility, no teratogenic potential, and no effect on pre- or post-natal development.