Menveo Mechanism of Action

Pharmacotherapeutic group: Meningococcal vaccines. ATC code: J07AH08.
Pharmacology: Pharmacodynamics: Immunogenicity: The efficacy of Menveo has been inferred by measuring the production of serogroup-specific anti-capsular antibodies with bactericidal activity. Serum bactericidal activity (SBA) was measured using human serum as the source of exogenous complement (hSBA). The hSBA was the original correlate of protection against meningococcal disease.
Immunogenicity was evaluated in randomized, multicenter, active controlled clinical trials that enrolled children (2-10 years of age), adolescents (11-18 years of age), adults (19-55 years of age) and older adults (56-65 years of age).
Immunogenicity in children 2 to 10 years of age: In the pivotal study V59P20 immunogenicity of Menveo was compared to ACWY-D; 1170 children were vaccinated with Menveo and 1161 received the comparator vaccine in the per protocol populations. In two supportive studies V59P8 and V59P10 immunogenicity of Menveo was compared to ACWY-PS.
In the pivotal, randomized, observer-blind study V59P20, in which participants were stratified by age (2 through 5 years and 6 through 10 years), the immunogenicity of a single dose of Menveo one month post vaccination was compared with the single dose of ACWY-D. Immunogenicity results one month after Menveo vaccination among subjects aged 2-5 years and 6-10 years are summarized as follows in Table 1.

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In another randomized, observer-blind study (V59P8) US children were immunized with a single dose of either Menveo (N=284) or ACWY-PS (N=285). In the children 2-10 years of age, as well as in each age strata (2-5 and 6-10 years), immune response as measured by percentage of subjects with seroresponse, hSBA≥1:8 and GMTs were not only non-inferior to comparator vaccine ACWY-PS, but all were statistically higher than the comparator for all serogroups and all immune measurements at 1 month post vaccination. At 1 year post vaccination, Menveo continued to be statistically higher than ACWY-PS for group A, W-135 and Y, as measured by percentage of subjects with hSBA≥1:8 and GMTs. Menveo was non-inferior on these endpoints for serogroup C (Table 2). The clinical relevance of higher post-vaccination immune responses is not known. (See Table 2.)

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In a randomized, observer-blind study (V59P10) conducted in Argentina, children were immunized with a single dose of either Menveo (N=949) or ACWY-PS (N=551). Immunogenicity was assessed in a subset of 150 subjects in each vaccine group. The immune response observed in the children 2-10 years of age was very similar to those observed in the V59P8 study shown previously: immune response to Menveo at 1 month post vaccination, as measured by percentage of subjects with seroresponse, hSBA≥1:8 and GMTs, was non-inferior to ACWY-PS.
A randomised, observer-blind study was conducted in children 12 to 59 months of age in Finland and Poland (V59P7). A total of 199 subjects 2-5 years of age were in the Menveo per protocol immunogenicity population and 81 subjects 3-5 years of age were in the ACWY-PS group.
At 1 month post-first vaccination, the percentages of subjects with hSBA ≥ 1:8 were consistently higher in the Menveo group for all four serogroups (63% vs 39%, 46% vs 39%, 78% vs 59%, and 65% vs 57% for Menveo as compared to ACWY-PS for serogroups A, C, W-135, and Y, respectively).
In a randomized, observer-blind study (V59_57) conducted in US, immunogenicity of a 2-dose series and a single dose of Menveo was compared in children 2 through 5 and 6 through 10 years of age (N=715).
At baseline, the percentage of subjects with hSBA ≥1:8 across the two age strata was 1%-5% for serogroup A, 13%-28% for serogroup C, 42%-64% for serogroup W-135, and 6%-19% for serogroup Y. At 1 month post last vaccination, the percentages of subjects with hSBA ≥1:8 in the 2-dose group and in the single dose group across the two age strata were: 90%-95% vs 76%–80% for serogroup A, 98%-99% vs 76%-87% for serogroup C, 99% vs 93%-96% for serogroup W-135, and 96% vs 65%-69% for serogroup Y. GMTs were higher in the 2-dose group than the single dose group at 1 month after vaccination in both age strata; however, this difference was less pronounced in the older age stratum.
At 1 year post last vaccination, the percentages of subjects with hSBA ≥1:8 after the 2-dose series and the single dose were both lower than at 1 month post-vaccination (30% after the 2-dose series, 11%-20% after the single dose for serogroup A; 61%-81% and 41%-55% for serogroup C; 92%-94% and 90%-91% for serogroup W-135; 67%-75% and 57%-65% for serogroup Y). The differences between hSBA GMTs in the 2-dose and the single dose groups at 1 year after vaccination were lower than those seen at 1 month post-vaccination.
The clinical benefit of a 2-dose vaccination series in children 2 through 10 years of age is not known.
Persistence of immune response and booster response in children 2 to 10 years of age: Antibody persistence at 5 years after primary vaccination was assessed in study V59P20E1, this was an extension of study V59P20. There was antibody persistence observed against serogroups C, W-135 and Y, with the percentages of subjects with hSBA ≥ 1:8 being 32% and 56% against serogroup C in subjects 2-5 and 6-10 years of age, respectively, 74% and 80% against serogroup W-135, and 48% and 53% against serogroup Y. GMTs were respectively 6.5 and 12 for serogroup C, 19 and 26 for serogroup W-135, and 8.13 and 10 for serogroup Y. For serogroup A, 14% and 22% of subjects 2-5 and 6-10 years of age, respectively, had hSBA ≥ 1:8 (GMTs 2.95 and 3.73).
The children also received a booster dose of Menveo, 5 years after a single dose primary vaccination. All subjects in both age groups had hSBA ≥ 1:8 across all serogroups, with antibody titers several fold higher than seen after the primary vaccination (Table 3). (See Table 3.)

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Immunogenicity in individuals 11 years of age and above: In the pivotal study (V59P13), participants received either a dose of Menveo (N = 2649) or comparator vaccine (ACWY-D) (N = 875). Sera were obtained both before vaccination and 1 month after vaccination.
In another study (V59P6) conducted in 524 adolescents, the immunogenicity of Menveo was compared to that of ACWY-PS.
Immunogenicity in adolescents: In the 11-18 year old population of the pivotal study, V59P13, the immunogenicity of a single dose of Menveo one month post vaccination is compared with the quadrivalent, ACWY-Diphtheria toxoid protein conjugate vaccine (ACWY-D). Immunogenicity results at one month after Menveo are summarized as follows in Table 4. (See Table 4).

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In the subset of subjects aged 11-18 years who were seronegative at baseline (hSBA < 1:4), the proportion of subjects who achieved a hSBA ≥ 1:8 after a dose of Menveo were as follows: serogroup A 75% (780/1039); serogroup C 80% (735/923); serogroup W135 94% (570/609); serogroup Y 81% (510/630).
In the non-inferiority study, V59P6, immunogenicity was assessed among adolescents aged 11-17 years who had been randomised to receive either Menveo or ACWY-PS. Menveo was shown to be non-inferior to ACWY-PS vaccine for all four serogroups (A, C, W-135 and Y) based on seroresponse, proportions achieving hSBA ≥1:8, and GMTs. (See Table 5.)

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At one year post vaccination in these same subjects, compared with ACWY-PS, a higher proportion of subjects vaccinated with Menveo had hSBA ≥1:8 for serogroups C, W-135, and Y, with comparable levels for serogroup A. Similar findings were observed in the comparison of hSBA GMTs.
Persistence of immune response and booster response in adolescents: In study V59P13E1, the persistence of immune responses against serogroups A, C, W-135 and Y was assessed at 21 months, 3 years and 5 years post primary vaccination among subjects aged 11-18 years at the time of vaccination. The percentages of subjects with hSBA ≥ 1:8 remained constant against serogroups C, W-135, and Y from 21 months to 5 years postvaccination in the Menveo group and decreased slightly over time against serogroup A (Table 6). At 5 years after primary vaccination, there were significantly higher percentages of subjects with hSBA ≥ 1:8 in the Menveo group than in the vaccine naive control subjects against all the four serogroups. (See Table 6.)

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A booster dose of Menveo was administered 3 years after primary vaccination with Menveo or ACWY-D. Both groups showed a robust response to the booster dose of Menveo at one month after vaccination (100% of subjects had hSBA ≥ 1:8 across serogroups) and this response largely persisted through 2 years after the booster dose for serogroups C, W-135 and Y (with 87% to 100% of subjects with hSBA ≥ 1:8 across serogroups). A small decline was observed in percentages of subjects with hSBA ≥ 1:8 against serogroup A, although percentages were still high (77% to 79%). GMTs declined over time as expected but remained between 2- and 8-fold higher than prebooster values (Table 8).
In study V59P6E1, at one year post vaccination, the percentage of Menveo recipients with hSBA ≥ 1:8 remained significantly higher compared with ACWY-PS recipients for serogroups C, W-135 and Y, and similar between the two study groups for serogroup A. hSBA GMTs for serogroups W-135 and Y were higher among Menveo recipients. In 5 years post vaccination, the percentage of Menveo recipients with hSBA ≥ 1:8 remained significantly higher compared with ACWY-PS recipients for serogroups C and Y. Higher hSBA GMTs were observed for serogroups W-135 and Y (Table 7). (See Table 7.)

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A booster dose of Menveo was administered 5 years after primary vaccination with Menveo or ACWY-PS. At 7 days after the booster dose, 98%-100% of subjects who previously received Menveo and 73%-84% of subjects who previously received ACWY-PS achieved hSBA ≥1:8 against serogroups A, C, W-135 and Y. At one month post vaccination, the percentages of subjects with hSBA≥1:8 were 98%-100% and 84%-96%, respectively.
A significant increase in the hSBA GMTs against all four serogroups was also observed at 7 and 28 days after the booster dose (Table 8). (See Table 8).

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Immunogenicity in adults: In the pivotal immunogenicity trial, V59P13, immune responses to Menveo were assessed among adults aged 19 to 55 years. Results are presented in Table 9. In the subset of subjects aged 19-55 years who were seronegative at baseline, the proportion of subjects who achieved a hSBA ≥ 1:8 after a dose of Menveo were as follows: serogroup A 67% (582/875); serogroup C 71% (401/563); serogroup W-135 82% (131/160); serogroup Y 66% (173/263). (See Table 9.)

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The onset of immune response after the primary vaccination with Menveo in healthy subjects 18 through 22 years of age was evaluated in study V59P6E1. At 7 days post vaccination, 64% of subjects achieved hSBA ≥1:8 against serogroup A and 88% through 90% of subjects had bactericidal antibodies against serogroups C, W-135 and Y. At one month post vaccination, 92% through 98% of subjects had hSBA ≥1:8 against serogroups A, C, W-135 and Y. A robust immune response as measured by hSBA GMTs against all serogroups was also observed at 7 days (GMTs 34 through 70) and 28 days (GMTs 79 through 127) after a single dose vaccination.
Immunogenicity in older adults: The comparative immunogenicity of Menveo vs. ACWY-PS was evaluated in subjects aged 56-65 years, in study V59P17. The proportion of subjects with hSBA ≥ 1:8 was non-inferior to ACWY-PS for all four serogroups and statistically superior for serogroups A and Y (Table 10). (See Table 10.)

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Available data in children 2 to 23 months of age: The immunogenicity of Menveo in children 2 to 23 months of age was evaluated in several studies. Although a high percentage of subjects achieved hSBA titres above 1:8 following 4-dose series of Menveo, with lower percentages in studies of 2-dose series and of a single dose, Menveo was compared to another meningococcal vaccine in only one pivotal study, where it failed to show a response at least equivalent to a monovalent conjugated serotype C vaccine (after a single dose at the age of 12 months). Currently available data are not sufficient to establish the efficacy of Menveo in children under 2 years of age. See Dosage & Administration for information on paediatric use.
Pharmacokinetics: Not applicable.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional repeated-dose and reproductive and developmental toxicity studies.
In laboratory animals, no adverse reactions were seen in vaccinated maternal rabbits or in their offspring through postnatal day 29.
No effects on fertility were observed in female rabbits receiving Menveo pre-mating and during pregnancy.