Nimenrix Mechanism of Action

Pharmacotherapeutic group: bacterial vaccines. ATC code: J07AH08.
Pharmacology: Pharmacodynamics: Mechanism of Action: Anti-capsular meningococcal antibodies protect against meningococcal disease via complement mediated bactericidal killing. Nimenrix induces the production of bactericidal antibodies against capsular polysaccharides of Neisseria meningitidis groups A, C, W-135 and Y when measured by assays using either rSBA or hSBA. By conjugating capsular polysaccharide to a protein carrier that contains T-cell epitopes, meningococcal conjugate vaccines like Nimenrix change the nature of immune response to capsular polysaccharide from T-cell independent to T-cell dependent.
Vaccine efficacy was inferred from the demonstration of immunologic non inferiority (based mainly on comparing proportions with rSBA titres at least 1:8) to licensed meningococcal vaccines. Immunogenicity was measured by using rSBA or hSBA which are biomarkers for protective efficacy against meningococcal groups A, C, W-135 and Y.
Immunogenicity in infants: In Study MenACWY-TT-083, the immunogenicity of a 2-dose primary vaccination schedule administered at 2 and 4 months of age was evaluated. Routinely used infant vaccines DTaP/IPV/Hib/HepB and a 10-valent pneumococcal vaccine were co-administered. For group C, rSBA and hSBA titres elicited by Nimenrix were compared to a 2-dose priming with licensed monovalent meningococcal conjugate group C vaccines, MenC-CRM and MenC-TT vaccines. Nimenrix elicited rSBA and hSBA titres against the four meningococcal groups. The response against group C was non-inferior to the one elicited by the licensed MenC-CRM and MenC-TT vaccines in terms of the percentage of subjects with rSBA titres ≥8 at 1 month after the second dose.
For subjects initially vaccinated in infancy with Nimenrix at 2 and 4 months of age and receiving a Nimenrix booster dose at 12 months of age, the increase in rSBA and hSBA titres 1 month post-booster dose ranged between 15 and 80-fold for all groups and more than 99.0% of all infants achieved post-booster titres above 8 for both assays. The observed booster response for group C was similar to that observed in subjects primed and boosted with a monovalent MenC conjugate vaccine (TT or CRM conjugated). Results are shown in Table 1. (See Table 1.)

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In Study MenACWY-TT-087, infants received either a single primary dose at 6 months followed by a booster dose at 15-18 months or three primary doses at 2, 4, and 6 months followed by a booster dose at 15-18 months. All subjects also received DTaP-IPV/Hib and 10-valent pneumococcal conjugate vaccines at all time points. A single primary dose administered at 6 months of age elicited robust rSBA titres to the four meningococcal groups, as measured by the percentage of subjects with rSBA titres ≥8, that were comparable to responses after the last dose of a three-dose primary series. A booster dose produced robust responses, comparable between the two dosing groups, against all four meningococcal groups. Results are shown in Table 2. (See Table 2.)

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Measurement of hSBA titres was a secondary endpoint in Study MenACWY-TT-087. Although similar responses to groups A and C were observed with both dosing schedules, a single primary dose in infants at 6 months was associated with lower hSBA titres to groups W-135 and Y as measured by the percentage of subjects with hSBA titres ≥8 [87.2% (95% CI: 74.3; 95.2) and 92.3% (95% CI: 81.5; 97.9), respectively] compared with three primary doses at 2, 4, and 6 months of age [100% (95% CI: 96.6; 100) and 100% (95% CI: 97.1; 100), respectively] (see Precautions). After a booster dose, hSBA titres to all four meningococcal groups were comparable between the two dosing schedules (Table 2).
Immunogenicity in toddlers aged 12-23 months: In clinical studies MenACWY-TT-039 and MenACWY-TT-040, a single dose of Nimenrix elicited SBA titres against the four meningococcal groups, with group C rSBA titres that were comparable to those elicited by a licensed MenC-CRM vaccine in terms of the percentage of subjects with rSBA titres ≥8. In Study MenACWY-TT-039, hSBA was also measured as a secondary endpoint. Results are shown in Table 3. (See Table 3.)

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Long term immunogenicity in toddlers: Study MenACWY-TT-104 evaluated the immunogenicity after 1 month and the persistence of the response up to 5 years following 1 or 2 doses (given 2 months apart) of Nimenrix in toddlers aged 12 to 14 months. One month following one or two doses administered 2 months apart Nimenrix elicited rSBA titres against all four meningococcal groups that were similar in terms of the percentage of subjects with rSBA titre ≥8 and GMT. As a secondary endpoint hSBA titres were measured. In terms of the percentage of subjects with hSBA titres ≥8, at 1 month post vaccination, hSBA titres against groups W-135 and Y were higher after two doses of Nimenrix than after one dose, while the hSBA titres against groups A and C were similar in the two dose groups. At Year 5 only a small difference in antibody persistence between one and two doses was observed, in terms of percentages of subjects with hSBA titres ≥8 against all groups. Antibody persistence was observed at Year 5 against groups C, W-135 and Y. After one and two doses the percentages of subjects with hSBA titres ≥8 for group C were 60.7% and 67.8%, group W-135 were 58.9% and 63.6% and group Y were 61.5% and 54.2%, respectively. For group A, 27.9% and 17.9% of subjects receiving one or two doses, respectively, had hSBA titres ≥8. (See Table 4.)

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In children vaccinated at toddler age, the persistence of rSBA and hSBA titres was evaluated up to 4 years in Study MenACWY-TT-048. Results are shown in Table 5. (See Table 5.)

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rSBA and hSBA titres were determined over a period of 10 years in children initially vaccinated with one dose of Nimenrix or MenC-CRM at 12 to 23 months of age in Study MenACWY-TT-027. Persistence of SBA titres was evaluated in two extension studies: MenACWY-TT-032 (up to 5 years) and MenACWY-TT-100 (up to 10 years). Study MenACWY-TT-100 also evaluated the response to a single booster dose of Nimenrix administered 10 years following the initial vaccination with Nimenrix or MenC-CRM. Results are shown in Table 6 (see Precautions). (See Table 6.)

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Persistence of booster response: Study MenACWY-TT-102 evaluated the persistence of SBA titres up to 6 years after a booster dose of Nimenrix or MenC-CRM₁₉₇ administered in Study MenACWY-TT-048 to children who initially received the same vaccine at 12 to 23 months of age in Study MenACWY-TT-039. A single booster dose was administered 4 years after the initial vaccination. Results are shown in Table 7 (see Precautions). (See Table 7.)

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Immune memory: In Study MenACWY-TT-014, the induction of immune memory was assessed 1 month after the administration of a fifth of the dose of ACWY-PS vaccine (10 µg of each polysaccharide) to children in the third year of life initially vaccinated in Study MenACWY-TT-013 with Nimenrix or a licensed MenC-CRM vaccine at the age of 12 to 14 months.
One month after the challenge dose, the GMTs elicited by the initial vaccination with Nimenrix increased by 6.5 to 8 fold for groups A, C, W-135, and Y, indicating that Nimenrix induces immune memory to all four meningococcal groups. The post-challenge rSBA-MenC GMT was similar in both study groups, indicating that Nimenrix induces an analogous immune memory to group C as the licensed MenC-CRM vaccine. Results are shown in Table 8. (See Table 8.)

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Immunogenicity in children aged 2-10 years: In two comparative studies conducted in subjects aged 2-10 years, one group of subjects received a dose of Nimenrix and a second group a dose of either a licensed MenC-CRM vaccine (Study MenACWY-TT-081) or the licensed ACWY-PS vaccine (Study MenACWY-TT-038) as comparator.
In Study MenACWY-TT-038, a single dose of Nimenrix was demonstrated to be non-inferior to the licensed ACWY-PS vaccine in terms of vaccine response to the four meningococcal groups as shown in Table 9. (See Table 9.)

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In Study MenACWY-TT-081, a single dose of Nimenrix (N = 268) was demonstrated to be non-inferior to another licensed MenC-CRM vaccine (N = 92) in terms of vaccine response to group C [94.8% (95% CI: 91.4; 97.1) and 95.7% (95% CI: 89.2; 98.8), respectively]. GMTs were lower for the Nimenrix group [2795 (95% CI: 2393; 3263)] versus the MenC-CRM vaccine [5292 (95% CI: 3815; 7340)].
In Study MenACWY-TT-088, the persistence of SBA titres was evaluated up to 68 months after vaccination in children 2-10 years of age initially vaccinated in Study MenACWY-TT-081. Results are shown in Table 10 (see Precautions). (See Table 10.)

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In Study MenACWY-TT-028, the persistence of hSBA titres was evaluated 1 year after vaccination in children aged 6-10 years who were initially vaccinated in Study MenACWY-TT-027. Results are shown in Table 11. (See Table 11.)

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SBA titres were determined over a period of 10 years in children initially vaccinated with one dose of Nimenrix or ACWY-PS at 2 to 10 years of age in Study MenACWY-TT-027. Persistence of SBA titres was evaluated in two extension studies: MenACWY-TT-032 (up to 5 years) and MenACWY-TT-100 (up to 10 years).
Study MenACWY-TT-100 also evaluated the response to a single booster dose of Nimenrix administered 10 years following the initial vaccination with Nimenrix or ACWY-PS. Results are shown in Table 12 (see Precautions). (See Table 12.)

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Immunogenicity in adolescents aged 11-17 years and adults aged ≥18 years: In two clinical studies, conducted in adolescents aged 11-17 years (Study MenACWY-TT-036) and in adults aged 18-55 years (Study MenACWY-TT-035), either one dose of Nimenrix or one dose of the ACWY-PS vaccine was administered.
In both adolescents and adults, Nimenrix was demonstrated to be immunologically non-inferior to the ACWY-PS vaccine in terms of vaccine response. rSBA titres to the four meningococcal groups elicited by Nimenrix were either similar to or higher than those elicited by the ACWY-PS vaccine as shown in Table 13. (See Table 13.)

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rSBA titres were determined over a period of 10 years in subjects initially vaccinated with one dose of Nimenrix or ACWY-PS at 11 to 17 years of age in Study MenACWY-TT-036. Persistence of rSBA titres was evaluated in two extension studies: MenACWY-TT-043 (up to 5 years) and MenACWY-TT-101 (at 10 years). Study MenACWY-TT-101 also evaluated the response to a single booster dose of Nimenrix administered 10 years following the initial vaccination with Nimenrix or ACWY-PS. Results are shown in Table 14. (See Table 14.)

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In Study MenACWY-TT-059, hSBA persistence was evaluated up to 5 years after vaccination in adolescents and adults aged 11-25 years initially vaccinated in Study MenACWY-TT-052.
For all meningococcal groups, the persistence of hSBA titres elicited by Nimenrix was similar to or higher than those induced by the licensed quadrivalent meningococcal diphtheria toxoid (DT) conjugate (ACWY-DT) vaccine as shown in Table 15. (See Table 15.)

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rSBA titres were determined over a period of 10 years in subjects initially vaccinated with one dose of Nimenrix or ACWY-PS at 11 to 55 years of age in Study MenACWY-TT-015. Persistence of rSBA titres was evaluated in two extension studies: MenACWY-TT-020 (up to 5 years) and MenACWY-TT-099 (up to 10 years). Study MenACWY-TT-099 also evaluated the response to a single booster dose of Nimenrix administered 10 years following the initial vaccination with Nimenrix or ACWY-PS. Results are shown in Table 16. (See Table 16.)

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In a descriptive study conducted in 194 adults aged 56 years and older (Study MenACWY-TT-085), Nimenrix was immunogenic, with a vaccine response rate ≥63.4% and with ≥97.4% of subjects with rSBA titres ≥8 against all four meningococcal groups. Moreover, at least 93.2% of subjects achieved the more conservative threshold of protection of rSBA titres ≥128.
Booster response for subjects previously vaccinated with a conjugate meningococcal vaccine against Neisseria meningitidis: Nimenrix booster vaccination in subjects previously primed with a monovalent (MenC-CRM) or a quadrivalent conjugate meningococcal vaccine (MenACWY-TT) was studied in subjects from 12 months of age onwards who received a booster vaccination. Robust anamnestic responses to the antigen(s) in the priming vaccine were observed (see Tables 6, 7, 12, 14, and 16).
Response to Nimenrix in subjects previously vaccinated with a plain polysaccharide meningococcal vaccine against Neisseria meningitidis: In Study MenACWY-TT-021 conducted in subjects aged 4.5-34 years, the immunogenicity of Nimenrix administered between 30 and 42 months after vaccination with a ACWY-PS vaccine was compared to the immunogenicity of Nimenrix administered to age-matched subjects who had not been vaccinated with any meningococcal vaccine in the preceding 10 years. The rSBA GMTs were significantly lower in the subjects who had received a dose of ACWY-PS vaccine 30-42 months prior to Nimenrix. The clinical relevance of this observation is unknown since all subjects achieved rSBA titres ≥8 for all four meningococcal groups. Results are shown in Table 17. (See Table 17.)

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Immunogenicity in children aged 2-17 years with anatomical or functional asplenia: Study MenACWY-TT-084 evaluated the immunogenicity of one and two doses of Nimenrix given 2 months apart in 43 at-risk subjects aged 2-17 years (at increased risk for meningococcal disease, i.e., asplenic subjects, and hyposplenic subjects) compared to 43 healthy age-matched subjects.
One month after the first vaccine dose, vaccine response rates (rSBA titre ≥1:32 or a ≥4-fold increase in rSBA titre from baseline) for groups A, C, W-135, and Y, respectively, were 100%, 92.5%, 100% and 97.5% in the at-risk group and were 97.5%, 97.5%, 97.5%, and 100% for healthy subjects. After the second vaccine dose, vaccine response rates in both at-risk and healthy subjects were 100% for each of the four meningococcal groups.
One month after Vaccination 1, hSBA response rates for groups A, C, W-135, and Y, respectively, were 69.7%, 77.1%, 55.6%, and 60.5% in the at-risk group and were 69.7%, 60.6%, 65.5%, and 76.3%, in the healthy group. One month after Vaccination 2, hSBA response rates were 84.8%, 100%, 80.6% and 73.0%, in the at-risk group and 75.0%, 85.3%, 77.4%, and 73.0% in the healthy group.
Impact of a single dose of Nimenrix: The Netherlands introduced Nimenrix into the national immunization program in 2018 as a single dose at 14 months of age. A catch-up campaign for individuals 14-18 years of age initiated in 2018 and in 2020 a single dose of Nimenrix at 14 years of age became routine, resulting in a toddler and adolescent national immunization program. Within two years, the incidence of meningococcal disease caused by groups C, W, and Y was significantly reduced by 100% (95% CI: 14, 100) in individuals 14-18 years of age, 85% (95% CI: 32, 97) in all vaccine eligible ages (direct effect), and 50% (95% CI: 28, 65) in non-vaccine eligible ages (indirect effect). In children 15 to 36 months, there were only 3 cases during the pre-vaccination period and 2 cases in the post-vaccination period, resulting in an IRR of 33% (95% CI: -302, 89). The low number of cases among this age group, does not allow for a reliable assessment of vaccine impact as indicated by the wide 95% CIs.
Pharmacokinetics: Not relevant for vaccines.
Toxicology: Preclinical Safety Data: Non-clinical data reveal no special hazard for humans based on local tolerance, acute toxicity, repeated dose toxicity, developmental/reproductive toxicity and fertility studies.