Vaccine Information: MenQuadfi (Page 2 of 3)

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Other Vaccines

In a clinical trial in adolescents 10 through 17 years of age, MenQuadfi was administered concomitantly with Tdap and HPV [see Adverse Reactions (6) and Clinical Studies (14.3)].

Lower geometric mean antibody concentrations (GMCs) for antibodies to the pertussis antigens filamentous hemagglutinin (FHA), pertactin (PRN) and fimbriae (FIM) were observed when MenQuadfi was co-administered with Tdap and HPV, compared to concomitant administration of Tdap and HPV (without MenQuadfi) [see Clinical Studies (14.3) ].

7.2 Immunosuppressive Treatments

Immunosuppressive therapies may reduce the immune response to MenQuadfi [see Warnings and Precautions (5) ].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to MenQuadfi during pregnancy. To enroll in or obtain information about the registry, call Sanofi Pasteur at 1-800-822-2463.

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

There are no clinical studies of MenQuadfi in pregnant women. Available human data on MenQuadfi administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy. A developmental toxicity study in female rabbits administered a full human dose (0.5 mL) prior to mating and during gestation period revealed no evidence of harm to the fetus due to MenQuadfi (see Animal Data).

Data

Animal Data

In a developmental toxicity study, female rabbits received a human dose of MenQuadfi by intramuscular injection on five occasions: 30 days and 10 days prior to mating, gestation days 6, 12 and 27. No adverse effects on pre-weaning development up to post-natal day 35 were observed. There were no vaccine-related fetal malformations or variations observed.

8.2 Lactation

Risk Summary

It is not known whether MenQuadfi is excreted in human milk. Data are not available to assess the effects of MenQuadfi on the breastfed infant or on milk production/excretion.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MenQuadfi and any potential adverse effects on the breastfed child from MenQuadfi or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

Safety and effectiveness of MenQuadfi have not been established in individuals younger than 2 years of age in the US.

8.5 Geriatric Use

A total of 249 participants 65 years of age and older, including 71 participants 75 years of age or older, in Study 4 received one dose of MenQuadfi [see Adverse Reactions (6.1) and Clinical Studies (14.1)].

MenQuadfi recipients ≥ 65 years of age had lower GMTs and seroresponse rates for all serogroups compared to MenQuadfi recipients 56 through 64 years of age [see Clinical Studies (14.1) ].

11 DESCRIPTION

MenQuadfi is a sterile liquid vaccine administered by intramuscular injection that contains Neisseria meningitidis serogroup A, C, W, and Y capsular polysaccharide antigens that are individually conjugated to tetanus toxoid protein. N. meningitidis A, C, W, and Y strains are cultured on Mueller Hinton agar medium and grown in Watson Scherp medium. The polysaccharides are extracted from the N. meningitidis cells and purified by centrifugation, detergent precipitation, alcohol precipitation, solvent extraction, and diafiltration. To prepare the polysaccharides for conjugation, Serogroup A is activated with carbonyldiimidazole (CDI), derivatized with adipic acid dihydrazide (ADH), and purified by diafiltration. Serogroups C, W, and Y are depolymerized, activated with periodate, and purified by diafiltration.

Clostridium tetani is fermented in media to generate tetanus toxin, which is purified by ammonium sulfate precipitation to yield purified tetanus toxin (PTT) and detoxified with formaldehyde to yield purified tetanus protein (PTP). The PTP is then concentrated and filtered to yield concentrated tetanus protein (CTP). The activated/derivatized polysaccharides are covalently linked to tetanus toxoid and purified by chromatography and serial diafiltration. The four meningococcal components, present as individual serogroup-specific glycoconjugates, compose the final formulated vaccine.

MenQuadfi is manufactured as a sterile, clear solution. Each 0.5 mL dose of vaccine contains 10 microgram each of meningococcal A, C, W, and Y polysaccharide antigens conjugated to approximately 55 micrograms tetanus toxoid protein carrier; 3.35 mg sodium chloride (0.67%), and 1.23 mg sodium acetate (30 mM). Potency of MenQuadfi is determined by quantifying the amount of each polysaccharide antigen that is conjugated to tetanus toxoid protein and the amount of unconjugated polysaccharide present.

No preservative or adjuvant is added during manufacture. Each 0.5 mL dose may contain residual amounts of formaldehyde of less than 3 mcg/mL, by calculation.

The vial in which the vaccine components are contained is composed of USP Type I borosilicate glass. The vial stopper is a chlorobutyl synthetic polyisoprene blend stopper (not made with natural rubber latex).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Invasive meningococcal disease (IMD) is caused by the bacterium N. meningitidis , a gram-negative diplococcus found exclusively in humans. The presence of bactericidal anti-capsular meningococcal antibodies in serum has been associated with protection from IMD. MenQuadfi induces the production of bactericidal antibodies specific to the capsular polysaccharides of N. meningitidis serogroups A, C, W, and Y.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

MenQuadfi has not been evaluated for carcinogenic or mutagenic potential or for impairment of male fertility. MenQuadfi administered to female rabbits had no effects on fertility [see Use in Specific Population (8.1) ].

14 CLINICAL STUDIES

To infer effectiveness of MenQuadfi, the immunogenicity in persons 2 years of age and older was evaluated using a serogroup-specific serum bactericidal assay with exogenous human complement (hSBA). The hSBA responses following a single dose of MenQuadfi for primary vaccination were assessed in four studies, and the hSBA responses following a single dose of MenQuadfi for booster vaccination were assessed in one study. Serum was collected at baseline and 30 days post-vaccination to measure antibodies with hSBA. The hSBA geometric mean titers (GMTs) and proportion of participants who achieved hSBA seroresponse (defined below) were evaluated.

  • Seroresponse rate for each serogroup: the proportion of participants with an hSBA
    • pre-vaccination titer < 1:8 who achieved a post-vaccination titer ≥ 1:16, or
    • pre-vaccination titer ≥ 1:8 who achieved a post-vaccination titer at least 4-fold greater than the pre-vaccination titer.

Non-inferiority of MenQuadfi seroresponse rates versus those for comparator vaccines was demonstrated for all 4 serogroups in individuals 2 years of age and older who received a primary vaccination and in individuals 15 years of age and older who received a booster vaccination at least 4 years following a previous dose of a meningococcal (Groups A, C, W, Y) conjugate vaccine.

14.1 Primary Vaccination

Immunogenicity in Children 2 through 9 Years of Age

Immunogenicity of MenQuadfi compared to Menveo in participants 2 through 9 years of age was evaluated in Study 1 (NCT03077438). The hSBA seroresponse rate and GMTs are presented in Table 5.

Immune non-inferiority, based on seroresponse rates, was demonstrated for MenQuadfi as compared to Menveo for all four serogroups.

Table 5: Comparison of Bactericidal Antibody Responses to MenQuadfi and Menveo 30 Days after Vaccination of Participants 2 through 9 Years of Age (Study 1)*
Endpoint MenQuadfi(95% CI) Menveo(95% CI) Percent difference MenQuadfi minus Menveo (95% CI)
N: number of participants in per-protocol analysis set with valid serology results.95% CI of the single proportion calculated from the exact binomial method.95% CI of the difference calculated from the Wilson Score method without continuity correction.
*
Clinical trial identifier NCT03077438
Seroresponse rate (primary end point) for each serogroup: the proportion of participants with an hSBA pre-vaccination titer < 1:8 who achieved a post-vaccination titer ≥ 1:16, or pre-vaccination titer ≥ 1:8 who achieved a post-vaccination titer at least 4-fold greater than the pre-vaccination titer.
Overall non-inferiority would be demonstrated if the lower limit of the 2-sided 95% CI is > -10% for all four serogroups.
A N=455-456 N=458
% Participants achieving Seroresponse 55.4(50.7; 60.0) 47.8(43.2; 52.5) 7.6(1.1, 14.0)
GMT 25(22; 28) 23(20; 26)
C N=458 N=458-459
% Participants achieving Seroresponse 95.2(92.8; 97.0) 47.8(43.2; 52.5) 47.4(42.2, 52.2)
GMT 238(209; 270) 17.0(14; 20)
W N=458 N=459
% Participants achieving Seroresponse 78.8(74.8; 82.5) 64.1(59.5; 68.4) 14.8(8.9, 20.5)
GMT 38(34; 42) 26(23; 30)
Y N=458 N=459
% Participants achieving Seroresponse 91.5(88.5; 93.9) 79.3(75.3; 82.9) 12.2(7.7, 16.7)
GMT 69(61; 77) 44(38; 50)

Immunogenicity in Adolescents 10 through 17 Years of Age

Immunogenicity of MenQuadfi compared to Menveo in participants 10 through 17 years of age was evaluated in Study 2 (NCT02199691). Study 2 was conducted in healthy meningococcal vaccine naïve participants and evaluated seroresponse rates following administration with either MenQuadfi alone, Menveo alone, MenQuadfi co-administered with Tdap, and HPV, or Tdap and HPV alone. The hSBA seroresponse rate and GMTs for Study 2 are presented in Table 6.

Immune non-inferiority, based on seroresponse, was demonstrated for MenQuadfi as compared to Menveo for all four serogroups.

Study 2 (NCT02199691) was conducted in healthy meningococcal vaccine naïve male and female participants and evaluated seroresponses following administration with either MenQuadfi alone; Menveo alone; MenQuadfi co-administered with Tdap, and HPV; or Tdap and HPV alone. The hSBA seroresponse rate and GMTs for the MenQuadfi alone and Menveo alone groups are presented in Table 6.

Table 6: Comparison of Bactericidal Antibody Responses to MenQuadfi and Menveo 30 Days after Vaccination of Participants 10 through 17 Years of Age Study 2*
Endpoint MenQuadfi(95% CI) Menveo(95% CI) Percent difference MenQuadfi minus Menveo (95% CI)
N: number of participants in per-protocol analysis set with valid serology results.95% CI of the single proportion calculated from the exact binomial method.95% CI of the difference calculated from the Wilson Score method without continuity correction.Overall non-inferiority would be demonstrated if the lower limit of the 2-sided 95% CI is > -10% for all four serogroups.
*
Clinical trial identifier NCT02199691
Seroresponse rate (primary end point) for each serogroup: the proportion of participants with an hSBA pre-vaccination titer < 1:8 who achieved a post-vaccination titer ≥ 1:16, or pre-vaccination titer ≥ 1:8 who achieved a post-vaccination titer at least 4-fold greater than the pre-vaccination titer.
post-vaccination hSBA titers ≥1:8 for participants with pre-vaccination hSBA titers < 1:8 or at least a 4-fold increase in hSBA titers from pre to post-vaccination for participants with pre-vaccination hSBA titers ≥1:8
A N=463 N=464
% Participants achieving Seroresponse 75.6(71.4; 79.4) 66.4(61.9; 70.7) 9.2(3.4; 15.0)
GMT 44(39; 50) 35(30; 41)
C N=462 N=463
% Participants achieving Seroresponse 97.2(95.2; 98.5) 72.6(68.3; 76.6) 24.6(20.3; 29.0)
GMT 387(329; 456) 51(41; 64)
W N=463 N=464
% Participants achieving Seroresponse 86.2(82.7; 89.2) 66.6(62.1; 70.9) 19.6(14.2; 24.8)
GMT 87(78; 97) 36(32; 41)
Y N=462-463 N=464
% Participants achieving Seroresponse 97.0(95.0; 98.3) 80.8(76.9; 84.3) 16.2(12.3; 20.2)
GMT 76(66; 87) 28(24; 32)

Study 3 evaluated the immunogenicity of MenQuadfi (N=1097-1098) compared to Menactra (N=300) in healthy meningococcal-naïve participants 10 through 17 years of age. Seroresponse rates for MenQuadfi were noninferior to those of Menactra for all serogroups based on the same noninferiority criteria defined for Study 2.

Immunogenicity in Adults 18 through 55 Years of Age

Immunogenicity of MenQuadfi compared to Menactra in participants 18 through 55 years of age was evaluated in Study 3 (NCT02842853). The hSBA seroresponse rate and GMTs are presented in Table 7.

Immune non-inferiority, based on seroresponse rates, was demonstrated for MenQuadfi as compared to Menactra for all four serogroups.

Table 7: Comparison of Bactericidal Antibody Responses to MenQuadfi and Menactra 30 Days after Vaccination of Participants 18 through 55 Years of Age Study 3*
Endpoint MenQuadfi(95% CI) Menactra (95% CI) Percent difference MenQuadfi minus Menactra (95% CI)
N: number of participants in per-protocol analysis set with valid serology results.95% CI of the single proportion calculated from the exact binomial method.95% CI of the difference calculated from the Wilson Score method without continuity correction.
*
Clinical trial identifier NCT02842853
Seroresponse rate (primary end point) for each serogroup: the proportion of participants with an hSBA pre-vaccination titer < 1:8 who achieved a post-vaccination titer ≥ 1:16, or pre-vaccination titer ≥ 1:8 who achieved a post-vaccination titer at least 4-fold greater than the pre-vaccination titer.
The overall non-inferiority would be demonstrated if the lower limit of the 2-sided 95% CI is > -10% for all four serogroups.
A N=1,406-1,408 N=293
% Participants achieving Seroresponse 73.5(71.2; 75.8) 53.9(48.0; 59.7) 19.6(13.5; 25.8)
GMT 106(97; 117) 52(43; 64)
C N=1,406-1,408 N=293
% Participants achieving Seroresponse 83.4(81.4; 85.3) 42.3(36.6; 48.2) 41.1(35.0; 46.9)
GMT 234(210; 261) 37(29; 49)
W N=1,408-1,410 N=293
% Participants achieving Seroresponse 77.0(74.7; 79.2) 50.2(44.3; 56.0) 26.8(20.7; 32.9)
GMT 76(69; 83) 33(26; 42)
Y N=1,408-1,410 N=293
% Participants achieving Seroresponse 88.1(86.3; 89.8) 60.8(54.9; 66.4) 27.4(21.7; 33.3)
GMT 219(200; 239) 55(42; 70)

Immunogenicity in Adults 56 Years of Age and Older

Immunogenicity of MenQuadfi compared to Menomune in participants 56 years and older was evaluated in Study 4 (NCT02842866).

Enrollment was stratified by age category: 56 through 64 years of age (44.3%), 65 through 74 years of age (39.7%), and 75 years of age and older (15.9%). The overall mean age of participants who received MenQuadfi was 66.9 years; range: 56 through 89.8 years of age. The mean age for participants in the 56 through 64 years age stratum who received MenQuadfi was 60.4 years, the mean age for participants ≥ 65 years age stratum who received MenQuadfi was 72.2 years.

The hSBA seroresponse rate and GMTs are presented in Table 8.

Immune non-inferiority, based on seroresponse rates, was demonstrated for MenQuadfi as compared to Menomune for all four serogroups.

Table 8: Comparison of Bactericidal Antibody Responses to MenQuadfi and Menomune in Naïve Older Adults and Elderly 30 Days after Vaccination Study 4*
Endpoint MenQuadfi(95% CI) Menomune(95% CI) Percent difference MenQuadfi minus Menomune (95% CI)
N: number of participants in per-protocol analysis set with valid serology results.95% CI of the single proportion calculated from the exact binomial method.95% CI of the difference calculated from the Wilson Score method without continuity correction.
*
Clinical trial identifier NCT02842866
Seroresponse rate (primary end point) for each serogroup: the proportion of participants with an hSBA pre-vaccination titer < 1:8 who achieved a post-vaccination titer ≥ 1:16, or pre-vaccination titer ≥ 1:8 who achieved a post-vaccination titer at least 4-fold greater than the pre-vaccination titer.
The overall non-inferiority would be demonstrated if the lower limit of the 2-sided 95% CI is > -10% for all four serogroups.
A N=433 N=431
% Participants achieving Seroresponse 58.2(53.4; 62.9) 42.5(37.7; 47.3) 15.7(9.08; 22.2)
GMT 55(47; 65) 31(27; 37)
C N=433 N=431
% Participants achieving Seroresponse 77.1(72.9; 81.0) 49.7(44.8; 54.5) 27.5(21.2; 33.5)
GMT 101(84; 123) 25(21; 30)
W N=433 N=431
% Participants achieving Seroresponse 62.6(57.8; 67.2) 44.8(40.0; 49.6) 17.8(11.2; 24.2)
GMT 28(24; 33) 15(13; 18)
Y N=433 N=431
% Participants achieving Seroresponse 74.4(70.0; 78.4) 43.4(38.7; 48.2) 31.0(24.6; 37.0)
GMT 69(59; 81) 21(17; 25)

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