Immunogenicity and safety of MenACWY-TT, a quadrivalent meningococcal tetanus toxoid conjugate vaccine recently licensed in the United States for individuals ≥2 years of age

Figures & data

Table 1. Quadrivalent (serogroups A, C, W, and Y) meningococcal vaccines currently licensed and available for use in the United States.

Vaccine	Manufacturer	Trade Name Reference	Year Licensed	Approved Age Group	Composition		Formulation (presentation)
					Polysaccharide Content	Carrier Protein
MenACWY-D	Sanofi , USA	Menactra® Prescribing Information^Citation41,Citation42	2005	9 months–55 years	4 μg of polysaccharide from each of serogroups A, C, W, and Y	48 μg of diphtheria toxoid (D) protein	Solution for injection (single-dose vials)
MenACWY-CRM	GlaxoSmithKline Vaccines Srl, Bellaria-Rosia, Sovicille, Italy	Menveo® Prescribing Information^Citation41,Citation43	2010	2 months–55 years	10 μg of serogroup A oligosaccharide and 5 μg each of oligosaccharides from serogroups C, W, and Y	32.7 μg to 64.1 μg of CRM197 protein (varies by serogroup)	Powder and solution for injection (single- or multi-dose packs; 2 vials per dose: lyophilized MenA conjugate component to be reconstituted with liquid MenCWY conjugate component prior to administration)
MenACWY-TT	Sanofi , USA	MenQuadfi® Prescribing Information^Citation41,Citation44	2020	≥2 years	10 μg of oligosaccharides from each of serogroups A, C, W and Y	55 μg of tetanus toxoid (TT) carrier protein	Solution for injection (single-dose vials)

CRM₁₉₇, Corynebacterium diphtheriae C7 cross-reacting material 197.

Table 2. Salient characteristics of the US-licensed MenACWY-TT conjugate vaccine.

Characteristic	Remarks	Reference(s)
Approved age range	≥2 years in the United States (the vaccine is approved in Australia, Brazil, Canada, and Europe as a single dose for individuals ≥12 months of age)	MenACWY-TT Prescribing Information^Citation44 and BLA Approval^Citation69
Composition	Each 0.5 mL dose contains 10 μg of capsular polysaccharide from each of 4 serogroups (A, C, Y, and W) conjugated to 55 μg of tetanus toxoid carrier protein
Pharmaceutical form	Solution for injection; available in single-dose vials
Dosage, Route of Administration, and Dosing Regimen	0.5 mL Intramuscular Primary vaccination: single dose Booster dose: single dose in individuals ≥15 years of age at continued risk for IMD, provided 4 years have elapsed since previous dose of quadrivalent meningococcal conjugate vaccine
Shelf life	36 months when stored at 2°C–8°C
Immunogenicity and safety	Immunological non-inferiority demonstrated through 6 studies comparing MenACWY-TT with locally licensed quadrivalent meningococcal vaccines (MenACWY-CRM, MenACWY-D, and MPSV4) in participants ≥2 years of age, including older adults (≥56 years of age) Immunological non-inferiority against comparators demonstrated both in meningococcal vaccine-naïve participants and those primed with licensed meningococcal vaccines, including MenACWY-CRM and MenACWY-D Immunogenicity assessed using both hSBA and rSBA assays and reported in terms of seroprotection, seroresponses, and GMTs to account for variations in global regulatory preferences for data supporting licensure Suitability of MenACWY-TT as a booster demonstrated in individuals primed with all licensed quadrivalent meningococcal conjugate vaccines (MenACWY-TT, MenACWY-CRM, and MenACWY-D) Immunological equivalence of multiple manufacturing lots of MenACWY-TT demonstrated, highlighting robust manufacturing process Immunogenicity and safety demonstrated following concomitant administration with routine adolescent vaccines (Tdap and HPV4) Favorable safety profile across all age groups in which the vaccine was evaluated	Baccarini et al.,^Citation71 Chang et al.,^Citation72 Dhingra et al.,^Citation73 Áñez et al.,^Citation74 Esteves-Jaramillo et al.,^Citation76 Kirstein et al.^Citation75

GMT, geometric mean titer; HPV4, quadrivalent human papilloma virus vaccine; hSBA, serum bactericidal assay with human complement; MenACWY-CRM, meningococcal (groups A, C, W, and Y) conjugate vaccine with modified diphtheria toxin (CRM₁₉₇) carrier (Menveo®, GlaxoSmithKline Vaccines Srl, Bellaria-Rosia, Italy); MenACWY-D, meningococcal (groups A, C, W, and Y) conjugate vaccine with diphtheria toxoid (D) carrier (Menactra®, Sanofi , USA); Tdap, tetanus, diphtheria, acellular pertussis vaccine.

Table 3. Summary of studies that supported the licensure of MenACWY-TT in the United States.

Study Title	Study Phase and Number Reference	Clinical Trial Registry Identifiers	Age Group	Study Design	Comparator
Study of an Investigational Quadrivalent Meningococcal Conjugate Vaccine Administered in Children Aged 2 to 9 Years	III; MET35* Baccarini et al.,^Citation71	ClinicalTrials.gov:NCT03077438 WHO: U1111-1161-2625	2–9 years	Randomized, active-controlled, modified double-blind study	MenACWY-CRM
Immunogenicity and Safety of an Investigational Quadrivalent Meningococcal Conjugate Vaccine in Healthy Adolescents	II; MET50* Chang et al.,^Citation72	ClinicalTrials.gov: NCT02199691 WHO: U1111-1143-8537	10–17 years	Open-label, randomized, parallel-group, multi-center study that included an evaluation of immunogenicity and safety when concomitantly administered with Tdap and HPV4 vaccines	MenACWY-CRM
Immune Lot Consistency, Immunogenicity, and Safety of an Investigational Quadrivalent Meningococcal Conjugate Vaccine	III; MET43* Dhingra et al.,^Citation73	ClinicalTrials.gov: NCT02842853 WHO: U1111-1161-3060	10–55 years	Randomized, active-controlled, modified double-blind study	MenACWY-D
Immunogenicity and Safety of a Booster Dose of an Investigational Quadrivalent Meningococcal Conjugate Vaccine	III; MET56* Áñez et al.,^Citation74	ClinicalTrials.gov: NCT02752906 WHO: U1111-1161-2710	≥15 years; participants had to have received MenACWY-D or MenACWY-CRM 4–10 years previously, at age ≥10 years	Randomized, active-controlled, modified double-blind study	MenACWY-D
Immunogenicity and Safety of an Investigational Quadrivalent Meningococcal Conjugate Vaccine in Adults 56 Years and Older	III; MET49* Esteves-Jaramillo et al.,^Citation76	ClinicalTrials.gov: NCT02842866	≥56 years	Randomized, active-controlled, modified double-blind study	MPSV4
Study of a Quadrivalent Meningococcal Conjugate Vaccine in Subjects Aged 56 and Older	II; MET44† Kirstein et al.,^Citation75	ClinicalTrials.gov: NCT01732627 WHO: U1111-1127-6804	≥56 years	Randomized, active-controlled, open-label study	MPSV4

MenACWY-CRM, meningococcal (groups A, C, W, and Y) conjugate vaccine with modified diphtheria toxin (CRM₁₉₇) carrier (Menveo®, GlaxoSmithKline Vaccines Srl, Siena, Italy); MenACWY-D, meningococcal (groups A, C, W, and Y) conjugate vaccine with diphtheria toxoid (D) carrier (Menactra®, Sanofi , USA).

*Pivotal studies and †ancillary study that supported the licensure of the MenACWY-TT conjugate vaccine in the United States.

Figure 1. Immunogenicity findings of pivotal Phase II and Phase III studies of MenACWY-TT: Seroprotection rates based on post-vaccination Day 30 hSBA titers. The seroprotection rate was defined as the proportion of participants with post-vaccination hSBA titers ≥1:8. White bars depict data for MenACWY-TT and gray bars depict data for comparator vaccines.

Figure 2. Immunogenicity findings of pivotal Phase II and Phase III studies of MenACWY-TT: Seroresponse rates based on post-vaccination Day 30 hSBA titers. The seroresponse rate was defined as the proportion of participants with post-vaccination hSBA titers ≥1:8 (for study MET50) and ≥1:16 (for all other studies) if pre-vaccination titers were <1:8 or with a ≥4-fold increase if pre-vaccination titers were ≥1:8. White bars depict data for MenACWY-TT and gray bars depict data for comparator vaccines.

Figure 3. Immunogenicity findings of pivotal Phase II and Phase III studies of MenACWY-TT: Geometric means of hSBA titers on post-vaccination Day 30 in the per-protocol population. White bars depict data for MenACWY-TT and gray bars depict data for comparator vaccines.

Figure 4. Immunogenicity of booster doses of MenACWY-TT among participants ≥15 years of age in Study MET56: seroprotection rates (top), seroresponse rates (middle), and GMTs (bottom) based on hSBA titers on post-vaccination Days 6 (left) and 30 (right) in the per-protocol population. White bars depict data for MenACWY-TT and gray bars depict data for MenACWY-D.

Figure 5. Immunogenicity of MenACWY-TT across age groups among adults ≥56 years of age in Study MET49: hSBA seroresponse rates on post-vaccination Day 30 in the per-protocol population. White bars depict data for MenACWY-TT and gray bars depict data for MPSV4.

Table 4. Summary of safety findings of phase II and phase III studies of MenACWY-TT, safety analysis population.

Study Number, Age Group, Participant Numbers, and Reference	Safety Findings
MET35* 2–9 Years MenACWY-TT (N = 498) vs MenACWY-CRM (N = 494) Baccarini et al.,^Citation71	Safety profiles of MenACWY-TT and MenACWY-CRM were comparable Similar proportions of participants in the respective vaccine groups reported solicited systemic reactions (34.5% and 37.0%) and injection site reactions (46.8% and 53.9%) 38.6% and 42.4% of participants in the MenACWY-TT and MenACWY-CRM groups reported pain, which represented the most frequent solicited injection site reaction 21.1% and 20.4% of participants in the MenACWY-TT and MenACWY-CRM groups reported malaise, the most frequent solicited systemic reaction No participants dropped out of the study due to AEs or ARs No SAEs considered to be related to vaccination were reported in both vaccine groups Vaccine safety profiles remained comparable even upon stratification by age (2–5 and 6–9 years)
MET50* 10–17 years Group 1: MenACWY-TT (N = 503) Group 2: MenACWY-CRM (N = 501) Group 3: MenACWY-TT + Tdap + HPV4 (N = 392) Group 4: Tdap + HPV (N = 296) Chang et al.,^Citation72	MenACWY-TT was safe whether administered alone or concomitantly with Tdap and HPV vaccines Solicited reactions from vaccination to Day 7 were reported by similar proportions of participants in Groups 1 and 2 (63.5% and 64.2%, respectively) and Groups 3 and 4 (88.9% and 89.0%, respectively) Reports of solicited injection site reactions were similar in Groups 1 and 2 (46.6% and 45.7%, respectively) and Groups 3 and 4 (84.5% and 82.4%, respectively); local reactogenicity was not materially impacted whether MenACWY-TT was administered alone or co-administered with Tdap and HPV4 Solicited systemic reactions were reported by similar proportions of participants in Groups 1 and 2 (52.0% and 51.0%, respectively) and Groups 3 and 4 (70.6% and 65.9%, respectively) Pain (45.2% in Groups 1 and 2; 47.2% in Group 3) erythema (5.0% in Group 1; 7.5% in Group 2; 3.9% in Group 3), and swelling (5.4% in Group 1; 6.5% in Group 2; 4.4% in Group 3) were the most frequently reported solicited injection site reactions to MenACWY-TT Immediate AEs occurring within the first 30 minutes were rare and not considered serious No participant dropped out of the study due to AEs Four of the 16 SAEs reported during the study occurred within the first 30 days; none of the 16 SAEs were considered to be related to vaccination No deaths were reported
MET 43* 10–55 years MenACWY-TT (3 Pooled Lots; N = 2676) vs MenACWY-D (N = 635) Dhingra et al.,^Citation73	AEs, ARs, SAEs, and MAAEs were reported by similar proportions of participants across study groups Pain, the most common solicited injection site reaction, was reported by 38.8% and 38.3% of participants in the MenACWY-TT (pooled lots) and MenACWY-D groups, respectively Myalgia, the most common solicited systemic reaction, was reported by 32.0% of participants in the MenACWY-TT (pooled lots) group and 31.2% of participants in the MenACWY-D group Headache, the second most common solicited systemic reaction, was reported by 27.9% and 27.8% of participants, respectively Dizziness within 30 minutes of vaccination was reported by 0.3% and 0.2% of participants in the 2 groups, respectively, with these events resolving on the same day Immediate SAEs, anaphylactic events, or life-threatening events were not reported by any participant No participants dropped out due to AEs No deaths were reported
MET56* ≥15 years MenACWY-TT (N = 402) vs MenACWY-D (N = 407) Áñez et al.,^Citation74	46.5% and 49.3% of participants in the MenACWY-TT and MenACWY-D groups, respectively, reported solicited injection site reactions Pain, the most common solicited injection site reaction, was reported by 44.7% and 48.8% of participants, respectively, in the 2 vaccine groups 55.3% and 54.2% of participants in the 2 vaccine groups, respectively, reported solicited systemic reactions Headache and myalgia were the most common solicited systemic reactions, occurring in 37.9% and 33.3% of participants and in 36.7% and 38.8% of participants in the 2 vaccine groups, respectively; all occurrences were of Grades 1 or 2 in severity No participants dropped out due to AEs or SAEs and no deaths were reported
MET49* ≥56 Years MenACWY-TT (N = 448) vs MPSV4 (N = 453) Esteves-Jaramillo et al.,^Citation76	Injection site reactions were more frequently reported by MenACWY-TT recipients (26.6%) than MPSV4 recipients (9.5%) Although pain was the most common injection site reaction (25.5% vs 9.6% in the 2 groups, respectively), there was no increase in its severity between groups (0.7% of participants in both groups reported Grade 3 pain) Solicited systemic reactions were reported by a greater proportion of participants in the MenACWY-TT group (31.2%) than those in the MPSV4 group (24.2%) Myalgia (21.9% vs 15.3%, respectively), headache (19.0% vs 14.6%, respectively), and malaise (14.5% vs 11.3%, respectively) were the most common solicited systemic reactions Immediate hypersensitivity reactions or SAEs were not reported by any recipient of either vaccine Two deaths in the MPSV4 group (one due to metastatic lung cancer and the other due to spinal column injury due following a road traffic accident) reported during the study were deemed unrelated to vaccination
MET44† ≥56 MenACWY-TT (N = 199) vs MPSV4 (N = 100) Kirstein et al.,^Citation75	Reactogenicity profiles of both vaccines were similar; no immediate hypersensitivity reactions were reported by participants in either group, while reports of solicited injection site reactions were similar between groups (35.7% and 35.0%, respectively) Solicited systemic reactions were reported by similar proportions of participants in the MenACWY-TT and MPSV4 groups (46.7% and 41.0%, respectively) Pain, the most commonly reported solicited injection site reaction, occurred in 30.7% and 32.0% of participants in the MenACWY-TT and MPSV4 groups, respectively Myalgia, the most commonly reported solicited systemic reaction, was reported by 35.2% and 26.0% of participants in the MenACWY-TT and MPSV4 groups, respectively The safety profile did not differ between participants 56–64 years of age and those ≥65 years of age There were no AEs or SAEs leading to study discontinuation or deaths during the study

AE, adverse event; AR, adverse reaction; CI, confidence intervals; MAAE, medically attended adverse event; MenACWY-CRM, meningococcal (groups A, C, W, and Y) conjugate vaccine with modified diphtheria toxin (CRM₁₉₇) carrier (Menveo®, GlaxoSmithKline Vaccines Srl, Siena, Italy); MenACWY-D, meningococcal (groups A, C, W, and Y) conjugate vaccine with diphtheria toxoid (D) carrier (Menactra®, Sanofi , USA); SAE, serious adverse event.

*Pivotal studies and †ancillary study that supported the licensure of the MenACWY-TT conjugate vaccine in the United States.

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