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

ABSTRACT

Vaccination offers the best way to prevent invasive meningococcal disease (IMD). As demonstrated in countries with national immunization programs (NIPs) against IMD, meningococcal conjugate vaccines have contributed to significant declines in incidence. Since some meningococcal vaccines are associated with modest immunogenicity in infants, possible immunological interference upon concomitant administration with some pediatric vaccines, and administration errors resulting from improper reconstitution, opportunities for improvement exist. A quadrivalent conjugate vaccine, MenQuadfi® (Meningococcal [Serogroups A, C, Y, and W] Conjugate Vaccine; Sanofi, Swiftwater, Pennsylvania), was approved in 2020 for the prevention of IMD caused by meningococcal serogroups A, C, W, and Y in individuals ≥2 years of age in the United States. Five pivotal studies and one ancillary study supported approval in the United States; clinical trials in infants are ongoing. Data on the immunogenicity and safety of this vaccine are presented, and its potential value in clinical practice is discussed.

KEYWORDS:

• Immunogenicity
• invasive meningococcal disease
• IMD
• MenACWY-CRM
• MenACWY-D
• MenACWY-TT
• MenACYW-TT
• MenQuadfi
• meningococcal conjugate vaccine
• safety
• vaccine recommendations

View correction statement:

Correction

Introduction

Invasive meningococcal disease (IMD) is an acute and often fatal infection that occurs globally.^1–3 The etiologic agent—Neisseria meningitidis—colonizes the nasopharynx in 8% to 25% of healthy adolescents and adults.⁴ Invasive meningococcal disease results when an encapsulated pathogenic strain enters the bloodstream of a nonimmune host, causing bacteremia, which can progress to sepsis, purpura fulminans, meningitis, or other focal infections.⁵ Events that trigger invasion, including bacterial and viral respiratory infections and smoking, tend to involve disruption of the normal upper respiratory mucosal barrier.^2–8 Case-fatality rates (CFRs) are as high as 10% to 15% despite appropriate antibiotic therapy, with up to 20% of survivors experiencing permanent sequelae including loss of digits or even limbs, neurologic complications, and/or hearing loss.^3,9 Incidence of IMD is highest in children younger than 5 years of age, particularly infants, with a second peak observed during adolescence and young adulthood; CFRs are highest among the elderly (i.e., those ≥65 years of age).^10–14

Although 12 serogroups of Neisseria meningitidis (distinguished by their polysaccharide capsule) have been identified, only serogroups A, B, C, W, X, and Y are associated with most cases of IMD. Regional variations in serogroup distribution are frequently observed. For example, serogroups B, C, and Y are frequently isolated in North America, while serogroup A is frequently isolated in parts of Africa and Asia.¹⁴ Temporal variations in serogroup prevalence, which are unpredictable, are best exemplified by the increasing reports of IMD caused by serogroups X in Africa and W and/or Y in Australia, Africa, South America, and Europe in recent years.^15–19 Serogroup W has been associated with IMD reported during mass gatherings such as the annual Hajj/Umrah pilgrimage.^11,20,21 Hypervirulent strains of serogroup W are associated with higher mortality and are known to present with atypical symptoms including diarrhea and myocarditis, confounding diagnosis and leaving open the possibility of delays in treatment.^22–26

In the United States, the overall incidence of IMD in 2018, the latest year for which final Active Bacterial Core Surveillance (ABCs) data are available, was 0.10 per 100,000 population. The incidence was highest (0.83/100,000 population) in infants, followed by children 1–4 years of age (0.18/100,000 population), adults ≥65 years of age (0.14/100,000 population), and adolescents and young adults 16–23 years of age (0.10/100,000 population).¹² A 2018 meta-analysis documented CFRs associated with laboratory-confirmed IMD cases to be 9% in infants, decreasing to 7% in 7-year-old children before increasing to 15% in young adults, remaining below 20% up to the age of 60 years and increasing to a high above 40% in the mid-eighties.²⁷ The pooled CFR was highest for serogroup W (12.8%), followed by serogroup C (12.0%), Y (10.8%), and B (6.9%).²⁷ It is important to note that incidence of IMD caused by serogroups A, C, W, and Y has declined substantially since 1996; some of that decline, which occurred prior to the introduction of quadrivalent meningococcal vaccine, might have been due to reduction in tobacco use and increased use of fluoroquinolones.²⁸ The additional decline in IMD incidence since 2005 is considered attributable to the introduction of quadrivalent meningococcal conjugate vaccines (MenACWY) (see below for discussion of the vaccines available in the United States). This is evident through annual reductions by 10.6% and 35.6% in IMD caused by serogroups C, W, and Y among adolescents (the focus of the meningococcal immunization program in the US) and young adults following receipt of primary and booster doses, respectively, with reductions in IMD incidence being more pronounced in states with high vaccination coverage.^13,29,30

Although antibiotic resistance has been uncommon among meningococcal isolates in the United States,³¹ the recent detection of serogroup Y isolates resistant to both penicillin and ciprofloxacin is a cause for concern.³² This, in the context of the rapidity of progression of IMD, high fatality rates despite treatment, and the likelihood of debilitating lifelong sequelae,^1–3,9 underscores the need for primary prevention through vaccination and secondary prophylaxis. Unconjugated polysaccharide vaccines against serogroups A, C, W, and Y do not induce a memory response, do not reduce nasopharyngeal carriage, may manifest hyporesponsiveness upon repeat dosing, and are weakly immunogenic in infants; all of these limitations are addressed by protein–polysaccharide conjugate vaccines.^33–35 Conjugate vaccines using serogroup-specific polysaccharide formulations against serogroups A, C, W, and Y, including monovalent and quadrivalent formulations, have been developed and included in national immunization programs (NIPs) globally.^11,36 For serogroup B, the poor immunogenicity of the capsular polysaccharide necessitated the development of vaccines based on subcapsular surface protein antigens.³⁷

Inclusion of meningococcal vaccines in NIPs is based on recommendations from national immunization technical advisory groups (NITAGs), which take into consideration the burden of IMD, epidemiological changes, vaccine availability, vaccine efficacy, and cost-effectiveness of available vaccines.³⁸ Although the vaccines introduced over time have collectively contributed to significant declines in the global incidence of IMD,^{10,11,13,29,30,34,39} revision of national immunization policies may be necessitated by local changes in meningococcal epidemiology, including serogroup distribution.⁴⁰

Three MenACWY are licensed and available in the United States (Table 1).⁴¹ The first, licensed in 2005, is MenACWY-D (Menactra®, Sanofi, Swiftwater, PA, USA), which uses a diphtheria toxoid (D) carrier protein and is approved for use in individuals 9 months through 55 years of age.⁴² The second, licensed in 2010, is MenACWY-CRM (Menveo®, GSK Vaccines Srl, Sovicille, Italy).⁴³ This vaccine uses a nontoxic variant of diphtheria toxin (CRM₁₉₇) as the carrier protein and is approved for use in persons 2 months through 55 years of age. The most recently introduced vaccine (licensed in 2020) is MenACWY-TT (MenQuadfi®, Sanofi, Swiftwater, PA, USA),⁴⁴ which features a tetanus toxoid (TT) carrier protein and is approved for use in individuals ≥2 years of age including adults ≥55 years of age. Studies conducted in the US regarding infants from ≥6 weeks of age are ongoing.

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.

The effectiveness and safety of both MenACWY-D and MenACWY-CRM have been extensively documented;^{13–29,30–45–47} however, there may be room for improvement. For example, while real-world effectiveness of MenACWY-D in adolescents and young adults has been demonstrated, immunogenicity in infants 2–6 months of age is modest.⁴⁸ Moreover, a descriptive/exploratory study in adults ≥56 years of age revealed the immunogenicity of MenACWY-D to be comparable but not appreciably better than that of an unconjugated quadrivalent polysaccharide vaccine (MPSV4; Menomune® – A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y, and W-135 Combined [Sanofi, Swiftwater, PA, USA]).⁴⁹ In the case of MenACWY-CRM, while one study documented immunogenicity in adults 56–65 years of age to be non-inferior compared with MPSV4,⁵⁰ two other studies on the immunogenicity of MenACWY-CRM in adults ≥56 years of age were inconclusive because the data were not sufficiently granular to assess immunogenicity in the age group of interest.^51,52

There appears to be immunological interference upon concomitant administration of MenACWY-D with some routine vaccines administered in childhood (e.g., the pneumococcal conjugate vaccine [PCV] and diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed [DTaP]),^42,53 although the clinical significance of the marginally lower responses against the pertussis antigen (fimbriae) in DTaP is not clear since no correlates of protection against pertussis have been defined.⁴² Similar reductions of the immune responses to pneumococcal and pertussis antigens have been documented upon concomitant administration of MenACWY-CRM with PCV7 or the 13-valent pneumococcal conjugate vaccine [PCV13]^43,54 or with DTaP,⁵⁵ although the attenuation of responses to pneumococcal antigens was restricted only to pneumococcal serotypes 6B and 23F and seen only after the third dose but not other doses of a four-dose series. Again, the clinical significance of lower responses to pertussis antigens is uncertain due to lack of defined correlates of protection against pertussis.⁴³ Finally, although it does not constitute concomitant administration, use of MenACWY-D 1 month after DTaP has been shown to result in attenuated responses to meningococcal antigens, prompting the suggestion that these two vaccines (MenACWY-D and DTaP) either be administered simultaneously or that MenACWY-D be administered prior to DTaP.

Although a few case reports soon after the introduction of MenACWY-D suggested a possible link between its use and the incidence of Guillain–Barré syndrome (GBS),⁵⁶ multiple subsequent studies found no association between the two.^41–57–61 A cohort study that evaluated the safety of MenACWY-CRM reported a higher risk for Bell’s palsy in individuals receiving concomitant vaccines compared with those receiving MenACWY-CRM alone, but it was not clear whether the observed association was a chance occurrence, due to concomitant vaccination, or due to an underlying predisposition to Bell’s palsy.⁶² No other significant safety concerns regarding MenACWY-D or MenACWY-CRM have been documented after licensure,^45,46,63,64 confirming the excellent safety profile of conjugate ACWY vaccines. However, administration errors are more common with MenACWY-CRM than with other vaccines, presumably due to the need for reconstitution of two components, which are supplied in separate vials.^45–65–67 The two components include the lyophilized MenA conjugate component and the liquid MenCWY component,⁴³ leaving open the possibility that reconstitution errors will result in lack of protection against some of the serogroups targeted by the vaccine.⁶⁵

MenACWY-TT was developed to help address some of the limitations associated with previously approved MenACWY. Preclinical screening studies by Sanofi that employed more than 100 glycoconjugates synthesized on a small scale to evaluate physicochemical properties, stability, ease of manufacturing, and immunogenicity in mouse models identified TT as being the most immunogenic carrier protein.⁶⁸ This finding led to the choice of TT as the carrier protein for the MenACWY-TT vaccine, with the expectation of improving immunogenicity in infants and the elderly.

The approval of MenACWY-TT in the United States was based on demonstrated noninferior immunogenicity and comparable safety versus licensed comparators in different age groups.⁶⁹ Salient characteristics of MenACWY-TT are listed in Table 2. MenACWY-TT was approved in 2020 for use in individuals ≥2 years of age in the United States and individuals ≥12 months of age as a single dose in the European Union and other countries. Clinical data from five pivotal studies (MET35, MET50, MET43, MET49, and MET56) and one ancillary study (MET44) conducted in the United States and Puerto Rico supported licensure of the vaccine in persons ≥2 years of age (Table 3).^70–76 Additional data on immunogenicity, safety, and compatibility with concomitantly administered vaccines are available from studies conducted in other countries that supported licensure outside the United States;^77–80 these were reviewed by Martinón-Torres et al.⁸¹ and included studies in which Nimenrix®, another MenACWY-TT vaccine licensed outside the US, was used as comparator. This manuscript provides an overview of the published data on the immunogenicity and safety of MenACWY-TT in individuals ≥2 years of age, including adults ≥56 years of age – an age group for which an FDA-approved meningococcal conjugate vaccine did not previously exist. We also discuss the vaccine’s potential role in clinical practice in the United States.

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.

Methods

In this overview of the immunogenicity and safety of MenACWY-TT, the intent was to focus on the clinical studies that supported the licensure of the vaccine in the United States for use in individuals ≥2 years of age. The PubMed/Medline database was searched on July 1, 2021, to retrieve the published peer-reviewed literature on the immunogenicity and safety of MenACWY, with studies focusing on the immunogenicity and safety of MenACWY-TT among participants in the United States being identified for inclusion through an iterative process as depicted in Supplementary Figure S1, which also provides details on the terms used in the literature search.

Results

Literature search

The literature search described above retrieved 106 primary articles. Following review of the titles and abstracts of each retrieved study, 5 primary articles (defined as articles directly reporting the findings of individual clinical studies on the immunogenicity and safety of MenACWY-TT) were retained; see Supplementary Figure S1 for an accounting of articles retrieved, eliminated, and retained. One primary article reporting the findings of a MenACWY-TT study conducted in children 2–9 years of age (MET35)⁷¹ was not retrieved through the search (possibly due to non-inclusion of the keyword ‘MenACWY-TT’ in the ‘substances’ section of the PubMed record for this article) but was captured based on the authors’ knowledge of its publication and suitability for inclusion. Accordingly, a total of six primary articles that documented the immunogenicity and safety of MenACWY-TT in individuals ≥2 years of age have been included (Table 3).^71–76 Study participants included meningococcal vaccine-naïve individuals, individuals primed with licensed MenACWY, and those concomitantly receiving other routinely administered adolescent vaccines. In each active-controlled study, a US-licensed meningococcal vaccine approved for use at the time of conduct of the study was used as the comparator: MenACWY-D, MenACWY-CRM, or the quadrivalent meningococcal polysaccharide vaccine (MPSV4). MPSV4, which was discontinued in 2017, was the only vaccine licensed for use in adults ≥56 years of age in the United States at the time two of the studies of MenACWY-TT in this age group (MET49 and MET44) were conducted.^75,76

Immunogenicity

For purposes of licensure, assessment of the immunogenicity of investigational meningococcal vaccines is based on serum bactericidal assays (SBAs) whose results have been shown to correlate with protection against IMD.⁸² The SBAs are performed either with human complement (hSBA) or with baby rabbit complement (rSBA).⁸³ In April 2011, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the United States Food and Drug Administration (FDA) endorsed the use of hSBA to infer the effectiveness of investigational meningococcal conjugate vaccines.^84,85 Assessment of the immunogenicity of MenACWY-TT was therefore based on hSBA, with immunogenicity being defined using the following parameters: seroprotection (hSBA titers ≥1:8 on post-vaccination Day 30); seroresponse (post-vaccination hSBA titers ≥1:8 [for the Phase II US study in adolescents]⁷² or ≥1:16 [for all other US studies]^71–73–76 if pre-vaccination titers were <1:8, or a ≥4-fold increase in hSBA titer by Day 30 following vaccination if pre-vaccination titers were ≥1:8); and geometric mean antibody titers (GMTs). Demonstration of immunological noninferiority required the lower limit of the 2-sided 95% confidence interval (CI) of the difference between proportions of participants in the MenACWY-TT group and the comparator group who achieved a seroresponse to be greater than −10% for all four serogroups. Immunogenicity findings of the studies (i.e., seroprotection rates, seroresponse rates, and hSBA GMTs) are depicted in Figures 1–5 and summarized in Supplementary Tables S1–3. Data on seroprotection are discussed below.

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.

Study MET35 (NCT03077438), a Phase III randomized study, compared the immunogenicity of a single dose of MenACWY-TT versus that of MenACWY-CRM in meningococcal vaccine-naïve children 2–9 years of age.⁷¹ On post-vaccination Day 30, seroprotection rates for MenACWY-TT were numerically higher than in the MenACWY-CRM group for all four serogroups (Supplementary Table S1 and Figure 1).

One Phase II and 2 Phase III studies evaluated the immunogenicity of primary or booster doses of MenACWY-TT in adolescents and adults.^72–74 In meningococcal vaccine-naïve adolescents 10–17 years of age, study MET50 (NCT02199691) compared the immunogenicity of a single dose of MenACWY-TT with that of MenACWY-CRM and additionally assessed the immunogenicity of MenACWY-TT when given concomitantly with tetanus, reduced diphtheria, and acellular pertussis vaccine (Tdap) and quadrivalent human papillomavirus vaccine (HPV4).⁷² Seroprotection rates for all serogroups were numerically higher for MenACWY-TT than for MenACWY-CRM (Supplementary Table S1 and Figure 1). Except for the findings noted below, concomitant administration of MenACWY-TT, Tdap, and HPV4 did not adversely affect the immunogenicity of the vaccines. Non-inferiority, as assessed by the geometric mean concentrations (GMCs) of antibodies against pertussis antigens, was met for only one antigen (pertussis toxoid [PT]). Non-inferiority was not met for fimbriae types 2 and 3 (FIM) and marginally missed for both filamentous hemagglutinin (FHA) and pertactin (PRN). Of note, lower anti-pertussis antibodies have been observed following concomitant administration of Tdap and other MenACWY; however, the clinical relevance of these findings, if any, is unknown.^86,87

Study MET43 (NCT02842853) evaluated the immunogenicity of three lots of MenACWY-TT versus MenACWY-D in meningococcal vaccine-naïve adolescents and adults 10–55 years of age, demonstrating lot-to-lot consistency and noninferior immunogenicity (pooled lot data)⁷³(Supplementary Table S1). The proportion of MenACWY-TT recipients achieving seroprotection was numerically higher for each serogroup than those receiving MenACWY-D (Supplementary Table S1 and Figure 1).

Finally, study MET56 (NCT02752906) compared the immunogenicity of a booster dose of MenACWY-TT with that of MenACWY-D in participants ≥15 years of age who had received a single dose of MenACWY-D or MenACWY-CRM 4–10 years earlier.⁷⁴ Seroprotection rates were high for both MenACWY-TT and MenACWY-D, ranging between 99.5% and 100% across all 4 serogroups on Day 30 (Supplementary Table S1 and Figure 4). The kinetics of the booster response were also evaluated, revealing MenACWY-TT and MenACWY-D each elicited robust immune responses as early as 6 days after booster vaccination, as assessed by seroprotection rates, seroresponse rates, and hSBA GMTs (Supplementary Table S1 and Figure 4).

One Phase II study and 1 Phase III study assessed the immunogenicity of a single dose of MenACWY-TT versus MPSV4 in meningococcal vaccine-naïve adults ≥56 years of age.^75,76 The Phase II study MET44 (NCT01732627) compared the immunogenicity of a single dose of MenACWY-TT with that of MPSV4,⁷⁵ demonstrating robust immunogenicity against all four serogroups. These findings were corroborated by the pivotal Phase III study MET49 (NCT02842866),⁷⁶ which documented numerically higher seroprotection rates in participants receiving a single dose of MenACWY-TT compared with those receiving MPSV4 for all four serogroups, with non-overlapping 95% CIs for serogroups C, W, and Y (Supplementary Table S1 and Figure 1). Non-inferiority of the immune responses elicited by MenACWY-TT, as measured by seroresponse rates on Day 30, was also apparent when the analyses were done by age group of the participants (Figure 5). This study also documented hSBA GMTs that were similar across age subgroups for all four meningococcal serogroups (Figure 5).⁷⁶

Safety

Regarding the safety monitoring protocol, participants were monitored for immediate reactions for 30 minutes following vaccination while at the study site. Solicited injection site and systemic reactions were recorded by participants or by parents/guardians in a diary card at home daily for 7 days following vaccination. All unsolicited adverse events that occurred within 30 days following vaccination were recorded by participants or by parents/guardians and collected by the study site at the next visit. Unsolicited adverse events that were medically attended (i.e., visits to an emergency room or an unexpected visit to a health care provider), and all serious adverse events (SAEs) were collected for at least 6 months after vaccination (except for MET44 study, wherein the SAEs were collected through 30 days).

As shown in Table 4, MenACWY-TT was well tolerated in all age groups studied, with its reactogenicity being comparable to that of licensed meningococcal vaccines (the sole exception being higher rates of local reactions seen with MenACWY-TT versus MPSV4, which may be a function of differences in reactogenicity between toxoid conjugated versus nonconjugated vaccines^88,89 and routes of administration, with MPSV4 being administered subcutaneously instead of intramuscularly). No safety concerns were apparent whether MenACWY-TT was administered alone or concomitantly with routine licensed vaccines (Tdap or HPV4).

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.

Discussion

The data summarized above attest to the immunogenicity of MenACWY-TT in individuals ≥2 years of age, including adults ≥56 years of age. Importantly, immunological non-inferiority of MenACWY-TT in terms of seroresponse rates was demonstrated for all serogroups and against all meningococcal vaccine comparators (MenACWY-CRM, MenACWY-D, and MPSV4). The included studies enrolled 8,076 individuals ≥2 years of age, including 1,207 participants ≥56 years of age and provide compelling evidence that MenACWY-TT is well tolerated and safe. Moreover, co-administration with routinely recommended adolescent vaccines does not appear to materially impact the immunogenicity of either MenACWY-TT or the concomitantly administered vaccines.⁷² Finally, MenACWY-TT elicits robust booster responses. These findings support the potential for MenACWY-TT to overcome some of the deficiencies of alternative formulations and to be incorporated into NIPs worldwide.

Of note, across studies and age groups (≥2 years of age), MenACWY-TT elicited more robust immune responses versus all comparator formulations against serogroup C,^71–76 which accounts for approximately one-third of all IMD cases in the United States.¹² Although the clinical significance of higher immune responses is not well understood, these robust serogroup-specific responses are potentially relevant to protection. Recent serogroup C disease outbreaks among men who have sex with men (MSM), and the increased incidence of meningococcal urethritis being reported in the United States,^90,91 suggest that MenACWY-TT may be useful in this population. Whether higher antibody levels against serogroup C ultimately translates into improved protection against IMD caused by this serogroup represents an area for further investigation. In addition, given the continued prevalence of serogroup C in locales outside the United States,⁹² MenACWY-TT may serve as a viable option for travel vaccination.

In the United States, MenACWY-TT offers the opportunity to build upon the successes of MenACWY-D and MenACWY-CRM. Immunogenicity of meningococcal conjugate vaccines is modulated by the carrier protein used: D conjugates seem to be less immunogenic in general, while some TT conjugates may dampen polysaccharide responses, and CRM conjugates may cause bystander interference.⁹³ MenACWY-TT has a novel formulation that involved a serogroup-specific conjugation strategy to link capsular polysaccharides to the carrier protein.⁶⁸ This strategy may contribute to its robust immunogenicity.

The demonstrated compatibility of MenACWY-TT with routine vaccines^72,94,95 argues well for its potential to be included in national vaccination schedules. Moreover, MenACWY-TT is available as a single-vial liquid formulation,⁴⁴ facilitating avoidance of reconstitution errors, which can help save time and keep costs down.^96–99 Elimination of the need for reconstitution would also help ensure protection against all four meningococcal serogroups targeted by the vaccine.⁶⁵

MenACWY-TT induces rapid booster responses in adolescents and adults irrespective of the type of priming vaccine (MenACWY-D or MenACWY-CRM).⁷⁴ Seroprotection rates of >96% in MenACWY-primed recipients by post-vaccination Day 6 suggests the potential value of the vaccine for control of outbreaks in closed communities such as scout camps and educational institutions,^100–102 where early protection is crucial to prevent additional cases of IMD. Immunization of vaccine-naïve or primed adolescents with MenACWY-TT may be highly beneficial in disease control given their role in transmission to infants and the elderly, who are more vulnerable.

Although no meningococcal conjugate vaccine was labeled for immunization of adults ≥56 years of age in the US until the licensure of MenACWY-TT,⁴¹ the higher incidence and CFRs documented with IMD in older adults in the United States^12,27supports the case for immunization of persons in this age group who are at increased risk for IMD (e.g., due to complement deficiencies, anatomic, or functional asplenia, HIV positivity, or enhanced exposure resulting from travel to areas where IMD is endemic or work as microbiologists). Although immunization of persons ≥56 years of age at increased risk for IMD is recommended by the ACIP, MenACWY-TT is currently the only quadrivalent conjugate vaccine in the US licensed for use in this age group and as such represents the only quadrivalent conjugate that can be used on-label in such high-risk populations.^41,103 Two studies conducted in the United States (MET49 [NCT02842866] and MET44 [NCT01732627])^75,76 have documented the immunogenicity and safety of MenACWY-TT in adults ≥56 years of age compared with MPSV4, which was licensed and available at the time of conduct of the studies. Immunogenicity and safety were analyzed by age group in both studies, with immunogenicity and safety being demonstrated even in adults ≥75 years of age. Of note, older adults are known to visit countries where serogroup W and/or Y has increasingly been implicated in IMD^17–19or participate in the annual Hajj or Umrah pilgrimage where outbreaks caused by serogroup W have been reported.^20,21 This group now has the option for on-label use of MenACWY-TT, enabling them to travel with greater confidence, taking into account the potential advantages of conjugate vaccines over previously available MPSV such as preventing acquisition of virulent meningococci and transmission to vulnerable individuals. Vaccination of such travelers assumes added importance given the sheer number of pilgrims participating in these events (more than 4 million globally annually, with projections of significant increases in the future) and the requirement by the Saudi Arabian government that all Hajj or Umrah pilgrims be immunized.²¹

The studies reviewed here also underscore the safety of MenACWY-TT across age groups when administered alone or concomitantly with routinely recommended adolescent vaccines. The safety of MenACWY-TT, viewed in conjunction with the previously documented safety of MenACWY-CRM⁴⁵and MenACWY-D,⁴⁶ suggests that MenACWY as a class is safe and well tolerated. Although concerns about the risk for GBS were raised shortly after MenACWY-D became available for use, several studies have refuted a heightened risk for GBS.^57–61 Evaluations of data from the Vaccine Safety Datalink (VSD) through 2014 and from the Vaccine Adverse Event Reporting System (VAERS) through 2016 have revealed no cause for concern regarding GBS in MenACWY-D recipients.⁴¹ Similarly, a comprehensive review of VAERS data collected between 2010 and 2015 revealed no safety concerns with MenACWY-CRM, including no heightened risk of GBS or Bell’s palsy following administration.⁴⁵

A unique strength of the MenACWY-TT clinical development program is the substantial number of participants enrolled (8,076 individuals ≥2 years of age, of whom 1,207 participants were ≥56 years of age). Another strength is that immunogenicity has been assessed using both SBA types accepted by regulatory authorities in different regions of the world (hSBA and rSBA, the latter of which has been performed in a subset of participants in all studies).^104,105 Immunogenicity has been assessed using multiple parameters (seroresponse, seroprotection, and GMTs) to satisfy regulatory requirements, with the primary objective being demonstration of non-inferiority as measured by seroresponse. The immunogenicity data are comparable across studies since they were all generated in the same laboratories for all studies, with all hSBAs being performed by the Sanofi Global Clinical Immunology laboratory in Swiftwater, Pennsylvania, and all rSBAs being performed at the UK Health Security Agency (formerly Public Health England) laboratory in Manchester.

Ongoing efforts to evaluate MenACWY-TT are worth mentioning. For example, although data on immunogenicity and safety of the vaccine in toddlers 12–23 months of age are available,^77,79,80 corresponding data in infants <12 months of age are currently restricted to a recently published Phase II study (NCT01049035; MET39) conducted by Cornish et al.¹⁰⁶ In this study, MenACWY-TT was evaluated in US infants and toddlers (from 6 weeks to 12 months of age). In this age group, MenACWY-TT induced robust immune responses and was well tolerated. Moreover, immunogenicity profiles of routine pediatric vaccines concomitantly administered with MenACWY-TT were similar whether administered with MenACWY-TT or without it. To further assess the performance of MenACWY-TT in young children, seven studies (Phase II or III) in infants as young as 6 weeks of age are currently ongoing and will shed more light not only on immunogenicity and safety but also help identify optimal vaccination schedules.^107–113 The findings of these studies are of particular interest since infants are among the age groups at increased risk of IMD. In addition, data on immunogenicity and safety in populations with high-risk conditions are not available. Finally, data on the persistence of immunity following vaccination with MenACWY-TT are limited. However, preliminary data from two Phase III studies evaluating antibody persistence following primary vaccination with MenACWY-TT, MenACWY-CRM, or MPSV4 are encouraging.^114,115 Study MET59 (NCT04084769)¹¹⁶ revealed antibody persistence for 3–6 years in adolescents and adults primed with MenACWY-TT.¹¹⁴ Study MEQ00066 (NCT04142242)¹¹⁷ documented antibody persistence for up to 7 years following primary vaccination with MenACWY-TT or MPSV4, with persistence being higher for serogroups C, W, and Y in patients ≥56 years of age receiving MenACWY-TT.¹¹⁵ However, it is unclear whether the level of antibodies that were observed for up to 7 years after primary vaccination translates into a longer duration of protection.

Conclusions

The comprehensive body of evidence on the immunogenicity and safety of MenACWY-TT summarized in this paper supports its use for the prevention of IMD in individuals ≥2 years of age in the United States, with accruing data on its immunogenicity and safety in infants as young as 6 weeks of age potentially enhancing its utility across the entire age spectrum. Compatibility of the vaccine with routinely recommended vaccines suggests that it can be seamlessly incorporated into NIPs. The use of tetanus toxoid protein as a carrier in MenACWY-TT did not adversely affect its reactogenicity or immunogenicity profile. The vaccine induced robust and rapid booster responses against all four meningococcal serogroups. The summarized data collectively demonstrate that MenACWY-TT is a safe and effective quadrivalent meningococcal conjugate vaccine. It offers convenience as it does not require reconstitution and has the potential to effectively address the burden of IMD globally.

Author’s contributions

GSM, SIP, CAR, and PO contributed to the literature search strategy, drafting, and review of the manuscript, and approval of the final version for submission.

Acknowledgements

The authors thank Jean-Sébastien Persico, MAS, and Sonal Gawande, MD, of Sanofi, Lyon, France, and Anirban Sanyal, PhD, Alok Vyas, PhD, and Priya Upadhyay of Sanofi, Hyderabad, India, for managing the development of the manuscript. Assistance with the preparation of the manuscript was provided by Prasad S. Kulkarni, PhD, CMPP of Asclepius Medical Communications LLC, Ridgewood. New Jersey, USA, and was funded by Sanofi, Lyon, France.

Disclosure statement

CAR and PO are employees of, and hold stock options in, Sanofi. GSM has been an investigator on clinical trials funded by GlaxoSmithKline, Merck, Novartis, Pfizer, Sanofi, and Seqirus, and has received honoraria from these companies for service on advisory boards. SIP has received honoraria from Sanofi for participation in advisory boards on meningococcal conjugate vaccines, influenza vaccines, and COVID-19 vaccines; grants, consulting fees, and honoraria from Pfizer, Inc. for participation in a Data and Safety Monitoring Board (DSMB) for pneumococcal vaccine studies; and honoraria from Seqirus for participation on advisory committees on influenza and COVID-19 vaccines.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2022.2099142.

Additional information

Funding

This work was supported by Sanofi, Lyon, France.