MENQUADFI solution for injection medication leaflet

MenQuadfi solution for injection

Meningococcal Group A, C, W and Y conjugate vaccine

MenACWY

One dose (0.5 mL) contains:

Neisseria meningitidis group A polysaccharide1 10 micrograms

Neisseria meningitidis group C polysaccharide1 10 micrograms

Neisseria meningitidis group W polysaccharide1 10 micrograms

Neisseria meningitidis group Y polysaccharide1 10 micrograms1Conjugated to tetanus toxoid carrier protein 55 micrograms

For the full list of excipients, see section 6.1.

Solution for injection

Clear colourless solution.

MenQuadfi is indicated for active immunisation of individuals from the age of 12 months and olderagainst invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W, and Y.

The use of this vaccine should be in accordance with available official recommendations.

* Individuals 12 months of age and older: One single dose (0.5 mL).

Booster vaccination:

* A single 0.5 mL dose of MenQuadfi may be used to boost subjects who have previously received ameningococcal vaccine containing the same serogroups (see section 5.1).

* Long-term antibody persistence data following vaccination with MenQuadfi are available up to7 years after vaccination (see sections 4.4 and 5.1).

* There are no data available to indicate the need for or timing of a booster dose of MenQuadfi (seesection 5.1).

The safety and immunogenicity of MenQuadfi in individuals under 12 months of age have not yet beenestablished.

For intramuscular injection only, preferably in the deltoid region or anterolateral thigh depending on therecipient's age and muscle mass.

For instructions on handling of the vaccine before administration, see section 6.6.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 or after previousadministration of the vaccine or a vaccine containing the same components.

In order to improve the traceability of biological medicinal products, the name and the batch number ofthe administered product should be clearly recorded.

MenQuadfi should not be administered subcutaneously, intravascularly or intradermally.

It is good clinical practice to precede vaccination by a review of the medical history (especially withregard to previous vaccination and possible occurrence of undesirable effects) and a clinical examination.

As with all injectable vaccines, appropriate medical treatment and supervision should always be readilyavailable in case of an anaphylactic event following administration of the vaccine.

Vaccination should be postponed in individuals suffering from an acute severe febrile illness. However,the presence of a minor infection, such as cold, should not result in the deferral of vaccination.

Syncope (fainting) and other anxiety‐related reactions can occur following or even before any vaccinationas a psychogenic response to the needle injection. Procedures should be in place to prevent falling orinjury and to manage syncope.

MenQuadfi should be given with caution to individuals with thrombocytopenia or any coagulationdisorder that would contraindicate intramuscular injection, unless the potential benefit clearly outweighsthe risk of administration.

MenQuadfi will only protect against Neisseria meningitidis groups A, C, W, and Y. The vaccine will notprotect against any other Neisseria meningitidis groups.

As with any vaccine, vaccination with MenQuadfi may not protect all vaccine recipients.

Waning of serum bactericidal antibody titres against serogroup A when using human complement in theassay (hSBA) has been reported for MenQuadfi and other quadrivalent meningococcal vaccines. Theclinical relevance of this observation is unknown. However, if an individual is expected to be at particularrisk of exposure to serogroup A and received a dose of MenQuadfi more than approximately one yearpreviously, consideration may be given to administering a booster dose.

Lower hSBA geometric mean titres (GMTs) against serogroup A have been observed after a single doseof MenQuadfi was administered to toddlers who previously received serogroup C meningococcalconjugate vaccine (MenC-CRM) during infancy. Nevertheless, seroprotection rates were comparablebetween treatment groups (see section 5.1). The clinical relevance of this observation is unknown. Thisaspect might be considered for individuals at high risk for MenA infection who received MenC-CRMvaccine in their first year of life.

Immunodeficiency

It may be expected that in patients receiving immunosuppressive treatment or patients withimmunodeficiency, an adequate immune response may not be elicited (see section 4.5). Persons withfamilial complement deficiencies (for example, C5 or C3 deficiencies) and persons receiving treatmentsthat inhibit terminal complement activation (for example, eculizumab) are at increased risk of invasivedisease caused by Neisseria meningitidis groups A, C, W, and Y, even if they develop antibodiesfollowing vaccination with MenQuadfi. No data on immunocompromised patients are available.

Immunisation with MenQuadfi vaccine does not substitute for routine tetanus immunisation.

Co-administration of MenQuadfi with a tetanus toxoid-containing vaccine does not impair the response totetanus toxoid or impact the safety.

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

Injection sites on separate limbs and separate syringes must be used in the case of concomitantadministration.

For ages 12-23 months, MenQuadfi can be co-administered with the measles-mumps-rubella vaccine(MMR) + varicella vaccine (V), combined diphtheria - tetanus - acellular pertussis (DTaP) vaccines,including combination DTaP vaccines with hepatitis B (HBV), inactivated poliovirus (IPV) or

Haemophilus influenzae type b (Hib) such as DTaP-IPV-HB-Hib (Hib conjugated to tetanus toxoid)vaccine and 13-valent pneumococcal polysaccharide conjugated vaccine (PCV-13).

There was no impact on the immune response to MenQuadfi when a meningococcal serogroup B vaccinewas co-administered.

MenQuadfi can be administered concomitantly with PCV-13. Lower hSBA GMTs on day 30 post-dosefor serogroup A have been observed when given concomitantly. The clinical relevance of this observationis unknown. As a precaution in children 12-23 months of age at high risk for serogroup A disease,consideration might be given for administration of MenQuadfi and PCV-13 vaccines separately.

For ages 10-17 years, MenQuadfi can be co-administered with diphtheria, tetanus, pertussis (acellular,component) vaccine (adsorbed, reduced antigen(s) content) (Tdap), or Tdap and inactivated poliovirusvaccine (Tdap-IPV), and 4-valent human papillomavirus vaccine (recombinant, adsorbed) (4vHPV) or9-valent HPV vaccine (9vHPV). However, the antibody responses to some of the antigens might beaffected by the co-administration.

Meningococcal vaccine naïve children and adolescents aged 10-17 years had non inferior response for PTand lower antibody responses to FHA, PRN and FIM when Tdap vaccine was administered concomitantlywith MenQuadfi and 4vHPV compared to co-administration with 4vHPV vaccine alone (immuneresponse assessed after the full series of HPV was completed). The clinical implications of the observedpertussis antigen responses also observed with other quadrivalent meningococcal conjugate vaccines areunknown.

The co-administration of MenQuadfi with Tdap-IPV and 9vHPV in children and adolescents aged10-17 years resulted in lower GMTs and seroresponse rates for serogroup A, lower GMTs for serogroup

W, lower responses to inactivated polio types 1 and 3, diphtheria, and anti-HPV types 6 and 58 (immuneresponse assessed after the first dose of 9vHPV) compared to when MenQuadfi was given sequentiallywith Tdap-IPV and 9vHPV. The clinical implication of the observed reduced titre responses is unclear.

Consideration might be given for sequential administration of MenQuadfi with Tdap-IPV and 9vHPV(e.g. for children and adolescents at higher risk).

Concomitant vaccines should always be administered at separate injection sites and preferablycontralateral.

Concomitant administration of MenQuadfi and other vaccines than those listed above has not beenstudied.

It may be expected that in patients receiving immunosuppressive treatment an adequate immune responsemay not be elicited (see also section 4.4).

There is limited amount of data on the use of MenQuadfi in pregnant women. Animal studies do notindicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

MenQuadfi should be used during pregnancy only if the expected benefits for the mother outweigh thepotential risks, including those for the foetus.

It is unknown whether MenQuadfi is excreted in human milk. MenQuadfi should only be used duringbreast-feeding when the possible advantages outweigh the potential risks.

A developmental and reproductive toxicity study was performed in female rabbits. There were no effectson mating performances or female fertility. No study was conducted on male fertility (see section 5.3).

MenQuadfi has no or negligible influence on the ability to drive and use machines.

However, some of the adverse reactions mentioned under section 4.8 “Undesirable effects” maytemporarily affect the ability to drive or use machines.

The safety of a single dose of MenQuadfi in individuals 12 months of age and older was evaluated inclinical trials where 6 308 subjects received either a primary dose (N = 5 906) or a booster dose (N = 402)of MenQuadfi. This included 1 389 toddlers aged 12 through 23 months of age, 498 children aged 2through 9 years, 2 289 children and adolescents aged 10 through 17 years, 1 684 adults aged 18 through55 years, 199 older adults aged 56 through 64 years, and 249 elderly aged 65 years and older. Of these,392 adolescents received MenQuadfi co-administered with Tdap and 4vHPV, and 589 toddlers received

MenQuadfi co-administered with MMR+V (N = 189), DTaP-IPV-HB-Hib (N = 200) or PCV-13(N = 200).

The most frequently reported adverse reactions within 7 days after vaccination with a single dose of

MenQuadfi alone in toddlers 12 through 23 months of age were irritability (36.7%) and injection sitetenderness (30.6%) and in ages 2 years and above were injection site pain (38.7%) and myalgia (30.5%).

These adverse reactions were mostly mild or moderate in intensity.

Rates of adverse reactions after a booster dose of MenQuadfi in adolescents and adults at least 15 years ofage were comparable to those seen in adolescents and adults who received a primary dose of MenQuadfi.

Rates of adverse reactions within 7 days following vaccination among toddlers were comparable when

MMR+V were given concomitantly with or without MenQuadfi, and when DTaP-IPV-HB-Hib was givenwith or without MenQuadfi. Overall, the rates of adverse reactions were higher in toddlers who received

PCV-13 given concomitantly with MenQuadfi (36.5%) than in toddlers who received PCV-13 alone(17.2%).

Children and adolescents aged 10-17 years of age were given either MenQuadfi alone (N = 171) or

MenQuadfi concomitantly with Tdap-IPV and the first dose of 9vHPV (N = 116). The rates of injectionsite pain at the 9vHPV injection site were higher when given concomitantly with Tdap-IPV and

MenQuadfi (83.6%) compared to when Tdap-IPV and 9vHPV were given without MenQuadfi (67.3%).

Overall, rates and intensity of adverse reactions were comparable between these two groups.

Adolescents and adults 13-26 years of age primed with MenQuadfi 3-6 years previously received

MenQuadfi co-administered with meningococcal serogroup B vaccine (MenB), MenB (recombinant,adsorbed) (N = 93) or MenB (rDNA, component, adsorbed) (N = 92). Rates and intensity of systemicadverse reactions within 7 days following vaccination tended to be higher when MenQuadfi was givenconcomitantly with MenB vaccine than when MenQuadfi was given alone. The most common solicitedsystemic adverse reaction was myalgia, of mild intensity, which was experienced more frequently inadolescents and adults who received MenQuadfi and MenB vaccine concomitantly (MenB [recombinant,adsorbed], 65.2%; or MenB [rDNA, component, adsorbed], 63%) compared to those who received

MenQuadfi alone (32.8%).

The following adverse reactions, as listed below, have been identified from clinical trials conducted with

MenQuadfi when given alone to subjects 2 years of age and older and post-marketing surveillance. Thesafety profile observed in toddlers aged 12 through 23 months is presented in the paediatric populationsection.

The adverse reactions are listed by MedDRA system organ class and by frequency according to thefollowing frequency categories:

Very common (≥ 1/10);

Common (≥ 1/100 to < 1/10);

Uncommon (≥ 1/1,000 to < 1/100);

Rare (≥ 1/10 000 to <1/1 000);

Very rare (< 1/10 000);

Not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions following administration of MenQuadfi from clinical trials and post-marketing surveillance in subjects 2 years of age and above

MedDRA system organ Frequency Adverse reactionsclass

Blood and lymphatic system Rare Lymphadenopathydisorders

Immune system disorders Very rare Anaphylaxis

Not known Hypersensitivity

Nervous system disorders Very common Headache

Uncommon Dizziness

Not known Febrile convulsions, seizures

Gastrointestinal disorders Uncommon Vomiting, nausea

Rare Diarrhoea, stomach pain

Skin and subcutaneous tissue Rare Urticaria, pruritus, rashdisorders

Musculoskeletal and Very common Myalgiaconnective tissue disorders Rare Pain in extremity

General disorders and Very common Malaiseadministration site conditions Injection site pain

Common Fever

At the injection site: swelling, erythema

Uncommon Fatigue

At the injection site: pruritus, warmth, bruising, rash

Rare Chills, axillary pain

At the injection site: induration

The safety profile of MenQuadfi in children and adolescents 2 through 17 years of age was generallycomparable to that in adults. Injection site erythema and swelling at the MenQuadfi injection site werereported more frequently in children 2 through 9 years of age (very common) than in the older agegroups.

In toddlers 12 through 23 months of age, injection site erythema and swelling (very common) at the

MenQuadfi injection site, vomiting (common) and diarrhoea (common), were reported more frequentlythan in the older age groups. The following additional reactions, as listed below in Table 2, have beenreported following administration of MenQuadfi in toddlers during clinical trials and post-marketingsurveillance:

Table 2: Adverse reactions following administration of MenQuadfi from clinical trials and post-marketing surveillance in subjects 12 months through 23 months

MedDRA system organ class Frequency Adverse reactions

Immune system disorders Very rare Anaphylaxis

Not known Hypersensitivity

Metabolic and nutrition Very common Appetite lostdisorders

Psychiatric disorders Very common Irritability

Uncommon Insomnia

Nervous system disorders Very common Drowsiness

Not known Febrile convulsions, seizures

Gastrointestinal disorders Common Vomiting, diarrhoea

Skin and subcutaneous tissue Uncommon Urticariadisorders

General disorders and Very common Abnormal cryingadministration site conditions At the injection site: tenderness/pain,erythema, swelling

Common Fever

Uncommon At the injection site: pruritus, induration,bruising, rash

Older population

Overall, within 7 days after vaccination with a single dose of MenQuadfi, the same injection site andsystemic adverse reactions were observed in older (≥ 56 years of age) and younger adults (18 through55 years old) but at lower frequencies; except for injection site pruritus, which was more frequent(common) in older adults. These adverse reactions mostly were mild or moderate in intensity.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Overdose with MenQuadfi is unlikely due to its presentation as a single dose vial. In the event ofoverdose, monitoring of vital functions and possible symptomatic treatment is recommended.

Pharmacotherapeutic group: meningococcal vaccines, ATC code: J07AH08

Anti-capsular meningococcal antibodies protect against meningococcal diseases via complementmediated bactericidal activity.

MenQuadfi induces the production of bactericidal antibodies specific to the capsular polysaccharides of

Neisseria meningitidis serogroups A, C, W, and Y.

The immunogenicity of a single dose of MenQuadfi for primary vaccination in toddlers (12-23 months ofage), children and adolescents (2-17 years of age), adults (18-55 years of age) and older adults (56 yearsand above) was assessed in six pivotal trials and in two additional trials in toddlers (12-23 months of age)and children and adolescents (10-17 years of age). The immunogenicity of a single dose of MenQuadfiwhen used as a booster vaccination was assessed in one pivotal trial (subjects 15-55 years of age) and infour additional trials: two in children 3 years and 5 years after primary vaccination as toddlers 12 through23 months of age, one in adolescents and adults 3-6 years after primary vaccination, and one in olderadults 3, 5 and 6-7 years after primary vaccination at ≥ 56 years of age. In addition, clinical data on thepersistence of antibody response from at least 3 years and up to 7 years after primary vaccination with

MenQuadfi are available in these additional trials.

Primary immunogenicity analyses were conducted by measuring serum bactericidal activity (SBA) usinghuman serum as the source of exogenous complement (hSBA). Rabbit complement (rSBA) data areavailable in subsets in all age groups and generally follows the trends observed with human complement(hSBA) data. In addition, all subjects were assessed for primary immunogenicity measured by hSBA andrSBA for serogroup C in MEQ00065 study [NCT03890367].

Immunogenicity in toddlers 12 to 23 months of age

Immunogenicity in subjects 12 through 23 months of age was evaluated in three clinical trials (MET51[NCT02955797], MET57 [NCT03205371] and MEQ00065 [NCT03890367]).

MET51 was conducted in subjects who were either meningococcal vaccine naïve or had been primed withmonovalent meningococcal C conjugate vaccines in their first year of life (see table 3).

Table 3: Comparison of bactericidal antibody responses to MenQuadfi and MenACWY-TT vaccine30 days after vaccination of meningococcal vaccine naïve subjects only or combined (naïve + MenCprimed) subjects 12 through 23 months of age (study MET51*)

Endpoint by MenQuadfi MenACWY-TT MenQuadfi MenACWY-TT

Serogroup (95% CI) (95% CI) (95% CI) (95% CI)

Naïve Naïve Combined (Naïve Combined (Naïve+ MenC Primed) + MenC Primed)

A N = 293 N = 295 N = 490 N = 393-394% ≥ 1:8 90.8 89.5 90.4 91.6(Seroprotection)** (86.9; 93.8) (85.4; 92.7) (87.4; 92.9) (88.4; 94.2)% Seroresponse 76.8 72.5 76.5 77.1(71.5; 81.5) (67.1; 77.6) (72.5; 80.2) (72.6; 81.2)hSBA GMT 28.7 28.0 29.9 34.5(25.2; 32.6) (24.4; 32.1) (26.9; 33.2) (30.5; 39.0)

C N = 293 N = 295 N = 489 N = 393-394% ≥ 1:8 99.3 81.4 99.2 85.5(Seroprotection)** (97.6; 99.9) (76.4; 85.6) (97.9; 99.8) (81.7; 88.9)% Seroresponse 98.3 71.5 97.1 77.4(96.1; 99.4) (66.0; 76.6) (95.2; 98.4) (72.9; 81.4)hSBA GMT 436 26.4 880 77.1(380; 500) (22.5; 31.0) (748; 1 035) (60.7; 98.0)

W N = 293 N = 296 N = 489 N = 393-394% ≥ 1:8 83.6 83.4 84.9 84.0(Seroprotection)** (78.9; 87.7) (78.7; 87.5) (81.4; 87.9) (80.0; 87.5)% Seroresponse 67.6 66.6 70.8 68.4(61.9; 72.9) (60.9; 71.9) (66.5; 74.8) (63.6; 73.0)hSBA GMT 22.0 16.4 24.4 17.7(18.9; 25.5) (14.4; 18.6) (21.8; 27.5) (15.8; 19.8)

Y N = 293 N = 296 N = 488-490 N = 394-395% ≥ 1:8 93.2 91.6 94.3 91.6(Seroprotection)** (89.7; 95.8) (87.8; 94.5) (91.8; 96.2) (88.5; 94.2)% Seroresponse 81.9 79.1 84.8 78.9(77.0; 86.1) (74.0; 83.5) (81.3; 87.9) (74.6; 82.9)hSBA GMT 38.0 32.2 41.7 31.9(33.0; 43.9) (28.0; 37.0) (37.5; 46.5) (28.4; 36.0)

* Clinical trial identifier NCT02955797

N: number of subjects in the per-protocol analysis set with valid serology results. The number of subjectsvaries depending on the timepoints and serogroup.95% CI of the single proportion calculated from the exact binomial method.

** Non-inferiority criterion met

The majority of monovalent meningococcal C conjugate vaccine primed toddlers (12 through 23 monthsof age) in study MET51 (NCT02955797) had hSBA titres ≥ 1:8 in the MenQuadfi group (N = 198)(≥ 86.7%) and in MenACWYTT group (N = 99) (≥ 85.7%) at D30 post-vaccination. These toddlersreceived during their infancy MenCTT or MenCCRM vaccines. Post-vaccination seroprotection rateswere comparable between MenQuadfi and MenACWY-TT for all serogroups regardless of the primingbackground.

In MenC-CRM primed subjects the GMTs for serogroup A were lower in the MenQuadfi group (N = 49)than in the MenACWY-TT group (N = 25) [12.0 (8.23; 17.5) vs 42.2 (25.9; 68.8)]. After administrationof MenQuadfi seroprotection rates (hSBA titres ≥ 1:8) for subjects primed with MenC-CRM were lowerbut still comparable for serogroups A and W compared with those in the MenACWY-TT group [A:68.8% (53.7; 81.3) vs 96.0% (79.6; 99.9); W: 68.1% (52.9; 80.9) vs 79.2% (57.8; 92.9)]. The rates forserogroup Y were higher but still comparable with those in the MenACWY-TT group [95.8% (85.7; 99.5)vs 80.0% (59.3; 93.2)]. The rates for serogroup C were comparable in both groups [95.7% (85.5; 99.5) vs92.0% (74.0; 99.0)]. The clinical relevance of these results is unknown. This aspect might be consideredfor individuals at high risk for MenA infection who received MenC-CRM vaccine in their first year oflife.

MET57 (NCT03205371) was conducted in meningococcal vaccine naïve toddlers 12 through 23 monthsof age to assess the immunogenicity of the concomitant administration of MenQuadfi with paediatricvaccines (MMR+V, DTaP-IPV-HB-Hib or PCV-13). Overall, the post-vaccination hSBA seroprotectionrates in subjects who received MenQuadfi was high for all serogroups (between 88.9% and 100%).

Seroresponse and seroprotection rates for serogroup A were comparable when MenQuadfi was co-administered with PCV-13 and alone (56.1%, [95% CI 48.9; 63.2] and 83.7% [95% CI 77.7; 88.6] vs71.9% [95%CI 61.8; 80.6] and 90.6% [95%CI 82.9; 95.6]). There were differences in the hSBA GMTsfor serogroup A when MenQuadfi was co-administered with PCV-13 (N = 196) compared with

MenQuadfi administered alone (N = 96) (24.6 [95%CI 20.2; 30.1] and 49.0 [95%CI 36.8; 65.3]).) Theclinical relevance of these results is unknown but this observation might be taken into consideration forindividuals at high risk for MenA infection and consequently vaccinations with MenQuadfi and PCV13might be performed separately.

MEQ00065 (NCT03890367) study was conducted in meningococcal vaccine naïve toddlers 12 through23 months of age to assess the immunogenicity of serogroup C using hSBA and rSBA assays followingadministration of a single dose of MenQuadfi compared to MenACWY-TT or to MenC-TT.

Superiority of MenQuadfi was demonstrated in comparison to MenACWY-TT vaccine for the hSBAseroprotection rate and hSBA and rSBA GMTs to meningococcal serogroup C. Non-inferiority wasdemonstrated for the rSBA seroprotection rate to meningococcal serogroup C.

Superiority of MenQuadfi was also demonstrated in comparison to MenC-TT vaccine for the rSBA andhSBA GMTs to meningococcal serogroup C and non-inferiority was demonstrated for the rSBA andhSBA seroprotection rates to meningococcal serogroup C (see table 4).

Table 4: Comparison of hSBA and rSBA bactericidal antibody responses for serogroup C to

MenQuadfi, MenACWY-TT and MenC-TT vaccines 30 days after vaccination of meningococcalvaccine naïve subjects 12 through 23 months of age (study MEQ00065*)

MenQuadfi MenACWY- MenC- MenQuadfi MenACWY- MenC-

Endpoints (95% CI) TT (95% TT (95%

CI) CI) (95% CI) TT (95% TT (95%

CI) CI)hSBA rSBA

N = 214 N = 211 N = 216 N = 213 N = 210 N = 215% ≥ 1:8 99.5# § 89.1 99.5(97.4; 100¶ 94.8 100(Seroprotection) (97.4; 100) (84.1; 93.0) 100) (98.3; 100) (90.8; 97.4) (98.3;100)% Seroresponse 99.5 83.4 99.1(96.7; 99.5 92.9 99.5(97.4; 100) (77.7; 88.2) 99.9) (97.4; 100) (88.5; 95.9) (97.4;100)¥515$ 31.6 227 2 143 315 1 624

GMTs (450; 591) ( 26.5; 37.6) (198; (1 870;260) 2 456) (252; 395) (1 425;1 850)

* Clinical trial identifier NCT03890367# superiority of MenQuadfi demonstrated versus MenACWY-TT (hSBA seroprotection rates)§ non inferiority of MenQuadfi demonstrated versus MenC-TT (hSBA seroprotection rates)$ superiority of MenQuadfi demonstrated versus MenACWY-TT and MenC-TT (hSBA GMTs)¶ non inferiority of MenQuadfi demonstrated versus MenACWY-TT and MenC-TT (rSBA seroprotectionrates)¥ superiority of MenQuadfi demonstrated versus MenACWY-TT and MenC-TT (rSBA GMTs)

N: number of subjects in the per-protocol analysis set with valid serology results95% CI of the single proportion calculated from the exact binomial method

Immunogenicity in children 2 through 9 years of age

Immunogenicity in subjects 2 through 9 years of age was evaluated in study MET35 (NCT03077438)(stratified by ages 2 through 5 and 6 through 9 years) comparing seroresponses following administrationof either MenQuadfi or MenACWY-CRM.

Overall, for subjects 2 through 9 years of age, immune non-inferiority, based on hSBA seroresponse, wasdemonstrated for MenQuadfi as compared to MenACWY-CRM for all four serogroups.

Table 5: Comparison of bactericidal antibody responses to MenQuadfi and MenACWY-CRM30 days after vaccination in meningococcal vaccine naïve subjects 2 through 5 years and 6 through9 years of age (study MET35*)2-5 years of age 6-9 years of age

Endpoint by MenQuadfi MenACWY-CRM MenQuadfi MenACWY-CRM

Serogroup (95% CI) (95% CI) (95% CI) (95% CI)

A N = 227-228 N = 221 N = 228 N = 237% ≥ 1:8 84.6 76.5 88.2 81.9(Seroprotection) (79.3; 89.1) (70.3; 81.9) (83.2; 92.0) (76.3; 86.5)% Seroresponse 52.4 44.8 58.3 50.6(45.7; 59.1) (38.1; 51.6) (51.6; 64.8) (44.1; 57.2)hSBA GMT 21.6 18.9 28.4 26.8(18.2; 25.5) (15.5; 23.0) (23.9; 33.8) (22.0; 32.6)

C N = 229 N = 222-223 N = 229 N = 236% ≥ 1:8 97.4 64.6 98.3 69.5(Seroprotection) (94.4; 99.0) (57.9; 70.8) (95.6; 99.5) (63.2; 75.3)% Seroresponse 94.3 43.2 96.1 52.1(90.5; 96.9) (36.6; 50.0) (92.7; 98.2) (45.5; 58.6)hSBA GMT 208 11.9 272 23.7(175; 246) (9.79; 14.6) (224; 330) (18.2; 31.0)

W N = 229 N = 222 N = 229 N = 237% ≥ 1:8 90.8 80.6 98.7 91.6(Seroprotection) (86.3; 94.2) (74.8; 85.6) (96.2; 99.7) (87.3; 94.8)% Seroresponse 73.8 61.3 83.8 66.7(67.6; 79.4) (54.5; 67.7) (78.4; 88.4) (60.3; 72.6)hSBA GMT 28.8 20.1 48.9 33.6(24.6; 33.7) (16.7; 24.2) (42.5; 56.3) (28.2; 40.1)

Y N = 229 N = 222 N = 229 N = 237% ≥ 1:8 97.8 86.9 99.1 94.5(Seroprotection) (95.0; 99.3) (81.8; 91.1) (96.9; 99.9) (90.8; 97.0)% Seroresponse 88.2 77.0 94.8 81.4(83.3; 92.1) (70.9; 82.4) (91.0; 97.3) (75.9; 86.2)hSBA GMT 49.8 36.1 95.1 51.8(43.0; 57.6) (29.2; 44.7) (80.2; 113) (42.5; 63.2)

* Clinical trial identifier NCT03077438

N: number of subjects in the per-protocol analysis set with valid serology results. The number of subjectsvaries depending on the timepoints and serogroup.95% CI of the single proportion calculated from the exact binomial method.

Immunogenicity in children and adolescents 10 through 17 years of age

Immunogenicity in subjects aged 10 through 17 years of age was evaluated in three trials comparingseroresponses following administration of MenQuadfi compared to either MenACWY-CRM (MET50[NCT02199691]) or MenACWY-DT (MET43 [NCT02842853]) or comparing seroprotection followingadministration of MenQuadfi compared to MenACWY-TT (MEQ00071) [NCT04490018]).

MET50 was conducted in meningococcal vaccine naïve subjects and seroresponse was evaluatedfollowing administration with either MenQuadfi alone, MenACWY-CRM alone, MenQuadfi co-administered with Tdap and 4vHPV or Tdap and 4vHPV alone.

Table 6: Comparison of bactericidal antibody responses to MenQuadfi and MenACWY-CRM30 days after vaccination in meningococcal vaccine naïve subjects 10 through 17 years of age (study

MET50*)

Endpoint by Serogroup MenQuadfi MenACWY-CRM(95% CI) (95% CI)

A N = 463 N = 464% ≥ 1:8 (Seroprotection) 93.5 (90.9; 95.6) 82.8 (79.0; 86.1)% Seroresponse**# 75.6 (71.4; 79.4) 66.4 (61.9; 70.7)hSBA GMT 44.1 (39.2; 49.6) 35.2 (30.3; 41.0)

C N = 462 N = 463% ≥ 1:8 (Seroprotection) 98.5 (96.9; 99.4) 76.0 (71.9; 79.8)% Seroresponse**# 97.2 (95.2; 98.5) 72.6 (68.3; 76.6)hSBA GMT 387 (329; 456) 51.4 (41.2; 64.2)

W N = 463 N = 464% ≥ 1:8 (Seroprotection) 99.1 (97.8; 99.8) 90.7 (87.7; 93.2)% Seroresponse**# 86.2 (82.7; 89.2) 66.6 (62.1; 70.9)hSBA GMT 86.9 (77.8; 97.0) 36.0 (31.5; 41.0)

Y N = 463 N = 464% ≥ 1:8 (Seroprotection) 97.2 (95.2; 98.5) 83.2 (79.5; 86.5)% Seroresponse**# 97.0 (95.0; 98.3) 80.8 (76.9; 84.3)hSBA GMT 75.7 (66.2; 86.5) 27.6 (23.8; 32.1)

* Clinical trial identifier NCT02199691

N: number of subjects in the per-protocol analysis set with valid serology results.95% CI of the single proportion calculated from the exact binomial method.

** Post-vaccination hSBA titres ≥1:8 for subjects with pre-vaccination hSBA titres < 1:8 or at least a 4-fold increase in hSBA titres from pre- to post-vaccination for subjects with pre-vaccination hSBA titres≥ 1:8# Non-inferiority criterion met.

Study MET43 was performed to evaluate the immunogenicity of MenQuadfi compared to

MenACWY-DT in children, adolescents and adults (10 through 55 years of age).

Table 7: Comparison of bactericidal antibody responses to MenQuadfi and MenACWY-DT 30 daysafter vaccination in meningococcal vaccine naïve subjects 10 through 17 years of age (study

MET43*)

Endpoint by Serogroup MenQuadfi MenACWY-DT(95% CI) (95% CI)

A N = 1 097 N = 300% ≥ 1:8 (Seroprotection) 96.2 (94.9; 97.2) 89.0 (84.9; 92.3)% Seroresponse** 74.0 (71.3; 76.6) 55.3 (49.5; 61.0)hSBA GMT 78 (71.4; 85.2) 44.2 (36.4; 53.7)

C N = 1 097-1 098 N = 300% ≥ 1:8 (Seroprotection) 98.5 (97.5; 99.1) 74.7 (69.3; 79.5)% Seroresponse** 95.6 (94.2; 96.8) 53.3 (47.5; 59.1)hSBA GMT 504 (456; 558) 44.1 (33.7; 57.8)

W N = 1 097 N = 300% ≥ 1:8 (Seroprotection) 98.3 (97.3; 99.0) 93.7 (90.3; 96.1)% Seroresponse** 84.5 (82.2; 86.6) 72.0 (66.6; 77.0)hSBA GMT 97.2 (88.3; 107) 59.2 (49.1; 71.3)

Y N = 1 097 N = 300% ≥ 1:8 (Seroprotection) 99.1 (98.3; 99.6) 94.3 (91.1; 96.7)% Seroresponse** 95.6 (94.2; 96.8) 85.7 (81.2; 89.4)hSBA GMT 208 (189; 228) 80.3 (65.6; 98.2)

* Clinical trial identifier NCT02842853

N: number of subjects in the per-protocol analysis set with valid serology results. The number of subjectsvaries depending on the timepoints and serogroup.95% CI of the single proportion calculated from the exact binomial method.

** Non-inferiority criterion met.

MEQ00071 was conducted in subjects who were either meningococcal vaccine naïve or had been primedwith MenC vaccines before two years of age. Seroprotection was evaluated 30 days followingadministration with either MenQuadfi alone, MenACWY-TT alone, or MenQuadfi co-administrated with

Tdap-IPV and 9vHPV.

Table 8: Comparison of bactericidal antibody responses to MenQuadfi and MenACWY-TT 30 daysafter vaccination in meningococcal vaccine naïve and MenC primed subjects 10 through 17 years ofage (study MEQ00071*)

Endpoint by Serogroup MenQuadfi MenACWY-TT(95% CI) (95% CI)

A N = 158-159 N = 159-160% ≥ 1:8 (Seroprotection)** 97.5 (93.7; 99.3) 92.5 (87.3; 96.1)% Seroresponse 88.0 (81.9; 92.6) 75.5 (68.0; 81.9)hSBA GMT 78.2 (64.6; 94.7) 56.0 (44.0; 71.2)

C N = 158-159 N = 160-161% ≥ 1:8 (Seroprotection)** 100 (97.7; 100) 95.0 (90.4; 97.8)% Seroresponse 99.4 (96.5; 100) 88.8 (82.8; 93.2)hSBA GMT 2 294 (1 675; 3 142) 619 (411; 931)

W N = 159 N = 159% ≥ 1:8 (Seroprotection)** 100 (97.7; 100) 98.8 (95.6; 99.8)% Seroresponse 93.1 (88.0; 96.5) 81.4 (74.5; 87.1)hSBA GMT 134 (109; 164) 64.6 (52.5; 79.4)

Y N = 158 N = 160% ≥ 1:8 (Seroprotection)** 99.4 (96.5; 100) 98.1 (94.6; 99.6)% Seroresponse 98.7 (95.5; 99.8) 88.1 (82.1; 92.7)hSBA GMT 169 (141; 202) 84.8 (68.3; 105)

* Clinical trial identifier NCT04490018

N: number of subjects in the per-protocol analysis set with valid serology results. The number of subjectsvaries depending on the timepoints and serogroup.95% CI of the single proportion calculated from the exact binomial method.

** Non-inferiority criterion met.

In an exploratory analysis in a non-random subset of participants (N = 60), the immune response andprotection rates were measured 6 and 30 days following co-administration of MenQuadfi with Tdap-IPVand 9vHPV. The proportion of subjects with seroprotection for serogroup A did not increase within6 days, whereas most of the subjects had seroprotection against serogroups C, W and Y (> 94%). After30 days, protection rates in this subset were comparable to the full trial population reported in table 8.

Response in subjects according to MenC vaccination status

The immunogenicity of serogroup C following administration of a single dose of MenQuadfi compared toa single dose of MenACWY-TT was assessed in both meningococcal vaccine naïve and MenC primed(before two years of age) subjects (MEQ00071). Overall, the post vaccination seroresponse and hSBA

GMTs against serogroup C were higher in meningococcal vaccine naive subjects who received

MenQuadfi than those who received MenACWY-TT, with seroprotection rates also trending higher. Nodifferences in antibody response were observed in MenC primed subjects between groups.

Immunogenicity in adults 18 through 55 years of age

Immunogenicity in subjects from 18 through 55 years of age was evaluated in study MET43(NCT02842853) comparing MenQuadfi to MenACWY-DT.

Table 9: Comparison of bactericidal antibody responses to MenQuadfi and MenACWY-DT 30 daysafter vaccination in meningococcal vaccine naïve subjects 18 through 55 years of age (study

MET43*)

Endpoint by Serogroup MenQuadfi MenACWY-DT (95% CI)(95% CI)

A N = 1 406-1 408 N = 293% ≥ 1:8 (Seroprotection) 93.5 (92.1; 94.8) 88.1 (83.8; 91.5)% Seroresponse** 73.5 (71.2; 75.8) 53.9 (48.0; 59.7)hSBA GMT 106 (97.2; 117) 52.3 (42.8; 63.9)

C N = 1 406-1 408 N = 293% ≥ 1:8 (Seroprotection) 93.5 (92.0; 94.7) 77.8 (72.6; 82.4)% Seroresponse** 83.4 (81.4; 85.3) 42.3 (36.6; 48.2)hSBA GMT 234 (210; 261) 37.5 (29.0; 48.5)

W N = 1 408-1 410 N = 293% ≥ 1:8 (Seroprotection) 94.5 (93.2; 95.7) 80.2 (75.2; 84.6)% Seroresponse** 77.0 (74.7; 79.2) 50.2 (44.3; 56.0)hSBA GMT 75.6 (68.7; 83.2) 33.2 (26.3; 42.0)

Y N = 1 408-1 410 N = 293% ≥ 1:8 (Seroprotection) 98.6 (97.8; 99.1) 81.2 (76.3; 85.5)% Seroresponse** 88.1 (86.3; 89.8) 60.8 (54.9; 66.4)hSBA GMT 219 (200; 239) 54.6 (42.3; 70.5)

* Clinical trial identifier NCT02842853

N: number of subjects in the per-protocol analysis set with valid serology results. The number of subjectsvaries depending on the timepoints and serogroup.95% CI of the single proportion calculated from the exact binomial method.

** Non-inferiority criterion met.

Immunogenicity in adults 56 years of age and older

Immunogenicity in adults ≥ 56 years of age (mean 67.1 years, range 56.0-97.2 years) was assessed instudy MET49 (NCT02842866) comparing the immunogenicity of MenQuadfi to MenACWYpolysaccharide vaccine.

Table 10: Comparison of bactericidal antibody responses to MenQuadfi and MenACWYpolysaccharide in meningococcal vaccine naïve in subjects 56 years of age and older 30 days aftervaccination (study MET49*)

Endpoint by Serogroup MenQuadfi MenACWY polysaccharide(95% CI) (95% CI)

A N = 433 N = 431% ≥ 1:8 (Seroprotection) 89.4 (86.1; 92.1) 84.2 (80.4; 87.5)% Seroresponse** 58.2 (53.4; 62.9) 42.5 (37.7; 47.3)hSBA GMT 55.1 (46.8; 65.0) 31.4 (26.9; 36.7)

C N = 433 N = 431% ≥ 1:8 (Seroprotection) 90.1 (86.9; 92.7) 71.0 (66.5; 75.2)% Seroresponse** 77.1 (72.9; 81.0) 49.7 (44.8; 54.5)hSBA GMT 101 (83.8; 123) 24.7 (20.7; 29.5)

W N = 433 N = 431% ≥ 1:8 (Seroprotection) 77.4 (73.1; 81.2) 63.1 (58.4; 67.7)% Seroresponse** 62.6 (57.8; 67.2) 44.8 (40.0; 49.6)hSBA GMT 28.1 (23.7; 33.3) 15.5 (13.0; 18.4)

Y N = 433 N = 431% ≥ 1:8 (Seroprotection) 91.7 (88.7; 94.1) 67.7 (63.1; 72.1)% Seroresponse** 74.4 (70.0; 78.4) 43.4 (38.7; 48.2)hSBA GMT 69.1 (58.7; 81.4) 21.0 (17.4; 25.3)

* Clinical trial identifier NCT02842866

N: number of subjects in the per-protocol analysis set with valid serology results.95% CI of the single proportion calculated from the exact binomial method.

** Non-inferiority criterion met.

Persistence of immune response and MenQuadfi booster response

Antibody persistence following primary vaccination in toddlers, adolescents and young adults, and olderadults was assessed from at least 3 years and up to 7 years after primary vaccination. The immunogenicityof a MenQuadfi booster dose was also assessed.

Persistence of immune response and MenQuadfi booster response in children 4 through 5 years of age

MET62 (NCT03476135) evaluated the antibody persistence of a primary dose, immunogenicity andsafety of a booster dose of MenQuadfi in children 4 through 5 years of age. These children were primedwith a single dose of MenQuadfi or MenACWY-TT 3 years before as part of the phase II study MET54when they were 12 through 23 months old. The antibody persistence prior to the MenQuadfi booster doseand the booster immune response were assessed according to the vaccine (MenQuadfi or MenACWY-TT)children had received 3 years ago (see Table 11).

For all serogroups, hSBA GMTs were higher at D30 post-primary dose than at 3 years (3Y) post-primarydose (D0 pre-booster) for MenQuadfi or MenACWY-TT. The 3Y post-primary (D0 pre-booster) GMTswere higher than the pre-primary GMTs, indicative of long-term persistence of immune response.

After the booster dose, seroprotection rates were nearly 100% for all serogroups in children primed with

MenQuadfi.

Table 11: Comparison of bactericidal antibody response 30 days after booster vaccination, andpersistence in children (4 through 5 years) primed with MenQuadfi or MenACWY - TT 3 yearsbefore in study MET54* - (study MET62**)

Endpoint by MenQuadfi Booster in MenQuadfi Booster in MenQuadfi Booster in

Serogroup MenQuadfi primed (95% MenACWY-TT primed (95% MenQuadfi primed +

CI) CI) MenACWY - TT primed (95%

CI)

Persistence# Booster$ Persistence# Booster$ Persistence# Booster$

N = 42 N = 40 N = 49 N = 44 N = 91 N = 84

D30- 3Y D30 - 3Y Post- D30 - 3Y Post-

Post- Post- Post- primary Post- primaryprimar primar primary dose primary dosey dose y dose dose (D0 - dose (D0 -(D0 - Pre- Pre-

Pre- booster boosterbooster dose) dose)dose)

A% ≥ 1:8 97.6 66.7 100 89.8 83.7 100 93.4 75.8 100(Seroprotection) (87.4; (50.5; (91.2; 100) (77.8; 96.6) (70.3; 92.7) (92.0; 100) (86.2; 97.5) (65.7; 84.2) (95.7; 100)99.9) 80.4)% Seroresponse - - 100 - - 95.5 - - 97.6(91.2; 100) (84.5; 99.4) (91.7; 99.7)hSBA GMT 83.3 11.9 763 49.6 14.7 659 63.0 13.3 706(63.9; (8.11; (521; (32.1; 76.7) (10.7; 20.2) (427; 1 017) (48.3; 82.2) (10.5; 17.0) (531; 940)109) 17.4) 1 117)

C% ≥ 1:8 100 100 100 87.8 57.1 100 93.4 76.9 100(Seroprotection) (91.6; (91.6; (91.2; 100) (75.2; 95.4) (42.2; 71.2) (92.0; 100) (86.2; 97.5) (66.9; 85.1) (95.7; 100)100) 100)% Seroresponse - - 95.0 - - 100 - - 97.6(83.1; (92.0; 100) (91.7; 99.7)99.4)hSBA GMT 594 103 5 894 29.4 11.6 1 592 118 31.8 2 969(445; (71.7; (4 325; (20.1; 43.1) (7.28; 18.3) (1 165; (79.3; 175) (21.9; 46.1) (2 293;793) 149) 8 031) 2 174) 3 844)

W% ≥ 1:8 100 97.6 97.5 95.9 83.7 100 97.8 90.1 98.8(Seroprotection) (91.6; (87.4; (86.8; (86.0; 99.5) (70.3; 92.7) (92.0; 100) (92.3; 99.7) (82.1; 95.4) (93.5; 100)100) 99.9) 99.9)% Seroresponse - - 97.5 - - 100 - - 98.8(86.8; (92.0; 100) (93.5; 100)99.9)hSBA GMT 71.8 50.0 2 656 40.1 21.2 3 444 52.5 31.5 3 043(53.3; (35.9; (1 601; (30.6; 52.6) (14.6; 30.9) (2 387; (42.7; 64.5) (24.2; 41.0) (2 248;96.7) 69.5) 4 406) 4 970) 4 120)

Y% ≥ 1:8 100 97.6 100 100 89.8 100 100 93.4 100(Seroprotection) (91.6; (87.4; (91.2; 100) (92.7; 100) (77.8; 96.6) (92.0; 100) (96.0; 100) (86.2; 97.5) (95.7; 100)100) 99.9)% Seroresponse - - 100 - - 100 - - 100(91.2; 100) (92.0; 100) (95.7; 100)

Endpoint by MenQuadfi Booster in MenQuadfi Booster in MenQuadfi Booster in

Serogroup MenQuadfi primed (95% MenACWY-TT primed (95% MenQuadfi primed +

CI) CI) MenACWY - TT primed (95%

CI)hSBA GMT 105 32.5 2 013 75.8 18.2 2 806 88.1 23.8 2 396(73.9; (24.8; (1 451; (54.2; 106) (13.8; 24.0) (2 066; (69.3; 112) (19.4; 29.1) (1 919;149) 42.7) 2 792) 3 813) 2 991)

* Clinical trial identifier MET54 - NCT03205358. The trial was conducted in toddlers 12-23 months old.

** Clinical trial identifier MET62 - NCT03476135$ N calculated using per protocol analysis set (PPAS) with valid serology results; booster dose=D30

MET62.# N calculated using full analysis set for persistence (FASP) with valid serology results; D30 post-primarydose=D30 MET54, 3Y Post-primary (D0 pre-booster dose)=D0 MET62.

Vaccine seroresponse: titre is < 1:8 at baseline with post-vaccination titre ≥ 1:16 or titre is ≥ 1:8 at baselinewith a ≥ 4-fold increase at post-vaccination.95% CI of the single proportion calculated from the exact binomial method.

Persistence of immune response and MenQuadfi booster response in children 6 through 7 years of age

MEQ00073 (NCT04936685) evaluated the antibody persistence of a primary dose, immunogenicity andsafety of a booster dose of MenQuadfi in children 6 through 7 years of age who had previously received aprimary dose of MenQuadfi 5 years earlier as part of study MET51 when they were 12 through 23 monthsof age (see Table 12).

For all serogroups, the 5Y post-primary (pre-booster) GMTs were higher than the pre-primary GMTs,indicative of persistence of immune response.

After the booster dose, seroprotection rates were nearly 100% for all serogroups in children primed with

MenQuadfi (98.9%, 97.7%, 100%, and 100% for serogroups A, C, W, and Y, respectively).

Table 12: Comparison of bactericidal antibody response 30 days after booster vaccination with

MenQuadfi, and persistence in children (6 through 7 years) primed with MenQuadfi 5 years beforein study MET51* - (study MEQ00073**)

MenQuadfi Booster in MenQuadfi primed (95% CI)

Persistence# Booster$

Endpoint by D30 - Post-primary dose 5Y Post-primary dose N = 88

Serogroup N = 208 (D0 - Pre-booster dose)

N = 208

A% ≥ 1:8(Seroprotection) 90.4 (85.5; 94.0) 76.0 (69.6; 81.6) 98.9 (93.8; 100)% Seroresponse - - 93.2 (85.7; 97.5)hSBA GMT 28.9 (24.5; 34.0) 14.5 (12.0; 17.5) 1 143 (820; 1 594)

C% ≥ 1:8(Seroprotection) 99.5 (97.4; 100) 85.1 (79.5; 89.6) 97.7 (92.0; 99.7)% Seroresponse - - 97.7 (92.0; 99.7)hSBA GMT 1 315 (1 002; 1 724) 37.6 (29.8; 47.4) 8 933 (6 252; 12 764)

W% ≥ 1:8(Seroprotection) 83.7 (77.9; 88.4) 84.6 (79.0; 89.2) 100 (95.9; 100)% Seroresponse - - 98.9 (93.8; 100)hSBA GMT 25.7 (21.3; 31.0) 30.7 (24.9; 37.9) 8 656 (6 393; 11 721)

Y% ≥ 1:8(Seroprotection) 92.3 (87.8; 95.5) 68.8 (62.0; 75.0) 100 (95.9; 100)% Seroresponse - - 98.9 (93.8; 100)hSBA GMT 41.6 (35.0; 49.6) 12.7 (10.5; 15.4) 3 727 (2 908; 4 776)

*Clinical trial identifier MET51 - NCT02955797. The trial was conducted in toddlers 12-23 months old.

**Clinical trial identifier MEQ00073 - NCT04936685# N calculated using full analysis set for persistence (FASP) with valid serology results; D30 post-primarydose = D30 MET51, 5Y Post-primary dose (D0 pre-booster dose)=D0 MEQ00073.$ N calculated using per protocol analysis set (PPAS1) with valid serology results; Booster = D30

MEQ00073 5 years after primary vaccination in MET51.

Vaccine seroresponse: titre is < 1:8 at baseline with post-vaccination titre ≥ 1:16 or titre is ≥ 1:8 at baselinewith a ≥ 4-fold increase at post-vaccination.95% CI of the single proportion calculated from the exact binomial method.

Response in subjects according to MenC vaccination status before priming with MenQuadfi in MET51

The antibody responses against serogroup C following administration of a booster dose of MenQuadfiwere comparable regardless of MenC vaccination status during their first year of life before priming with

MenQuadfi 5 years earlier in MET51.

Persistence of immune response and MenQuadfi booster response in adolescents and adults 13 through26 years of age

MET59 (NCT04084769) evaluated the antibody persistence of a primary dose, immunogenicity andsafety of a booster dose of MenQuadfi in adolescents and adults 13 through 26 years of age who hadreceived a single dose of MenQuadfi in study MET50 or MET43 or MenACWY-CRM in study MET50or outside of Sanofi Pasteur trials 3-6 years prior. The antibody persistence prior to the MenQuadfibooster dose and the booster immune response were assessed according to the vaccine (MenQuadfi or

MenACWY-CRM) subjects had received 3-6 years previously (see Table 13).

For all serogroups, hSBA GMTs were higher at D30 post-primary dose than at 3-6 Year (3-6Y) post-primary dose (D0 pre-booster) for MenQuadfi and MenACWY-CRM primed subjects. The 3-6Y post-primary dose (D0 pre-booster) GMTs were higher than the pre-primary GMTs, indicative of long-termpersistence of immune response.

After the booster dose, seroprotection rates were nearly 100% for all serogroups in adolescents and adultsprimed with MenQuadfi.

Table 13: Comparison of bactericidal antibody response 6 and 30 days after booster vaccination,and persistence in adolescents and adults (13 through 26 years) primed with MenQuadfi or

MenACWY-CRM 3-6 years before in study MET50*, MET43** or outside of Sanofi Pasteur trials- (study MET59***)

Endpoint by MenQuadfi Booster in MenQuadfi MenQuadfi Booster in MenACWY-

Serogroup primed (95% CI) CRM primed (95% CI)

Persistence^ Booster$ Persistence^ Booster$

D30 - 3-6Y D06 - D30 - D30 3-6Y D06- D30 -

Post- Post- Post- Post- Post- Post- Post- Post-primar primar booste booster primar primar booster boostery dose y dose r dose dose y dose y dose dose dose(D0 - (D0 -

N = 376 Pre- N = 46 N = N = Pre- N = 45 N = 176booster 174 132-133 boosterdose) dose)

N = N = 140379-380

A% ≥ 1:8 94.7 72.8 91.3 99.4 81.2 71.4 95.6 99.4(Seroprotection) (91.9; (68.0; (79.2; (96.8; (73.5; (63.2; (84.9; (96.9;96.7) 77.2) 97.6) 100) 87.5) 78.7) 99.5) 100)% Seroresponse 82.6 94.8 77.8 93.2

- - (68.6; (90.4; - - (62.9; (88.4;92.2) 97.6) 88.8) 96.4)hSBA GMT 45.2 12.5 289 502 32.8 11.6 161 399(39.9; (11.1; (133; (388; (25.0; (9.41; (93.0; (318;51.1) 14.1) 625) 649) 43.1) 14.3) 280) 502)

C% ≥ 1:8 98.1 86.3 100 100 74.2 49.3 97.8 100(Seroprotection) (96.2; (82.4; (92.3; (97.9; (65.9; (40.7; (88.2; (97.9;99.2) 89.6) 100) 100) 81.5) 57.9) 99.9) 100)% Seroresponse 89.1 97.1 93.3 98.9

- - (76.4; (93.4; - - (81.7; (96.0;96.4) 99.1) 98.6) 99.9)hSBA GMT 417 37.5 3 799 3 708(2 504 (3 146; 49.7 11.0 919 2 533(348; (31.6; (32.4; (8.09; (500; (2 076;500) 44.5) ; 4 369) 76.4) 14.9) 1 690) 3 091)5 763)

W% ≥ 1:8 100 88.9 100 100 93.2 76.4 100 100(Seroprotection) (99.0; (85.3; (92.3; (97.9; (87.5; (68.5; (92.1; (97.9;100) 91.9) 100) 100) 96.9) 83.2) 100) 100)% Seroresponse 97.8 97.7 88.9 98.9

- - (88.5; (94.2; - - (75.9; (96.0;99.9) 99.4) 96.3) 99.9)

Endpoint by MenQuadfi Booster in MenQuadfi MenQuadfi Booster in MenACWY-

Serogroup primed (95% CI) CRM primed (95% CI)

Persistence^ Booster$ Persistence^ Booster$

D30 - 3-6Y D06 - D30 - D30 3-6Y D06- D30 -

Post- Post- Post- Post- Post- Post- Post- Post-primar primar booste booster primar primar booster boostery dose y dose r dose dose y dose y dose dose dose(D0 - (D0 -

N = 376 Pre- N = 46 N = N = Pre- N = 45 N = 176booster 174 132-133 boosterdose) dose)

N = N = 140379-380

AhSBA GMT 82.7 28.8 1 928 2 290 14.9 708 2 574(73.6; (25.1; (1 187 (1 934; 45.1; 2 711) (34.3; (11.9; (463; (2 178;92.9) 33.0) 59.4) 18.6) 1 082) 3 041)3 131)

Y% ≥ 1:8 97.9 81.8 97.8 100 88.7 52.1 100 100(Seroprotection) (95.9; (77.5; (88.5; (97.9; (82.1; (43.5; (92.1; (97.9;99.1) 85.5) 99.9) 100) 93.5) 60.7) 100) 100)% Seroresponse 95.7 98.9 91.1 100

- - (85.2; (95.9; - - (78.8; (97.9;99.5) 99.9) 97.5) 100)hSBA GMT 91.0 21.8 1 658 2 308 36.1 8.49 800 3 036(78.6; (18.8; (973; (1 925; (27.2; (6.50; (467; (2 547;105) 25.1) 2 826) 2 767) 47.8) 11.1) 1 371) 3 620)

*MET50 - The study was conducted in adolescents (10-17 years of age).

**MET43 - The study was conducted in children, adolescents and adults (10-55 years of age).

***MET59 - NCT04084769$N calculated using per protocol analysis set (PPAS 1 and 2) with valid serology results; post-boosterdose=D06 or D30 of MET59^N calculated using full analysis set for persistence (FASP) with valid serology results. The number ofsubjects varies depending on the timepoints and serogroup; post-primary dose=D30 MET50 or MET43, 3-6 Y post-primary dose (pre-booster dose)=D0 MET59.

Vaccine seroresponse: titre is < 1:8 at baseline with post-vaccination titre ≥ 1:16 or titre is ≥ 1:8 at baselinewith a ≥ 4-fold increase at post-vaccination.95% CI of the single proportion calculated from the exact binomial method.

Persistence of immune response and MenQuadfi booster response in adults 59 years of age and older

MEQ00066 (NCT04142242) evaluated the antibody persistence of a primary dose, immunogenicity, andsafety of a booster dose of MenQuadfi in adults ≥ 59 years of age who had received a single dose of

MenQuadfi or MenACWY-PS ≥ 3 years previously in study MET49 or MET44.

3-year persistence

The antibody persistence prior to the MenQuadfi booster dose and the booster immune response wereassessed according to the vaccine (MenQuadfi or MenACWY-PS) subjects had received 3 yearspreviously in MET49 (Table 14).

For all serogroups, hSBA GMTs were higher at D30 post-primary dose than at 3 Year (3Y) post-primarydose (D0 pre-booster) for both MenQuadfi-primed and MenACWY-PS-primed adults. In addition, forboth primed groups, the 3 Year (3Y) post-primary dose (pre-booster) GMTs were higher than the pre-primary GMTs for serogroups C, W and Y (indicative of long-term persistence of immune response forthese serogroups) and were comparable for serogroup A.

Table 14: Comparison of bactericidal antibody response 6 and 30 days after booster vaccination,and persistence in adults (≥ 59 years) primed with MenQuadfi or MenACWY-PS 3 years before instudy MET49* - (study MEQ00066#)

Endpoint by MenQuadfi Booster in MenQuadfi MenQuadfi Booster in MenACWY-PS

Serogroup primed (95% CI) primed (95% CI)

Persistence^ Booster$ Persistence^ Booster$

D30 - 3Y D06 - D30 - D30 3Y D06 - D30 -

Post- Post- Post- Post- Post- Post- Post- Post-primar primar booste booster primar primar booster boostery dose y dose r dose dose y dose y dose dose dose(D0 - N = 58 N = (D0 - N = 62 N = 130

N = 214 Pre- 145 Pre-booster N = 169 boosterdose) dose)

N = 214 N = 169

A% ≥ 1:8 89.6 65.0 91.4 93.8 85.7 65.7 72.6 87.7(Seroprotection) (84.7; (58.2; (81.0; (88.5; (79.5; (58.0; (59.8; (80.8;93.4) 71.3) 97.1) 97.1) 90.6) 72.8) 83.1) 92.8)% Seroresponse 36.2 79.3 8.1 (2.7; 60.8

- - (24.0; (71.8; - - 17.8) (51.8;49.9) 85.6) 69.2)hSBA GMT 48.9 12.2 43.7 162 37.7 11.6 13.1 56.6(39.0; (10.2; (26.5; (121; (29.3; (9.53; (9.60; (41.5;61.5) 14.6) 71.9) 216) 48.7) 14.1) 17.8) 77.2)

C% ≥ 1:8 88.2 73.4 98.3 99.3 71.4 47.9 51.6 85.3(Seroprotection) (83.1; (66.9; (90.8; (96.2; (64.0; (40.2; (38.6; (78.0;92.2) 79.2) 100) 100) 78.1) 55.7) 64.5) 90.9)% Seroresponse 77.6 93.1 8.1 (2.7; 55.0

- - (64.7; (87.7; - - 17.8) (46.0;87.5) 96.6) 63.8)hSBA GMT 84.8 17.7 206 638 26.7 8.47 11.1 56.0(64.0; (14.3; (126; (496; (19.8; (6.76; (7.17; (39.7;112) 21.9) 339) 820) 36.0) 10.6) 17.1) 78.9)

W% ≥ 1:8 78.8 66.8 89.7 98.6 60.1 39.6 46.8 80.8

Endpoint by MenQuadfi Booster in MenQuadfi MenQuadfi Booster in MenACWY-PS

Serogroup primed (95% CI) primed (95% CI)

Persistence^ Booster$ Persistence^ Booster$

D30 - 3Y D06 - D30 - D30 3Y D06 - D30 -

Post- Post- Post- Post- Post- Post- Post- Post-primar primar booste booster primar primar booster boostery dose y dose r dose dose y dose y dose dose dose(D0 - N = 58 N = (D0 - N = 62 N = 130

N = 214 Pre- 145 Pre-booster N = 169 boosterdose) dose)

N = 214 N = 169(Seroprotection) (72.6; (60.1; (78.8; (95.1; (52.3; (32.2; (34.0; (72.9;84.1) 73.1) 96.1) 99.8) 67.6) 47.4) 59.9) 87.2)% Seroresponse 70.7 90.3 - 6.5 (1.8; 49.2

- - (57.3; (84.3; - 15.7) (40.4;81.9) 94.6) 58.1)hSBA GMT 28.0 14.2 118 419 14.7 6.54 9.89 31.0(22.2; (11.6; (64.0; (317; (11.0; (5.28; (6.45; (22.6;35.3) 17.4) 216) 553) 19.8) 8.11) 15.2) 42.6)

Y% ≥ 1:8 92.5 68.2 94.8 100 65.5 40.8 45.2 81.5(Seroprotection) (88.0; (61.5; (85.6; (97.5; (57.8; (33.3; (32.5; (73.8;95.6) 74.4) 98.9) 100) 72.6) 48.6) 58.3) 87.8)% Seroresponse 72.4 92.4 - - 8.1 (2.7; 49.2

- - (59.1; (86.8; 17.8) (40.4;83.3) 96.2) 58.1)hSBA GMT 65.3 15.3 151 566 19.6 7.49 11.1 40.5(51.8; (12.3; (83.4; (433; (14.4; (5.72; (6.31; (29.0;82.2) 19.1) 274) 740 26.7) 9.82) 19.4) 56.4)

* Clinical trial identifier: NCT02842866# Clinical trial identifier: NCT04142242^N calculated using full analysis set for persistence (FASP) with valid serology results; Post primarydose=D30 of MET49, 3Y post-primary dose (Pre-booster dose)=D0 of MEQ00066$N calculated using per protocol analysis Set 2 and 1 (PPAS2 and PPAS1) with valid serology results.

Post booster dose=D06 or D30 of MEQ00066

Vaccine seroresponse - titre is < 1:8 at baseline with post-vaccination titre ≥ 1:16 or titre is ≥ 1:8 atbaseline with a ≥ 4-fold increase at post-vaccination.95% CI of the single proportion calculated using the exact binomial method.

5-year persistence

A subset of subjects (N = 52) who were assessed for antibody persistence at 3 years and did not receivethe booster dose were re-assessed for antibody persistence at 5 years at which time they received abooster dose of MenQuadfi. In MenQuadfi-primed subjects, hSBA GMTs for serogroups C, W and Y 5Ypost-primary dose trended higher than the pre-priming GMTs (and were comparable for serogroup A).

Following the MenQuadfi booster dose, seroprotection rates were 100% for serogroups A, C, and Y, and95.0% for serogroup W in subjects primed with MenQuadfi and 87.5%, 62.5%, 87.5% and 68.8% forserogroups A, C, W and Y, respectively, for those primed with MenACWY-PS. Additionally, hSBA

GMTs were higher and seroresponse rates were higher or trended higher for all serogroups in subjectsprimed with MenQuadfi compared to those primed with MenACWY-PS.

6-7 year persistence

The antibody persistence was assessed according to the vaccine (MenQuadfi or MenACWY-PS) subjectshad received 6-7 years previously in study MET44 (Table 15).

For all serogroups, hSBA GMTs were higher at D30 post-primary dose than at 6-7 Year (6-7Y) post-primary dose for MenQuadfi-primed adults. The 6-7Y post-primary GMTs were higher than the pre-primary GMTs for serogroup C, W, and Y in MenQuadfi-primed adults, indicative of long-termpersistence of immune response for these serogroups, and were comparable for serogroup A.

Table 15: Comparison of bactericidal antibody persistence in adults (≥ 59 years) primed with

MenQuadfi or MenACWY-PS 6-7 years before in MET44^ - (study MEQ00066#)

MenQuadfi primed (95% CI) MenACWY-PS primed (95% CI)

Endpoint by D30 - Post- 6-7Y Post- D30 - Post- 6-7Y Post-

Serogroup primary dose$ primary dose# primary dose$ primary dose#

N = 59 N = 59 N = 26 N = 26

A% ≥ 1:8 91.4 (81.0; 97.1) 55.9 (42.4; 68.8) 76.9 (56.4; 91.0) 50.0 (29.9; 70.1)(Seroprotection)

GMT 48.0 (30.6; 75.4) 9.00 (6.44; 12.6) 27.3 (13.8; 54) 9.64 (5.18; 17.9)

C% ≥ 1:8 74.1 (61.0; 84.7) 59.3 (45.7; 71.9) 76.9 (56.4; 91.0) 42.3 (23.4; 63.1)(Seroprotection)

GMT 52.2 (27.4; 99.7) 11.9 (7.67; 18.5) 23.9 (11.9; 48.1) 7.58 (4.11; 14.0)

W% ≥ 1:8 75.9 (62.8; 86.1) 66.1 (52.6; 77.9) 73.1 (52.2; 88.4) 38.5 (20.2; 59.4)(Seroprotection)

GMT 31.2 (18.8; 52.0) 11.9 (7.97; 17.8) 18.8 (10.1; 34.9) 4.95 (3.39; 7.22)

Y% ≥ 1:8 81.0 (68.6; 90.1) 59.3 (45.7; 71.9) 73.1 (52.2; 88.4) 46.2 (26.6; 66.6)(Seroprotection)

GMT 45.8 (26.9; 78.0) 11.2 (7.24; 17.5) 25.9 (12.4; 53.8) 7.19 (4.09; 12.6)^Clinical trial identifier: NCT01732627#Clinical trial identifier: NCT04142242

N: number of subjects in full analysis set for persistence (FASP) with valid serology results.$ Post primary dose=D30 of MET44# 6-7Y Post-primary dose=D0 of MEQ0006695% CI of the single proportion calculated from the exact binomial method.

Booster response in adolescents and adults at least 15 years of age primed with other MenACWYvaccines

Study MET56 (NCT02752906) compared the immunogenicity of a booster dose of MenQuadfi with abooster dose of MenACWY-DT in subjects at least 15 years of age. These subjects were primed with aquadrivalent meningococcal conjugate vaccine (MenACWY-CRM (11.3%) or with MenACWY-DT(86.3%)) 4 to 10 years earlier.

At baseline, hSBA seroprotection and GMT were similar for serogroups A, C, W, and Y.

Table 16: Comparison of bactericidal antibody responses to MenQuadfi and MenACWY-DT30 days after booster vaccination in subjects at least 15 years of age primed with MenACWY-CRMor MenACWY-DT 4 to 10 years earlier (study MET56*)

Endpoint by Serogroup MenQuadfi MenACWY-DT (95% CI)(95% CI)

A N = 384 N = 389% ≥ 1:8 (Seroprotection) 100.0 (99.0; 100.0) 99.0 (97.4; 99.7)% Seroresponse** 92.2 (89.0; 94.7) 87.1 (83.4; 90.3)hSBA GMT 497 (436; 568) 296 (256; 343)

C N = 384 N = 389% ≥ 1:8 (Seroprotection) 99.5 (98.1; 99.9) 99.0 (97.4; 99.7)% Seroresponse** 97.1 (94.9; 98.6) 91.8 (88.6; 94.3)hSBA GMT 2 618 (2 227; 3 078) 599 (504; 711)

W N = 384 N = 389% ≥ 1:8 (Seroprotection) 100.0 (99.0; 100.0) 99.7 (98.6; 100.0)% Seroresponse** 98.2 (96.3; 99.3) 90.7 (87.4; 93.4)hSBA GMT 1 747 (1 508; 2 025) 723 (614; 853)

Y N = 384 N = 389% ≥ 1:8 (Seroprotection) 99.7 (98.6; 100.0) 99.5 (98.2; 99.9)% Seroresponse** 97.4 (95.3; 98.7) 95.6 (93.1; 97.4)hSBA GMT 2 070 (1 807; 2 371) 811 (699; 941)

* Clinical trial identifier NCT02752906

N: number of subjects in the per-protocol analysis set with valid serology results.95% CI of the single proportion calculated from the exact binomial method.

** Non-inferiority criterion met.

The European Medicines Agency has deferred the obligation to submit the results of trials within one ormore subsets of the paediatric population under 12 months of age (see 4.2 for information on paediatricuse).

No pharmacokinetic studies have been performed.

Non-clinical safety data revealed no special risks for humans based on a developmental and reproductivetoxicity study in female rabbits.

The administration of MenQuadfi to female rabbits at a full human dose showed no effects on matingperformance, female fertility, no teratogenic potential, and no effect on pre- or post-natal development.

Sodium chloride

Sodium acetate (E 262)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

4 years

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Stability data indicate that the vaccine components are stable at temperatures up to 25°C for 72 hours. Atthe end of this period, MenQuadfi should be used or discarded. These data are intended to guidehealthcare professionals in case of temporary temperature excursion only.

Solution in a Type I borosilicate clear glass vial with a 13 mm chlorobutyl stopper and a flip off seal.

Pack of 1, 5 or 10 single dose (0.5 mL) vials.

Pack of 1 single dose (0.5 mL) vial co-packaged with 1 single use empty luer-lok syringe (polypropylene)with a plunger-stopper (synthetic elastomer), and 2 separate needles (stainless steel) with needle-shield(polypropylene).

Not all pack sizes may be marketed.

The vaccine should be inspected visually for any particulate matter and/or variation of physical aspect (ordiscolouration) prior to administration. In the event of either being observed, discard the vaccine.

Pack of 1, 5 or 10 single dose (0.5 mL) vials

Remove the vial flip off seal and using a suitable syringe and needle, withdraw 0.5 mL of solution fromthe vial, ensuring no air bubbles are present before injection.

To attach the needle to the syringe, gently twist the needle clockwise into the syringe until slightresistance is felt. Before injection, remove the vial flip off seal and withdraw 0.5 mL of solution from thevial, ensuring no air bubbles are present. A new needle should be used to administer the vaccine.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Sanofi Winthrop Industrie82 Avenue Raspail94250 Gentilly

France

EU/1/20/1483/001

EU/1/20/1483/002

EU/1/20/1483/003

EU/1/20/1483/004

Date of first authorisation: 18 November 2020

Date of latest renewal: 02 July 2025

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.