VAXNEUVANCE suspension for injection in pre-filled syringe medication leaflet

Vaxneuvance suspension for injection in pre-filled syringe

Pneumococcal polysaccharide conjugate vaccine (15-valent, adsorbed)

1 dose (0.5 mL) contains:

Pneumococcal polysaccharide serotype 11,2 2.0 micrograms

Pneumococcal polysaccharide serotype 31,2 2.0 micrograms

Pneumococcal polysaccharide serotype 41,2 2.0 micrograms

Pneumococcal polysaccharide serotype 51,2 2.0 micrograms

Pneumococcal polysaccharide serotype 6A1,2 2.0 micrograms

Pneumococcal polysaccharide serotype 6B1,2 4.0 micrograms

Pneumococcal polysaccharide serotype 7F1,2 2.0 micrograms

Pneumococcal polysaccharide serotype 9V1,2 2.0 micrograms

Pneumococcal polysaccharide serotype 141,2 2.0 micrograms

Pneumococcal polysaccharide serotype 18C1,2 2.0 micrograms

Pneumococcal polysaccharide serotype 19A1,2 2.0 micrograms

Pneumococcal polysaccharide serotype 19F1,2 2.0 micrograms

Pneumococcal polysaccharide serotype 22F1,2 2.0 micrograms

Pneumococcal polysaccharide serotype 23F1,2 2.0 micrograms

Pneumococcal polysaccharide serotype 33F1,2 2.0 micrograms1Conjugated to CRM197 carrier protein. CRM197 is a nontoxic mutant of diphtheria toxin (originatingfrom Corynebacterium diphtheriae C7) expressed recombinantly in Pseudomonas fluorescens.2Adsorbed on aluminium phosphate adjuvant.

1 dose (0.5 mL) contains 125 micrograms aluminium (Al3+) and approximately 30 micrograms

CRM197 carrier protein.

For the full list of excipients, see section 6.1.

Suspension for injection (injection).

The vaccine is an opalescent suspension.

Vaxneuvance is indicated for active immunisation for the prevention of invasive disease, pneumoniaand acute otitis media caused by Streptococcus pneumoniae in infants, children and adolescents from6 weeks to less than 18 years of age.

Vaxneuvance is indicated for active immunisation for the prevention of invasive disease andpneumonia caused by Streptococcus pneumoniae in individuals 18 years of age and older.

See sections 4.4 and 5.1 for information on protection against specific pneumococcal serotypes.

The use of Vaxneuvance should be in accordance with official recommendations.

Routine vaccination schedule in infants and children aged 6 weeks to less than 2 years

Two-dose primary series The recommended immunisation regimen consists of 3 doses offollowed by a booster dose Vaxneuvance, each of 0.5 mL. The first dose is given as early as6 weeks of age, with a second dose administered 8 weeks later. Thethird (booster) dose is recommended between 11 through 15 monthsof age.

Three-dose primary series An immunisation regimen consisting of 4 doses of Vaxneuvance,followed by a booster dose each of 0.5 mL, may be given. This primary series consists of3 doses, with the first dose given as early as 6 weeks of age, with aninterval of 4 to 8 weeks between doses in the primary series. Thefourth (booster) dose is recommended between 11 through15 months of age and at least 2 months after the third dose.

Preterm infants (<37 weeks The recommended immunisation regimen consists of a three-dosegestation at birth) primary series of Vaxneuvance followed by a fourth (booster) dose,each of 0.5 mL, as per three-dose primary series followed by abooster dose posology (see sections 4.4 and 5.1).

Prior vaccination with Infants and children who have begun immunisation with anotheranother pneumococcal pneumococcal conjugate vaccine may switch to Vaxneuvance atconjugate vaccine any point in the schedule (see section 5.1).

Catch-up vaccination schedule for children 7 months to less than 18 years of age

Unvaccinated infants 7 to 3 doses, each of 0.5 mL, with the first two doses given at leastless than 12 months of age 4 weeks apart. A third (booster) dose is recommended after12 months of age, separated from the second dose by at least2 months.

Unvaccinated children 12 2 doses, each of 0.5 mL, with an interval of 2 months betweenmonths to less than 2 years doses.of age

Unvaccinated or not fully 1 dose (0.5 mL).vaccinated children andadolescents 2 to less than 18 If a previous pneumococcal conjugate vaccine was administered, atyears of age least 2 months should elapse before administering Vaxneuvance.

Vaccination schedule for individuals 18 years of age and older

Individuals 18 years of age 1 dose (0.5 mL).and older

The need for revaccination with a subsequent dose of Vaxneuvancehas not been established.

One or more doses of Vaxneuvance may be given to individuals who have one or more underlyingconditions predisposing them to an increased risk of pneumococcal disease (such as individuals withsickle cell disease or living with human immunodeficiency virus (HIV) infection or recipients ofhaematopoietic stem cell transplant (HSCT) or immunocompetent individuals 18 to 49 years of agewith risk factors for pneumococcal disease; see section 5.1).

The vaccine should be administered by intramuscular injection. The preferred site is the anterolateralaspect of the thigh in infants or the deltoid muscle of the upper arm in children and adults.

No data are available for administration via the intradermal route.

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

Hypersensitivity to the active substances, to any of the excipients listed in section 6.1, or to anydiphtheria toxoid-containing vaccine.

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

Precaution related to route of administration

Vaxneuvance must not be administered intravascularly.

Anaphylaxis

As with all injectable vaccines, appropriate medical treatment and supervision should always bereadily available in case of a rare anaphylactic event following the administration of the vaccine.

Vaccination should be postponed in individuals suffering from acute severe febrile illness or acuteinfection. The presence of a minor infection and/or low-grade fever should not delay vaccination.

As with other intramuscular injections, the vaccine should be given with caution to individualsreceiving anticoagulant therapy, or to those with thrombocytopenia or any coagulation disorder suchas haemophilia. Bleeding or bruising may occur following an intramuscular administration in theseindividuals. Vaxneuvance may be given subcutaneously if the potential benefit clearly outweighs therisks (see section 5.1).

Apnoea in premature infants

The potential risk of apnoea and the need for respiratory monitoring for 48-72 hours should beconsidered when administering the primary immunisation series to very premature infants (born ≤ 28weeks of gestation) and particularly for those with a previous history of respiratory immaturity. As thebenefit of vaccination is high in this group of infants, vaccination generally should not be withheld ordelayed.

Immunocompromised individuals, whether due to the use of immuno-suppressive therapy, a geneticdefect, HIV infection, or other causes, may have reduced antibody response to active immunisation.

Safety and immunogenicity data for Vaxneuvance are available for individuals with sickle cell diseaseor living with HIV infection or with a haematopoietic stem cell transplant (see section 5.1). Safety andimmunogenicity data for Vaxneuvance are not available for individuals in other specificimmunocompromised groups and vaccination should be considered on an individual basis.

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

Vaxneuvance will only protect against Streptococcus pneumoniae serotypes included in the vaccine(see sections 2 and 5.1).

This medicinal product contains less than 1 mmol sodium (23 milligrams) per dose, i.e. essentially‘sodium-free’.

Different injectable vaccines should always be administered at different injection sites.

Immunosuppressive therapies may reduce the immune responses to vaccines.

Infants and children aged 6 weeks to less than 2 years

Vaxneuvance can be given concomitantly with any of the following vaccine antigens, either asmonovalent or combination vaccines: diphtheria, tetanus, pertussis, poliomyelitis (serotypes 1, 2and 3), hepatitis A, hepatitis B, Haemophilus influenzae type b, measles, mumps, rubella, varicella androtavirus vaccine.

Children and adolescents 2 to less than 18 years of age

There are no data on the concomitant administration of Vaxneuvance with other vaccines.

Data from a post-marketing clinical study evaluating the impact of prophylactic use of antipyretics(ibuprofen and paracetamol) on the immune response to other pneumococcal vaccines suggest thatadministration of antipyretics concomitantly or within the same day of vaccination may reduce theimmune response after the infant series. Responses to the booster dose administered at 12 months wereunaffected. The clinical significance of this observation is unknown.

Vaxneuvance can be administered concomitantly with seasonal quadrivalent influenza vaccine (splitvirion, inactivated). There are no data on the concomitant administration of Vaxneuvance with othervaccines.

There is limited experience with the use of Vaxneuvance in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,embryo/foetal development, parturition or post-natal development (see section 5.3).

Administration of Vaxneuvance in pregnancy should only be considered when the potential benefitsoutweigh any potential risks for the mother and the foetus.

It is unknown whether Vaxneuvance is excreted in human milk.

No human data on the effect of Vaxneuvance on fertility are available. Animal studies in female ratsdo not indicate harmful effects (see section 5.3).

Vaxneuvance has no or negligible influence on the ability to drive and use machines. However, someof the effects mentioned under section 4.8 “Undesirable effects” may temporarily affect the ability todrive or use machines.

Infants and children aged 6 weeks to less than 2 years

The safety of Vaxneuvance in healthy infants, including preterm infants (from 6 weeks of age at firstvaccination) and children (11 through 15 months of age) was assessed as a 3 dose or 4 dose regimen in5 clinical studies with a total of 7,229 participants.

All 5 studies evaluated the safety of Vaxneuvance when administered concomitantly with otherroutine paediatric vaccines. In these studies, 4,286 participants received a complete regimen of

Vaxneuvance, 2,405 participants received a complete regimen of the 13-valent pneumococcalconjugate vaccine (PCV) and 538 participants received Vaxneuvance when used to complete aregimen initiated with the 13-valent PCV (mixed dose regimen).

The most frequent adverse reactions were pyrexia ≥38 °C (75.2%), irritability (74.5%), somnolence(55.0%), injection-site pain (44.4%), injection-site erythema (41.7%), decreased appetite (38.2%),injection-site induration (28.3%) and injection-site swelling (28.2%) based on results in 3,589participants (Table 1), excluding participants who received a mixed dose regimen. The majority ofsolicited adverse reactions were mild to moderate (based on intensity or size) and of short duration(≤3 days). Severe reactions (defined as being extremely distressed or unable to do usual activities orsize of injection site reaction >7.6 cm) occurred in ≤3.5% of infants and children following any dose,with the exception of irritability which occurred in 11.4% of participants.

Children and adolescents 2 to less than 18 years of age

The safety of Vaxneuvance in healthy children and adolescents was assessed in a study that included352 participants 2 to less than 18 years of age, of whom 177 received a single dose of Vaxneuvance.

In this age cohort, 42.9% of all participants had a history of previous vaccination with a lower valencypneumococcal conjugate vaccine.

The most frequent adverse reactions were injection-site pain (54.8%), myalgia (23.7%), injection-siteswelling (20.9%), injection-site erythema (19.2%), fatigue (15.8%), headache (11.9%), injection-siteinduration (6.8%), and pyrexia ≥38 °C (5.6%) (Table 1). The majority of solicited adverse reactionswere mild to moderate (based on intensity or size) and of short duration (≤3 days); severe reactions(defined as being extremely distressed or unable to do usual activities or size of injection sitereaction >7.6 cm) occurred in ≤4.5% of children and adolescents.

Adults 18 years of age and older

The safety of Vaxneuvance in healthy and immunocompetent adults was assessed in 6 clinical studiesin 7,136 adults ≥18 years of age. An additional clinical study assessed 302 adults ≥18 years of ageliving with HIV. Vaxneuvance was administered to 5,630 adults; 1,241 were 18 to 49 years of age,1,911 were 50 to 64 years of age, and 2,478 were 65 years of age and older. Of those who received

Vaxneuvance, 1,134 were immunocompetent adults 18 to 49 years of age who had no (n=285), 1(n=620) or ≥ 2 (n=229) risk factors for pneumococcal disease and 152 were adults ≥18 years of ageliving with HIV. In addition, 5,253 adults were pneumococcal vaccine-naïve and 377 adults werepreviously vaccinated with 23-valent pneumococcal polysaccharide vaccine (PPV23) at least 1 yearprior to enrollment.

The most frequently reported adverse reactions following vaccination with Vaxneuvance weresolicited. In the pooled analysis of the 7 studies, the most frequent adverse reactions were injection-site pain (64.6%), fatigue (23.4%), myalgia (20.7%), headache (17.3%), injection-site swelling(16.1%), injection-site erythema (11.3%) and arthralgia (7.9%) (Table 1). The majority of solicitedadverse reactions were mild (based on intensity or size) and of short duration (≤3 days); severereactions (defined as an event that prevents normal daily activity or size of injection sitereaction >10 cm) occurred in ≤1.5% of adults across the clinical program.

Older adults reported fewer adverse reactions than younger adults.

In clinical studies of adults, local and systemic adverse reactions were solicited daily after vaccinationfor 5 and 14 days, respectively and in infants, children and adolescents up to 14 days after vaccination.

In all populations, unsolicited adverse reactions were reported for 14 days after vaccination.

Adverse reactions reported for all age groups are listed in this section per system organ class, indecreasing order of frequency and seriousness. The frequency is defined as follows:

- 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).

Table 1: Tabulated list of adverse reactions

System Organ Adverse Reactions Frequency

Class Infants/Children/Adolescents Adults6W to <2Y 2 to <18Y§

Metabolism and Decreased appetite Very common Common -nutrition disorders

Psychiatric Irritability Very common Common -disorders

Immune system Hypersensitivity - - Raredisorders reaction includingtongue oedema,flushing, and throattightness

Nervous system Somnolence Very common Common -disorders Headache - Very common Very common

Dizziness - - Uncommon†

Skin and Urticaria Common Common Raresubcutaneous Rash Common Not known ‡ Uncommontissue disorders

Gastrointestinal Nausea - Common Uncommon†disorders Vomiting Common Uncommon Uncommon

Musculoskeletal Myalgia - Very common Very commonand connective Arthralgia - - Common*tissue disorders

General disorders Pyrexia⸸ Very common Common Uncommon†and ≥39°C Very common - -administration site ≥40 °C Common - -conditions Injection-site pain Very common Very common Very common

Injection-site erythema Very common Very common Very common

Injection-site swelling Very common Very common Very common

Injection-site induration Very common Common -

Injection-site urticaria Uncommon - -

Fatigue - Very common Very common

Injection-site pruritus - - Common

Injection-site warmth - - Uncommon

Injection-site Common Common Uncommonbruising/haematoma

Chills - - Uncommon†§Different systemic adverse events were solicited for participants 2 to <3 years of age, than for participants ≥3 to less than 18 years of age.

For participants <3 years of age (Vaxneuvance N=32, 13-valent PCV N=28), decreased appetite, irritability, somnolence and urticaria weresolicited from Day 1 through Day 14 following vaccination. For participants ≥3 to less than 18 years of age, fatigue, headache, myalgia, andurticaria were solicited from Day 1 through Day 14 following vaccination.†common in adults 18 to 49 years of age‡In clinical trials, no events were observed following Vaxneuvance in healthy children and adolescents and two events were observed inspecial populations (sickle cell disease and HIV).

*very common in adults 18 to 49 years of age⸸defined as temperature ≥38 °C

Additional information for other dosing regimens, vaccination schedules and special populations

Mixed dose regimen of different pneumococcal conjugate vaccines

The safety profiles of mixed 4-dose regimens of Vaxneuvance and the 13-valent PCV in healthyinfants and children were generally comparable to those of complete 4-dose regimens of either

Vaxneuvance or the 13-valent PCV (see section 5.1).

Catch-up vaccination schedule

Safety was also assessed as a catch-up vaccination schedule in 126 healthy infants and children from7 months to less than 2 years of age who received 2 or 3 doses of Vaxneuvance based on age atenrollment. The safety profile of the catch-up vaccination schedule was generally consistent with thesafety profile of the routine vaccination schedule initiated from 6 weeks of age (see section 5.1).

Children and adolescents with sickle cell disease or living with HIV

Safety was also assessed in 69 children and adolescents 5 to less than 18 years of age with sickle celldisease and in 203 children and adolescents 6 to less than 18 years of age living with HIV, all ofwhom received a single dose of Vaxneuvance. The safety profile of Vaxneuvance in children withthese conditions was generally consistent with the safety profile in healthy children (see section 5.1).

Children and adults receiving Haematopoietic Stem Cell Transplant

Safety was also assessed in 131 adults and 8 children ≥3 years of age who had received an allogeneichaematopoietic stem cell transplant (allo-HSCT) 3 to 6 months prior to enrollment, all of whomreceived between 1 and 4 doses of Vaxneuvance. The safety profile of Vaxneuvance in recipients ofallo-HSCT was generally consistent with the safety profile in a healthy population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There are no data with regard to overdose.

Pharmacotherapeutic group: vaccines, pneumococcal vaccines, ATC code: J07AL02

Vaxneuvance contains 15 purified pneumococcal capsular polysaccharides from Streptococcuspneumoniae (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, with the additional serotypes 22F and33F), each conjugated to a carrier protein (CRM197). Vaxneuvance elicits a T-cell dependent immuneresponse to induce antibodies that enhance opsonisation, phagocytosis, and killing of pneumococci toprotect against pneumococcal disease.

Immune responses following natural exposure to Streptococcus pneumoniae or followingpneumococcal vaccination can be determined by measuring opsonophagocytic activity (OPA) andimmunoglobulin G (IgG) responses. OPA represents functional antibodies and is considered animportant immunologic surrogate measure of protection against pneumococcal disease in adults. Inchildren, a serotype-specific IgG antibody level corresponding to ≥0.35 µg/mL using the WHOenzyme linked immunosorbent assay (ELISA) has been used as the threshold value for the clinicalevaluation of pneumococcal conjugate vaccines.

Clinical immunogenicity in healthy infants, children and adolescents

Immunogenicity was assessed by serotype-specific IgG response rates (the proportion of participantsmeeting the serotype-specific IgG threshold value of ≥0.35 µg/mL) and IgG geometric meanconcentrations (GMCs) at 30 days following the primary series and/or following the toddler (booster)dose. In a subset of participants, OPA geometric mean titres (GMTs) were also measured at 30 daysfollowing the primary series and/or following the toddler dose.

Infants and children receiving a routine vaccination schedule3-dose regimen (2-dose primary series + 1 toddler dose)

In the double-blind, active comparator-controlled study (Protocol 025), 1,184 participants wererandomised to receive Vaxneuvance or the 13-valent PCV in a 3-dose regimen. The first two doseswere administered to infants at 2 and 4 months of age (primary series) and the third dose wasadministered to children at 11 through 15 months of age (toddler dose). Participants also receivedother paediatric vaccines concomitantly, including Rotavirus vaccine (live) with the infant primaryseries and Diphtheria, Tetanus, Pertussis (acellular), Hepatitis B (rDNA), Poliomyelitis (inactivated),

Haemophilus influenzae type b conjugate vaccine (adsorbed) with all 3 doses in the complete regimen.

Vaxneuvance elicits immune responses, as assessed by IgG response rates, IgG GMCs and OPA

GMTs, for all 15 serotypes contained in the vaccine. At 30 days following the two-dose primaryseries, serotype-specific IgG response rates and GMCs were generally comparable for the 13 sharedserotypes and higher for the 2 additional serotypes (22F and 33F) in Vaxneuvance recipients,compared to the 13-valent PCV recipients (Table 2). At 30 days following the toddler dose,

Vaxneuvance is noninferior to the 13-valent PCV for the 13 shared serotypes and superior for the2 additional serotypes, as assessed by IgG response rate and IgG GMCs (Table 3).

Table 2: Serotype-specific IgG response rates and IgG GMCs at 30 days following the 2-doseprimary series (3-dose regimen, Protocol 025)

IgG response rates ≥0.35 µg/mL IgG GMCs13-valent 13-valent

Percentage

Vaxneuvance PCV Vaxneuvance PCV

Point GMC Ratio**

Pneumococcal (n=497) (n=468- (n=497) (n=468-

Difference* (Vaxneuvance/

Serotype 469) 469)(Vaxneuvance - 13-valent PCV)

Observed Observed13-valent PCV) (95% CI)**

Response Response GMC GMC(95% CI)*

Percentage Percentage13 Shared Serotypes†1 95.6 97.4 -1.9 (-4.3, 0.5) 1 . 3 0 1.60 0 . 81 (0.74, 0.89)3 93.2 66.1 27.1 (22.3, 31.9) 0 . 8 7 0.45 1 . 91 (1.75, 2.08)4 93.8 96.8 -3.0 (-5.9, -0.4) 1 . 4 0 1.25 1 . 12 (1.01, 1.24)5 84.1 88.1 -4.0 (-8.3, 0.4) 0 . 8 8 1.03 0 . 86 (0.76, 0.97)72.6 92.3 -19.7 (-24.3, - 0.64 1.39 0 . 46 (0.40, 0.53)6A15.1)6B 57.7 50.2 7.5 (1.2, 13.8) 0 . 4 3 0.33 1 . 31 (1.11, 1.56)7F 97.8 98.9 -1.1 (-3.0, 0.5) 2 . 0 3 2.42 0 . 84 (0.76, 0.92)9V 88.3 95.3 -7.0 (-10.5, -3.6) 1 . 2 3 1.39 0 . 88 (0.78, 0.99)14 96.8 97.2 -0.4 (-2.7, 1.8) 3 . 8 1 4.88 0 . 78 (0.68, 0.90)18C 92.2 92.5 -0.4 (-3.8, 3.0) 1 . 1 6 1.30 0 . 89 (0.80, 0.99)19A 96.2 97.2 -1.1 (-3.4, 1.3) 1 . 6 8 2.09 0 . 81 (0.72, 0.90)19F 98.8 99.4 -0.6 (-2.0, 0.8) 2 . 6 3 3.35 0 . 79 (0.71, 0.87)23F 77.9 70.1 7.8 (2.3, 13.3) 0 . 7 5 0.58 1 . 30 (1.14, 1.50)2 Additional Serotypes in Vaxneuvance‡95.6 5.3 90.2 (87.1, 92.6) 2 . 7 4 0.05 57.67 (50.95,22F65.28)33F 48.1 3.0 45.1 (40.4, 49.7) 0 . 3 0 0.05 6 . 11 (5.32, 7.02)

* Estimated difference and CI for the percentage point difference are based on the Miettinen & Nurminen method.

** GMC ratio and CI are calculated using the t-distribution with the variance estimate from a serotype-specific linear model utilising thenatural log-transformed antibody concentrations as the response and a single term for vaccination group.† A conclusion of non-inferiority for the 13 shared serotypes is based on the lower bound of the 95% CI being > -10 percentage points for thedifference in IgG response rates (Vaxneuvance - 13-valent PCV) or > 0.5 for the IgG GMC ratio (Vaxneuvance/13-valent PCV).‡ A conclusion of superiority for the 2 additional serotypes is based on the lower bound of the 95% CI being > 10 percentage points for thedifference in IgG response rates (Vaxneuvance - 13-valent PCV) or > 2.0 for the IgG GMC ratio (Vaxneuvance/13-valent PCV).n=Number of participants randomised, vaccinated and contributing to the analysis.

CI=confidence interval; GMC=geometric mean concentration (µg/mL); IgG=immunoglobulin G.

Table 3: Serotype-specific IgG response rates and IgG GMCs at 30 days following the toddlerdose (3-dose regimen, Protocol 025)

IgG response rates ≥0.35 µg/mL IgG GMCs13-valent 13-valent

Percentage

Vaxneuvance PCV Vaxneuvance PCV

Point GMC Ratio**

Pneumococcal (n=510-511) (n=504- (n=510-511) (n=504-

Difference* (Vaxneuvance/

Serotype 510) 510)(Vaxneuvance - 13-valent PCV)

Observed Observed13-valent PCV) (95% CI)**

Response Response GMC GMC(95% CI)*

Percentage Percentage13 Shared Serotypes†1 96.5 99.4 -2.9 (-5.0, -1.3) 1.28 2.05 0.62 (0.57, 0.68)3 91.8 83.7 8.1 (4.1, 12.1) 0.84 0.66 1.29 (1.18, 1.41)4 95.7 97.8 -2.1 (-4.5, 0.0) 1.29 1.74 0.74 (0.67, 0.82)5 99.0 100.0 -1.0 (-2.3, -0.2) 1.98 3.01 0.66 (0.60, 0.72)6A 98.4 98.8 -0.4 (-2.0, 1.2) 3.09 4.53 0.68 (0.61, 0.76)6B 97.3 99.0 -1.8 (-3.7, -0.1) 4.15 4.33 0.96 (0.85, 1.08)7F 99.8 99.8 0.0 (-0.9, 0.9) 3.08 3.89 0.79 (0.73, 0.86)9V 98.8 100.0 -1.2 (-2.5, -0.4) 2.14 2.97 0.72 (0.66, 0.78)14 99.8 100.0 -0.2 (-1.1, 0.6) 5.22 6.90 0.76 (0.68, 0.84)18C 98.8 99.2 -0.4 (-1.8, 1.0) 1.93 2.18 0.89 (0.81, 0.97)19A 99.0 100.0 -1.0 (-2.3, -0.2) 4.65 5.61 0.83 (0.75, 0.92)19F 99.6 100.0 -0.4 (-1.4, 0.4) 4.06 4.59 0.89 (0.81, 0.97)23F 96.9 97.2 -0.4 (-2.6, 1.8) 1.52 1.69 0.90 (0.81, 1.00)2 Additional Serotypes in Vaxneuvance‡5.97 0.08 71.76 (64.88,22F 99.6 5.9 93.7 (91.2, 95.5)79.38)3.38 0.07 46.38 (41.85,33F 99.0 4.4 94.7 (92.3, 96.3)51.40)

* Estimated difference and CI for the percentage point difference are based on the Miettinen & Nurminen method.

** GMC ratio and CI are calculated using the t-distribution with the variance estimate from a serotype-specific linear model utilising thenatural log-transformed antibody concentrations as the response and a single term for vaccination group.† A conclusion of non-inferiority for the 13 shared serotypes is based on the lower bound of the 95% CI being > -10 percentage points for thedifference in IgG response rates (Vaxneuvance - 13-valent PCV) or > 0.5 for the IgG GMC ratio (Vaxneuvance/13-valent PCV).‡ A conclusion of superiority for the 2 additional serotypes is based on the lower bound of the 95% CI being > 10 percentage points for thedifference in IgG response rates (Vaxneuvance - 13-valent PCV) or > 2.0 for the IgG GMC ratio (Vaxneuvance/13-valent PCV).n=Number of participants randomised, vaccinated and contributing to the analysis.

CI=confidence interval; GMC=geometric mean concentration (µg/mL); IgG=immunoglobulin G.

Additionally, Vaxneuvance elicits functional antibodies, as assessed by serotype-specific OPA GMTsat 30 days following the toddler dose, that are generally comparable but slightly lower for the13 serotypes shared with 13-valent PCV. The clinical relevance of this slightly lower response isunknown. OPA GMTs for both 22F and 33F were higher in Vaxneuvance recipients compared to the13-valent PCV recipients.

In another double-blind, active comparator-controlled study (Protocol 026), 1,191 participants wererandomised to receive Vaxneuvance or the 13-valent PCV as a 3-dose regimen given concomitantlywith other paediatric vaccines including Vaxelis with all three doses and M-M-RvaxPro and Varivaxwith the toddler dose. The primary series was administered to infants at 3 and 5 months of agefollowed by the toddler dose at 12 months of age.

Vaxneuvance elicits immune responses, as assessed by IgG response rates, IgG GMCs and OPA

GMTs, for all 15 serotypes contained in the vaccine. At 30 days following the toddler dose,

Vaxneuvance is non-inferior to the 13-valent PCV for the 13 shared serotypes and superior for the2 additional serotypes, 22F and 33F, as assessed by IgG response rates. Similarly, Vaxneuvance isnon-inferior to the 13-valent PCV for the 13 shared serotypes and superior to the 13-valent PCV forthe 2 additional serotypes, as assessed by IgG GMCs. Following the toddler dose, Vaxneuvancegenerates functional antibodies (OPA GMTs) for all 15 serotypes that are generally comparable withthe 13-valent PCV.

4-dose regimen (3-dose primary series + 1 toddler dose)

A 4-dose regimen was evaluated in healthy infants in one phase 2 and three phase 3 studies. Theprimary series were administered to infants at 2, 4, and 6 months of age and the toddler dose wasadministered to children at 12 through 15 months of age.

In a double-blind, active comparator-controlled study (Protocol 029), 1,720 participants wererandomised to receive Vaxneuvance or the 13-valent PCV. Participants also received other paediatricvaccines concomitantly, including HBVaxPro (Hepatitis B Vaccine [Recombinant]), RotaTeq(Rotavirus Vaccine, Live, Oral, Pentavalent) and Diphtheria, Tetanus Toxoids, Acellular Pertussis

Adsorbed, Poliomyelitis (inactivated), Haemophilus b Conjugate (Tetanus Toxoid Conjugate) Vaccinein the infant series. Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate), M-M-RvaxPro(Measles, Mumps, and Rubella Virus Vaccine Live), Varivax (Varicella Virus Vaccine Live) and

Vaqta (Hepatitis A Vaccine, Inactivated) were administered concomitantly with the toddler dose of

Vaxneuvance.

Vaxneuvance elicits immune responses, as assessed by IgG response rates, IgG GMCs and OPA

GMTs for all 15 serotypes contained in the vaccine. At 30 days following the primary series,

Vaxneuvance is noninferior to the 13-valent PCV for the 13 shared serotypes, as assessed by IgGresponse rates (Table 4). Vaxneuvance is noninferior for the 2 additional serotypes, as assessed by the

IgG response rates for serotypes 22F and 33F in recipients of Vaxneuvance compared with theresponse rate for serotype 23F in recipients of the 13-valent PCV (the lowest response rate for any ofthe shared serotypes, excluding serotype 3), with percentage point differences of 6.7% (95% CI: 4.6,9.2) and -4.5% (95% CI: -7.8, -1.3), respectively.

At 30 days following the primary series, serotype-specific IgG GMCs are noninferior to the 13-valent

PCV for 12 of the 13 shared serotypes. The IgG response to serotype 6A narrowly missed theprespecified noninferiority criteria by a small margin (0.48 versus >0.5) (Table 4). Vaxneuvance isnoninferior to the 13-valent PCV for the 2 additional serotypes, as assessed by serotype-specific IgG

GMCs for serotypes 22F and 33F in recipients of Vaxneuvance compared with the IgG GMCs forserotype 4 in recipients of the 13-valent PCV (the lowest IgG GMC for any of the shared serotypes,excluding serotype 3) with a GMC ratio of 3.64 and 1.24, respectively.

Additionally, Vaxneuvance induces immune responses to shared serotype 3 and the 2 additionalserotypes, which were substantially higher compared to the immune response induced by the 13-valent

PCV as assessed by IgG response rates and IgG GMCs at 30 days following the primary series(Table 4).

Table 4: Serotype-specific IgG response rates and IgG GMCs at 30 days following the 3-doseprimary series (4-dose regimen, Protocol 029)

IgG response rates ≥0.35 µg/mL IgG GMCs13-valent Percentage 13-valent

Vaxneuvance PCV Point Vaxneuvance PCV

GMC Ratio**

Pneumococcal (n=698-702) (n=660- Difference* (n=698-702) (n=660-(Vaxneuvance/

Serotype 665) (Vaxneuvance 665)13-valent PCV)

Observed Observed - 13-valent(95% CI)**

Response Response PCV) GMC GMC

Percentage Percentage (95% CI)*13 Shared Serotypes†1 95.7 99.1 -3.4 (-5.2, -1.8) 1 . 2 1 1.89 0 .64 (0.59, 0.69)94.7 79.2 15.6 (12.1, 1.08 0.62 1 .73 (1.61, 1.87)19.2)4 96.4 98.6 -2.2 (-4.0, -0.6) 1 . 2 9 1.35 0 .95 (0.88, 1.03)5 95.3 97.4 -2.1 (-4.2, -0.2) 1 . 6 3 2.25 0 .72 (0.66, 0.80)6A 93.7 98.6 -4.9 (-7.1, -3.0) 1 . 5 5 2.95 0 .52 (0.48, 0.58)6B 88.6 92.0 -3.4 (-6.6, -0.3) 1 . 6 0 1.97 0 .81 (0.71, 0.93)7F 99.0 99.8 -0.8 (-1.9, -0.1) 2 . 4 8 3.23 0 .77 (0.71, 0.83)9V 97.1 98.2 -1.0 (-2.8, 0.6) 1 . 7 3 1.89 0 .91 (0.84, 1.00)14 97.9 97.9 -0.0 (-1.6, 1.6) 4 . 7 8 6.80 0 .70 (0.63, 0.78)18C 97.4 98.3 -0.9 (-2.6, 0.7) 1 . 5 3 2.00 0 .76 (0.70, 0.83)19A 97.9 99.7 -1.8 (-3.2, -0.8) 1 . 6 3 2.29 0 .71 (0.65, 0.77)19F 99.0 100.0 -1.0 (-2.1, -0.4) 2 . 0 1 2.72 0 .74 (0.69, 0.79)23F 91.5 91.8 -0.3 (-3.2, 2.7) 1 . 3 1 1.47 0 .89 (0.80, 0.99)2 Additional Serotypes in Vaxneuvance98.6 3.5 95.1 (93.1, 4.91 0.05 92.03 (83.47,22F96.5) 101.47)87.3 2.1 85.2 (82.3, 1.67 0.06 29.50 (26.16,33F87.7) 33.26)

* Estimated difference and CI for the percentage point difference are based on the Miettinen & Nurminen method.

** GMC ratio and CI are calculated using the t-distribution with the variance estimate from a serotype-specific linear model utilising thenatural log-transformed antibody concentrations as the response and a single term for vaccination group.† A conclusion of non-inferiority for the 13 shared serotypes is based on the lower bound of the 95% CI being > -10 percentage points for thedifference in IgG response rates (Vaxneuvance - 13-valent PCV) or > 0.5 for the IgG GMC ratio (Vaxneuvance/13-valent

PCV).n=Number of participants randomised, vaccinated and contributing to the analysis.

CI=confidence interval; GMC=geometric mean concentration (µg/mL); IgG=immunoglobulin G.

At 30 days following the toddler dose, serotype-specific IgG GMCs for Vaxneuvance are noninferiorto the 13-valent PCV for all 13 shared serotypes and for the 2 additional serotypes as assessed by the

IgG GMCs for serotypes 22F and 33F in Vaxneuvance recipients compared with the IgG GMC forserotype 4 in the 13-valent PCV recipients (the lowest IgG GMC for any of the shared serotypes,excluding serotype 3) with a GMC ratio of 4.69 and 2.59, respectively (Table 5).

Vaxneuvance induces immune responses to shared serotype 3 and the 2 additional serotypes, whichwere substantially higher compared to the immune response induced by the 13-valent PCV, asassessed by IgG response rates and IgG GMCs at 30 days following the toddler dose (Table 5).

Table 5: Serotype-specific IgG response rates and IgG GMCs at 30 days following the toddlerdose (4-dose regimen, Protocol 029)

IgG response rates ≥0.35 µg/mL IgG GMCs13-valent 13-valent

Percentage

Vaxneuvance PCV Vaxneuvance PCV

Point GMC Ratio**

Pneumococcal (n=712-716) (n=677- (n=712-716) (n=677-

Difference* (Vaxneuvance/

Serotype 686) 686)(Vaxneuvance - 13-valent PCV)

Observed Observed13-valent PCV) (95% CI)**

Response Response GMC GMC(95% CI)*

Percentage Percentage13 Shared Serotypes†1 96.6 9 9 .4 - 2 . 8 ( - 4.4, -1.4) 1 . 3 5 2.03 0 .66 (0.62, 0.72)3 94.0 8 6.9 7 . 1 ( 4 .0, 10.2) 0 . 9 6 0.71 1 .35 (1.25, 1.46)4 95.1 9 7 .5 - 2 . 4 ( - 4 .5, -0.4) 1 . 2 3 1.60 0 .77 (0.71, 0.84)5 99.2 9 9 . 9 - 0 . 7 ( - 1.7, 0.1) 2 . 4 9 3.95 0 .63 (0.58, 0.69)6A 98.7 9 9 . 3 - 0 . 5 ( - 1.7, 0.6) 3 . 7 0 6.21 0 .60 (0.54, 0.65)6B 98.7 9 9 .3 - 0 . 5 ( -1.7, 0.6) 4 . 7 6 6.43 0 .74 (0.67, 0.81)7F 99.6 9 9 .9 - 0 . 3 ( -1.1, 0.4) 3 . 4 2 4.85 0 .70 (0.65, 0.77)9V 99.4 9 9 .7 - 0 . 3 ( - 1 .2, 0.6) 2 . 4 0 3.29 0 .73 (0.67, 0.80)14 99.3 9 9 .6 - 0 . 3 ( - 1 .2, 0.7) 5 . 6 1 6.95 0 .81 (0.73, 0.89)18C 99.7 9 9 .6 0 . 2 ( - 0 .6, 1.0) 2 . 6 2 3.08 0 .85 (0.78, 0.93)19A 99.9 9 9 .9 0 . 0 ( - 0 .7, 0.7) 4 . 1 0 5.53 0 .74 (0.68, 0.80)19F 99.7 9 9 . 7 0 . 0 ( - 0.8, 0.8) 3 . 5 5 4.47 0 .79 (0.74, 0.86)23F 98.6 9 9 .0 - 0 . 4 ( - 1 .7, 0.9) 2 . 0 4 3.32 0 .61 (0.56, 0.68)2 Additional Serotypes in Vaxneuvance99.6 7 . 2 9 2 . 4 (90.1, 94.2) 7 . 5 2 0.11 68.80 (63.10,22F75.02)98.9 6 . 2 9 2.7 (90.4, 94.4) 4 . 1 5 0.09 44.91 (41.04,33F49.14)

* Estimated difference and CI for the percentage point difference are based on the Miettinen & Nurminen method.

** GMC ratio and CI are calculated using the t-distribution with the variance estimate from a serotype-specific linear model utilising thenatural log-transformed antibody concentrations as the response and a single term for vaccination group.† A conclusion of non-inferiority for the 13 shared serotypes is based on the lower bound of the 95% CI being > 0.5 for the IgG GMC ratio(Vaxneuvance/13-valent PCV).n=Number of participants randomised, vaccinated and contributing to the analysis.

CI=confidence interval; GMC=geometric mean concentration (µg/mL); IgG=immunoglobulin G.

Vaxneuvance elicits functional antibodies, as assessed by serotype-specific OPA GMTs at 30 daysfollowing the primary series and following the toddler dose, that are generally comparable but slightlylower for the 13 serotypes shared with 13-valent PCV. The clinical relevance of this slightly lowerresponse is unknown. OPA GMTs for both 22F and 33F were higher in Vaxneuvance recipientscompared to the 13-valent PCV recipients.

Infants and children receiving a mixed dose regimen of different pneumococcal conjugate vaccines

In a double-blind, active comparator-controlled, descriptive study (Protocol 027), 900 participantswere randomised in a 1:1:1:1:1 ratio to one of five vaccination groups to receive a complete or mixeddosing regimen of pneumococcal conjugate vaccines. In two vaccination groups, participants receiveda 4-dose regimen of either Vaxneuvance or the 13-valent PCV. In the three other vaccination groups,the vaccination series were initiated with the 13-valent PCV and changed to Vaxneuvance at Dose 2,

Dose 3 or Dose 4. Participants also received other paediatric vaccines concomitantly, including

HBVaxPro (Hepatitis B Vaccine [Recombinant]) and RotaTeq (Rotavirus Vaccine, Live, Oral,

Pentavalent). Serotype-specific IgG GMCs at 30 days following the toddler dose were generallycomparable for participants administered mixed regimens of Vaxneuvance and the 13-valent PCV andfor participants administered a complete dosing regimen of the 13-valent PCV for the 13 sharedserotypes, as assessed by IgG GMC ratios.

Higher antibodies to serotypes 22F and 33F were only observed when at least one dose of

Vaxneuvance was administered during primary infant series and at the toddler age.

Immunogenicity in preterm infants

The immune responses (serotype-specific IgG and OPA) in preterm infants receiving 4 doses ofpneumococcal conjugate vaccine in 4 double-blind, active comparator-controlled studies(Protocol 025, Protocol 027, Protocol 029 and Protocol 031), were generally consistent with thoseobserved in the overall healthy infant population in these studies (including preterm and term infants).

Infants, children and adolescents receiving a catch-up vaccination schedule

In a double-blind, active comparator-controlled, descriptive study (Protocol 024), 606 children whowere either pneumococcal vaccine-naïve or not fully vaccinated or completed a dosing regimen withlower valency pneumococcal conjugate vaccines were randomised to receive 1 to 3 doses of

Vaxneuvance or the 13-valent PCV in three different age cohorts (7 through 11 months, 12 through23 months and 24 months to less than 18 years of age), according to an age-appropriate schedule.

Catch-up vaccination with Vaxneuvance elicited immune responses in children 7 months to less than18 years of age that are comparable to the 13-valent PCV for the shared serotypes and higher than the13-valent PCV for the additional serotypes 22F and 33F. Within each age cohort, serotype-specific

IgG GMCs at 30 days following the last dose of vaccine were generally comparable between thevaccination groups for the 13 shared serotypes and higher in Vaxneuvance for the 2 additionalserotypes.

Immune responses after subcutaneous administration in infants and children

In a double-blind, active comparator-controlled, descriptive study (Protocol 033), 694 healthy

Japanese infants from 2 to 6 months of age were randomised to receive either Vaxneuvance or the 13-valent PCV as a 4-dose regimen via a subcutaneous route of administration. The first dose was givenat 2 to 6 months of age and second and third dose were given at an interval of ≥27 days from the priordose. The fourth dose was administered at 12 to 15 months of age. Vaxneuvance elicited serotype-specific immune responses (IgG and OPA) in healthy infants and toddlers that were generallycomparable to the 13-valent PCV for the shared serotypes and higher in Vaxneuvance for the 2additional serotypes.

Clinical immunogenicity in immunocompetent adults ≥18 years of age

Five clinical studies (Protocol 007, Protocol 016, Protocol 017, Protocol 019, and Protocol 021)conducted in the Americas, Europe and Asia Pacific evaluated the immunogenicity of Vaxneuvance inhealthy and immunocompetent adults across different age groups including individuals with or withoutprevious pneumococcal vaccination. Each clinical study included adults with stable underlyingmedical conditions (e.g., diabetes mellitus, renal disorders, chronic heart disease, chronic liver disease,chronic lung disease including asthma) and/or behavioural risk factors (e.g., current tobacco use,increased alcohol consumption) that are known to increase the risk of pneumococcal disease.

In each study, immunogenicity was assessed by serotype-specific OPA and IgG responses at 30 dayspostvaccination. Study endpoints included OPA geometric mean titres (GMTs) and IgG geometricmean concentrations (GMCs). The pivotal study (Protocol 019) aimed to show noninferiority of the

OPA GMTs for 12 of 13 serotypes that Vaxneuvance shares with the 13-valent pneumococcalpolysaccharide conjugate vaccine, noninferiority and superiority for the shared serotype 3, andsuperiority for serotypes 22F and 33F, additional to Vaxneuvance. Superiority assessment of

Vaxneuvance to the 13-valent pneumococcal polysaccharide conjugate vaccine was based on thebetween-group comparisons of OPA GMTs and the proportions of participants with a ≥4-fold rise inserotype-specific OPA titres from prevaccination to 30 days postvaccination.

Pneumococcal vaccine-naïve adults

In the pivotal, double-blind, active comparator-controlled study (Protocol 019),1,205 immunocompetent pneumococcal vaccine-naïve subjects ≥50 years of age were randomised toreceive Vaxneuvance or the 13-valent pneumococcal polysaccharide conjugate vaccine. The medianage of participants was 66 years (range: 50 to 92 years), with approximately 69% over 65 years of age,and approximately 12% over 75 years of age. 57.3% were female and 87% reported history of at leastone underlying medical condition.

The study demonstrated that Vaxneuvance is noninferior to the 13-valent pneumococcalpolysaccharide conjugate vaccine for the 13 shared serotypes and superior for the 2 additionalserotypes and for the shared serotype 3. Table 6 summarises the OPA GMTs at 30 dayspostvaccination. IgG GMCs were generally consistent with the results observed for the OPA GMTs.

Table 6: Serotype-specific OPA GMTs at 30 days Postvaccination in Pneumococcal

Vaccine-Naïve Adults ≥50 Years of age (Protocol 019)

Pneumococcal Vaxneuvance 13-valent PCV GMT Ratio*

Serotype (N = 602) (N = 600) (Vaxneuvance/13-valent PCV)n GMT* n GMT* (95% CI)*13 Shared Serotypes†1 598 256.3 598 322.6 0.79 (0.66, 0.96)3‡ 598 216.2 598 135.1 1.60 (1.38, 1.85)4 598 1125.6 598 1661.6 0.68 (0.57, 0.80)5 598 447.3 598 563.5 0.79 (0.64, 0.98)6A 596 5407.2 598 5424.5 1.00 (0.84, 1.19)6B 598 4011.7 598 3258.2 1.23 (1.02, 1.48)7F 597 4617.3 598 5880.6 0.79 (0.68, 0.90)9V 598 1817.3 597 2232.9 0.81 (0.70, 0.94)14 598 1999.3 598 2656.7 0.75 (0.64, 0.89)18C 598 2757.7 598 2583.7 1.07 (0.91, 1.26)19A 598 3194.3 598 3979.8 0.80 (0.70, 0.93)19F 598 1695.1 598 1917.8 0.88 (0.76, 1.02)23F 598 2045.4 598 1740.4 1.18 (0.96, 1.44)2 Serotypes Additional to Vaxneuvance§22F 594 2375.2 586 74.6 31.83 (25.35, 39.97)33F 598 7994.7 597 1124.9 7.11 (6.07, 8.32)

*GMTs, GMT ratio, and 95% CI are estimated from a cLDA model.†A conclusion of non-inferiority for the 13 shared serotypes is based on the lower bound of the 95% CI for the estimated GMT ratio(Vaxneuvance/13-valent PCV) being >0.5.‡A conclusion of superiority for serotype 3 is based on the lower bound of the 95% CI for the estimated GMT ratio(Vaxneuvance/13-valent PCV) being >1.2.§A conclusion of superiority for the 2 additional serotypes is based on the lower bound of the 95% CI for the estimated GMT ratio(Vaxneuvance/13-valent PCV) being >2.0.

N=Number of participants randomised and vaccinated; n=Number of participants contributing to the analysis.

CI=confidence interval; cLDA=constrained longitudinal data analysis; GMT=geometric mean titre (1/dil); OPA=opsonophagocyticactivity; PCV=pneumococcal conjugate vaccine.

In a double-blind, descriptive study (Protocol 017), 1,515 immunocompetent subjects 18 to 49 years ofage with or without risk factors for pneumococcal disease were randomised 3:1 and received

Vaxneuvance or the 13-valent pneumococcal polysaccharide conjugate vaccine, followed by PPV236 months later. Risk factors for pneumococcal disease included the following: diabetes mellitus,chronic heart disease including heart failure, chronic liver disease with compensated cirrhosis, chroniclung disease including persistent asthma and chronic obstructive pulmonary disease (COPD), currenttobacco use, and increased alcohol consumption. Overall, of those who received Vaxneuvance,285 (25.2%) had no risk factor, 620 (54.7%) had 1 risk factor, and 228 (20.1%) had 2 or more riskfactors.

Vaxneuvance elicited immune responses to all 15 serotypes contained in the vaccine as assessed by

OPA GMTs (Table 7) and IgG GMCs. OPA GMTs and IgG GMCs were generally comparablebetween the two vaccination groups for the 13 shared serotypes and higher in the Vaxneuvance groupfor the 2 additional serotypes. Following vaccination with PPV23, OPA GMTs and IgG GMCs weregenerally comparable between the two vaccination groups for all 15 serotypes.

In a subgroup analysis based on the number of reported risk factors, Vaxneuvance elicited immuneresponses to all 15 serotypes contained in the vaccine as assessed by OPA GMTs and IgG GMCs at30 days postvaccination in adults with no, 1, or 2 or more risk factors. The results in each subgroupwere generally consistent with those observed in the overall study population. Sequentialadministration of Vaxneuvance followed 6 months later by PPV23 was also immunogenic for all15 serotypes contained in Vaxneuvance.

Table 7: Serotype-specific OPA GMTs at 30 days Postvaccination in Pneumococcal

Vaccine-Naïve Adults 18-49 Years of Age With or Without Risk Factors for Pneumococcal

Disease (Protocol 017)

Pneumococcal Vaxneuvance 13-valent PCV

Serotype (N = 1,133) (N = 379)n Observed 95% CI* n Observed 95% CI*

GMT GMT13 Shared Serotypes1 1019 268.6 (243.7, 296.0) 341 267.2 (220.4, 323.9)3 1004 199.3 (184.6, 215.2) 340 150.6 (130.6, 173.8)4 1016 1416.0 (1308.9, 1531.8) 342 2576.1 (2278.0, 2913.2)5 1018 564.8 (512.7, 622.2) 343 731.1 (613.6, 871.0)6A 1006 12928.8 (11923.4, 14019.0) 335 11282.4 (9718.8, 13097.5)6B 1014 10336.9 (9649.4, 11073.4) 342 6995.7 (6024.7, 8123.2)7F 1019 5756.4 (5410.4, 6124.6) 342 7588.9 (6775.3, 8500.2)9V 1015 3355.1 (3135.4, 3590.1) 343 3983.7 (3557.8, 4460.7)14 1016 5228.9 (4847.6, 5640.2) 343 5889.8 (5218.2, 6647.8)18C 1014 5709.0 (5331.1, 6113.6) 343 3063.2 (2699.8, 3475.5)19A 1015 5369.9 (5017.7, 5746.8) 343 5888.0 (5228.2, 6631.0)19F 1018 3266.3 (3064.4, 3481.4) 343 3272.7 (2948.2, 3632.9)23F 1016 4853.5 (4469.8, 5270.2) 340 3887.3 (3335.8, 4530.0)2 Serotypes Additional to Vaxneuvance22F 1005 3926.5 (3645.9, 4228.7) 320 291.6 (221.8, 383.6)33F 1014 11627.8 (10824.6, 12490.7) 338 2180.6 (1828.7, 2600.2)

*The within-group 95% CIs are obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution.

N=Number of participants randomised and vaccinated; n=Number of participants contributing to the analysis.

CI=confidence interval; GMT=geometric mean titre (1/dil); OPA=opsonophagocytic activity; PCV=pneumococcal conjugate vaccine.

Sequential administration of pneumococcal vaccines in adults

The sequential administration of Vaxneuvance followed by PPV23 was assessed in Protocol 016,

Protocol 017 (see section 5.1, Pneumococcal vaccine-naïve adults), and Protocol 018 (see section 5.1,

Adults living with HIV).

In a double-blind, active comparator-controlled study (Protocol 016), 652 pneumococcalvaccine-naïve subjects ≥50 years of age were randomised to receive Vaxneuvance or the 13-valentpneumococcal polysaccharide conjugate vaccine, followed by PPV23 one year later.

Following vaccination with PPV23, OPA GMTs and IgG GMCs were comparable between the twovaccination groups for all 15 serotypes in Vaxneuvance.

Immune responses elicited by Vaxneuvance persisted up to 12 months postvaccination as assessed by

OPA GMTs and IgG GMCs. Serotype-specific OPA GMTs declined over time, as they were lower at

Month 12 than Day 30, but remained above baseline levels for all the serotypes contained in either

Vaxneuvance or the 13-valent pneumococcal polysaccharide conjugate vaccine. OPA GMTs and IgG

GMCs were generally comparable between the intervention groups at Month 12 for the 13 sharedserotypes and higher for the 2 additional serotypes among recipients of Vaxneuvance.

Adults with prior pneumococcal vaccination

In a double-blind, descriptive study (Protocol 007), 253 subjects ≥65 years of age who werepreviously vaccinated with PPV23 at least one year prior to study entry were randomised to receive

Vaxneuvance or the 13-valent pneumococcal polysaccharide conjugate vaccine.

IgG GMCs and OPA GMTs were generally comparable between the two vaccination groups for the13 shared serotypes and higher in the Vaxneuvance group for the 2 additional serotypes.

In a clinical study, in which another PCV was administered ≤1 year after PPV23, reduced immuneresponses were observed for the common serotypes compared to immune responses observed when

PCV was given either alone or before PPV23. The clinical significance of this is unknown.

Clinical immunogenicity in special populations

Children living with HIV

In a double-blind, descriptive study (Protocol 030), Vaxneuvance was evaluated in 203 children 6 toless than 18 years of age living with HIV. Of these children, 17 (8.4%) had a CD4+ T-cell count<500 cells/μL and plasma HIV RNA value <50,000 copies/mL. In this study, 407 participants wererandomised to receive a single dose of either Vaxneuvance or the 13-valent PCV, followed by PPV 232 months later. Vaxneuvance was immunogenic as assessed by serotype-specific IgG GMCs and OPA

GMTs at 30 days postvaccination for all 15 serotypes contained in Vaxneuvance. Serotype-specific

IgG GMCs and OPA GMTs were generally comparable for the 13 shared serotypes and higher for the2 additional serotypes (22F and 33F). After sequential administration with PPV 23, IgG GMCs and

OPA GMTs were generally comparable at 30 days postvaccination between the two vaccinationgroups for all 15 serotypes contained in Vaxneuvance.

Adults living with HIV

In a double-blind, descriptive study (Protocol 018), 302 pneumococcal vaccine-naïve subjects≥ 18 years of age living with HIV with CD4+ T-cell count ≥50 cells/µL and plasma HIV ribonucleicacid (RNA) <50,000 copies/mL were randomised to receive Vaxneuvance or the 13-valentpneumococcal polysaccharide conjugate vaccine, followed by PPV23 2 months later. The majority ofparticipants had a CD4+ T-cell count ≥200 cells/µL; 4 (1.3%) had a CD4+ T-cell count ≥50 to<200 cells/µL, 152 (50.3%) had a CD4+ T-cell count ≥200 to <500 cells/µL, and 146 (48.3%) had a

CD4+ T-cell count ≥500 cells/µL.

Vaxneuvance elicited immune responses to all 15 serotypes contained in the vaccine as assessed by

OPA GMTs and IgG GMCs at 30 days postvaccination. Immune responses seen in the HIV-infectedparticipants were consistently lower compared to healthy participants but comparable for bothvaccination groups, except for serotype 4. OPA GMT and IgG GMC for serotype 4 were lower for

Vaxneuvance. After sequential administration with PPV23, OPA GMTs and IgG GMCs weregenerally comparable between the two vaccination groups for all 15 serotypes.

Children with Sickle Cell Disease

In a double-blind, descriptive study (Protocol 023), Vaxneuvance was evaluated in children 5 to lessthan 18 years of age with sickle cell disease. In this study, participants enrolled may have receivedroutine pneumococcal vaccines during the first two years of life but had not received pneumococcalvaccines in the 3 years prior to study entry. A total of 104 participants were randomised 2:1 to receivea single dose of either Vaxneuvance or the 13-valent PCV. Vaxneuvance was immunogenic asassessed by serotype-specific IgG GMCs and OPA GMTs at 30 days postvaccination for all15 serotypes contained in Vaxneuvance. Serotype-specific IgG GMCs and OPA GMTs were generallycomparable between the two vaccination groups for the 13 shared serotypes and higher in

Vaxneuvance for the two additional serotypes 22F and 33F.

Children and adults receiving Haematopoietic Stem Cell Transplant

In a double-blind, descriptive study (Protocol 022), Vaxneuvance was evaluated in adults andchildren ≥3 years of age who had received an allogeneic haematopoietic stem cell transplant(allo-HSCT) 3 to 6 months prior to enrollment. In this study, 277 participants were randomised toreceive 3 doses of Vaxneuvance or the 13-valent PCV, administered one month apart. Twelve monthsafter allo-HSCT, participants without chronic graft-versus-host disease (cGvHD) received a singledose of PPV23 and those with cGvHD received a fourth dose of either Vaxneuvance or the 13-valent

PCV. Vaxneuvance was immunogenic in recipients of allo-HSCT, as assessed by IgG GMCs and OPA

GMTs at 30 days following the third dose of Vaxneuvance for all 15 serotypes contained in thevaccine. Serotype-specific IgG GMCs and OPA GMTs were generally comparable between the twovaccination groups for the 13 shared serotypes and higher in Vaxneuvance for the two additionalserotypes (22F and 33F). Similarly, in participants who received either Vaxneuvance or the 13-valent

PCV twelve months after allo-HSCT, IgG GMCs and OPA GMTs at 30 days following vaccinationwere generally comparable between the two vaccination groups for the 13 shared serotypes and higherin Vaxneuvance for the two additional serotypes (22F and 33F). In participants who received PPV23twelve months after allo-HSCT, IgG GMCs and OPA GMTs at 30 days following vaccination weregenerally comparable between the two vaccination groups for all 15 serotypes contained in

Vaxneuvance.

Not applicable.

Non-clinical study data revealed no hazard for humans based on conventional studies of repeated dosetoxicity and toxicity to reproduction and development.

Vaxneuvance administered to female rats had no effects on mating performance, fertility,embryonic/foetal development, or development of the offspring.

Vaxneuvance administered to pregnant female rats resulted in detectable antibodies to all 15 serotypesin offspring. This was attributable to the acquisition of maternal antibodies via placental transferduring gestation and possibly via lactation.

Sodium chloride (NaCl)

L-histidine

Polysorbate 20

Water for injections

For adjuvant, see section 2.

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

3 years

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

Vaxneuvance should be administered as soon as possible after being removed from the refrigerator.

In the event of temporary temperature excursions, stability data indicate that Vaxneuvance is stable attemperatures up to 25 °C for 48 hours.

0.5 mL suspension in pre-filled syringe (Type I glass) with a plunger stopper (latex-free bromobutylrubber) and a tip cap (latex-free styrene-butadiene or latex-free isoprene-bromobutyl rubber).

Pack sizes of 1 or 10 pre-filled syringes, either without needles, with 1 separate needle, or with2 separate needles.

Multipacks containing 50 (5 packs of 10) pre-filled syringes without needles.

Not all pack sizes may be marketed.

* The vaccine should be used as supplied.

* Immediately prior to use, hold the pre-filled syringe horizontally and shake vigorously to obtainan opalescent suspension. Do not use the vaccine if it cannot be resuspended.

* Inspect the suspension visually for particulate matter and discolouration prior to administration.

Discard the vaccine if particulates are present and/or if it appears discoloured.

* Attach a needle with Luer lock connection by twisting in a clockwise direction until the needlefits securely on the syringe.

* Inject immediately using the intramuscular (IM) route, preferably in the anterolateral aspect ofthe thigh in infants or in the deltoid area of the upper arm in children and adults.

* Exercise care to avoid harm from an accidental needle stick.

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

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/21/1591/001

EU/1/21/1591/002

EU/1/21/1591/003

EU/1/21/1591/004

EU/1/21/1591/005

EU/1/21/1591/006

EU/1/21/1591/007

Date of first authorisation: 13 December 2021

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

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