Vaxneuvance is indicated for active immunisation for the prevention of invasive disease, pneumonia and acute otitis media caused by Streptococcus pneumoniae in infants, children and adolescents from 6 weeks to less than 18 years of age.

Vaxneuvance is indicated for active immunisation for the prevention of invasive disease and pneumonia 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.

Posology

Special populations

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

Method of administration

The vaccine should be administered by intramuscular injection. The preferred site is the anterolateral aspect 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.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of 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 be readily available in case of a rare anaphylactic event following the administration of the vaccine.

Concurrent illness

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

Thrombocytopenia and coagulation disorders

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

Apnoea in premature infants

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

Immunocompromised individuals

Immunocompromised individuals, whether due to the use of immuno-suppressive therapy, a genetic defect, 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 disease or living with HIV infection or with a haematopoietic stem cell transplant (see section 5.1). Safety and immunogenicity data for Vaxneuvance are not available for individuals in other specific immunocompromised groups and vaccination should be considered on an individual basis.

Protection

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).

Sodium

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 as monovalent or combination vaccines: diphtheria, tetanus, pertussis, poliomyelitis (serotypes 1, 2 and 3), hepatitis A, hepatitis B, Haemophilus influenzae type b, measles, mumps, rubella, varicella and rotavirus 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 that administration of antipyretics concomitantly or within the same day of vaccination may reduce the immune response after the infant series. Responses to the booster dose administered at 12 months were unaffected. The clinical significance of this observation is unknown.

Adults

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

Pregnancy

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 benefits outweigh any potential risks for the mother and the foetus.

Breast‑feeding

It is unknown whether Vaxneuvance is excreted in human milk.

Fertility

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

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

Summary of the safety profile

Paediatric population

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 first vaccination) and children (11 through 15 months of age) was assessed as a 3 dose or 4 dose regimen in 5 clinical studies with a total of 7,229 participants.

All 5 studies evaluated the safety of Vaxneuvance when administered concomitantly with other routine 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 pneumococcal conjugate vaccine (PCV) and 538 participants received Vaxneuvance when used to complete a regimen 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 3,589 participants (Table 1), excluding participants who received a mixed dose regimen. The majority of solicited 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 or size 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 included 352 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 valency pneumococcal conjugate vaccine.

The most frequent adverse reactions were injection-site pain (54.8%), myalgia (23.7%), injection-site swelling (20.9%), injection-site erythema (19.2%), fatigue (15.8%), headache (11.9%), injection-site induration (6.8%), and pyrexia ≥38 °C (5.6%) (Table 1). The majority of solicited 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 or size of injection site reaction >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 studies in 7,136 adults ≥18 years of age. An additional clinical study assessed 302 adults ≥18 years of age living 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 age living with HIV. In addition, 5,253 adults were pneumococcal vaccine‑naïve and 377 adults were previously vaccinated with 23‑valent pneumococcal polysaccharide vaccine (PPV23) at least 1 year prior to enrollment.

The most frequently reported adverse reactions following vaccination with Vaxneuvance were solicited. 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 solicited adverse reactions were mild (based on intensity or size) and of short duration (≤3 days); severe reactions (defined as an event that prevents normal daily activity or size of injection site reaction >10 cm) occurred in ≤1.5% of adults across the clinical program.

Older adults reported fewer adverse reactions than younger adults.

Tabulated list of adverse reactions

In clinical studies of adults, local and systemic adverse reactions were solicited daily after vaccination for 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, in decreasing 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

^§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 were solicited from Day 1 through Day 14 following vaccination. For participants ≥3 to less than 18 years of age, fatigue, headache, myalgia, and urticaria 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 in special 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 healthy infants 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 from 7 months to less than 2 years of age who received 2 or 3 doses of Vaxneuvance based on age at enrollment. The safety profile of the catch-up vaccination schedule was generally consistent with the safety 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 cell disease and in 203 children and adolescents 6 to less than 18 years of age living with HIV, all of whom received a single dose of Vaxneuvance. The safety profile of Vaxneuvance in children with these 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 allogeneic haematopoietic stem cell transplant (allo-HSCT) 3 to 6 months prior to enrollment, all of whom received between 1 and 4 doses of Vaxneuvance. The safety profile of Vaxneuvance in recipients of allo-HSCT was generally consistent with the safety profile in a healthy population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

To report any side effect(s):

·       Saudi Arabia:

The National Pharmacovigilance Centre (NPC):

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

·       Other GCC States:

Please contact the relevant competent authority.

There are no data with regard to overdose.

5.1     Pharmacodynamic properties

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

Mechanism of action

Vaxneuvance contains 15 purified pneumococcal capsular polysaccharides from Streptococcus pneumoniae (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, with the additional serotypes 22F and 33F), each conjugated to a carrier protein (CRM₁₉₇). Vaxneuvance elicits a T‑cell dependent immune response to induce antibodies that enhance opsonisation, phagocytosis, and killing of pneumococci to protect against pneumococcal disease.

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

Clinical immunogenicity in healthy infants, children and adolescents

Immunogenicity was assessed by serotype‑specific IgG response rates (the proportion of participants meeting the serotype‑specific IgG threshold value of ≥0.35 µg/mL) and IgG geometric mean concentrations (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 days following the primary series and/or following the toddler dose.

Infants and children receiving a routine vaccination schedule

3-dose regimen (2-dose primary series + 1 toddler dose)

In the double-blind, active comparator-controlled study (Protocol 025), 1,184 participants were randomised to receive Vaxneuvance or the 13-valent PCV in a 3-dose regimen. The first two doses were administered to infants at 2 and 4 months of age (primary series) and the third dose was administered to children at 11 through 15 months of age (toddler dose). Participants also received other paediatric vaccines concomitantly, including Rotavirus vaccine (live) with the infant primary series 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 primary series, serotype-specific IgG response rates and GMCs were generally comparable for the 13 shared serotypes 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 the 2 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-dose primary series (3-dose regimen, Protocol 025)

* 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 the natural 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 the difference 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 the difference 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 toddler dose (3-dose regimen, Protocol 025)

* 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 the natural 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 the difference 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 the difference 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 GMTs at 30 days following the toddler dose, that are generally comparable but slightly lower for the 13  serotypes shared with 13-valent PCV. The clinical relevance of this slightly lower response is unknown. OPA GMTs for both 22F and 33F were higher in Vaxneuvance recipients compared to the 13-valent PCV recipients.

In another double‑blind, active comparator‑controlled study (Protocol 026), 1,191 participants were randomised to receive Vaxneuvance or the 13-valent PCV as a 3‑dose regimen given concomitantly with other paediatric vaccines including Vaxelis with all three doses and M-M-RvaxPro and Varivax with the toddler dose. The primary series was administered to infants at 3 and 5 months of age followed 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 the 2 additional serotypes, 22F and 33F, as assessed by IgG response rates. Similarly, Vaxneuvance is non-inferior to the 13-valent PCV for the 13 shared serotypes and superior to the 13-valent PCV for the 2 additional serotypes, as assessed by IgG GMCs. Following the toddler dose, Vaxneuvance generates functional antibodies (OPA GMTs) for all 15 serotypes that are generally comparable with the 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. The primary series were administered to infants at 2, 4, and 6 months of age and the toddler dose was administered to children at 12 through 15 months of age.

In a double‑blind, active comparator‑controlled study (Protocol 029), 1,720 participants were randomised to receive Vaxneuvance or the 13-valent PCV. Participants also received other paediatric vaccines 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) Vaccine in 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 IgG response 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 the response rate for serotype 23F in recipients of the 13-valent PCV (the lowest response rate for any of the 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 the prespecified noninferiority criteria by a small margin (0.48 versus >0.5) (Table 4). Vaxneuvance is noninferior 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 for serotype 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 additional serotypes, 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-dose primary series (4-dose regimen, Protocol 029)

* 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 the natural 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 the difference 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 noninferior to 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 for serotype 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, 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 toddler dose (Table 5).

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

* 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 the natural 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 days following the primary series and following the toddler dose, that are generally comparable but slightly lower for the 13 serotypes shared with 13-valent PCV. The clinical relevance of this slightly lower response is unknown. OPA GMTs for both 22F and 33F were higher in Vaxneuvance recipients compared 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 participants were randomised in a 1:1:1:1:1 ratio to one of five vaccination groups to receive a complete or mixed dosing regimen of pneumococcal conjugate vaccines. In two vaccination groups, participants received a 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 generally comparable for participants administered mixed regimens of Vaxneuvance and the 13-valent PCV and for participants administered a complete dosing regimen of the 13-valent PCV for the 13 shared serotypes, 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 of pneumococcal conjugate vaccine in 4 double-blind, active comparator-controlled studies (Protocol 025, Protocol 027, Protocol 029 and Protocol 031), were generally consistent with those observed 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 who were either pneumococcal vaccine-naïve or not fully vaccinated or completed a dosing regimen with lower 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 through 23 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 than 18 years of age that are comparable to the 13-valent PCV for the shared serotypes and higher than the 13-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 the vaccination groups for the 13 shared serotypes and higher in Vaxneuvance for the 2 additional serotypes.

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 given at 2 to 6 months of age and second and third dose were given at an interval of ≥27 days from the prior dose. 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 generally comparable to the 13-valent PCV for the shared serotypes and higher in Vaxneuvance for the 2

additional 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 in healthy and immunocompetent adults across different age groups including individuals with or without previous pneumococcal vaccination. Each clinical study included adults with stable underlying medical 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 days postvaccination. Study endpoints included OPA geometric mean titres (GMTs) and IgG geometric mean 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 pneumococcal polysaccharide conjugate vaccine, noninferiority and superiority for the shared serotype 3, and superiority for serotypes 22F and 33F, additional to Vaxneuvance. Superiority assessment of Vaxneuvance to the 13‑valent pneumococcal polysaccharide conjugate vaccine was based on the between‑group comparisons of OPA GMTs and the proportions of participants with a ≥4‑fold rise in serotype‑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 to receive Vaxneuvance or the 13‑valent pneumococcal polysaccharide conjugate vaccine. The median age 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 least one underlying medical condition.

The study demonstrated that Vaxneuvance is noninferior to the 13‑valent pneumococcal polysaccharide conjugate vaccine for the 13 shared serotypes and superior for the 2 additional serotypes and for the shared serotype 3. Table 6 summarises the OPA GMTs at 30 days postvaccination. 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)

*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=opsonophagocytic activity; PCV=pneumococcal conjugate vaccine.

In a double‑blind, descriptive study (Protocol 017), 1,515 immunocompetent subjects 18 to 49 years of age 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 PPV23 6 months later. Risk factors for pneumococcal disease included the following: diabetes mellitus, chronic heart disease including heart failure, chronic liver disease with compensated cirrhosis, chronic lung disease including persistent asthma and chronic obstructive pulmonary disease (COPD), current tobacco 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 risk factors.

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 comparable between the two vaccination groups for the 13 shared serotypes and higher in the Vaxneuvance group for the 2 additional serotypes. Following vaccination with PPV23, OPA GMTs and IgG GMCs were generally comparable between the two vaccination groups for all 15 serotypes.

In a subgroup analysis based on the number of reported risk factors, Vaxneuvance elicited immune responses to all 15 serotypes contained in the vaccine as assessed by OPA GMTs and IgG GMCs at 30 days postvaccination in adults with no, 1, or 2 or more risk factors. The results in each subgroup were generally consistent with those observed in the overall study population. Sequential administration of Vaxneuvance followed 6 months later by PPV23 was also immunogenic for all 15 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)

*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 pneumococcal vaccine‑naïve subjects ≥50 years of age were randomised to receive Vaxneuvance or the 13‑valent pneumococcal polysaccharide conjugate vaccine, followed by PPV23 one year later.

Following vaccination with PPV23, OPA GMTs and IgG GMCs were comparable between the two vaccination 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 shared serotypes 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 were previously 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 the 13 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 immune responses 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 to less 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 were randomised to receive a single dose of either Vaxneuvance or the 13-valent PCV, followed by PPV 23 2 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 the 2 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 vaccination groups 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 ribonucleic acid (RNA) <50,000 copies/mL were randomised to receive Vaxneuvance or the 13‑valent pneumococcal polysaccharide conjugate vaccine, followed by PPV23 2 months later. The majority of participants 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-infected participants were consistently lower compared to healthy participants but comparable for both vaccination 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 were generally 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 less than 18 years of age with sickle cell disease. In this study, participants enrolled may have received routine pneumococcal vaccines during the first two years of life but had not received pneumococcal vaccines in the 3 years prior to study entry. A total of 104 participants were randomised 2:1 to receive a single dose of either Vaxneuvance or the 13-valent PCV. 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 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 and children ≥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 to receive 3 doses of Vaxneuvance or the 13-valent PCV, administered one month apart. Twelve months after allo‑HSCT, participants without chronic graft-versus-host disease (cGvHD) received a single dose 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 the vaccine. Serotype-specific IgG GMCs and OPA GMTs were generally comparable between the two vaccination groups for the 13 shared serotypes and higher in Vaxneuvance for the two additional serotypes (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 vaccination were generally comparable between the two vaccination groups for the 13 shared serotypes and higher in Vaxneuvance for the two additional serotypes (22F and 33F). In participants who received PPV23 twelve months after allo-HSCT, IgG GMCs and OPA GMTs at 30 days following vaccination were generally 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 dose toxicity 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 serotypes in offspring. This was attributable to the acquisition of maternal antibodies via placental transfer during 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.

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 at temperatures up to 25 °C for 48 hours.

0.5 mL suspension in pre‑filled syringe (Type I glass) with a plunger stopper (latex‑free bromobutyl rubber) 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 with 2 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 obtain an 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 needle fits securely on the syringe.

·            Inject immediately using the intramuscular (IM) route, preferably in the anterolateral aspect of the 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 local requirements.