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Pharmacology: Pharmacodynamics: 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. 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 1). (See Tables 1 and 2.)
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Click on icon to see table/diagram/imageAdditionally, 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.
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, Inactivated Poliovirus, 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 3). 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 3). 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 3). (See Table 3.)
Click on icon to see table/diagram/imageAt 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 4).
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 4). (See Table 4.)
Click on icon to see table/diagram/imageVaxneuvance 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 (P025, P027, P029 and P031), 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.
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 5 summarises the OPA GMTs at 30 days postvaccination. IgG GMCs were generally consistent with the results observed for the OPA GMTs. (See Table 5.)
Click on icon to see table/diagram/imageIn 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 6) 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. (See Table 6.)
Click on icon to see table/diagram/imageSequential administration of pneumococcal vaccines in adults: The sequential administration of Vaxneuvance followed by PPV23 was assessed in Protocol 016, Protocol 017 (see Pneumococcal vaccine-naïve adults as previously mentioned), and Protocol 018 (see Clinical immunogenicity in special populations: Adults living with HIV as follows).
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 PPV23 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 PPV23, 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.
Pharmacokinetics: Not applicable.
Toxicology: Preclinical safety data: 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.
