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Pharmacology: 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 opsonization, 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 Studies: Clinical Trials Experience in Children 6 Weeks Through 17 Years of Age: Five double-blind, clinical studies (Protocol 008, Protocol 024, Protocol 025, Protocol 027, and Protocol 029) conducted across the Americas, Europe and Asia Pacific evaluated the immunogenicity of VAXNEUVANCE in healthy infants, children and adolescents. In each study, immunogenicity was assessed by serotype-specific immunoglobulin G (IgG) response rates (the proportion of participants meeting the serotype-specific IgG threshold value of ≥0.35 mcg/mL) and IgG geometric mean concentrations (GMCs) at 30 days following the primary series and/or following the toddler dose. In a subset of participants, opsonophagocytic activity (OPA) geometric mean titers (GMTs) were also measured at 30 days following the primary series and/or following the toddler dose.
Infants and Toddlers Receiving a Routine Vaccination Schedule: 3-Dose Regimen: In a pivotal, double-blind, active comparator-controlled study (Protocol 025), 1,184 participants were randomized to receive VAXNEUVANCE or Prevenar 13 as a 3-dose regimen. The primary series was administered to infants at 2 and 4 months of age and the toddler dose was administered at 11 through 15 months of age. Participants also received other pediatric vaccines concomitantly, including Rotarix [rotavirus vaccine, live] with the infant primary series and INFANRIX hexa [diphtheria, tetanus, pertussis (acellular), hepatitis B (rDNA), poliomyelitis (inactivated) and Haemophilus influenzae type b conjugate vaccine (adsorbed)] with all 3 doses in the complete regimen [see Concomitant Vaccination as follows].
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, serotype-specific IgG response rates and IgG GMCs were generally comparable for the 13 shared serotypes and higher for the 2 unique serotypes (22F and 33F) in VAXNEUVANCE recipients, compared to Prevenar 13 recipients. At 30 days following the toddler dose, VAXNEUVANCE is non-inferior to Prevenar 13 for the 13 shared serotypes and superior for the 2 unique serotypes, as assessed by the proportion of participants meeting the serotype-specific IgG threshold value of ≥0.35 mcg/mL (response rate) (Table 1). Serotype-specific IgG GMCs are non-inferior to Prevenar 13 for the 13 shared serotypes and superior to Prevenar 13 for the 2 unique serotypes at 30 days following the toddler dose (Table 2). (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 to Prevenar 13 for the 13 shared serotypes. OPA GMTs for both 22F and 33F were higher in VAXNEUVANCE recipients compared to Prevenar 13 recipients.
4-Dose Regimen: In a double-blind, active comparator-controlled study (Protocol 008), 1,051 participants were randomized in a 1:1:1 ratio to receive one of two lots of VAXNEUVANCE or Prevenar 13 as a 4-dose regimen. The primary series was administered to infants at 2, 4 and 6 months of age and the toddler dose was administered at 12 through 15 months of age. VAXNEUVANCE met non-inferiority criteria (the lower bound of the 2-sided 95% CI of the differences in the response rates [VAXNEUVANCE - Prevenar 13] was greater than -15 percentage points) for the 13 shared serotypes as assessed by the serotype-specific IgG response rates at 30 days after the primary series. Serotype-specific IgG GMCs at 30 days following the primary series and 30 days following the toddler dose were generally comparable across both lots of VAXNEUVANCE and Prevenar 13 for the13 shared serotypes and higher in VAXNEUVANCE for the 2 unique serotypes (22F and 33F).
In a pivotal, double-blind, active comparator-controlled study (Protocol 029), 1,720 participants were randomized to receive VAXNEUVANCE or Prevenar 13 as a 4-dose regimen. The primary series was administered to infants at 2, 4, and 6 months of age and the toddler dose was administered at 12 through 15 months of age. Participants also received other pediatric vaccines concomitantly, including RECOMBIVAX HB (Hepatitis BVaccine [Recombinant]), RotaTeq (Rotavirus Vaccine, Live, Oral, Pentavalent) and Pentacel (Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate [Tetanus Toxoid Conjugate] Vaccine) in the infant primary series. HIBERIX (Haemophilus b Conjugate Vaccine [Tetanus Toxoid Conjugate]), M-M-R II (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 [see Concomitant Vaccination as follows].
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 non-inferior to Prevenar 13 for the 13 shared serotypes, as assessed by IgG response rates (Table 3). VAXNEUVANCE is non-inferior for the 2 unique 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 Prevenar 13 (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.
Additionally, VAXNEUVANCE is superior to Prevenar 13 for the 2 unique serotypes and for shared serotype 3 as assessed by IgG response rates at 30 days following the primary series (Table 3). (See Table 3.)
Click on icon to see table/diagram/imageAt 30 days following the primary series, serotype-specific IgG GMCs are non-inferior to Prevenar 13 for 12 of the 13 shared serotypes. The IgG response to serotype 6A narrowly missed the prespecified non-inferiority criteria by a small margin (the lower bound of the 2-sided 95% CI for the GMC ratio [VAXNEUVANCE/Prevenar 13] being 0.48 versus >0.5) (Table 4). VAXNEUVANCE is non-inferior to Prevenar 13 for the 2 unique serotypes, as assessed by serotype-specific IgG GMCs for serotypes 22F and 33F in recipients of VAXNEUVANCE compared with the IgG GMC for serotype 4 in recipients of Prevenar 13 (the lowest IgG GMC for any of the shared serotypes, excluding serotype 3) with a GMC ratio of 3.64 (95% CI: 3.33, 3.98) and 1.24 (95% CI: 1.10, 1.39), respectively.
VAXNEUVANCE is also superior to Prevenar 13 for the 2 unique serotypes and for shared serotype 3 as assessed by IgG GMCs at 30 days following the primary series (Table 4). (See Table 4.)
Click on icon to see table/diagram/imageAt 30 days following the toddler dose, serotype-specific IgG GMCs for VAXNEUVANCE are non-inferior to Prevenar 13 for all 13 shared serotypes and for the 2 unique serotypes as assessed by the IgG GMCs for serotypes 22F and 33F in VAXNEUVANCE recipients compared with the IgG GMC for serotype 4 in Prevenar 13 recipients (the lowest IgG GMC for any of the shared serotypes, excluding serotype 3) with a GMC ratio of 4.69 (95% CI:4.30, 5.11) and 2.59 (95% CI: 2.36, 2.83), respectively (Table 5).
VAXNEUVANCE is superior to Prevenar 13 for the 2 unique serotypes and for shared serotype 3, as assessed by IgG GMCs at 30 days following the toddler dose (Table 5). (See Table 5.)
Click on icon to see table/diagram/imageVAXNEUVANCE elicits functional antibodies, as assessed by serotype-specific OPA GMT sat 30 days following the primary series and following the toddler dose, that are generally comparable to Prevenar 13 for the 13 shared serotypes and higher in VAXNEUVANCE for the 2 unique serotypes.
Infants and Toddlers Receiving a Mixed Dose Regimen of Different Pneumococcal Conjugate Vaccines: In a double-blind, active comparator-controlled, descriptive study (Protocol 027), 900 participants were randomized 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 Prevenar 13. In the three other vaccination groups, the vaccination series was initiated with Prevenar 13 and changed to VAXNEUVANCE at Dose 2, Dose 3 or Dose 4. Participants also received other pediatric vaccines concomitantly, including RECOMBIVAX HB (Hepatitis B Vaccine [Recombinant]) and RotaTeq (Rotavirus Vaccine, Live, Oral, Pentavalent) [see Concomitant Vaccination as follows]. Serotype-specific IgG GMCs at 30 days following the toddler dose were generally comparable for participants administered mixed regimens of VAXNEUVANCE and Prevenar 13 and for participants administered a complete dosing regimen of Prevenar 13 for the 13 shared serotypes, as assessed by IgG GMC ratios.
Infants, Children and Adolescents Receiving a Catch-Up Vaccination Schedule: In a double-blind, active comparator-controlled, descriptive study (Protocol 024), 606 participants were randomized to receive 1 to 3 doses of VAXNEUVANCE or Prevenar 13, depending on age at enrollment. Children who were either pneumococcal vaccine-naïve or not fully vaccinated or completed a dosing regimen with lower-valency pneumococcal conjugate vaccines were randomized into three different age cohorts (7 through 11 months of age, 12 through 23 months of age and 2 through 17 years of age), to receive 3, 2 or 1 dose of VAXNEUVANCE or Prevenar 13 respectively, according to an age-appropriate schedule [see Posology under Dosage & Administration]. VAXNEUVANCE elicited serotype-specific immune responses, as assessed by IgG GMC sat 30 days following the last dose of vaccine within each age cohort, for all 15 serotypes contained in the vaccine. Catch-up vaccination with VAXNEUVANCE elicited immune responses in children 7 months through 17 years of age that are comparable to Prevenar 13 for the shared serotypes and higher than Prevenar 13 for the unique 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 unique serotypes.
Clinical Trials Experience in Adults 18 Years of Age and Older: Six double-blind, clinical studies (Protocol 007, Protocol 016, Protocol 017, Protocol 019, Protocol 020 and Protocol 021) conducted across 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. The clinical studies 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 behavioral risk factors (e.g., smoking, increased alcohol use) that are known to increase the risk of pneumococcal disease.
In each study, immunogenicity was assessed by serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) responses at 30 days postvaccination. Study endpoints included OPA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs). The pivotal study (Protocol 19) was designed to show noninferiority of the OPA GMTs compared to Prevenar 13 [Pneumococcal 13 valent Conjugate Vaccine (Diphtheria CRM197 Protein)] (PCV13) for the 13 shared serotypes (in common between VAXNEUVANCE and Prevenar 13) and superiority for the 2 serotypes unique toVAXNEUVANCE (22F and 33F) and for shared serotype 3. Superiority assessment was based on the between-group comparisons of OPA GMTs and proportions of participants with a ≥4-fold rise in serotype-specific OPA titers from prevaccination to 30 days postvaccination.
Clinical Trials Conducted in Pneumococcal Vaccine-Naïve Adults: In the pivotal, double-blind, active comparator-controlled study (Protocol 019), 1,205 pneumococcal vaccine-naïve adults aged 50 years or older were randomized to receive either VAXNEUVANCE or Prevenar 13. The study demonstrated that VAXNEUVANCE is noninferior to Prevenar 13 for the 13 shared serotypes and superior for the 2 unique serotypes and for shared serotype 3. Table 6 summarizes the OPA GMTs at 30 days postvaccination. Serotype-specific IgG GMCs were generally consistent with the results observed for the OPA GMTs. (See Table 6.)
Click on icon to see table/diagram/imageIn a double-blind, lot consistency study (Protocol 020), 2,340 pneumococcal vaccine-naïve adults 50 years of age and older were randomized in a 3:3:3:1 ratio to receive 1 of 3 lots of VAXNEUVANCE or Prevenar 13. The study demonstrated that all 3 lots are equivalent as the lower and upper limits of the 95% CI of the serotype-specific OPA GMT ratios between any 2 lots were within the equivalence margin (0.5 to 2.0) for all 15 serotypes. Immune responses following vaccination with VAXNEUVANCE were comparable to Prevenar 13 for the shared serotypes.
In a double-blind, descriptive study (Protocol 017), 1,515 immunocompetent adults 18 to 49 years of age with or without risk factors for pneumococcal disease were randomized 3:1 to receive either VAXNEUVANCE or Prevenar 13, followed by PNEUMOVAX 23 [pneumococcal vaccine polyvalent] six months later. VAXNEUVANCE elicited immune responses to all 15 serotypes 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 VAXNEUVANCE for the 2 unique serotypes. Following vaccination with PNEUMOVAX 23, OPA GMTs and IgG GMCs were generally comparable between the two vaccination groups for all 15 serotypes in VAXNEUVANCE.
Immune responses in adults with no risk factors (n=285; 25.2%) who received VAXNEUVANCE were generally consistent with those observed in the overall study population. (See Table 7.)
Click on icon to see table/diagram/imageSequential Administration of Pneumococcal Vaccines in Adults: In a double-blind, active comparator-controlled study (Protocol 016), 652 pneumococcal vaccine-naïve adults 50 years of age and older were randomized to receive either VAXNEUVANCE or Prevenar 13, followed by PNEUMOVAX 23 one year later. Following vaccination with PNEUMOVAX 23, 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. Immune responses at 30 days and 12 months postvaccination were comparable between the two vaccination groups for the 13 shared serotypes and higher in VAXNEUVANCE for the 2 unique serotypes.
The sequential administration of VAXNEUVANCE followed by PNEUMOVAX 23 was evaluated with an interval of 2 months in immunocompromised individuals (Protocol 018) and an interval of 6 months in immunocompetent individuals with or without risk factors for pneumococcal disease (Protocol 017). [See Individuals at Increased Risk for Pneumococcal Disease under Precautions.]
Clinical Trials Conducted in Adults with Prior Pneumococcal Vaccination: In a double-blind, descriptive study (Protocol 007), 253 adults 65 years of age and older who were previously vaccinated with PNEUMOVAX 23 at least 1 year prior to study entry were randomized to receive either VAXNEUVANCE or Prevenar 13. IgG GMCs and OPA GMTs were generally comparable between the vaccination groups for the 13 shared serotypes and higher in VAXNEUVANCE for the 2 unique serotypes.
Concomitant Vaccination: Infants and Toddlers: The immunogenicity of routine infant vaccines administered concomitantly with VAXNEUVANCE was evaluated within 3 double-blind, active comparator-controlled studies (Protocol 025, Protocol 029 and Protocol 027). In Protocol 025, approximately 1,200 participants received Rotarix concomitantly with the infant primary series and INFANRIX hexa concomitantly with the infant primary series and toddler dose of VAXNEUVANCE or Prevenar 13. Immune responses to Rotarix administered concomitantly with VAXNEUVANCE met non-inferiority criteria, as assessed by anti-rotavirus immunoglobulin A GMTs at 30 days following completion of the primary series. Similarly, immune responses to INFANRIX hexa administered concomitantly with VAXNEUVANCE met non-inferiority criteria, as assessed by the antigen-specific response rate to each antigen in INFANRIX hexa at 30 days following the toddler dose.
In Protocol 029, approximately 1,700 participants received Pentacel administered concomitantly with the infant primary series of VAXNEUVANCE or Prevenar 13. Approximately 1,500 participants received VAQTA, HIBERIX, M-M-R II and VARIVAX, administered concomitantly with the toddler dose of VAXNEUVANCE or Prevenar 13. At 30 days following completion of the primary series, immune responses to all antigens contained in Pentacel met non-inferiority criteria when administered concomitantly with VAXNEUVANCE. At 30 days following the toddler dose, immune responses to vaccine-specific antigens for VAQTA, HIBERIX, M-M-R II and VARIVAX met non-inferiority criteria when administered concomitantly with VAXNEUVANCE.
In Protocol 027, approximately 900 participants received RECOMBIVAX HB and RotaTeq concomitantly with VAXNEUVANCE or Prevenar 13 in the infant primary series. At 30 days following the primary series, immune responses to vaccine-specific antigens for RECOMBIVAX HB and RotaTeq met non-inferiority criteria when administered concomitantly with VAXNEUVANCE.
These studies support the concomitant administration of VAXNEUVANCE with any of the following vaccine antigens: diphtheria, tetanus, pertussis, poliomyelitis (serotypes 1, 2 and 3), hepatitis A, hepatitis B, Haemophilus influenzae type b, measles, mumps, rubella, varicella and rotavirus vaccine, either as monovalent or combination vaccines.
Adults: In a double-blind, randomized study (Protocol 021), 1,200 adults 50 years of age and older, with or without a history of prior PNEUMOVAX 23 vaccination, were randomized to receive VAXNEUVANCE concomitantly or nonconcomitantly with seasonal inactivated quadrivalent influenza vaccine (QIV). One vaccination group received VAXNEUVANCE and QIV concomitantly, followed by placebo 30 days later. A second vaccination group received QIV and placebo concomitantly, followed by VAXNEUVANCE 30 days later.
VAXNEUVANCE administered concomitantly with QIV is noninferior to VAXNEUVANCE administered nonconcomitantly with QIV (based on a 2-fold noninferiority margin), as assessed by pneumococcal OPA GMTs at 30 days postvaccination with VAXNEUVANCE for all 15 serotypes contained in the vaccine. OPA GMTs were slightly lower for some serotypes when VAXNEUVANCE was administered concomitantly with QIV compared to VAXNEUVANCE administered alone. QIV administered concomitantly with VAXNEUVANCE is noninferior to QIV administered nonconcomitantly (based on a 2-fold noninferiority margin) as assessed by influenza strain-specific hemagglutination inhibition (HAI) GMTs at 30 days postvaccination with QIV for all 4 influenza strains.
Animal Toxicology: Repeat Dose Toxicity and Local Tolerance: Repeat-dose toxicity studies in rats at doses up to 17 times the infant human dose and up to 200 times the adult human dose on a mcg/kg basis, which included an evaluation of single-dose toxicity and local tolerance, revealed no hazards to humans.
Carcinogenesis: VAXNEUVANCE has not been evaluated for the potential to cause carcinogenicity.
Mutagenesis: VAXNEUVANCE has not been evaluated for the potential to cause genotoxicity.
Reproduction: VAXNEUVANCE administered to female rats at a dose approximately 200 times the adult human dose on a mcg/kg basis had no effects on mating performance, fertility or embryonic/fetal survival.
Development: VAXNEUVANCE administered to female rats at a dose approximately 200 times the adult human dose on a mcg/kg basis had no adverse effects on pre-weaning development. Antibodies to all 15 serotypes contained in VAXNEUVANCE were detected in offspring, attributable to the acquisition of maternal antibodies via placental transfer during gestation and possibly via lactation.
