Vaxneuvance Mechanism of Action

Therapeutic Class: Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) is a conjugated polysaccharide vaccine that protects against invasive disease, pneumonia and acute otitis media caused by Streptococcus pneumoniae.
Pharmacology: Mechanism of Action: Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) contains serotype-specific pneumococcal capsular polysaccharides, each of which is conjugated to a carrier protein (CRM₁₉₇), and elicits antibodies that enhance opsonization, phagocytosis, and killing of pneumococci to protect against pneumococcal disease. Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) elicits a T-cell dependent immune response. Carrier protein-specific helper T-cells support specificity, functionality and maturation of serotype-specific B cells.
Immune responses following natural exposure to S. pneumoniae or following pneumococcal vaccination can be determined through the measurements of OPA and IgG responses. OPA represents functional antibodies capable of opsonizing pneumococcal capsular polysaccharides for presentation to phagocytic cells for engulfment and subsequent killing and are considered an important immunologic surrogate measure of protection against pneumococcal disease in adults. OPA titers are expressed as the reciprocal of the highest serum dilution that reduces survival of the pneumococci by at least 50%. Serotype-specific immune responses (OPA and IgG) for the 15 serotypes contained in Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) were measured using a validated multiplexed opsonophagocytic assay (MOPA) and a validated pneumococcal electrochemiluminescence (Pn ECL) assay, bridged to the WHO reference enzyme linked immunosorbent assay (ELISA). In children, a serotype-specific IgG antibody level corresponding to ≥0.35 mcg/mL using the WHO ELISA has been used as the threshold value for the clinical evaluation of pneumococcal conjugate vaccines.
Clinical Studies: Burden of Disease: Pneumococcal disease is associated with significant morbidity and mortality in both children and adults worldwide. Although all age groups may be affected by pneumococcal disease, the highest rates of disease occur in young children <5 years of age and adults ≥65 years of age. Among children, the incidence of IPD and mortality associated with IPD is highest among infants <1 year of age. In addition, mortality rates are elevated in older adults, adults with comorbid conditions (e.g., diabetes mellitus, chronic lung disease, chronic liver disease), and especially in immunocompromised individuals (e.g., HIV infection, cancer, transplant, immunosuppressive therapies). Adults with 2 or more comorbid conditions may have a risk of pneumococcal disease that is comparable to that of immunocompromised individuals.
Clinical syndromes include both invasive pneumococcal disease (IPD) (i.e. sepsis, meningitis, and bacteremic pneumonia) and noninvasive disease (e.g., non-bacteremic pneumonia and acute otitis media). Bacteremic pneumococcal pneumonia represents approximately 80-90% of IPD cases in adults. Community acquired pneumonia (CAP) remains one of the most important causes of death from infection in many countries, with S. pneumoniae being one of the most commonly identified bacterial pathogens. Acute otitis media, a middle ear infection frequently caused by S. pneumoniae, is one of the most common infectious diseases of childhood and is a major cause of morbidity and antibiotic usage.
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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 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].
Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) recipients, compared to Prevnar 13 recipients. At 30 days following the toddler dose, Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) is non-inferior to Prevnar 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 Prevnar 13 for the 13 shared serotypes and superior to Prevnar 13 for the 2 unique serotypes at 30 days following the toddler dose (Table 2). (See Tables 1 and 2.)

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Additionally, Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) elicits functional antibodies, as assessed by serotype-specific OPA GMTs at 30 days following the toddler dose, that are generally comparable to Prevnar 13 for the 13 shared serotypes. OPA GMTs for both 22F and 33F were higher in Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) recipients compared to Prevnar 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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 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. Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) met non-inferiority criteria (the lower bound of the 2-sided 95% CI of the differences in the response rates [Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) - Prevnar 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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) and Prevnar 13 for the 13 shared serotypes and higher in Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 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 B Vaccine [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].
Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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, Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) is non-inferior to Prevnar 13 for the 13 shared serotypes, as assessed by IgG response rates (Table 3). Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) is non-inferior for the 2 unique serotypes, as assessed by the IgG response rates for serotypes 22F and 33F in recipients of Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) compared with the response rate for serotype 23F in recipients of Prevnar 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, Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) is superior to Prevnar 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.)

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At 30 days following the primary series, serotype-specific IgG GMCs are non-inferior to Prevnar 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 [Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE)/Prevnar 13] being 0.48 versus >0.5) (Table 4). Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) is non-inferior to Prevnar 13 for the 2 unique serotypes, as assessed by serotype-specific IgG GMCs for serotypes 22F and 33F in recipients of Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) compared with the IgG GMC for serotype 4 in recipients of Prevnar 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.
Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) is also superior to Prevnar 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.)

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At 30 days following the toddler dose, serotype-specific IgG GMCs for Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) are non-inferior to Prevnar 13 for all 13 shared serotypes and for the 2 unique serotypes as assessed by the IgG GMCs for serotypes 22F and 33F in Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) recipients compared with the IgG GMC for serotype 4 in Prevnar 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).
Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) is superior to Prevnar 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.)

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Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 to Prevnar 13 for the 13 shared serotypes and higher in Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 13. In the three other vaccination groups, the vaccination series was initiated with Prevnar 13 and changed to Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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]. Serotype-specific IgG GMCs at 30 days following the toddler dose were generally comparable for participants administered mixed regimens of Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) and Prevnar 13 and for participants administered a complete dosing regimen of Prevnar 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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 13 respectively, according to an age-appropriate schedule [see Dosage & Administration]. Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) elicited serotype-specific immune responses, as assessed by IgG GMCs at 30 days following the last dose of vaccine within each age cohort, for all 15 serotypes contained in the vaccine. Catch-up vaccination with Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) elicited immune responses in children 7 months through 17 years of age that are comparable to Prevnar 13 for the shared serotypes and higher than Prevnar 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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 019) was designed to show non-inferiority of the OPA GMTs compared to Prevnar 13 for the 13 shared serotypes (in common between Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) and Prevnar 13) and superiority for the 2 serotypes unique to Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 13. The study demonstrated that Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) is non-inferior to Prevnar 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.)

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In 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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) were comparable to Prevnar 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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 13, followed by PNEUMOVAX 23 six months later. Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE).
Immune responses in adults with no risk factors (n=285; 25.2%) who received Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) were generally consistent with those observed in the overall study population. (See Table 7.)

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Sequential 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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE).
Immune responses elicited by Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) for the 2 unique serotypes.
The sequential administration of Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Use in Specific Populations 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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 13. IgG GMCs and OPA GMTs were generally comparable between the vaccination groups for the 13 shared serotypes and higher in Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) for the 2 unique serotypes.
Concomitant Vaccination: Infants and Toddlers: The immunogenicity of routine infant vaccines administered concomitantly with Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 13. Immune responses to Rotarix administered concomitantly with Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 13. Approximately 1,500 participants received VAQTA, HIBERIX, M-M-R II and VARIVAX, administered concomitantly with the toddler dose of Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE).
In Protocol 027, approximately 900 participants received RECOMBIVAX HB and RotaTeq concomitantly with Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) or Prevnar 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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE).
These studies support the concomitant administration of Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) concomitantly or nonconcomitantly with seasonal inactivated quadrivalent influenza vaccine (QIV). One vaccination group received Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) and QIV concomitantly, followed by placebo 30 days later. A second vaccination group received QIV and placebo concomitantly, followed by Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) 30 days later.
Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) administered concomitantly with QIV is non-inferior to Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) administered nonconcomitantly with QIV (based on a 2-fold non-inferiority margin), as assessed by pneumococcal OPA GMTs at 30 days postvaccination with Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) for all 15 serotypes contained in the vaccine. OPA GMTs were slightly lower for some serotypes when Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) was administered concomitantly with QIV compared to Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) administered alone. QIV administered concomitantly with Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) is non-inferior to QIV administered nonconcomitantly (based on a 2-fold non-inferiority margin) as assessed by influenza strain-specific hemagglutination inhibition (HAI) GMTs at 30 days postvaccination with QIV for all 4 influenza strains.
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: Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) has not been evaluated for the potential to cause carcinogenicity.
Mutagenesis: Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) has not been evaluated for the potential to cause genotoxicity.
Reproduction: Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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: Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (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 Pneumococcal Polysaccharide Conjugate Vaccine, 15-Valent (Adsorbed) (VAXNEUVANCE) were detected in offspring, attributable to the acquisition of maternal antibodies via placental transfer during gestation and possibly via lactation.