DailyMed Label: PREVNAR 13

DailyMed Label: PREVNAR 13

2018

DailyMed Prescription

PREVNAR 13

pneumococcal 13-valent conjugate vaccine

A-S Medication Solutions

NDC: 50090-1944

NDC: 50090-1944

NDC: 50090-1944

Prevnar 13, Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM 197 Protein) is a sterile suspension of saccharides of the capsular antigens of Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, individually linked to non-toxic diphtheria CRM 197 protein. Each serotype is grown in soy peptone broth. The individual polysaccharides are purified through centrifugation, precipitation, ultrafiltration, and column chromatography. The polysaccharides are chemically activated to make saccharides, which are directly conjugated by reductive amination to the protein carrier CRM 197 , to form the glycoconjugate. CRM 197 is a nontoxic variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheriae strain C7 (β197) grown in a casamino acids and yeast extract-based medium or in a chemically-defined medium. CRM 197 is purified through ultrafiltration, ammonium sulfate precipitation, and ion-exchange chromatography. The individual glycoconjugates are purified by ultrafiltration and column chromatography and analyzed for saccharide to protein ratios, molecular size, free saccharide, and free protein. The individual glycoconjugates are compounded to formulate Prevnar 13. Potency of the formulated vaccine is determined by quantification of each of the saccharide antigens and by the saccharide to protein ratios in the individual glycoconjugates. Each 0.5 mL dose of the vaccine is formulated to contain approximately 2.2 µg of each of Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 23F saccharides, 4.4 μg of 6B saccharides, 34 µg CRM 197 carrier protein, 100 µg polysorbate 80, 295 µg succinate buffer and 125 µg aluminum as aluminum phosphate adjuvant. The tip cap and rubber plunger of the prefilled syringe are not made with natural rubber latex.

In children 6 weeks through 5 years of age (prior to the 6 th birthday), Prevnar 13 is indicated for: active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. ( 1.1 ) active immunization for the prevention of otitis media caused by S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. No otitis media efficacy data are available for serotypes 1, 3, 5, 6A, 7F, and 19A. ( 1.1 ) In children 6 years through 17 years of age (prior to the 18 th birthday), Prevnar 13 is indicated for: active immunization for the prevention of invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. ( 1.2 ) In adults 18 years of age and older, Prevnar 13 is indicated for: active immunization for the prevention of pneumonia and invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. ( 1.3 ) Limitations of Prevnar 13 Use and Effectiveness Prevnar 13 does not protect against disease caused by S. pneumoniae serotypes that are not in the vaccine. ( 1.4 ) In children 6 weeks through 5 years of age (prior to the 6 th birthday), Prevnar 13 ® is indicated for: active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae s erotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. active immunization for the prevention of otitis media caused by S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. No otitis media efficacy data are available for serotypes 1, 3, 5, 6A, 7F, and 19A. In children 6 years through 17 years of age (prior to the 18 th birthday), Prevnar 13 is indicated for: active immunization for the prevention of invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. In adults 18 years of age and older, Prevnar 13 is indicated for: active immunization for the prevention of pneumonia and invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. Prevnar 13 does not protect against disease caused by S. pneumoniae serotypes that are not in the vaccine.

Children 6 weeks through 5 years: The four-dose immunization series consists of a 0.5 mL intramuscular injection administered at 2, 4, 6, and 12–15 months of age. ( 2.3 ) Children 6 through 17 years of age: a single dose. ( 2.5 ) Adults 18 years and older: a single dose. ( 2.6 ) Since this product is a suspension containing an adjuvant, shake vigorously immediately prior to use to obtain a homogenous, white suspension in the vaccine container. Do not use the vaccine if it cannot be resuspended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration [see Description (11) ] . This product should not be used if particulate matter or discoloration is found. Do not mix Prevnar 13 with other vaccines/products in the same syringe. For intramuscular injection only. Each 0.5 mL dose is to be injected intramuscularly using a sterile needle attached to the supplied prefilled syringe. The preferred sites for injection are the anterolateral aspect of the thigh in infants and the deltoid muscle of the upper arm in toddlers, children and adults. The vaccine should not be injected in the gluteal area or areas where there may be a major nerve trunk and/or blood vessel. Prevnar 13 is to be administered as a four-dose series at 2, 4, 6, and 12–15 months of age. Table 1: Vaccination Schedule for Infants and Toddlers Dose Dose 1 Dose 1 may be given as early as 6 weeks of age. , The recommended dosing interval is 4 to 8 weeks. Dose 2 Dose 3 Dose 4 The fourth dose should be administered at approximately 12–15 months of age, and at least 2 months after the third dose. Age at Dose 2 months 4 months 6 months 12–15 months For children 7 months through 5 years of age who have not received Prevnar ® or Prevnar 13, the catch-up schedule in Table 2 applies: Table 2: Vaccination Schedule for Unvaccinated Children 7 Months of Age Through 5 Years of Age Age at First Dose Total Number of 0.5 mL Doses 7–11 months of age 3 The first 2 doses at least 4 weeks apart; third dose after the one-year birthday, separated from the second dose by at least 2 months. 12–23 months of age 2 Two doses at least 2 months apart. 24 months through 5 years of age (prior to the 6 th birthday) 1 The immune responses induced by this catch-up schedule may result in lower antibody concentrations for some serotypes, compared to antibody concentrations following 4 doses of Prevnar 13 (given at 2, 4, 6, and 12–15 months). In children 24 months through 5 years of age, lower antibody concentrations were observed for some serotypes, compared to antibody concentrations following 3 doses of Prevnar 13 (given at 2, 4, and 6 months). In children 6 years through 17 years of age, Prevnar 13 is administered as single dose. If Prevnar was previously administered, then at least 8 weeks should elapse before receiving Prevnar 13. Prevnar 13 is administered as a single dose.

Prevnar 13 is a suspension for intramuscular injection available in 0.5 mL single-dose prefilled syringes. 0.5 mL suspension for intramuscular injection, supplied in a single-dose prefilled syringe. ( 3 )

Severe allergic reaction (e.g., anaphylaxis) to any component of Prevnar 13 or any diphtheria toxoid-containing vaccine [see Description (11) ] . Severe allergic reaction (e.g., anaphylaxis) to any component of Prevnar 13 or any diphtheria toxoid-containing vaccine. ( 4 )

Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including Prevnar 13, to infants born prematurely should be based on consideration of the individual infant's medical status, and the potential benefits and possible risks of vaccination. ( 5.3 ) Epinephrine and other appropriate agents used to manage immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur following administration of Prevnar 13. Individuals with altered immunocompetence, including those at higher risk for invasive pneumococcal disease (e.g., individuals with congenital or acquired splenic dysfunction, HIV infection, malignancy, hematopoietic stem cell transplant, nephrotic syndrome), may have reduced antibody responses to immunization with Prevnar 13 [see Use in Specific Populations (8.6) ] . Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including Prevnar 13, to infants born prematurely should be based on consideration of the individual infant's medical status and the potential benefits and possible risks of vaccination.

Because clinical trials are conducted under widely varying conditions, adverse-reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

In clinical trials with infants and toddlers, Prevnar 13 was administered concomitantly with the following US-licensed vaccines: Pediarix [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined] (DTaP-HBV-IPV) and ActHIB [Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)] (PRP-T) for the first three doses and with PedvaxHIB [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] (PRP-OMP), M-M-R II [Measles, Mumps, Rubella Virus Vaccine Live] (MMR) and Varivax [Varicella Virus Vaccine Live], or ProQuad [Measles, Mumps, Rubella and Varicella Virus Vaccine Live] (MMRV) and VAQTA [Hepatitis A vaccine, Inactivated] (HepA) for dose 4 [see Clinical Studies (14.2) and Adverse Reactions (6.1) ] . In children and adolescents, data are insufficient to assess the concomitant administration of Prevnar 13 with Human Papillomavirus Vaccine (HPV), Meningococcal Conjugate Vaccine (MCV4) and Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (Tdap). In adults, Prevnar 13 was administered concomitantly with US-licensed inactivated influenza vaccines, trivalent and quadrivalent (Studies 10, 11 and 13) [see Clinical Studies (14.4) and Adverse Reactions (6.2) ]. There are no data on the concomitant administration of Prevnar 13 with diphtheria toxoid-containing vaccines and other vaccines licensed for use in adults 50 years of age and older. When Prevnar 13 is administered at the same time as another injectable vaccine(s), the vaccines should always be administered with different syringes and given at different injection sites. Do not mix Prevnar 13 with other vaccines/products in the same syringe. Individuals with impaired immune responsiveness due to the use of immunosuppressive therapy (including irradiation, corticosteroids, antimetabolites, alkylating agents, and cytotoxic agents) may not respond optimally to active immunization. A post-marketing clinical study conducted in Poland using a non-US vaccination schedule (2, 3, 4, and 12 months of age) evaluated the impact of prophylactic oral acetaminophen on antibody responses to Prevnar 13. The data show that 3 doses of acetaminophen (the first dose administered at the time of each vaccination and the subsequent doses at 6 to 8 hour intervals) reduced the antibody response to some serotypes following the third dose of Prevnar 13, compared with responses among infants who received antipyretics only as needed for treatment. Reduced antibody responses were not observed after the fourth dose of Prevnar 13 when acetaminophen was administered prophylactically. Prior receipt of PPSV23 within 1 year results in diminished immune responses to Prevnar 13 compared to PPSV23 naïve individuals [see Clinical Studies (14.3) ].

Pediatric Use: Safety and effectiveness of Prevnar 13 in children below the age of 6 weeks have not been established. ( 8.4 ) Risk Summary All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Available data on Prevnar 13 administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy. A developmental toxicity study has been performed in female rabbits administered Prevnar 13 prior to mating and during gestation. Each dose was approximately 20 times the human dose. This study revealed no evidence of harm to the fetus due to Prevnar 13 (see 8.1 Data ). Data Animal In a developmental toxicity study, female rabbits were administered Prevnar 13 by intramuscular injection twice prior to mating (17 days and 3 days prior to mating) and twice during gestation (gestation days 10 and 24), 0.5 mL/rabbit/occasion (each dose approximately 20 times the human dose). No adverse effects on pre-weaning development were observed. There were no vaccine-related fetal malformations or variations. Risk Summary Data are not available to assess the effects of Prevnar 13 on the breastfed infant or on milk production/excretion. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Prevnar 13 and any potential adverse effects on the breastfed child from Prevnar 13 or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine. Safety and effectiveness of Prevnar 13 in children below the age of 6 weeks have not been established. Of the total number of Prevnar 13 recipients aged 50 years and older in clinical studies (N=47,907), 94.5% (45,291 of 47,907 ) were 65 years and older and 30.3 % (14,498 of 47,907) were 75 years and older [see Clinical Studies (14.1) and (14.3) ] . Individuals with the diseases or conditions listed below are at increased risk of pneumococcal disease. Immunogenicity and safety data in these populations are limited. Infants Born Prematurely Immune responses elicited by Prevnar 13 administered on a US schedule to preterm infants have not been studied. When preterm infants (<37 weeks gestational age, N=100) were administered 4 doses of Prevnar 13 on a non-US schedule, the serotype-specific IgG antibody responses after the third and fourth dose were lower compared to responses among term infants (≥37 weeks gestational age, N=100) for some serotypes; the effectiveness of Prevnar 13 in preterm infants cannot be established from this study. Children with Sickle Cell Disease In an open-label, single-arm, descriptive study, 2 doses of Prevnar 13 were administered 6 months apart to children ≥6 to <18 years of age with sickle cell disease who previously received PPSV23 at least 6 months prior to enrollment. Children with a prior history of pneumococcal conjugate vaccination were excluded. For all vaccine serotypes, anti-pneumococcal opsonophagocytic activity (OPA) geometric mean antibody titers (GMTs) were higher after the first dose compared to pre-vaccination (N=95–131); OPA GMTs following the first and second dose were comparable. The effectiveness of Prevnar 13 in this specific population has not been established. Individuals with Hematopoietic Stem Cell Transplant In an open-label, single-arm, descriptive study, 4 doses of Prevnar 13 were administered to subjects ≥2 years of age (range 2 to 71 years) who had received an allogeneic hematopoietic stem cell transplant 3 to 6 months prior to enrollment. All subjects had a history of stable engraftment (absolute neutrophil count>1000/µL, platelet count >50,000/µL), and did not have uncontrolled graft versus host disease. The first three doses of Prevnar 13 were administered one month apart, followed by a fourth dose of Prevnar 13 six months after the third dose. Sera were obtained approximately one month after each vaccination. Immune responses (IgG GMCs) after the first dose of Prevnar 13 were numerically higher for all serotypes compared with baseline. In addition, after each subsequent dose of Prevnar 13, IgG GMCs for all serotypes were numerically higher than responses after the previous dose. A post hoc analysis of the immune responses as measured by OPA antibody assay showed the pattern of functional antibody responses to be consistent with IgG responses for each serotype. The effectiveness of Prevnar 13 in this specific population has not been established. Individuals with HIV Infection In an open-label, single-arm, descriptive study, 3 doses of Prevnar 13 were administered 6 months apart to HIV-infected adults ≥18 years of age (median age 48 years), with CD4 counts ≥200 cells/µL and serum HIV RNA titer <50,000 copies/mL. All subjects had been vaccinated previously with PPSV23 at least 6 months prior to enrollment. For all vaccine serotypes anti-pneumococcal OPA GMTs were numerically higher after the first dose compared to pre-vaccination (N=227–253); OPA GMTs following the first, second and third dose were generally comparable. The effectiveness of Prevnar 13 in this specific population has not been established. In an open-label, single-arm, descriptive study, 3 doses of Prevnar 13 were administered 1 month apart to HIV-infected subjects ≥6 years of age with CD4 counts ≥200 cells/µL, and serum HIV RNA titer <50,000 copies/mL. Subjects had not previously been vaccinated with a pneumococcal vaccine. For all vaccine serotypes anti-pneumococcal OPA GMTs were numerically higher after the first dose compared to pre-vaccination (N=197–257); OPA GMTs following the first, second and third dose were generally comparable. The effectiveness of Prevnar 13 in this specific population has not been established.

Product: 50090-1944 NDC: 50090-1944-0 .5 mL in a VIAL / 1 in a POUCH

Prevnar 13, comprised of pneumococcal polysaccharides conjugated to a carrier protein (CRM 197 ), elicits a T-cell dependent immune response. Protein carrier-specific T-cells provide the signals needed for maturation of the B-cell response. Nonclinical and clinical data support opsonophagocytic activity, as measured by opsonophagocytic activity (OPA) antibody assay, as a contributor to protection against pneumococcal disease. The OPA antibody assay provides an in vitro measurement of the ability of serum antibodies to eliminate pneumococci by promoting complement-mediated phagocytosis and is believed to reflect relevant in vivo mechanisms of protection against pneumococcal disease. OPA antibody titers are expressed as the reciprocal of the highest serum dilution that reduces survival of the pneumococci by at least 50%. In infants that have received Prevnar 13, opsonophagocytic activity correlates well with serotype specific anti-capsular polysaccharide IgG levels as measured by ELISA. A serum anti-capsular polysaccharide antibody concentration of 0.35 µg/mL as measured by ELISA one month after the third dose as a single antibody reference concentration was used to estimate the effectiveness of Prevnar 13 against invasive pneumococcal disease (IPD) in infants and children. The assay used for this determination is a standardized ELISA involving pre-absorption of the test sera with pneumococcal C-polysaccharide and serotype 22F polysaccharide to reduce non-specific background reactivity. The single antibody reference value was based on pooled efficacy estimates from three placebo-controlled IPD efficacy trials with either Prevnar or the investigational 9-valent CRM 197 conjugate pneumococcal polysaccharide vaccine. This reference concentration is only applicable on a population basis and cannot be used to predict protection against IPD on an individual basis. Functional antibodies elicited by the vaccine (as measured by a dribble opsonophagocytic activity [dOPA] antibody assay) were also evaluated in infants. In adults, an antipolysaccharide binding antibody IgG level to predict protection against invasive pneumococcal disease or non-bacteremic pneumonia has not been defined. Noninferiority trials for Prevnar 13 were designed to show that functional OPA antibody responses (as measured by a microcolony OPA [mcOPA] antibody assay) for the Prevnar 13 serotypes are noninferior and for some serotypes superior to the common serotypes in the currently licensed pneumococcal polysaccharide vaccine (PPSV23). OPA antibody titers measured in the mcOPA antibody assay cannot be compared directly to titers measured in the dOPA antibody assay.

Prevnar 13 has not been evaluated for the potential to cause carcinogenicity, genotoxicity, or impairment of male fertility. In a study in rabbits, no vaccine-related effects were found regarding reproductive performance including female fertility [see Use in Specific Populations (8.1) ] .

Prevnar Efficacy Data Invasive Pneumococcal Disease (IPD) Prevnar (Pneumococcal 7-valent Conjugate Vaccine [Diphtheria CRM '197 Protein]) was licensed in the US for infants and children in 2000, following a randomized, double-blind clinical trial in a multiethnic population at Northern California Kaiser Permanente (NCKP) from October 1995 through August 20, 1998, in which 37,816 infants were randomized to receive either Prevnar or a control vaccine (an investigational meningococcal group C conjugate vaccine [MnCC]) at 2, 4, 6, and 12–15 months of age. In this study, the efficacy of Prevnar against invasive disease due to S. pneumoniae in cases accrued during this period was 100% in both the per-protocol and intent-to-treat analyses (95% confidence interval [CI]: 75.4%, 100% and 81.7%, 100%, respectively). Data accumulated through an extended follow-up period to April 20, 1999, resulted in similar efficacy estimates of 97.4% in the per-protocol analysis and 93.9% in the intent-to-treat analysis (95% CI: 82.7%, 99.9% and 79.6%, 98.5%, respectively). Acute Otitis Media (AOM) The efficacy of Prevnar against otitis media was assessed in two clinical trials: a trial in Finnish infants at the National Public Health Institute and the efficacy trial in US infants at Northern California Kaiser Permanente (NCKP). The Finnish Otitis Media (FinOM) trial was a randomized, double-blind trial in which 1,662 infants were equally randomized to receive either Prevnar or a control vaccine Recombivax HB (Hepatitis B vaccine (Recombinant) [Hep B]) at 2, 4, 6, and 12–15 months of age. In this study, conducted between December 1995 and March 1999, parents of study participants were asked to bring their children to the study clinics if the child had respiratory infections or symptoms suggesting acute otitis media (AOM). If AOM was diagnosed, tympanocentesis was performed, and the middle-ear fluid was cultured. If S. pneumoniae was isolated, serotyping was performed; the primary endpoint was efficacy against AOM episodes caused by vaccine serotypes in the per-protocol population. In the NCKP trial, the efficacy of Prevnar against otitis media was assessed from the beginning of the trial in October 1995 through April 1998. The otitis media analysis included 34,146 infants randomized to receive either Prevnar (N=17,070), or the control vaccine (N=17,076), at 2, 4, 6, and 12–15 months of age. In this trial, no routine tympanocentesis was performed, and no standard definition of otitis media was used by study physicians. The primary otitis media endpoint was efficacy against all otitis media episodes in the per-protocol population. The vaccine efficacy against AOM episodes due to vaccine serotypes assessed in the Finnish trial, was 57% (95% CI: 44%, 67%) in the per-protocol population and 54% (95% CI: 41%, 64%) in the intent-to-treat population. The vaccine efficacy against AOM episodes due to vaccine-related serotypes (6A, 9N, 18B, 19A, 23A), also assessed in the Finnish trial, was 51% (95% CI: 27, 67) in the per-protocol population and 44% (95% CI: 20, 62) in the intent-to-treat population. There was a nonsignificant increase in AOM episodes caused by serotypes unrelated to the vaccine in the per-protocol population, compared to children who received the control vaccine, suggesting that children who received Prevnar appeared to be at increased risk of otitis media due to pneumococcal serotypes not represented in the vaccine. However, vaccination with Prevnar reduced pneumococcal otitis media episodes overall. In the NCKP trial, in which the endpoint was all otitis media episodes regardless of etiology, vaccine efficacy was 7% (95% CI: 4%, 10%) and 6% (95% CI: 4%, 9%), respectively, in the per-protocol and intent-to-treat analyses. Several other otitis media endpoints were also assessed in the two trials. Recurrent AOM, defined as 3 episodes in 6 months or 4 episodes in 12 months, was reduced by 9% in both the per-protocol and intent-to-treat populations (95% CI: 3%, 15% in per-protocol and 95% CI: 4%, 14% in intent-to-treat) in the NCKP trial; a similar trend was observed in the Finnish trial. The NCKP trial also demonstrated a 20% reduction (95% CI: 2, 35) in the placement of tympanostomy tubes in the per-protocol population and a 21% reduction (95% CI: 4, 34) in the intent-to-treat population. Data from the NCKP trial accumulated through an extended follow-up period to April 20, 1999, in which a total of 37,866 children were included (18,925 in Prevnar group and 18,941 in MnCC control group), resulted in similar otitis media efficacy estimates for all endpoints. Prevnar 13 Adult Efficacy Data The efficacy of Prevnar 13 against vaccine-type (VT) pneumococcal community-acquired pneumonia (CAP) and IPD was assessed in a randomized, double-blind, placebo-controlled study conducted over ~ 4 years in the Netherlands 12 (Study 12). A total of 84,496 subjects 65 years and older received a single dose of either Prevnar 13 or placebo in a 1:1 randomization; 42,240 subjects were vaccinated with Prevnar 13 and 42,256 subjects were vaccinated with placebo. The primary objective was to demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of confirmed VT-CAP (defined as presence of ≥2 specified clinical criteria; chest X-ray consistent with CAP as determined by a central committee of radiologists; and positive VT-specific Urinary Antigen Detection assay (UAD) or isolation of VT S. pneumoniae from blood or other sterile site). The secondary objectives were to demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of 1) confirmed nonbacteremic/noninvasive (NB/NI) VT-CAP (an episode of VT-CAP for which the blood culture result and any other sterile site culture results were negative for S. pneumoniae) and 2) VT-IPD (the presence of S. pneumoniae in a sterile site). Surveillance for suspected pneumonia and IPD began immediately after vaccination and continued through identification of a prespecified number of cases. Subjects who had a CAP or IPD episode with symptom onset less than 14 days after vaccination were excluded from all analyses. The median duration of follow-up per subject was 3.93 years. Prevnar 13 demonstrated statistically significant vaccine efficacy (VE) in preventing first episodes of VT pneumococcal CAP, nonbacteremic/noninvasive (NB/NI) VT pneumococcal CAP, and VT-IPD (Table 15). Table 15 - Vaccine Efficacy for the Primary and Secondary Efficacy Endpoints – Per-Protocol Population Vaccine Group Prevnar 13 Placebo N=42240 N=42256 Efficacy Endpoint Total Number of Episodes n n VE (%) (95.2% CI) Abbreviations: CAP = community-acquired pneumonia; CI = confidence interval; NB/NI = nonbacteremic/noninvasive; IPD = invasive pneumococcal disease; VE = vaccine efficacy; VT = vaccine-type. Primary endpoint: First case of confirmed VT pneumococcal CAP 139 49 90 45.6 (21.8, 62.5) Secondary endpoint: First episode of confirmed NB/NI VT pneumococcal CAP 93 33 60 45 (14.2, 65.3) Secondary endpoint: First episode of VT-IPD 35 7 28 75 (41.1, 90.9) Infants and Children 6 Weeks Through 17 Months of Age Prevnar 13 effectiveness against invasive pneumococcal disease was inferred from comparative studies to a US-licensed 7-valent pneumococcal conjugate vaccine, Prevnar, in which Prevnar 13 elicited antipolysaccharide binding and functional OPA antibodies, as measured by ELISA and dOPA assays, respectively. These studies were designed to evaluate immunologic noninferiority of Prevnar 13 to Prevnar. Clinical trials have been conducted in the US using a 2, 4, 6, and 12–15 month schedule. The US noninferiority study 2 (Study 2) was a randomized, double-blind, active-controlled trial in which 2 month-old infants were randomly assigned to receive either Prevnar 13 or Prevnar in a 1:1 ratio. The two vaccine groups were well balanced with respect to race, ethnicity, and age and weight at enrollment. Most subjects were White (69.1%), 19.6% were Black or African-American, and 2.4% were Asian; 82.1% of subjects were non-Hispanic and non-Latino and 17.3% were Hispanic or Latino. Overall, 54.0% of subjects were male infants. In Study 2, immune responses were compared in subjects receiving either Prevnar 13 or Prevnar using a set of noninferiority criteria. Co-primary endpoints included the percentage of subjects with serum pneumococcal anti-capsular polysaccharide IgG ≥0.35 µg/mL measured one month after the third dose and serum pneumococcal anti-capsular polysaccharide IgG geometric mean concentrations (GMCs) one month after the fourth dose. The assay used for this determination was a standardized ELISA involving pre-absorption of the test sera with pneumococcal C-polysaccharide and serotype 22F polysaccharide to reduce non-specific background reactivity. Responses to the 7 common serotypes in Prevnar 13 and Prevnar recipients were compared directly. Responses to the 6 additional serotypes in Prevnar 13 recipients were each compared to the lowest response observed among the Prevnar serotypes in Prevnar recipients. Pneumococcal Immune Responses Following Three Doses In Study 2, the noninferiority criterion for the proportion of subjects with pneumococcal anti-capsular polysaccharide IgG antibody concentrations ≥0.35 μg/mL one month after the third dose was met for 10 of the 13 serotypes. The exceptions were serotypes 6B, 9V, and 3. Although the response to serotypes 6B and 9V did not meet the pre-specified noninferiority criterion, the differences were marginal. The percentage of infants achieving pneumococcal anti-capsular polysaccharide IgG antibody concentrations ≥0.35 μg/mL one month after the third dose is shown below (Table 16). Table 16: Percentage of Subjects With Anti-capsular Antibody Concentration ≥0.35 µg/mL One Month After a Three Dose Series Administered at 2, 4 and 6 Months of Age, Study 2 Studies conducted in US NCT00373958 (Study 2). , Evaluable Immunogenicity Population. , Noninferiority was met when the lower limit of the 95% CI for the difference between groups (Prevnar 13 minus Prevnar) was greater than -10%. , Antibody measured by a standardized ELISA involving pre-absorption of the test sera with pneumococcal C-polysaccharide and serotype 22F polysaccharide to reduce non-specific background reactivity. Serotype Prevnar 13 N=249–252 (95% CI) Prevnar N=250–252 (95% CI) Difference in % responders (95% CI) Prevnar Serotypes 4 94.4 (90.9, 96.9) 98.0 (95.4, 99.4) -3.6 (-7.3, -0.1) 6B 87.3 (82.5, 91.1) 92.8 (88.9, 95.7) -5.5 (-10.9, -0.1) 9V 90.5 (86.2, 93.8) 98.4 (96.0, 99.6) -7.9 (-12.4, -4.0) 14 97.6 (94.9, 99.1) 97.2 (94.4, 98.9) 0.4 (-2.7, 3.5) 18C 96.8 (93.8, 98.6) 98.4 (96.0, 99.6) -1.6 (-4.7, 1.2) 19F 98.0 (95.4, 99.4) 97.6 (99.4, 99.1) 0.4 (-2.4, 3.4) 23F 90.5 (86.2, 93.8) 94.0 (90.4, 96.6) -3.6 (-8.5, 1.2) Additional Serotypes Comparison for the 6 additional serotypes was to the lowest responder of the 7 common serotypes in Prevnar recipients, which for this analysis was serotype 6B (92.8%; 95% CI: 88.9, 95.7). 1 95.6 (92.3, 97.8) 2.8 (-1.3, 7.2) 3 63.5 (57.1, 69.4) -29.3 (-36.2, -22.4) 5 89.7 (85.2, 93.1) -3.1 (-8.3, 1.9) 6A 96.0 (92.8, 98.1) 3.2 (-0.8, 7.6) 7F 98.4 (96.0, 99.6) 5.6 (1.9, 9.7) 19A 98.4 (96.0, 99.6) 5.6 (1.9, 9.7) Functional dOPA antibody responses were elicited for all 13 serotypes, as shown in Table 17. Table 17: Pneumococcal dOPA Antibody Geometric Mean Titers One Month After a Three Dose Series Administered at 2, 4 and 6 Months of Age, Study 2 Studies conducted in US NCT00373958 (Study 2). , The dOPA (opsonophagocytic activity) antibody assay measures the ability of immune sera, in conjunction with complement, to mediate the uptake and killing of S. pneumoniae by phagocytic cells. , Evaluable Immunogenicity Population. Serotype Prevnar 13 N=91–94 (95% CI) Prevnar N=89–94 (95% CI) Prevnar Serotypes 4 359 (276, 468) 536 (421, 681) 6B 1055 (817, 1361) 1514 (1207, 1899) 9V 4035 (2933, 5553) 3259 (2288, 4641) 14 1240 (935, 1646) 1481 (1133, 1934) 18C 276 (210, 361) 376 (292, 484) 19F 54 (40, 74) 45 (34, 60) 23F 791 (605, 1034) 924 (709, 1204) Additional Serotypes 1 52 (39, 69) 4 (4, 5) 3 121 (92, 158) 7 (5, 9) 5 91 (67, 123) 4 (4, 4) 6A 980 (783, 1226) 100 (66, 152) 7F 9494 (7339, 12281) 128 (80, 206) 19A 152 (105, 220) 7 (5, 9) Pneumococcal Immune Responses Following Four Doses In Study 2, post-dose 4 antibody concentrations were higher for all 13 serotypes than those achieved after the third dose. The noninferiority criterion for pneumococcal anti-capsular polysaccharide GMCs after 4 doses was met for 12 of the 13 pneumococcal serotypes. The noninferiority criterion was not met for the response to serotype 3 (Table 18). Table 18: Pneumococcal IgG GMCs (µg/mL) One Month After a Four Dose Series Administered at 2, 4, 6 and 12–15 Months, Study 2 Studies conducted in US NCT00373958 (Study 2). , Evaluable Immunogenicity Population. , Noninferiority was declared if the lower limit of the 2-sided 95% CI for Geometric Mean Ratio (Prevnar 13:Prevnar) was greater than 0.5. , Antibody measured by a standardized ELISA involving pre-absorption of the test sera with pneumococcal C-polysaccharide and serotype 22F polysaccharide to reduce non-specific background reactivity. Serotype Prevnar 13 N=232–236 (95% CI) Prevnar N=222–223 (95% CI) GMC Ratio (95% CI) Prevnar Serotypes 4 3.73 (3.28, 4.24) 5.49 (4.91, 6.13) 0.68 (0.57, 0.80) 6B 11.53 (9.99, 13.30) 15.63 (13.80, 17.69) 0.74 (0.61, 0.89) 9V 2.62 (2.34, 2.94) 3.63 (3.25, 4.05) 0.72 (0.62, 0.85) 14 9.11 (7.95, 10.45) 12.72 (11.22, 14.41) 0.72 (0.60, 0.86) 18C 3.20 (2.82, 3.64) 4.70 (4.18, 5.28) 0.68 (0.57, 0.81) 19F 6.60 (5.85, 7.44) 5.60 (4.87, 6.43) 1.18 (0.98, 1.41) 23F 5.07 (4.41, 5.83) 7.84 (6.91, 8.90) 0.65 (0.54, 0.78) Additional Serotypes Comparison for the 6 additional serotypes was to the lowest responder of the 7 common serotypes in Prevnar recipients, which for this analysis was serotype 9V (3.63; 95% CI 3.25, 4.05). 1 5.06 (4.43, 5.80) 1.40 (1.17, 1.66) 3 0.94 (0.83, 1.05) 0.26 (0.22, 0.30) 5 3.72 (3.31, 4.18) 1.03 (0.87, 1.20) 6A 8.20 (7.30, 9.20) 2.26 (1.93, 2.65) 7F 5.67 (5.01, 6.42) 1.56 (1.32, 1.85) 19A 8.55 (7.64, 9.56) 2.36 (2.01, 2.76) Following the fourth dose, the functional dOPA antibody response for each serotype was quantitatively greater than the response following the third dose (see Table 19 ). Table 19: Pneumococcal dOPA Antibody Geometric Mean Titers One Month After the Fourth Dose-Evaluable Toddler Immunogenicity Population, Study 2 Studies conducted in US NCT00373958 (Study 2). , The dOPA (opsonophagocytic activity) antibody assay measures the ability of immune sera, in conjunction with complement, to mediate the uptake and killing of S. pneumoniae by phagocytic cells. Serotype Prevnar 13 N=88–92 (95% CI) Prevnar N=92–96 (95% CI) Prevnar Serotypes 4 1180 (847, 1643) 1492 (1114, 1999) 6B 3100 (2337, 4111) 4066 (3243, 5098) 9V 11856 (8810, 15955) 18032 (14125, 23021) 14 2002 (1453, 2760) 2366 (1871, 2992) 18C 993 (754, 1308) 1722 (1327, 2236) 19F 200 (144, 276) 167 (121, 230) 23F 2723 (1961, 3782) 4982 (3886, 6387) Additional Serotypes 1 164 (114, 237) 5 (4, 6) 3 380 (300, 482) 12 (9, 16) 5 300 (229, 393) 5 (4, 6) 6A 2242 (1707, 2945) 539 (375, 774) 7F 11629 (9054, 14938) 268 (164, 436) 19A 1024 (774, 1355) 29 (19, 44) Previously Unvaccinated Older Infants and Children 7 Months Through 5 Years of Age In an open-label descriptive study of Prevnar 13 in Poland 4 (Study 4), children 7 months through 11 months of age, 12 months through 23 months of age and 24 months through 5 years of age (prior to the 6 th birthday) who were naïve to pneumococcal conjugate vaccine, were given 3, 2 or 1 dose of Prevnar 13 respectively, according to the age-appropriate schedules in Table 2. Serum IgG concentrations were measured one month after the final dose in each age group and the data are shown in Table 20. Table 20: Pneumococcal Anti-capsular Polysaccharide IgG Antibody Geometric Mean Concentrations (μg/mL) One Month After the Final Prevnar 13 Catch-Up Dose in Pneumococcal Vaccine Naïve Children 7 Months Through 5 Years of Age by Age Group, Study 4 Studies conducted in Poland NCT00452452 (Study 4). , Open label administration of Prevnar 13. Serotype 3 doses Prevnar 13 7 through 11 months N=83–84 (95% CI) 2 doses Prevnar 13 12 through 23 months N=104–110 (95% CI) 1 dose Prevnar 13 24 months through 5 years N=135–152 (95% CI) Note – ClinicalTrials.gov NCT number is as follows: NCT00452452 (Poland). 1 2.88 (2.44, 3.39) 2.74 (2.37, 3.16) 1.78 (1.52, 2.08) 3 1.94 (1.68, 2.24) 1.86 (1.60, 2.15) 1.42 (1.23, 1.64) 4 3.63 (3.11, 4.23) 4.28 (3.78, 4.86) 3.37 (2.95, 3.85) 5 2.85 (2.34, 3.46) 2.16 (1.89, 2.47) 2.33 (2.05, 2.64) 6A 3.72 (3.12, 4.45) 2.62 (2.25, 3.06) 2.96 (2.52, 3.47) 6B 4.77 (3.90, 5.84) 3.38 (2.81, 4.06) 3.41 (2.80, 4.16) 7F 5.30 (4.54, 6.18) 5.99 (5.40, 6.65) 4.92 (4.26, 5.68) 9V 2.56 (2.21, 2.96) 3.08 (2.69, 3.53) 2.67 (2.32, 3.07) 14 8.04 (6.95, 9.30) 6.45 (5.48, 7.59) 2.24 (1.71, 2.93) 18C 2.77 (2.39, 3.23) 3.71 (3.29, 4.19) 2.56 (2.17, 3.03) 19A 4.77 (4.28, 5.33) 4.94 (4.31, 5.65) 6.03 (5.22, 6.97) 19F 2.88 (2.35, 3.54) 3.07 (2.68, 3.51) 2.53 (2.14, 2.99) 23F 2.16 (1.82, 2.55) 1.98 (1.64, 2.39) 1.55 (1.31, 1.85) Children 15 Months Through 59 Months of Age Previously Vaccinated with Prevnar In an open-label descriptive study in the US 5 (Study 5), children 15 months through 59 months previously vaccinated with 3 or 4 doses of Prevnar, received 2 doses of Prevnar 13 (children >15 through 23 months of age) or 1 dose of Prevnar 13 (children 24 months through 59 months of age). The data following one dose of Prevnar 13 in children 24 months through 59 months of age are shown in Table 21. Table 21: Pneumococcal Anti-capsular Polysaccharide IgG Antibody Geometric Mean Concentrations (μg/mL) One Month After One Prevnar 13 Catch-Up Dose in Children 24 Through 59 Months of Age With 3 or 4 Prior Doses of Prevnar, US Catch-Up Study 5 Studies conducted in US NCT00761631 (Study 5). , Open label administration of Prevnar 13. Serotype 1 dose Prevnar 13 24 months through 59 months N=173–175 (95% CI) 1 2.43 (2.15, 2.75) 3 1.38 (1.17, 1.61) 5 2.13 (1.89, 2.41) 6A 12.96 (11.04, 15.21) 7F 4.22 (3.74, 4.77) 19A 14.18 (12.37, 16.25) Children 5 Through 17 Years of Age In a US study 5 (Study 5), a single dose of Prevnar 13 was administered to children 5 through 9 years of age, who were previously vaccinated with at least one dose of Prevnar, and to pneumococcal vaccine-naïve children 10 through 17 years of age. In children 5 through 9 years of age, serotype-specific IgG concentrations measured 1 month after vaccination were noninferior (i.e., the lower limit of the 2-sided 95% CI for the geometric mean ratio [GMR] of >0.5) to the corresponding IgG concentrations in toddlers (Study 3) 1 month after a fourth pneumococcal vaccination (after the 4 th dose of Prevnar for the 7 common serotypes and after the 4 th dose of Prevnar 13 for the 6 additional serotypes) as shown in Tables 22 and 23 respectively. Table 22: Pneumococcal IgG GMCs (µg/mL) One Month After Vaccination for 7 Common Serotypes, Prevnar 13 in Children 5 through 9 Years of Age in Study 5 Relative to Prevnar in Study 3 (Post-toddler) Studies conducted in US NCT00761631 (Study 5) and NCT00444457 (Study 3). , Evaluable Immunogenicity Population. , Noninferiority was declared if the lower limit of the 2-sided 95% CI for geometric mean ratio was greater than 0.5. Vaccine Group (as Enrolled/Randomized) Prevnar 13 5 Through 9 Years (Study 5) Prevnar Post-Toddler Dose (Study 3) Serotype n n = Number of subjects with a determinate antibody concentration for the specified serotype. GMC Geometric mean concentrations (GMCs) were calculated using all subjects with available data for the specified blood draw. GMC after a 4-dose vaccination series with Prevnar (Study 3, post-toddler). (95% CI Confidence intervals (CIs) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the concentrations. ) n GMC (95% CI ) GMC Ratio Ratio of GMCs: Prevnar 13 (Study 5) to Prevnar (Study 3) reference. (95% CI CIs for the ratio are back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures [Prevnar 13 (Study 5) – Prevnar (Study 3)]. ) Common   4 169 8.45 (7.24, 9.87) 173 2.79 (2.45, 3.18) 3.03 (2.48, 3.71)   6B 171 53.56 (45.48, 63.07) 173 9.47 (8.26, 10.86) 5.66 (4.57, 6.99)   9V 171 9.51 (8.38, 10.78) 172 1.97 (1.77, 2.19) 4.83 (4.10, 5.70)   14 169 29.36 (24.78, 34.78) 173 8.19 (7.31, 9.18) 3.58 (2.93, 4.39)   18C 171 8.23 (7.13, 9.51) 173 2.33 (2.05, 2.65) 3.53 (2.91, 4.29)   19F 171 17.58 (14.95, 20.67) 173 3.31 (2.87, 3.81) 5.31 (4.29, 6.58)   23F 169 11.26 (9.79, 12.95) 173 4.49 (3.86, 5.23) 2.51 (2.04, 3.08) Table 23: Pneumococcal IgG GMCs (µg/mL) One Month After Vaccination for Additional 6 Serotypes, Prevnar 13 in Children 5 through 9 Years of Age in Study 5 Relative to Prevnar 13 in Study 3 (Post-toddler) Studies conducted in US NCT00761631 (Study 5) and NCT00444457 (Study 3). , Evaluable Immunogenicity Population. . Noninferiority was declared if the lower limit of the 2-sided 95% CI for geometric mean ratio was greater than 0.5. Vaccine Group (as Enrolled/Randomized) Prevnar 13 5 Through 9 Years (Study 5) Prevnar 13 Post-Toddler Dose (Study 3) Serotype n n = Number of subjects with a determinate antibody concentration for the specified serotype. GMC Geometric mean concentrations (GMCs) were calculated using all subjects with available data for the specified blood draw. GMC after a 4-dose vaccination series with Prevnar 13 (Study 3, post-toddler). (95% CI Confidence intervals (CIs) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the concentrations. ) n GMC (95% CI ) GMC Ratio Ratio of GMCs: Prevnar 13 (Study 5) to Prevnar 13 (Study 3). (95% CI CIs for the ratio are back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures [Prevnar 13 (Study 5) – Prevnar 13 (Study 3)]. )   Additional   1 171 3.57 (3.05, 4.18) 1068 2.90 (2.75, 3.05) 1.23 (1.07, 1.42)   3 171 2.38 (2.07, 2.74) 1065 0.75 (0.72, 0.79) 3.17 (2.78, 3.62)   5 171 5.52 (4.82, 6.32) 1068 2.85 (2.72, 2.98) 1.94 (1.71, 2.20)   6A 169 21.51 (18.15, 25.51) 1063 7.11 (6.78, 7.46) 3.03 (2.64, 3.47)   7F 170 6.24 (5.49, 7.08) 1067 4.39 (4.18, 4.61) 1.42 (1.24, 1.62)   19A 170 17.18 (15.01, 19.67) 1056 8.44 (8.05, 8.86) 2.03 (1.78, 2.32) In children 10 through 17 years of age OPA GMTs, as measured by the mcOPA assay, 1 month after vaccination were noninferior (i.e., the lower limit of the 2-sided 95% CI for the GMR of >0.5) to mcOPA GMTs in the 5 through 9 year old group for 12 of 13 serotypes (except for serotype 3), as shown in Table 24. Table 24: Comparison of Pneumococcal mcOPA GMTs One Month After Vaccination, Prevnar 13, in Children 10 through 17 Years of Age Relative to Prevnar 13 in Children 5 through 9 Years of Age Studies conducted in US NCT00761631 (Study 5). , Evaluable Immunogenicity Population. , Noninferiority was declared if the lower limit of the 2-sided 95% CI for geometric mean ratio was greater than 0.5. , Individual mcOPA antibody assay values below the assay LLOQ (lower limit of quantitation) were set at 0.50*LLOQ for the purpose of calculating the mcOPA antibody GMT. Vaccine Group (as Enrolled) Prevnar 13 (10 through 17 Years) Prevnar 13 (5 through 9 Years) Serotype n n= Number of subjects with a determinate antibody titer for the specified serotype. GMT Geometric mean titers (GMTs) were calculated using all subjects with available data for the specified blood draw. (95% CI Confidence intervals (CIs) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the titers. ) n GMT (95% CI ) GMT Ratio Ratio of GMTs: Prevnar 13(10 through 17 years of age) to Prevnar 13 (5 through 9 years of age). (95% CI CIs for the ratio are back transformations of a confidence interval based on the Student t distribution for the mean difference of the logarithms of the measures [Prevnar 13(10 through 17 years of age) – Prevnar 13(5 through 9 years of age)] Study 5. )   Common   4 188 6912 (6101, 7831) 181 4629 (4017, 5334) 1.5 (1.24, 1.80)   6B 183 14224 (12316, 16427) 178 14996 (13164, 17083) 0.9 (0.78, 1.15)   9V 186 4485 (4001, 5028) 180 4733 (4203, 5328) 0.9 (0.80, 1.12)   14 187 6894 (6028, 7884) 176 4759 (4120, 5497) 1.4 (1.19, 1.76)   18C 182 6263 (5436, 7215) 175 8815 (7738, 10041) 0.7 (0.59, 0.86)   19F 184 2280 (1949, 2668) 178 1591 (1336, 1893) 1.4 (1.14, 1.81)   23F 187 3808 (3355, 4323) 176 3245 (2819, 3736) 1.2 (0.97, 1.42)   Additional   1 189 322 (275, 378) 179 191 (165, 221) 1.7 (1.36, 2.10)   3 181 114 (101, 130) 178 203 (182, 226) 0.6 (0.48, 0.67)   5 183 360 (298, 436) 178 498 (437, 568) 0.7 (0.57, 0.91)   6A 182 9928 (8457, 11655) 178 7514 (6351, 8891) 1.3 (1.05, 1.67)   7F 185 6584 (5829, 7436) 178 10334 (9099, 11737) 0.6 (0.53, 0.76)   19A 187 1276 (1132, 1439) 180 1180 (1048, 1329) 1.1 (0.91, 1.28) Six Phase 3 or Phase 4 clinical trials 6–8,10,11,13 were conducted in the US and Europe evaluating the immunogenicity of Prevnar 13 in different adult age groups, in individuals who were either not previously vaccinated with PPSV23 (PPSV23 unvaccinated) or who had received one dose of PPSV23 (PPSV23 previously vaccinated). Each study included healthy adults and immunocompetent adults with stable underlying conditions including chronic cardiovascular disease, chronic pulmonary disease, renal disorders, diabetes mellitus, chronic liver disease, and medical risk conditions and behaviors (e.g., alcoholism and smoking) that are known to increase the risk of serious pneumococcal pneumonia and invasive pneumococcal disease. A stable medical condition was defined as a medical condition not requiring significant change in therapy (i.e., change to new therapy category due to worsening disease) or hospitalization for worsening disease 6–12 weeks prior to receipt of the study vaccine. Immune responses elicited by Prevnar 13 and PPSV23 were measured by a mcOPA antibody assay for the 13 pneumococcal serotypes contained in Prevnar 13. Serotype-specific mcOPA antibody GMTs measured 1 month after each vaccination were calculated. For the 12 serotypes in common to both vaccines, noninferiority between vaccines was met if the lower limit of the 2-sided 95% confidence interval (CI) of the GMT ratio (Prevnar 13/PPSV23) was greater than 0.5. The response to the additional serotype 6A, which is contained in Prevnar 13 but not in PPSV23, was assessed by demonstration of a ≥4-fold increase in the anti-6A mcOPA antibody titer above preimmunization levels. A statistically significantly greater response for Prevnar 13 was defined, for the difference in percentages (Prevnar 13 minus PPSV23) of adults achieving a ≥4-fold increase in anti-6A mcOPA antibody titer, as the lower limit of the 2-sided 95% CI greater than zero. For comparison of mcOPA antibody GMTs, a statistically greater response for serotype 6A was defined as the lower limit of the 2-sided 95% CI of the GMT ratio (Prevnar 13/PPSV23) greater than 2. Of the 6 Phase 3 or Phase 4 clinical trials, 2 noninferiority trials 6,7 were conducted in which the immune responses to Prevnar 13 were compared with the immune responses to PPSV23; one in PPSV23 unvaccinated adults aged 18 through 64 years 6 (Study 6), and one in PPSV23 previously vaccinated adults aged ≥70 years 7 (Study 7). A third study compared immune responses to a single dose of Prevnar 13 to the response to Prevnar 13 administered one year after a dose of PPSV23 in adults aged 60 through 64 years who were PPSV23 unvaccinated at enrollment 8 (Study 8). The study also compared immune responses of PPSV23 as a single dose to the responses to PPSV23 administered one year after a dose of Prevnar 13. Two studies assessed the concomitant administration of Prevnar 13 with seasonal inactivated Fluarix (IIV3) in the US 10 (Study 10) and Europe 11 (Study 11). One study (Study 13) assessed the concomitant administration of Prevnar 13 with seasonal inactivated Fluzone Quadrivalent (IIV4) in PPSV23 previously vaccinated adults ≥50 years of age in the US. Overall across the clinical studies evaluating the immunogenicity of Prevnar 13 in adults, persons 18 through 64 years of age responded at least as well as persons 65 years and older, the age group evaluated in a clinical endpoint efficacy trial. Clinical Trials Conducted in PPSV23 Unvaccinated Adults In an active-controlled modified Modified double-blind means that the site staff dispensing and administering the vaccine were unblinded, but all other study personnel including the principal investigator and subject were blinded. double-blind clinical trial 6 (Study 6) of Prevnar 13 in the US, PPSV23 unvaccinated adults aged 60 through 64 years were randomly assigned (1:1) to receive Prevnar 13 or PPSV23. In addition, adults aged 18 through 49 years and 50 through 59 years were enrolled and received one dose of Prevnar 13 (open-label). In adults aged 60 through 64 years, the mcOPA antibody GMTs elicited by Prevnar 13 were noninferior to those elicited by PPSV23 for the 12 serotypes in common to both vaccines (see Table 24 ). In addition, the lower limit of the 95% confidence interval for the mcOPA antibody GMT ratio (Prevnar 13/PPSV23) was greater than 1 for 8 of the serotypes in common. For serotype 6A, which is unique to Prevnar 13, the proportion of subjects with a ≥4-fold increase after Prevnar 13 (88.5%) was statistically significantly greater than after PPSV23 (49.3%) in PPSV23-unvaccinated adults aged 60 through 64 years. OPA antibody GMTs for serotype 6A were statistically significantly greater after Prevnar 13 compared with after PPSV23 (see Table 25 ). The mcOPA antibody GMTs elicited by Prevnar 13 in adults aged 50 through 59 years were noninferior to the corresponding mcOPA antibody GMTs elicited by Prevnar 13 in adults aged 60 through 64 years for all 13 serotypes (see Table 25 ). In adults aged 18 through 49 years, the mcOPA antibody GMTs elicited by Prevnar 13 were noninferior to those elicited by Prevnar 13 in adults aged 60 through 64 years for all 13 serotypes (see Table 25 ). Table 25: mcOPA Antibody GMTs in PPSV23-Unvaccinated Adults Aged 18 Through 49 Years or Aged 50 Through 59 Years Given Prevnar 13 and in Adults Aged 60 Through 64 Years Given Prevnar 13 or PPSV23 (Study 6) Study conducted in US NCT00427895 (Study 6). , Noninferiority was defined for the 13 serotypes in adults aged 18 to 49 years, for the 12 common serotypes in adults aged 60 to 64 years and for the 13 serotypes in adults aged 50 to 59 years as the lower limit of the 2-sided 95% CI for GMT ratio greater than 0.5. , mcOPA antibody for the 11 serotypes unique to PPSV23 but not contained in Prevnar 13 were not measured. , Individual mcOPA antibody assay values below the assay LLOQ (lower limit of quantitation) were set at 0.50*LLOQ for the purpose of calculating the mcOPA antibody GMT. , Evaluable Immunogenicity Population. Prevnar 13 Prevnar 13 Prevnar 13 PPSV23 Prevnar 13 18–49 Relative to 60–64 Years Prevnar 13 50–59 Relative to 60–64 Years Prevnar 13 Relative to PPSV23, 60–64 Years For serotype 6A, which is unique to Prevnar 13, a statistically significantly greater response was defined for analysis in cohort 1 as the lower limit of the 2-sided 95% CI for the GMT ratio (Prevnar 13/PPSV23) greater than 2. Serotype 18–49 Years Open label administration of Prevnar 13. N=836–866 50–59 Years N=350–384 60–64 Years N=359–404 60–64 Years N=367–402 GMT GMT GMT GMT GMT Ratio (95% CI) GMT Ratio (95% CI) GMT Ratio (95% CI) GMT, Geometric Mean Titer. 1 353 211 158 119 2.4 (2.03, 2.87) 1.3 (1.07, 1.65) 1.3 (1.07, 1.65) 3 91 94 96 90 1.0 (0.84, 1.13) 1.0 (0.82, 1.18) 1.1 (0.89, 1.29) 4 4747 2904 2164 1405 2.3 (1.92, 2.76) 1.3 (1.06, 1.70) 1.5 (1.18, 2.00) 5 386 322 236 198 1.9 (1.55, 2.42) 1.4 (1.08, 1.74) 1.2 (0.95, 1.50) 6A 6A is a serotype unique to Prevnar 13 but not contained in PPSV23. 5746 4469 2766 343 2.2 (1.84, 2.67) 1.6 (1.28, 2.03) 8.1 (6.11, 10.67) 6B 9813 3350 2212 998 4.9 (4.13, 5.93) 1.5 (1.20, 1.91) 2.2 (1.70, 2.89) 7F 3249 1807 1535 829 2.9 (2.41, 3.49) 1.2 (0.98, 1.41) 1.9 (1.52, 2.26) 9V 3339 2190 1701 1012 2.9 (2.34, 3.52) 1.3 (1.08, 1.53) 1.7 (1.40, 2.02) 14 2983 1078 733 819 4.9 (4.01, 5.93) 1.5 (1.14, 1.89) 0.9 (0.69, 1.16) 18C 3989 2077 1834 1074 2.3 (1.91, 2.79) 1.1 (0.89, 1.44) 1.7 (1.32, 2.21) 19A 1580 968 691 368 2.3 (2.02, 2.66) 1.4 (1.17, 1.68) 1.9 (1.53, 2.30) 19F 1533 697 622 636 3.0 (2.44, 3.60) 1.1 (0.89, 1.41) 1.0 (0.78, 1.23) 23F 1570 531 404 87 4.2 (3.31, 5.31) 1.3 (0.96, 1.80) 4.6 (3.37, 6.38) Clinical Trials Conducted in PPSV23 Previously Vaccinated Adults In a Phase 3 active-controlled, modified double-blind clinical trial 7 (Study 7) of Prevnar 13 in the US and Sweden, PPSV23 previously vaccinated adults aged ≥70 years who had received one dose of PPSV23 ≥5 years prior were randomly assigned (1:1) to receive either Prevnar 13 or PPSV23. The mcOPA antibody GMTs elicited by Prevnar 13 were noninferior to those elicited by PPSV23 for the 12 serotypes in common, when Prevnar 13 or PPSV23 were administered at a minimum of 5 years after a prior dose of PPSV23. In addition, the lower limit of the 95% confidence interval for the mcOPA antibody GMT ratio (Prevnar 13/PPSV23) was greater than 1 for 9 of the serotypes in common. For serotype 6A, which is unique to Prevnar 13, the proportion of subjects with a ≥4-fold increase in mcOPA antibody titers after Prevnar 13 (71.1%) was statistically significantly greater than after PPSV23 (27.3%) in PPSV23 previously vaccinated adults aged ≥70 years. mcOPA antibody GMTs for serotype 6A were statistically significantly greater after Prevnar 13 compared with after PPSV23. This clinical trial demonstrated that in adults aged ≥70 years and previously vaccinated with PPSV23 ≥5 years prior, vaccination with Prevnar 13 elicited noninferior immune responses as compared with re-vaccination with PPSV23 (see Table 26 ). Table 26: mcOPA Antibody GMTs in PPSV23-Previously Vaccinated Adults Aged ≥70 Years Given Prevnar 13 or PPSV23 (Study 7) Study conducted in US and Sweden NCT00546572 (Study 7). , For the 12 common serotypes, noninferiority was defined as the lower limit of the 2-sided 95% CI for GMT ratio (Prevnar 13/PPSV23) greater than 0.5. , For serotype 6A, which is unique to Prevnar 13, a statistically significantly greater response was defined as the lower limit of the 2-sided 95% CI for the GMT ratio (Prevnar 13/PPSV23) greater than 2. , mcOPA antibody for the 11 serotypes unique to PPSV23 but not contained in Prevnar 13 were not measured. , Individual mcOPA antibody assay values below the assay LLOQ (lower limit of quantitation) were set at 0.50*LLOQ for the purpose of calculating the mcOPA antibody GMT. , Evaluable Immunogenicity Population. Serotype Prevnar 13 N=400–426 PPSV23 N=395–445 Prevnar 13 Relative to PPSV23 GMT GMT GMT Ratio (95% CI) GMT, Geometric Mean Titer. 1 93 66 1.4 (1.14, 1.72) 3 59 53 1.1 (0.92, 1.31) 4 613 263 2.3 (1.76, 3.10) 5 100 61 1.6 (1.35, 2.00) 6A 6A is a serotype unique to Prevnar 13 but not contained in PPSV23. 1056 160 6.6 (5.14, 8.49) 6B 1450 565 2.6 (2.00, 3.29) 7F 559 481 1.2 (0.97, 1.39) 9V 622 491 1.3 (1.08, 1.49) 14 355 366 1.0 (0.76, 1.23) 18C 972 573 1.7 (1.33, 2.16) 19A 366 216 1.7 (1.40, 2.07) 19F 422 295 1.4 (1.16, 1.77) 23F 177 53 3.3 (2.49, 4.47) Clinical Trial of Sequential Vaccination of Prevnar 13 and PPSV23 in PPSV23 Unvaccinated Adults In a randomized clinical trial conducted in PPSV23-unvaccinated adults 60 through 64 years of age 8 (Study 8), 223 subjects received PPSV23 followed by Prevnar 13 one year later (PPSV23/Prevnar 13), and 478 received only Prevnar 13. mcOPA antibody titers were measured 1 month after vaccination with Prevnar 13 and are shown in Table 26. mcOPA antibody GMTs in those that received Prevnar 13 one year after PPSV23 were diminished when compared to those who received Prevnar 13 alone. Similarly, in exploratory analyses in PPSV23 previously vaccinated adults ≥70 years of age in Study 7, diminished mcOPA antibody GMTs were observed in those that received Prevnar 13 one year after PPSV23 when compared to those who received Prevnar 13 alone. Table 27: mcOPA Antibody GMTs for the Prevnar 13 Serotypes in PPSV23 Unvaccinated Adults Aged 60 Through 64 Years Given Prevnar 13 Alone or Prevnar 13 One Year After PPSV23 (Study 8) (PPSV23/Prevnar 13) Study conducted in US NCT00574548 (Study 8). , Evaluable Immunogenicity Population. , mcOPA antibody for the 11 serotypes unique to PPSV23 but not contained in Prevnar 13 were not measured. , Individual mcOPA antibody assay values below the assay LLOQ (lower limit of quantitation) were set at 0.50*LLOQ for the purpose of calculating the mcOPA antibody GMT. Prevnar 13 N=410–457 PPSV23/Prevnar 13 N=180–196 Serotype GMT (95% CI) GMT (95% CI) GMT =Geometric Mean Titer. 1 219 (191, 252) 88 (72, 109) 3 78 (69, 88) 54 (45, 65) 4 2590 (2257, 2973) 988 (802, 1218) 5 258 (218, 305) 112 (90, 139) 6A 6A is a serotype unique to Prevnar 13 but not contained in PPSV23. 2947 (2536, 3426) 1210 (962, 1522) 6B 2165 (1845, 2540) 832 (654, 1059) 7F 1518 (1339, 1721) 407 (342, 485) 9V 1279 (1142, 1432) 495 (426, 575) 14 790 (663, 941) 515 (402, 659) 18C 1683 (1437, 1971) 650 (504, 839) 19A 717 (629, 818) 299 (248, 361) 19F 812 (702, 939) 360 (293, 442) 23F 384 (312, 472) 142 (104, 193) Also in Study 8, 266 subjects received Prevnar 13 followed by PPSV23 one year later (Prevnar 13/PPSV23). mcOPA antibody GMTs following PPSV23 administered one year after Prevnar 13 (Prevnar 13/PPSV23) were noninferior to those following a single dose of PPSV23 (N=237) for the 12 common serotypes [the lower limit of the 95% CI for the GMT ratio [Prevnar 13/PPSV23 relative to PPSV23] was >0.5] (see Table 27 ). In Study 6, which was conducted in PPSV23-unvaccinated adults 60 through 64 years of age, 108 subjects received PPSV23 3.5 to 4 years after Prevnar 13 (Prevnar 13/PPSV23) and 414 received a single dose of PPSV23. Higher serotype-specific mcOPA antibody GMT ratios [(Prevnar 13/PPSV23) / PPSV23] were generally observed compared to the one year dosing interval in Study 8. Table 28: mcOPA Antibody GMTs for the Prevnar 13 Serotypes in PPSV23-Unvaccinated Adults Aged 60 Through 64 Years Given PPSV23 One Year After Prevnar 13 Relative to PPSV23 Alone (Study 8) Study conducted in US NCT00574548 (Study 8). , Evaluable Immunogenicity Population. , mcOPA antibody for the 11 serotypes unique to PPSV23 but not contained in Prevnar 13 were not measured. , Individual mcOPA antibody assay values below the assay LLOQ (lower limit of quantitation) were set at 0.50*LLOQ for the purpose of calculating the mcOPA antibody GMT. Prevnar 13/PPSV23 N=216–233 PPSV23 N=214–229 GMT Ratio (Prevnar 13/PPSV23) / PPSV23 Serotype GMT 95% CI GMT 95% CI Ratio 95% CI GMT =Geometric Mean Titer. 1 155 (131, 182) 161 (131, 198) 1.0 (0.74, 1.25) 3 127 (111, 145) 83 (71, 98) 1.5 (1.23, 1.87) 4 1409 (1202, 1651) 1468 (1139, 1893) 1.0 (0.71, 1.29) 5 220 (184, 264) 178 (144, 222) 1.2 (0.93, 1.64) 6A 6A is a serotype unique to Prevnar 13 but not contained in PPSV23. Anti-6A mcOPA antibody GMTs were descriptive in nature. 1366 (1122, 1663) 400 (306, 524) 3.4 (2.45, 4.77) 6B 1345 (1113, 1625) 875 (689, 1111) 1.5 (1.14, 2.08) 7F 748 (653, 857) 719 (598, 865) 1.0 (0.83, 1.31) 9V 848 (731, 984) 824 (694, 977) 1.0 (0.82, 1.29) 14 711 (580, 872) 869 (677, 1115) 0.8 (0.59, 1.13) 18C 1115 (925, 1344) 912 (707, 1177) 1.2 (0.89, 1.67) 19A 471 (408, 543) 390 (318, 477) 1.2 (0.94, 1.55) 19F 819 (697, 963) 626 (504, 779) 1.3 (1.00, 1.71) 23F 216 (169, 277) 84 (62, 114) 2.6 (1.74, 3.79) Infants and Toddlers The concomitant administration of routine US infant vaccines [see Drug Interactions (7.1) ] with Prevnar 13 was evaluated in two studies: Study 2 [see Clinical Studies (14.2) ] , Pneumococcal Immune Responses Following Three Doses 2 , and the US lot consistency study 3 (Study 3). In Study 3, subjects were randomly assigned to receive one of 3 lots of Prevnar 13 or Prevnar in a 2:2:2:1 ratio. The total number of infants vaccinated was 663 2 (Study 2) and 1699 3 (Study 3). Immune responses to concomitant vaccine antigens were compared in infants receiving Prevnar and Prevnar 13. Responses to diphtheria toxoid, tetanus toxoid, pertussis, polio types 1, 2, and 3, hepatitis B, PRP-T, PRP-OMP, measles, and varicella antigens in Prevnar 13 recipients were similar to those in Prevnar recipients. Based on limited data, responses to mumps and rubella antigens in Prevnar 13 recipients were similar to those in Prevnar recipients. Adults ≥50 Years of Age Concomitant Administration with QIV Prevnar 13 was administered to PPSV23 previously vaccinated adults ≥50 years of age concomitantly with a US-licensed inactivated influenza vaccine, quadrivalent (IIV4) (Fluzone Quadrivalent) for the 2014/2015 influenza season (Study 13) [see Adverse Reactions (6.2) and Drug Interactions (7.1) ] . One study group received Prevnar 13 and IIV4 concurrently, followed approximately one month later by placebo. A second study group received IIV4 and placebo concurrently, followed approximately one month later by Prevnar 13. Serotype-specific pneumococcal antibody responses were measured one month after Prevnar 13 vaccination as OPA GMTs. Noninferiority was demonstrated for each pneumococcal serotype if the lower limit of the 2-sided 95% CI for the GMT ratio (Prevnar 13 + IIV4 relative to Prevnar 13 alone) was >0.5. Although OPA antibody responses to Prevnar 13 generally appeared to be slightly lower when Prevnar 13 was administered concomitantly with IIV4 compared to Prevnar 13 administered alone, noninferiority was demonstrated for all Prevnar 13 pneumococcal serotypes evaluated in Study 13. Strain-specific influenza antibody responses were measured one month after IIV4 as hemagglutinin inhibition assay (HAI) titers. HAI GMTs were evaluated for each IIV4 strain in Study 13. Noninferiority was demonstrated if the lower limit of the 2-sided 95% CI for the HAI GMT ratio (Prevnar 13 + IIV4 relative to IIV4 + Placebo) was >0.5. Noninferiority was demonstrated for each IIV4 vaccine strain evaluated in Study 13. Concomitant Administration with TIV Two randomized, double-blind clinical trials evaluated the immunogenicity of Prevnar 13 given with IIV3 (Fall 2007/ Spring 2008 Fluarix, A/H1N1, A/H3N2, and B strains) in PPSV23 unvaccinated adults aged 50 through 59 years 10 (Study 10, conducted in the US) and in adults ≥65 years 11 (Study 11, conducted in Europe). Based on analysis of the primary pre-specified comparison of serotype specific anti-capsular polysaccharide IgG GMCs, noninferiority was met for all serotypes in adults 50–59 years of age and for 12 of 13 serotypes in adults ≥65years of age.

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