PREVNAR 13 Rx

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. 

• The approval was based on a randomized, double-blind clinical trial in a multiethnic population at Northern California Kaiser Permanente (NCKP) from October 1995 through August 20, 1998, which included 37,816 infants who were randomly assigned 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. 

• 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)

2 clinical trials evaluated the efficacy of Prevnar against otitis media: (1) the Finnish Otitis Media (FinOM trial) and (2) the Northern California Kaiser Permanente (NCKP) efficacy trial.

Finnish Otitis Media (FinOM trial)

• The randomized, double-blind trial included 1662 infants who were randomly assigned equally 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. The study was conducted between December 1995 and March 1999 and included children who had respiratory infections or symptoms suggesting acute otitis media (AOM). The primary endpoint was efficacy against AOM episodes caused by vaccine serotypes 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. 

NCKP trial

• The efficacy of Prevnar against otitis media was evaluated from October 1995 through April 1998 and included 34,146 infants who were randomly assigned to receive either Prevnar or the control vaccine at 2, 4, 6, and 12–15 months of age. The primary otitis media endpoint was efficacy against all otitis media episodes regardless of etiology in the per-protocol population.

• The 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. 

• There was also 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

• In a randomized, double-blind, placebo-controlled study conducted over approximately 4 years in the Netherlands, the efficacy of Prevnar 13 was evaluated against vaccine-type (VT) pneumococcal community-acquired pneumonia (CAP) and IPD in 84,496 patients 65 years of age and older. Patients were randomly assigned 1:1 to receive a single dose of either Prevnar 13 or 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).

• 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.

• The VE was 45.6% against the first case of confirmed VT pneumococcal CAP (primary endpoint).

• The VE was 45% against the first episode of confirmed NB/NI VT pneumococcal CAP (secondary endpoint).

• The VE was 75% against the first episode of VT-IPD (secondary endpoint).

Infants and Children 6 Weeks Through 17 Months of Age

• Comparative studies evaluated the efficacy of Prevnar 13 against invasive pneumococcal disease to a US-licensed 7-valent pneumococcal conjugate vaccine (Prevnar). Patients received a 2, 4, 6, and 12–15 month schedule.

• US Noninferiority Study (Study 2)

• The randomized, double-blind, active-controlled trial included 2-month old infants who were randomly assigned 1:1 to receive either Prevnar 13 or Prevnar.

• Coprimary 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. 

• Following 3 doses, the noninferiority criterion for the proportion of subjects with pneumococcal anti-capsular polysaccharide IgG antibody concentrations ≥0.35 μg/mL was met for 10 of the 13 serotypes. The exceptions were serotypes 6B, 9V, and 3.

• Following 4 doses, the 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.

Previously Unvaccinated Older Infants and Children 7 Months Through 5 Years of Age

• In an open-label descriptive study of Prevnar 13 in Poland (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 6th birthday) who were naïve to pneumococcal conjugate vaccine, were given 3, 2 or 1 dose of Prevnar 13 respectively.

• Serum IgG concentrations were measured one month after the final dose in each age group (see full labeling for data in Table 20).

Children 15 Months Through 59 Months of Age Previously Vaccinated with Prevnar

• In an open-label descriptive study in the US (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). 

• See full labeling for data following one dose of Prevnar 13 in children 24 months through 59 months of age (Table 21).

Children 5 Through 17 Years of Age

• In a US study (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 4th dose of Prevnar for the 7 common serotypes and after the 4th dose of Prevnar 13 for the 6 additional serotypes). See full labeling for data in Tables 22 and 23.

• 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). See full labeling for data in Tables 24.

Prevnar 13 Immunogenicity Clinical Trials in Adults

• Six phase 3 or phase 4 clinical trials 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. 

• Serotype-specific mcOPA antibody GMTs measured 1 month after each vaccination were calculated. The noninferiority criterion was met for the 12 serotypes in common to both vaccines, if the lower limit of the 2-sided 95% 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. 

• Prevnar 13 achieved a statistically significantly greater response 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.

• 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 double-blind clinical trial (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 noninferiority criterion was met for the mcOPA antibody GMTs elicited by Prevnar 13 to those elicited by PPSV23 for the 12 serotypes in common to both vaccines. The lower limit of the 95% CI 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.

• 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.

• 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. 

Clinical Trials Conducted in PPSV23 Previously Vaccinated Adults

• In a Phase 3 active-controlled, modified double-blind clinical trial (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.

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 (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.

• 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]. 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.

Concomitant Vaccine Administration

• Infants and Toddlers

• The concomitant administration of routine US infant vaccines with Prevnar 13 was evaluated in two studies: Study 2, Pneumococcal Immune Responses Following Three Doses, and the US lot consistency study (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. 

• 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

• 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). 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.

• 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.

• 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: Noninferiority was met for all serotypes in adults 50–59 years of age and for 12 of 13 serotypes in adults ≥65years of age.