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 Netherlands12 (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).
| 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 study2 (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).
| 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¶ | |||
| 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.
| 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).
| 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¶ | |||
| 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).
| 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 Poland4 (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, 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.
| 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 US5 (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.
| 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 study5 (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) as shown in Tables 22 and 23 respectively.
| Vaccine Group (as Enrolled/Randomized) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Prevnar 13 5 Through 9 Years (Study 5) | Prevnar Post-Toddler Dose (Study 3) | |||||||
| Serotype | n§ | GMC¶ | (95% CI#) | n§ | GMC¶ | (95% CI#) | GMC RatioÞ | (95% CIß) |
| ||||||||
| 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) |
| Vaccine Group (as Enrolled/Randomized) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Prevnar 13 5 Through 9 Years (Study 5) | Prevnar 13 Post-Toddler Dose (Study 3) | |||||||
| Serotype | n§ | GMC¶ | (95% CI#) | n§ | GMC¶ | (95% CI#) | GMC RatioÞ | (95% CIß) |
| ||||||||
| 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.
| Vaccine Group (as Enrolled) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Prevnar 13 (10 through 17 Years) | Prevnar 13 (5 through 9 Years) | |||||||
| Serotype | n¶ | GMT# | (95% CIÞ) | n¶ | GMT# | (95% CIÞ) | GMT Ratioß | (95% CIà) |
| ||||||||
| 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 trials6–8,10,11,13 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 trials6,7 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 years6 (Study 6), and one in PPSV23 previously vaccinated adults aged ≥70 years7 (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 enrollment8 (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 US10 (Study 10) and Europe11 (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 modified1 double-blind clinical trial6 (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).
| 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# | |
|---|---|---|---|---|---|---|---|
| Serotype | 18–49 YearsÞ N=836–866 | 50–59 YearsÞ 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) |
| 6Aß | 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 trial7 (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).
| 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) |
| 6AÞ | 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 age8 (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.
| 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¶ | 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.
| 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¶ | 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 Doses2, and the US lot consistency study3 (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 6632 (Study 2) and 16993 (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 years10 (Study 10, conducted in the US) and in adults ≥65 years11 (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.
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 Netherlands12 (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).
| 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 study2 (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).
| 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¶ | |||
| 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.
| 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).
| 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¶ | |||
| 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).
| 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 Poland4 (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, 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.
| 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 US5 (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.
| 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 study5 (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) as shown in Tables 22 and 23 respectively.
| Vaccine Group (as Enrolled/Randomized) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Prevnar 13 5 Through 9 Years (Study 5) | Prevnar Post-Toddler Dose (Study 3) | |||||||
| Serotype | n§ | GMC¶ | (95% CI#) | n§ | GMC¶ | (95% CI#) | GMC RatioÞ | (95% CIß) |
| ||||||||
| 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) |
| Vaccine Group (as Enrolled/Randomized) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Prevnar 13 5 Through 9 Years (Study 5) | Prevnar 13 Post-Toddler Dose (Study 3) | |||||||
| Serotype | n§ | GMC¶ | (95% CI#) | n§ | GMC¶ | (95% CI#) | GMC RatioÞ | (95% CIß) |
| ||||||||
| 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.
| Vaccine Group (as Enrolled) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Prevnar 13 (10 through 17 Years) | Prevnar 13 (5 through 9 Years) | |||||||
| Serotype | n¶ | GMT# | (95% CIÞ) | n¶ | GMT# | (95% CIÞ) | GMT Ratioß | (95% CIà) |
| ||||||||
| 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 trials6–8,10,11,13 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 trials6,7 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 years6 (Study 6), and one in PPSV23 previously vaccinated adults aged ≥70 years7 (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 enrollment8 (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 US10 (Study 10) and Europe11 (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 modified1 double-blind clinical trial6 (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).
| 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# | |
|---|---|---|---|---|---|---|---|
| Serotype | 18–49 YearsÞ N=836–866 | 50–59 YearsÞ 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) |
| 6Aß | 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 trial7 (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).
| 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) |
| 6AÞ | 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 age8 (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.
| 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¶ | 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.
| 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¶ | 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 Doses2, and the US lot consistency study3 (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 6632 (Study 2) and 16993 (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 years10 (Study 10, conducted in the US) and in adults ≥65 years11 (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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