# Vaccine Information: PREVNAR 13 (Page 5 of 8)

### 14.2 Prevnar 13 Clinical Trials in Children 6 Weeks Through 17 Years of Age

**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).

Serotype | Prevnar 13N=249–252(95% CI) | PrevnarN=250–252(95% CI) | Difference in % responders(95% CI) |
---|---|---|---|

- *
- 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.
- ¶
- 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).
| |||

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 13N=91–94(95% CI) | PrevnarN=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 13N=232–236(95% CI) | PrevnarN=222–223(95% CI) | GMC Ratio(95% CI) |
---|---|---|---|

- *
- 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.
- ¶
- 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).
| |||

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 13N=88–92(95% CI) | PrevnarN=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.

Serotype | 3 doses Prevnar 137 through 11 months N=83–84(95% CI) | 2 doses Prevnar 1312 through 23 monthsN=104–110(95% CI) | 1 dose Prevnar 1324 months through 5 yearsN=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.

Serotype | 1 dose Prevnar 1324 months through 59 monthsN=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.

Vaccine Group (as Enrolled/Randomized) | ||||||||
---|---|---|---|---|---|---|---|---|

Prevnar 135 Through 9 Years(Study 5) | PrevnarPost-Toddler Dose(Study 3) | |||||||

Serotype | n § | GMC ¶ | (95% CI #) | n § | GMC ¶ | (95% CI #) | GMC Ratio Þ | (95% CI ß) |

- *
- 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.
- §
- n = Number of subjects with a determinate antibody concentration for the specified serotype.
- ¶
- 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).
- #
- Confidence intervals (CIs) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the concentrations.
- Þ
- Ratio of GMCs: Prevnar 13 (Study 5) to Prevnar (Study 3) reference.
- ß
- 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) |

Vaccine Group (as Enrolled/Randomized) | ||||||||
---|---|---|---|---|---|---|---|---|

Prevnar 135 Through 9 Years(Study 5) | Prevnar 13Post-Toddler Dose(Study 3) | |||||||

Serotype | n § | GMC ¶ | (95% CI #) | n § | GMC ¶ | (95% CI #) | GMCRatio Þ | (95% CI ß) |

- *
- 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.
- §
- n = Number of subjects with a determinate antibody concentration for the specified serotype.
- ¶
- 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).
- #
- Confidence intervals (CIs) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the concentrations.
- Þ
- Ratio of GMCs: Prevnar 13 (Study 5) to Prevnar 13 (Study 3).
- ß
- 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.

Vaccine Group (as Enrolled) | ||||||||
---|---|---|---|---|---|---|---|---|

Prevnar 13(10 through 17 Years) | Prevnar 13(5 through 9 Years) | |||||||

Serotype | n ¶ | GMT # | (95% CI Þ) | n ¶ | GMT # | (95% CI Þ) | GMT Ratio ß | (95% CI à) |

- *
- 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.
- ¶
- n= Number of subjects with a determinate antibody titer for the specified serotype.
- #
- Geometric mean titers (GMTs) were calculated using all subjects with available data for the specified blood draw.
- Þ
- Confidence intervals (CIs) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the titers.
- ß
- Ratio of GMTs: Prevnar 13(10 through 17 years of age) to Prevnar 13 (5 through 9 years of age).
- à
- 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) |

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