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 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) |
|
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) |
|
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) |
| |
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) |
| |
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 |
| 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 Ratio Þ | (95% CI ß ) |
| ||||||||
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 Ratio Þ | (95% CI ß ) |
| ||||||||
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 ) |
| ||||||||
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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