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).

Table 16: Percentage of Subjects With Anti-capsular Antibody Concentration ≥0.35 µg/mL One Month After a Three Dose Series Administered at 2, 4 and 6 Months of Age, Study 2*^, †^, ‡^, §

Serotype	Prevnar 13 N=249–252 (95% CI)	Prevnar N=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.

Table 17: Pneumococcal dOPA Antibody Geometric Mean Titers One Month After a Three Dose Series Administered at 2, 4 and 6 Months of Age, Study 2*^, †^, ‡

Serotype	Prevnar 13 N=91–94 (95% CI)	Prevnar N=89–94 (95% CI)
* Studies conducted in US NCT00373958 (Study 2). † The dOPA (opsonophagocytic activity) antibody assay measures the ability of immune sera, in conjunction with complement, to mediate the uptake and killing of S. pneumoniae by phagocytic cells. ‡ Evaluable Immunogenicity Population.
Prevnar Serotypes
4	359 (276, 468)	536 (421, 681)
6B	1055 (817, 1361)	1514 (1207, 1899)
9V	4035 (2933, 5553)	3259 (2288, 4641)
14	1240 (935, 1646)	1481 (1133, 1934)
18C	276 (210, 361)	376 (292, 484)
19F	54 (40, 74)	45 (34, 60)
23F	791 (605, 1034)	924 (709, 1204)
Additional Serotypes
1	52 (39, 69)	4 (4, 5)
3	121 (92, 158)	7 (5, 9)
5	91 (67, 123)	4 (4, 4)
6A	980 (783, 1226)	100 (66, 152)
7F	9494 (7339, 12281)	128 (80, 206)
19A	152 (105, 220)	7 (5, 9)

Pneumococcal Immune Responses Following Four Doses

In Study 2, post-dose 4 antibody concentrations were higher for all 13 serotypes than those achieved after the third dose. The noninferiority criterion for pneumococcal anti-capsular polysaccharide GMCs after 4 doses was met for 12 of the 13 pneumococcal serotypes. The noninferiority criterion was not met for the response to serotype 3 (Table 18).

Table 18: Pneumococcal IgG GMCs (µg/mL) One Month After a Four Dose Series Administered at 2, 4, 6 and 12–15 Months, Study 2*^, †^, ‡^, §

Serotype	Prevnar 13 N=232–236 (95% CI)	Prevnar N=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).

Table 19: Pneumococcal dOPA Antibody Geometric Mean Titers One Month After the Fourth Dose-Evaluable Toddler Immunogenicity Population, Study 2*^, †

Serotype	Prevnar 13 N=88–92 (95% CI)	Prevnar N=92–96 (95% CI)
* Studies conducted in US NCT00373958 (Study 2). † The dOPA (opsonophagocytic activity) antibody assay measures the ability of immune sera, in conjunction with complement, to mediate the uptake and killing of S. pneumoniae by phagocytic cells.
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 6^th birthday) who were naïve to pneumococcal conjugate vaccine, were given 3, 2 or 1 dose of Prevnar 13 respectively, according to the age-appropriate schedules in Table 2. Serum IgG concentrations were measured one month after the final dose in each age group and the data are shown in Table 20.

Table 20: Pneumococcal Anti-capsular Polysaccharide IgG Antibody Geometric Mean Concentrations (μg/mL) One Month After the Final Prevnar 13 Catch-Up Dose in Pneumococcal Vaccine Naïve Children 7 Months Through 5 Years of Age by Age Group, Study 4*^, †

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).
* Studies conducted in Poland NCT00452452 (Study 4). † Open label administration of Prevnar 13.
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.

Table 21: Pneumococcal Anti-capsular Polysaccharide IgG Antibody Geometric Mean Concentrations (μg/mL) One Month After One Prevnar 13 Catch-Up Dose in Children 24 Through 59 Months of Age With 3 or 4 Prior Doses of Prevnar, US Catch-Up Study 5*^, †

Serotype	1 dose Prevnar 13 24 months through 59 months N=173–175 (95% CI)
* Studies conducted in US NCT00761631 (Study 5). † Open label administration of Prevnar 13.
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 4^th dose of Prevnar for the 7 common serotypes and after the 4^th dose of Prevnar 13 for the 6 additional serotypes) as shown in Tables 22 and 23 respectively.

Table 22: Pneumococcal IgG GMCs (µg/mL) One Month After Vaccination for 7 Common Serotypes, Prevnar 13 in Children 5 through 9 Years of Age in Study 5 Relative to Prevnar in Study 3 (Post-toddler)*^, †^, ‡

	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 )
* 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)

Table 23: Pneumococcal IgG GMCs (µg/mL) One Month After Vaccination for Additional 6 Serotypes, Prevnar 13 in Children 5 through 9 Years of Age in Study 5 Relative to Prevnar 13 in Study 3 (Post-toddler)*^, †^. ‡

	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 )
* 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.

Table 24: Comparison of Pneumococcal mcOPA GMTs One Month After Vaccination, Prevnar 13, in Children 10 through 17 Years of Age Relative to Prevnar 13 in Children 5 through 9 Years of Age *^, †^, ‡^, §

	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)