Vaccine Information: Prevnar 20 (Page 4 of 6)

14.2 Prevnar 20 Clinical Trials in Individuals 6 Weeks Through 15 Months of Age

Immunogenicity of Prevnar 20 in Individuals 6 Weeks Through 15 Months of Age

Prevnar 20 effectiveness against invasive pneumococcal disease in individuals 6 weeks through 15 months of age was demonstrated based on comparisons of serotype-specific antibody responses at 1 month after Dose 3 and 1 month after Dose 4 of Prevnar 20 to the antibody responses after vaccination with Prevnar 13.

Antibody responses elicited by Prevnar 20 and Prevnar 13 in these age groups were measured using a serotype-specific multiplex direct-binding Luminex® immunoassay (dLIA), designed to determine the concentration of serotype-specific polysaccharide-binding IgG antibodies, and OPA assays to measure serotype-specific functional OPA titers for the 20 pneumococcal serotypes of Prevnar 20. A serotype-specific IgG antibody concentration corresponding to ≥0.35 µg/mL using the World Health Organization (WHO) enzyme linked immunosorbent assay (ELISA) has been used as the threshold value for the clinical evaluation of pneumococcal conjugate vaccines when measured one month after Dose 3 of the 4-dose immunization series. The dLIA, used to measure the IgG antibody concentration, was bridged to the WHO ELISA to establish dLIA specific threshold values for each vaccine serotype that correspond to the established ≥0.35 µg/mL WHO ELISA threshold value.

In Study 8, a multicenter, randomized, active-controlled, double-blind trial, participants were randomized in a 1:1 ratio to receive Prevnar 20 (N=1004) or Prevnar 13 (N=993) in a 4-dose schedule; vaccine was administered at 2, 4, 6, and 12 through 15 months of age. Pediarix and Hiberix were administered concomitantly with each of the 3 infant doses. M-M-R II and VARIVAX were administered with the fourth dose [see Adverse Reactions (6.1) and Clinical Studies (14.3)].

Study 8 assessed serotype-specific IgG response rates, IgG geometric mean concentrations (GMCs) and OPA GMTs measured at one month after Dose 3 and one month after Dose 4 for all 20 serotypes contained in Prevnar 20. For each of the 13 matched serotypes, IgG response in the Prevnar 20 group were compared with the corresponding response in the Prevnar 13 group. For the 7 additional serotypes (serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F), IgG response in the Prevnar 20 group were compared with the lowest response among the 13 matched vaccine serotypes excluding serotype 3 in the Prevnar 13 group.

Pneumococcal IgG Antibody Responses Following 3 Doses of Prevnar 20

IgG antibody responses following Prevnar 20 were noninferior to those following Prevnar 13 for 8 of the 13 matched serotypes and 6 of the 7 additional serotypes, as assessed by the percentage of participants meeting the predefined serotype-specific IgG concentration one month after Dose 3, using a 10% noninferiority criterion (the lower bound of the 2-sided 95% CI for the difference in percentages [Prevnar 20 minus Prevnar 13] greater than -10%). Five of the 13 matched serotypes (serotypes 1, 3, 4, 9V and 23F) did not meet the pre-specified noninferiority criterion, as the lower bounds of the 2-sided 95% CIs for the difference in percentages (Prevnar 20 minus Prevnar 13) were -12.1%, -20.1%, -12.0%, -11.3%, and -11.4% respectively. One additional serotype (serotype 12F) also did not meet the NI criterion when compared to serotype 23F (the Prevnar 13 serotype with the lowest percentage excluding serotype 3) in the Prevnar 13 group, the lower bound of the 2-sided 95% CI for the difference in percentage (Prevnar 20 minus lowest Prevnar 13) was -41.6% (Table 9).

Additional IgG GMC data at one month after Dose 3 and OPA data at one month after Dose 3, presented in Tables 10 and 12 respectively, support the effectiveness of Prevnar 20 for each of the 6 serotypes that failed to meet the pre-specified non-inferiority criterion.

Table 9. Percentage of Participants Meeting Predefined Serotype-Specific Pneumococcal IgG Concentrations One Month After Dose 3 in Participants Vaccinated at 2, 4, and 6 Months of Age – Study 8*
Abbreviation: IgG = immunoglobulin G.
Note: The predefined IgG concentration was ≥0.35 µg/mL for all serotypes except for serotypes 5, 6B, 12F, and 19A which were ≥0.23 µg/mL, ≥0.10 µg/mL, ≥0.69 µg/mL and ≥0.12 µg/mL respectively.
*
Study 8 was conducted in the United States and the territory of Puerto Rico (NCT04382326).
N = number of participants with valid assay results. These values are the denominators for the corresponding percentage calculations.
Exact 2-sided CI, based on the Clopper and Pearson method.
§
Noninferiority for a serotype was met if the lower bound of the 2-sided CI for the percentage difference (Prevnar 20 minus Prevnar 13) >-10% (10% NI criterion) for that serotype.
2-Sided CI based on the Miettinen and Nurminen method for the difference in proportions, expressed as a percentage.
#
For the 7 additional serotypes, the percentage of participants with the predefined IgG concentration to serotype 23F (Prevnar 13 serotype with the lowest percentage, excluding serotype 3) in the Prevnar 13 group was used in the calculation of the percentage difference.
Þ
For the 7 additional serotypes, percentages of participants with predefined IgG concentrations to serotypes 8, 10A, 11A, 12F, 15B, 22F and 33F in the Prevnar 13 group were 1.6%, 1.2%, 1.5%, 0.1%, 2.6%, 0.9% and 1.1%, respectively.

Prevnar 20

N =831-833

Prevnar 13

N =801-802

Prevnar 20 minus Prevnar 13

% (95% CI )

% (95% CI )

Percentage Difference § (95% CI § , )

Serotypes

1

79.8 (76.9, 82.5)

88.4 (86.0, 90.5)

-8.6 (-12.1, -5.1)

3

52.1 (48.6, 55.5)

67.6 (64.2, 70.8)

-15.5 (-20.1, -10.8)

4

79.7 (76.8, 82.4)

88.2 (85.7, 90.3)

-8.4 (-12.0, -4.9)

5

82.5 (79.7, 85.0)

86.8 (84.2, 89.1)

-4.3 (-7.8, -0.8)

6A

93.5 (91.6, 95.1)

95.9 (94.3, 97.2)

-2.4 (-4.6, -0.2)

6B

88.3 (85.9, 90.4)

92.4 (90.3, 94.1)

-4.1 (-7.0, -1.2)

7F

96.6 (95.2, 97.8)

97.6 (96.3, 98.6)

-1.0 (-2.7, 0.7)

9V

81.9 (79.1, 84.4)

89.8 (87.5, 91.8)

-7.9 (-11.3, -4.6)

14

93.4 (91.5, 95.0)

94.1 (92.3, 95.7)

-0.8 (-3.1, 1.6)

18C

92.6 (90.6, 94.2)

93.1 (91.2, 94.8)

-0.6 (-3.1, 1.9)

19A

97.1 (95.7, 98.1)

98.1 (96.9, 98.9)

-1.0 (-2.6, 0.5)

19F

96.9 (95.5, 98.0)

96.6 (95.1, 97.8)

0.2 (-1.5, 2.0)

23F

77.9 (74.9, 80.7)

85.5 (82.9, 87.9)

-7.6 (-11.4, -3.9)

Additional Serotypes #

8

96.8 (95.3, 97.9)

# Þ

11.2 (8.6, 14.0)

10A

82.2 (79.5, 84.8)

# Þ

-3.3 (-6.9, 0.3)

11A

92.7 (90.7, 94.4)

# Þ

7.1 (4.2, 10.2)

12F

48.0 (44.6, 51.5)

# Þ

-37.5 (-41.6, -33.3)

15B

98.2 (97.0, 99.0)

# Þ

12.7 (10.2, 15.4)

22F

98.3 (97.2, 99.1)

# Þ

12.8 (10.3, 15.5)

33F

86.7 (84.2, 88.9)

# Þ

1.1 (-2.2, 4.5)

At 1 month after Dose 3, IgG GMCs in the Prevnar 20 group were noninferior to the corresponding IgG GMCs in the Prevnar 13 group for all 20 vaccine serotypes, including the 6 serotypes that missed the noninferiority criterion based on the percentage of participants meeting pre-defined IgG concentrations at one month after Dose 3. For each of the 13 matched serotypes, IgG GMCs in the Prevnar 20 group were noninferior to the corresponding IgG GMCs in the Prevnar 13 group. For each of the 7 additional serotypes, IgG GMCs in the Prevnar 20 group were noninferior to the IgG GMC for serotype 19A (the lowest result among the 13 matched vaccine serotypes excluding serotype 3) in the Prevnar 13 group (Table 10).

Table 10. Serotype-Specific Pneumococcal IgG GMCs (µg/mL) and GMC Ratios One Month After Dose 3 in Participants Vaccinated at 2, 4, 6 and 12 through 15 Months of Age – Study 8*
Abbreviations: GMC = geometric mean concentration; IgG = immunoglobulin G; LLOQ = lower limit of quantitation.
Note: Assay results below the LLOQ were set to 0.5 × LLOQ in the analysis.
*
Study 8 was conducted in the United States and the territory of Puerto Rico (NCT04382326).
N = Number of participants with valid IgG concentrations.
GMCs and 2-sided CIs were calculated by exponentiating the mean logarithm of the concentrations and the corresponding CIs (based on the Student t distribution).
§
Noninferiority for a serotype was met if the lower bound of the 2-sided CI of IgG GMC ratio (Prevnar 20/Prevnar 13) >0.5 (2-fold NI criterion) for that serotype.
2-Sided CIs were calculated by exponentiating the mean differences of the logarithms of the IgG concentrations (Prevnar 20 minus Prevnar 13) and the corresponding CIs (based on the Student t distribution).
#
For the 7 additional serotypes, the IgG GMC to serotype 19A (Prevnar 13 serotype with the lowest IgG GMC, excluding serotype 3) in the Prevnar 13 group was used in the calculation of the GMC ratio.
Þ
For the 7 additional serotypes, the IgG GMCs to serotypes 8, 10A, 11A, 12F, 15B, 22F and 33F in the Prevnar 13 group were 0.02 µg/mL, 0.01 µg/mL, 0.02 µg/mL, 0.01 µg/mL, 0.03 µg/mL, 0.01 µg/mL and 0.02 µg/mL, respectively.

Pneumococcal Serotype

Prevnar 20

N =831-833

Prevnar 13

N =801-802

Prevnar 20/Prevnar 13

GMC (95% CI )

GMC (95% CI )

GMC Ratio § (95% CI § )

Serotype

1

0.74 (0.70, 0.79)

1.14 (1.06, 1.22)

0.65 (0.59, 0.72)

3

0.36 (0.33, 0.38)

0.51 (0.48, 0.55)

0.70 (0.64, 0.76)

4

0.75 (0.70, 0.81)

1.08 (1.00, 1.17)

0.70 (0.63, 0.78)

5

0.66 (0.61, 0.71)

0.96 (0.88, 1.04)

0.69 (0.61, 0.77)

6A

1.95 (1.81, 2.10)

2.69 (2.48, 2.92)

0.72 (0.65, 0.81)

6B

0.61 (0.55, 0.68)

1.02 (0.91, 1.14)

0.60 (0.51, 0.70)

7F

1.71 (1.62, 1.81)

2.29 (2.16, 2.43)

0.75 (0.69, 0.81)

9V

0.87 (0.81, 0.93)

1.21 (1.12, 1.30)

0.72 (0.65, 0.80)

14

2.16 (2.01, 2.33)

2.72 (2.51, 2.95)

0.79 (0.71, 0.89)

18C

1.31 (1.23, 1.39)

1.71 (1.59, 1.84)

0.77 (0.70, 0.84)

19A

0.72 (0.67, 0.76)

0.91 (0.85, 0.97)

0.79 (0.72, 0.86)

19F

1.59 (1.50, 1.67)

2.00 (1.88, 2.12)

0.79 (0.73, 0.86)

23F

0.82 (0.75, 0.90)

1.25 (1.14, 1.37)

0.66 (0.58, 0.75)

Additional Serotypes #

8

1.80 (1.70, 1.91)

# Þ

1.98 (1.81, 2.16)

10A

1.21 (1.09, 1.33)

# Þ

1.32 (1.18, 1.49)

11A

1.39 (1.30, 1.48)

# Þ

1.52 (1.39, 1.67)

12F

0.55 (0.50, 0.60)

# Þ

0.60 (0.54, 0.67)

15B

4.40 (4.11, 4.71)

# Þ

4.82 (4.39, 5.30)

22F

3.71 (3.45, 3.99)

# Þ

4.06 (3.68, 4.48)

33F

1.49 (1.36, 1.64)

# Þ

1.64 (1.46, 1.83)

Pneumococcal IgG Antibody Responses Following 4 Doses of Prevnar 20

For each of the 13 matched serotypes, IgG GMCs in the Prevnar 20 group were noninferior to the corresponding IgG GMCs in the Prevnar 13 group. For each of the 7 additional serotypes, IgG GMCs in the Prevnar 20 group were noninferior to the IgG GMC for serotype 1 (the lowest result among the 13 matched vaccine serotypes excluding serotype 3) in the Prevnar 13 group (Table 11).

Table 11. Serotype-Specific Pneumococcal IgG GMCs (µg/mL) and GMC Ratios One Month After Dose 4 in Participants Vaccinated at 2, 4, 6 and 12 through 15 Months of Age – Study 8*
Prevnar 20 N =753-755 Prevnar 13 N =744-745 Prevnar 20/Prevnar 13
GMC (95% CI ) GMC (95% CI ) GMC Ratio § (95% CI § )
Abbreviations: GMC = geometric mean concentration; IgG = immunoglobulin G; LLOQ = lower limit of quantitation.Note: Assay results below the LLOQ were set to 0.5 × LLOQ in the analysis.
*
Study 8 was conducted in the United States and the territory of Puerto Rico (NCT04382326).
N = Number of participants with valid IgG concentrations.
GMCs and 2-sided CIs were calculated by exponentiating the mean logarithm of the concentrations and the corresponding CIs (based on the Student t distribution).
§
Noninferiority for a serotype was met if the lower bound of the 2-sided CI of IgG GMC ratio (Prevnar 20/Prevnar 13) >0.5 (2-fold NI criterion) for that serotype.
2-Sided CIs were calculated by exponentiating the mean differences of the logarithms of the IgG concentrations (Prevnar 20 minus Prevnar 13) and the corresponding CIs (based on the Student t distribution).
#
For the 7 additional serotypes, the IgG GMC to serotype 1 (Prevnar 13 serotype with the lowest IgG GMC, excluding serotype 3) in the Prevnar 13 group was used in the calculation of the GMC ratio.
Þ
For the 7 additional serotypes, the IgG GMCs to serotypes 8, 10A, 11A, 12F, 15B, 22F and 33F in the Prevnar 13 group were 0.03 µg/mL, 0.01 µg/mL, 0.02 µg/mL, 0.01 µg/mL, 0.02 µg/mL, 0.00 µg/mL and 0.01 µg/mL, respectively.

Serotypes

1

1.47 (1.37, 1.57)

2.12 (1.97, 2.27)

0.69 (0.63, 0.76)

3

0.56 (0.53, 0.60)

0.85 (0.80, 0.90)

0.66 (0.61, 0.73)

4

3.77 (3.52, 4.04)

4.84 (4.50, 5.22)

0.78 (0.70, 0.86)

5

1.87 (1.74, 2.00)

2.51 (2.33, 2.70)

0.74 (0.67, 0.82)

6A

9.01 (8.45, 9.61)

11.69 (10.91, 12.53)

0.77 (0.70, 0.85)

6B

4.01 (3.70, 4.35)

5.74 (5.27, 6.24)

0.70 (0.62, 0.79)

7F

3.91 (3.70, 4.14)

5.18 (4.88, 5.49)

0.76 (0.70, 0.82)

9V

3.44 (3.23, 3.67)

4.30 (4.02, 4.59)

0.80 (0.73, 0.88)

14

5.68 (5.27, 6.12)

6.34 (5.88, 6.83)

0.90 (0.81, 1.00)

18C

3.46 (3.24, 3.70)

4.69 (4.34, 5.05)

0.74 (0.67, 0.82)

19A

3.53 (3.30, 3.77)

4.13 (3.84, 4.45)

0.85 (0.77, 0.94)

19F

5.01 (4.68, 5.36)

5.79 (5.36, 6.25)

0.86 (0.78, 0.96)

23F

3.95 (3.63, 4.31)

6.18 (5.66, 6.75)

0.64 (0.57, 0.72)

Additional Serotypes #

8

3.97 (3.73, 4.22)

# Þ

1.87 (1.71, 2.06)

10A

6.22 (5.75, 6.72)

# Þ

2.94 (2.64, 3.26)

11A

3.53 (3.31, 3.78)

# Þ

1.67 (1.51, 1.84)

12F

1.85 (1.73, 1.99)

# Þ

0.88 (0.79, 0.97)

15B

12.59 (11.78, 13.45)

# Þ

5.95 (5.39, 6.55)

22F

10.60 (9.92, 11.33)

# Þ

5.01 (4.54, 5.52)

33F

9.31 (8.71, 9.96)

# Þ

4.40 (3.99, 4.85)

Opsonophagocytic Activity Responses After 3 and 4 doses of Prevnar 20

Serotype-specific OPA GMTs at 1 month after Dose 3 and 1 month after Dose 4 were descriptively evaluated in a subset of participants who had received Prevnar 20 and Prevnar 13 in Study 8 (Table 12). For serotypes 1, 3, 4, 9V, 23F and 12F, for which non-inferiority was not met 1 month after Dose 3 (for the percentage of participants meeting the pre-defined serotype-specific IgG concentration), OPA GMTs at 1 month after Dose 3 were numerically similar across groups for the 5 matched serotypes and an OPA antibody response was generated to additional serotype 12F.

Table 12. Pneumococcal OPA GMTs One Month After Dose 3 and Dose 4 of a 4-Dose Series– Study 8*
Abbreviations: GMT = geometric mean titer; LLOQ = lower limit of quantitation; OPA = opsonophagocytic activity.
Note: Assay results below the LLOQ were set to 0.5 × LLOQ in the analysis.
Note: OPA titers were determined on serum from randomly selected subsets of participants assuring equal representation of both vaccine groups.
*
Study 8 was conducted in the United States and the territory of Puerto Rico (NCT04382326).
N = Number of participants with valid OPA titers.
GMTs and 2-sided CIs were calculated by exponentiating the mean logarithm of the titers and the corresponding CIs (based on the Student t distribution).

Prevnar 20

N = 85-105

After Dose 3

Prevnar 13

N = 84-113

After Dose 3

Prevnar 20

N = 80-99

After Dose 4

Prevnar 13

N = 77-103

After Dose 4

GMT (95% CI )

GMT (95% CI )

GMT (95% CI )

GMT (95% CI )

Serotypes

1

26 (21, 33)

34 (27, 42)

36 (27, 48)

66 (50, 87)

3

51 (43, 61)

63 (53, 76)

62 (49, 78)

102 (86, 120)

4

339 (252, 455)

280 (207, 378)

621 (435, 887)

961 (714, 1294)

5

32 (27, 39)

39 (32, 47)

55 (45, 67)

69 (54, 87)

6A

910 (763, 1084)

936 (757, 1156)

1384 (1092, 1753)

1767(1329, 2348)

6B

318 (242, 419)

516 (409, 651)

666 (489, 906)

1211 (861, 1703)

7F

1222 (1020, 1465)

1149 (926, 1424)

2022 (1673, 2444)

2099 (1741, 2531)

9V

661 (482, 906)

594 (421, 838)

2609 (1913, 3558)

3210 (2500, 4123)

14

415 (323, 535)

420 (330, 535)

667 (523, 850)

593 (462, 761)

18C

1153 (910, 1460)

996 (754, 1317)

1973 (1472, 2643)

2425 (1914, 3072)

19A

108 (78, 149)

109 (79, 151)

844 (622, 1145)

1357 (1007, 1829)

19F

84 (67, 105)

116 (90, 149)

246 (179, 337)

373 (272, 513)

23F

255 (186, 350)

295 (215, 406)

827 (554, 1235)

1532 (1118, 2100)

Additional Serotypes

8

665 (503, 880)

18 (17, 20)

1228 (901, 1673)

26 (21, 31)

10A

2558 (1869, 3501)

37 (33, 42)

3674 (2746, 4916)

57 (44, 74)

11A

289 (212, 395)

50 (46, 55)

2728 (1975, 3768)

69 (53, 89)

12F

7677 (5952, 9901)

28 (24, 33)

9320 (7037, 12343)

31 (26, 37)

15B

1560 (1090, 2233)

18 (16, 22)

3035 (2138, 4308)

23 (17, 30)

22F

6797 (5170, 8936)

9 (9, 9)

11077 (7956, 15422)

15 (11, 20)

33F

7388 (4803, 11365)

198 (177, 220)

19216 (13193, 27990)

363 (292, 451)

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