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Prevnar 13

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Prevnar 13

CLINICAL PHARMACOLOGY

Mechanism Of Action

Prevnar 13, comprised of pneumococcal polysaccharides conjugated to a carrier protein (CRM197), elicits a T-cell dependent immune response. Protein carrier-specific T-cells provide the signals needed for maturation of the B-cell response.

Nonclinical and clinical data support opsonophagocytic activity, as measured by opsonophagocytic activity (OPA) antibody assay, as a contributor to protection against pneumococcal disease. The OPA antibody assay provides an in vitro measurement of the ability of serum antibodies to eliminate pneumococci by promoting complement-mediated phagocytosis and is believed to reflect relevant in vivo mechanisms of protection against pneumococcal disease. OPA antibody titers are expressed as the reciprocal of the highest serum dilution that reduces survival of the pneumococci by at least 50%.

In infants that have received Prevnar 13, opsonophagocytic activity correlates well with serotype specific anti-capsular polysaccharide IgG levels as measured by ELISA. A serum anti-capsular polysaccharide antibody concentration of 0.35 μg/mL as measured by ELISA one month after the third dose as a single antibody reference concentration was used to estimate the effectiveness of Prevnar 13 against invasive pneumococcal disease (IPD) in infants and children. The assay used for this determination is a standardized ELISA involving pre-absorption of the test sera with pneumococcal C-polysaccharide and serotype 22F polysaccharide to reduce non-specific background reactivity. The single antibody reference value was based on pooled efficacy estimates from three placebo-controlled IPD efficacy trials with either Prevnar or the investigational 9-valent CRM197 conjugate pneumococcal polysaccharide vaccine. This reference concentration is only applicable on a population basis and cannot be used to predict protection against IPD on an individual basis. Functional antibodies elicited by the vaccine (as measured by a dribble opsonophagocytic activity [dOPA] antibody assay) were also evaluated in infants.

In adults, an antipolysaccharide binding antibody IgG level to predict protection against invasive pneumococcal disease or non-bacteremic pneumonia has not been defined. Noninferiority trials for Prevnar 13 were designed to show that functional OPA antibody responses (as measured by a microcolony OPA [mcOPA] antibody assay) for the Prevnar 13 serotypes are non-inferior and for some serotypes superior to the common serotypes in the currently licensed pneumococcal polysaccharide vaccine (PPSV23). OPA antibody titers measured in the mcOPA antibody assay cannot be compared directly to titers measured in the dOPA antibody assay.

Clinical Studies

Prevnar Efficacy Data

Invasive Pneumococcal Disease (IPD)

Prevnar 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% 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 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 (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 15). ≥ 0.35

Table 15: Percentage of Subjects With Anti-capsular Antibody Concentration μg/mL One Month After a Three Dose Series Administered at 2, 4 and 6 Months of Age, Study2a,b,c,d

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 Serotypese
1 95.6 (92.3, 97.8) e 2.8 (-1.3, 7.2)
3 63.5 (57.1, 69.4) e -29.3 (-36.2, -22.4)
5 89.7 (85.2, 93.1) e -3.1 (-8.3, 1.9)
6A 96.0 (92.8, 98.1) e 3.2 (-0.8, 7.6)
7F 98.4 (96.0, 99.6) e 5.6 (1.9, 9.7)
19A 98.4 (96.0, 99.6) e 5.6 (1.9, 9.7)
aStudies conducted in US NCT00373958 (Study 2).
bEvaluable Immunogenicity Population.
cNoninferiority was met when the lower limit of the 95% CI for the difference between groups (Prevnar 13 minus Prevnar) was greater than -10%.
dAntibody 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.
eComparison 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).

Functional dOPA antibody responses were elicited for all 13 serotypes, as shown in Table 16.

Table 16: Pneumococcal dOPA Antibody Geometric Mean Titers One Month After a Three Dose Series Administered at 2, 4 and 6 Months of Age, Study 2a,b,c

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)
a Studies conducted in US NCT00373958 (Study 2).
b 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.
c Evaluable Immunogenicity Population.

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 17).

Table 17: Pneumococcal IgG GMCs (μg/mL) One Month After a Four Dose Series Administered at 2, 4, 6 and 12-15 Months, Study 2a,b,c,d

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 Serotypese
1 5.06 (4.43, 5.80) e 1.40 (1.17, 1.66)
3 0.94 (0.83, 1.05) e 0.26 (0.22, 0.30)
5 3.72 (3.31, 4.18) e 1.03 (0.87, 1.20)
6A 8.20 (7.30, 9.20) e 2.26 (1.93, 2.65)
7F 5.67 (5.01, 6.42) e 1.56 (1.32, 1.85)
19A 8.55 (7.64, 9.56) e 2.36 (2.01, 2.76)
a Studies conducted in US NCT00373958 (Study 2).
b Evaluable Immunogenicity Population.
c 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.
dAntibody 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.
e 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).

Following the fourth dose, the functional dOPA antibody response for each serotype was quantitatively greater than the response following the third dose (see Table 18).

Table 18: Pneumococcal dOPA Antibody Geometric Mean Titers One Month After the Fourth Dose-Evaluable Toddler Immunogenicity Population, Study 2a,b

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)
a Studies conducted in US NCT00373958 (Study 2).
b 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.

Previously Unvaccinated Older Infants and Children 7 Months Through 5 Years of Age

In an open-label descriptive study of Prevnar 13 in Poland (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 naļve 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 19.

Table 19: Pneumococcal Anti-capsular Polysaccharide IgG Antibody Geometric Mean Concentrations (μg/mL) One Month After the Final Prevnar 13 Catch-Up Dose in Pneumococcal Vaccine Naļve Children 7 Months Through 5 Years of Age by Age Group, Study 4a,b

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)
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)
a Studies conducted in Poland NCT00452452 (Study 4).
bOpen label administration of Prevnar 13.
Note – ClinicalTrials.gov NCT number is as follows: NCT00452452 (Poland).

Children 15 Months Through 59 Months of Age Previously Vaccinated with Prevnar

In an open-label descriptive study in the US (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 20.

Table 20: 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 5a,b

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)
a Studies conducted in US NCT00761631 (Study 5).
bOpen label administration of Prevnar 13.

Children 5 Through 17 Years of Age

In a US study (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-naļve 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 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 21 and 22 respectively.

Table 21: 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)a,g,h

Serotype Vaccine Group (as Enrolled/Randomized)    
Prevnar 13
5 Through 9 Years
(Study 5)
Prevnar
Post-Toddler Dose
(Study 3)
   
nb GMCc (95% CId) nb GMCc (95% CId) GMC Ratioe (95% CIf)
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)
a Studies conducted in US NCT00761631 (Study 5) and NCT00444457 (Study 3).
b n = Number of subjects with a determinate antibody concentration for the specified serotype.
c 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).
d Confidence intervals (CIs) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the concentrations.
e Ratio of GMCs: Prevnar 13 (Study 5) to Prevnar (Study 3) reference.
f 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)].
g Evaluable Immunogenicity Population.
hNoninferiority was declared if the lower limit of the 2-sided 95% CI for geometric mean ratio was greater than 0.5.

Table 22: 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)a,g,h

Serotype Vaccine Group (as Enrolled/Randomized)    
Prevnar 13
5 Through 9 Years
(Study 5)
Prevnar 13
Post-Toddler Dose
(Study 3)
   
nb GMCc (95% CId) nb GMCc (95% CId) GMC Ratioe (95% CIf)
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)
a Studies conducted in US NCT00761631 (Study 5) and NCT00444457 (Study 3).
b n = Number of subjects with a determinate antibody concentration for the specified serotype.
c 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).
d Confidence intervals (CIs) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the concentrations.
e Ratio of GMCs: Prevnar 13 (Study 5) to Prevnar 13 (Study 3).
f 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)].
g Evaluable Immunogenicity Population.
hNoninferiority was declared if the lower limit of the 2-sided 95% CI for geometric mean ratio was greater than 0.5.

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 23.

Table 23: 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 Agea,g,h,i

Serotype Vaccine Group (as Enrolled)    
Prevnar 13
(10 through 17 Years)
Prevnar 13
(5 through 9 Years)
   
nb GMTc (95% CId) nb GMTc (95% CId) GMT Ratioe (95% CIf)
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)
a Studies conducted in US NCT00761631 (Study 5).
b n= Number of subjects with a determinate antibody titer for the specified serotype.
c Geometric mean titers (GMTs) were calculated using all subjects with available data for the specified blood draw.
d Confidence intervals (CIs) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the titers.
e Ratio of GMTs: Prevnar 13(10 through 17 years of age) to Prevnar 13 (5 through 9 years of age).
f 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.
g Evaluable Immunogenicity Population.
hNoninferiority was declared if the lower limit of the 2-sided 95% CI for geometric mean ratio was greater than 0.5.
i 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.

Prevnar 13 Immunogenicity Clinical Trials In Adults

Five phase 3 clinical trials 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 12 weeks before receipt of the study vaccine.

Immune responses elicited by Prevnar 13 and PPSV23 were measured by a mcOPA antibody assay for the thirteen 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 five phase 3 clinical trials, 2 noninferiority trials were conducted in which the immune responses to Prevnar 13 were compared with the immune responses to PPSV23; one in PPSV23 unvaccinated adults aged 50 through 64 years (Study 6), and one in PPSV23 prevaccinated adults aged ≥ 70 years (Study 7). A third study compared immune responses of Prevnar 13 as a single dose compared 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 enrollment (Study 8). The study also compared immune responses of PPSV23 as a single dose compared 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 (TIV) in the US (Study 10) and Europe (Study 11).

Clinical Trials Conducted in PPSV23 Unvaccinated Adults

In an active-controlled modifieda double-blind clinical trial (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 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 proportions 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 24).

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 24).

Table 24: mcOPA Antibody GMTs in PPSV23-Unvaccinated Adults Aged 50 Through 59 Years Given Prevnar 13; and in Adults Aged 60 Through 64 Years Given Prevnar 13 or PPSV23 (Study 6)a,b,c,d

Serotype Prevnar13 Prevnar13 PPSV23 Prevnar13 50-59 Relative to 60-64 Years Prevnar 13 Relative to PPSV23, 60-64 Yearsf
50-59 Yearsh
N=350-384
60-64 Years
N=359-404
60-64 Years
N=367-402
GMT GMT GMT GMT Ratio (95% CI) GMT Ratio (95% CI)
1 211 158 119 1.3 (1.07, 1.65) 1.3 (1.07, 1.65)
3 94 96 90 1.0 (0.82, 1.18) 1.1 (0.89, 1.29)
4 2904 2164 1405 1.3 (1.06, 1.70) 1.5 (1.18, 2.00)
5 322 236 198 1.4 (1.08, 1.74) 1.2 (0.95, 1.50)
6Ag 4469 2766 343 1.6 (1.28, 2.03) 8.1 (6.11, 10.67)
6B 3350 2212 998 1.5 (1.20, 1.91) 2.2 (1.70, 2.89)
7F 1807 1535 829 1.2 (0.98, 1.41) 1.9 (1.52, 2.26)
9V 2190 1701 1012 1.3 (1.08, 1.53) 1.7 (1.40, 2.02)
14 1078 733 819 1.5 (1.14, 1.89) 0.9 (0.69, 1.16)
18C 2077 1834 1074 1.1 (0.89, 1.44) 1.7 (1.32, 2.21)
19A 968 691 368 1.4 (1.17, 1.68) 1.9 (1.53, 2.30)
19F 697 622 636 1.1 (0.89, 1.41) 1.0 (0.78, 1.23)
23F 531 404 87 1.3 (0.96, 1.80) 4.6 (3.37, 6.38)
GMT, Geometric Mean Titer.
a Study conducted in US NCT00427895 (Study 6).
bNoninferiority was defined for the 12 common serotypes in adults aged 60 to 64 years and for the 13 serotypes in adults aged 50 to 59 years as the lower limit of the 2-sided 95% CI for GMT ratio greater than 0.5.
c mcOPA antibody for the 11 serotypes unique to PPSV23 but not contained in Prevnar 13 were not measured.
d 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.
e Evaluable Immunogenicity Population.
fFor serotype 6A, which is unique to Prevnar 13, a statistically significantly greater response was defined for analysis in cohort 1 as the lower limit of the 2-sided 95% CI for the GMT ratio (Prevnar 13/PPSV23) greater than 2
g 6A is a serotype unique to Prevnar 13 but not contained in PPSV23.
hOpen label administration of Prevnar 13.

Clinical Trials Conducted in PPSV23 Previously Vaccinated Adults

In a phase 3 active-controlled, modified double-blind clinical trial (Study 7) of Prevnar 13 in the US and Sweden, PPSV23 prevaccinated 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-prevaccinated 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 prevaccinated with PPSV23 ≥ 5 years prior, vaccination with Prevnar 13 elicited noninferior immune responses as compared with re-vaccination with PPSV23 (see Table 25).

Table 25: mcOPA Antibody GMTs in PPSV23-Previously Vaccinated Adults Aged ≥ 70 Years Given Prevnar 13 or PPSV23 (Study 7)a,b,c,d,e,f

Serotype N=400-426
GMT
N=395-445
GMT
Relative to PPSV23
GMT Ratio (95% CI)
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)
6Ag 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)
GMT, Geometric Mean Titer.
a Study conducted in US and Sweden NCT00546572 (Study 7).
b For the 12 common serotypes, noninferiority was defined as the lower limit of the 2-sided 95% CI for GMT ratio (Prevnar 13/PPSV23) greater than 0.5.
c For serotype 6A, which is unique to Prevnar 13, a statistically significantly greater response was defined as the lower limit of the 2-sided 95% CI for the GMT ratio (Prevnar 13/PPSV23) greater than 2.
d mcOPA antibody for the 11 serotypes unique to PPSV23 but not contained in Prevnar 13 were not measured.
e 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.
f Evaluable Immunogenicity Population.
g 6A is a serotype unique to Prevnar 13 but not contained in PPSV23.

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 age (Study 8), 223 persons 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-pre-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.

Table 26: mcOPA Antibody GMTs for the Prevnar 13 Serotypes in PPSV23 Unvaccinated Adults Aged 60 Through 64 Years Given Prevnar 13 Alone or Prevnar 13 One Year After PPSV23 (Study 8) (PPSV23/Prevnar 13)a,b,c,d

Serotype GMT Prevnar 13
N=410-457
PPSV23/Prevnar 13
N=180-196
(95% CI) GMT (95% CI)
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)
6Ae 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)
GMT =Geometric Mean Titer.
a Study conducted in US NCT00574548 (Study 8).
b Evaluable Immunogenicity Population.
c mcOPA antibody for the 11 serotypes unique to PPSV23 but not contained in Prevnar 13 were not measured.
d 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.
e 6A is a serotype unique to Prevnar 13 but not contained in PPSV23.

No data are available on a dosing interval greater than 1 year. No data are available in response to Prevnar 13 given one year after PPSV23 in previously unvaccinated persons.

Also in Study 8, 266 persons 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 persons 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.

Table 27: mcOPA Antibody GMTs for the Prevnar 13 Serotypes in PPSV23-Unvaccinated Adults Aged 60 Through 64 Years Given PPSV23 One Year After Prevnar 13 Relative to PPSV23 Alone (Study 8)a,b,c,d

Serotype Prevnar 13/PPSV23
N=216-233
PPSV23
N=214-229
GMT Ratio (Prevnar 13/PPSV23) / PPSV23
GMT 95% CI GMT 95% CI Ratio 95% CI
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)
6Ae 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)
GMT =Geometric Mean Titer.
a Study conducted in US NCT00574548 (Study 8).
bEvaluable Immunogenicity Population.
c mcOPA antibody for the 11 serotypes unique to PPSV23 but not contained in Prevnar 13 were not measured.
d 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.
e 6A is a serotype unique to Prevnar 13 but not contained in PPSV23. Anti-6A mcOPA antibody GMTs were descriptive in nature.

Concomitant Vaccine Administration

Infants and Toddlers

The concomitant administration of routine US infant vaccines [see DRUG INTERACTIONS] with Prevnar 13 was evaluated in two studies: Study 2 [see Clinical Studies], Pneumococcal Immune Responses Following Three Doses] and the US lot consistency study (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 663 (Study 2) and 1699 (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

Two randomized, double-blind clinical trials evaluated the immunogenicity of Prevnar 13 given with inactivated TIV (Fall 2007/ Spring 2008 Fluarix, A/H1N1, A/H3N2, and B strains) in PPSV23 unvaccinated adults aged 50 through 59 years (Study 10, conducted in the U.S.) and in adults ≥ 65 years (Study 11, conducted in Europe). In each clinical trial one group received Prevnar 13 and TIV concurrently, followed approximately one month later by placebo. The other group received TIV and placebo concurrently, followed approximately one month later by Prevnar 13.

Antibody responses elicited by TIV were measured by hemagglutination inhibition assay (HAI) one month after TIV vaccination. The proportion of subjects achieving a ≥ 4-fold increase in HAI titer (responder) for each TIV strain was evaluated 1 month after vaccination. Noninferiority was demonstrated for each TIV vaccine antigen if the lower limit of the 95% CI for the difference in proportions of responders between the two groups [concomitant minus (TIV+Placebo)] was greater than -10%.

In subjects 50 through 59 years of age, noninferiority was demonstrated for each of the 3 TIV strains after Prevnar 13 given concomitantly with TIV compared with TIV given alone.

In subjects ≥ 65 years of age, noninferiority was demonstrated for A/H1N1 and B-strains, but not for A/H3N2, which had a lower limit of the 95% CI of -10.4%.

The studies also assessed the antibody responses of Prevnar 13 when Prevnar 13 was given concomitantly with TIV compared with Prevnar 13 given alone. The antipolysaccharide binding antibody responses (IgG) were measured by ELISA IgG one month after Prevnar 13 vaccination in a subset of subjects. Noninferiority was demonstrated if the lower limit of the 2-sided, 95% CI for the IgG GMC ratios (Prevnar 13+ TIV relative to Prevnar 13 alone) was > 0.5. In a post hoc analysis, mcOPA antibody response was evaluated using the same criterion.

In subjects 50 through 59 years of age, Prevnar 13 IgG antibody responses, as measured by ELISA, met noninferiority for all 13 serotypes after Prevnar 13 was given concomitantly with TIV compared to Prevnar 13 given alone, and noninferiority of the mcOPA antibody GMT ratios was observed for 10 of 13 serotypes.

In subjects ≥ 65 years of age, Prevnar 13 IgG antibody responses, as measured by ELISA, met noninferiority for 12 of 13 serotypes after Prevnar 13 was given concomitantly with TIV compared with Prevnar 13 given alone, and noninferiority of the mcOPA antibody GMT ratios was observed for all of the 13 serotypes.

REFERENCES

a Modified double-blind means that the site staff dispensing and administering the vaccine were unblinded, but all other study personnel including the principal investigator and subject were blinded.

Last reviewed on RxList: 9/19/2014
This monograph has been modified to include the generic and brand name in many instances.

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