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PREVNAR 20™ Clinical Studies (pneumococcal 20-valent conjugate vaccine)

14 CLINICAL STUDIES

14.1 Prevnar 13 Adult Efficacy Data

Efficacy and effectiveness of Prevnar 13 are relevant to Prevnar 20, since the vaccines are manufactured similarly and contain 13 of the same polysaccharide conjugates.

The efficacy of Prevnar 13 against vaccine-type (VT) pneumococcal community-acquired pneumonia (CAP) and invasive pneumococcal disease (IPD) was assessed in a randomized, double-blind, placebo-controlled study (Community-Acquired Pneumonia Immunization Trial in Adults [CAPiTA]) conducted over ~4 years in the Netherlands. A total of 84,496 participants 65 years of age and older received a single dose of either Prevnar 13 or placebo in a 1:1 randomization; 42,240 participants were vaccinated with Prevnar 13 and 42,256 participants were vaccinated with placebo. Chronic medical conditions (asthma, diabetes, heart, liver, and/or lung diseases) were reported in 42.3% of study participants at baseline.

The primary objective was to demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of confirmed VT-CAP (defined as presence of ≥2 specified clinical criteria, chest X-ray consistent with CAP as determined by a central committee of radiologists, and positive VT-specific urinary antigen detection assay [UAD] or isolation of VT S. pneumoniae from blood or other sterile site). The secondary objectives were to demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of 1) confirmed nonbacteremic/noninvasive (NB/NI) VT-CAP (an episode of VT-CAP for which the blood culture result and any other sterile site culture results were negative for S. pneumoniae) and 2) VT-IPD (the presence of S. pneumoniae in a sterile site).

Surveillance for suspected pneumonia and IPD began immediately after vaccination and continued through identification of a prespecified number of cases. Participants who had a CAP or IPD episode with symptom onset less than 14 days after vaccination were excluded from all analyses.

The median duration of follow-up per participant was 3.93 years. Prevnar 13 demonstrated statistically significant vaccine efficacy (VE) in preventing first episodes of VT pneumococcal CAP, NB/NI VT pneumococcal CAP, and VT-IPD (see Table 5).

Table 5. Vaccine Efficacy for the Primary and Secondary Efficacy Endpoints – Per-Protocol Population
Vaccine Group
Prevnar 13Placebo
N=42,240N=42,256
Efficacy EndpointTotal Number of EpisodesnnVE (%)(95.2% CI)
Abbreviations: CAP = community-acquired pneumonia; CI = confidence interval; NB/NI = nonbacteremic/noninvasive; IPD = invasive pneumococcal disease; VE = vaccine efficacy; VT = vaccine-type.
Primary endpoint:
First case of confirmed VT pneumococcal CAP
139499045.6(21.8, 62.5)
Secondary endpoint:
First episode of confirmed NB/NI VT pneumococcal CAP
93336045(14.2, 65.3)
Secondary endpoint:
First episode of VT-IPD
3572875(41.1, 90.9)

14.2 Prevnar 20 Clinical Trials

Immunogenicity of Prevnar 20 in Pneumococcal Vaccine Naïve Adults

Prevnar 20 effectiveness against invasive pneumococcal disease caused by the 20 vaccine serotypes and against pneumonia caused by the 13 serotypes in Prevnar 13 was inferred from comparative immunogenicity to US-licensed pneumococcal vaccines (Prevnar 13 and PPSV23). Study 1, conducted in the United States and Sweden, was designed to evaluate immunologic noninferiority of Prevnar 20 to Prevnar 13 (for the 13 original S. pneumoniae serotypes) and PPSV23 (for the 7 new S. pneumoniae serotypes) in pneumococcal vaccine naive adults ≥60 years of age. Immune responses elicited by Prevnar 20 and the control pneumococcal vaccines were measured by an OPA assay. OPA assays were used to measure functional antibodies to S. pneumoniae.

Study 1 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., smoking) that are known to increase the risk of serious pneumococcal pneumonia and IPD. A stable medical condition was defined as a medical condition not requiring significant change in therapy in the previous 6 weeks (i.e., change to new therapy category due to worsening disease) or any hospitalization for worsening disease within 12 weeks before receipt of the study vaccine.

Comparison of Immune Responses of Prevnar 20 to Prevnar 13 and PPSV23 in Pneumococcal Vaccine Naïve Adults ≥60 Years of Age

In a randomized, active-controlled, double-blind noninferiority clinical trial (Study 1) of Prevnar 20 in the United States and Sweden, pneumococcal vaccine -naïve adults 18 years of age and older were enrolled into 1 of 3 cohorts based on their age at enrollment and randomized to receive either Prevnar 20 or control. Participants 60 years of age and older were randomly assigned (1:1 ratio) to Prevnar 20 followed 1 month later with saline placebo or to Prevnar 13 followed 1 month later with PPSV23.

Serotype-specific OPA GMTs were measured before the first vaccination and 1 month after each vaccination. Noninferiority of immune responses, OPA GMTs 1 month after vaccination, with Prevnar 20 to a control vaccine for a serotype was declared if the lower bound of the 2 sided 95% CI for the GMT ratio (Prevnar 20/Prevnar 13; Prevnar 20/PPSV23) for that serotype was greater than 0.5.

In adults 60 years of age and older, immune responses to all 13 matched serotypes elicited by Prevnar 20 were noninferior to the immune responses to the serotypes elicited by Prevnar 13 one month after vaccination. Immune responses to 6 out of the 7 additional serotypes induced by Prevnar 20 were noninferior to the immune responses to these same serotypes induced by PPSV23 one month after vaccination. The response to serotype 8 missed the prespecified statistical noninferiority criterion by a small margin (the lower bound of the 2-sided 95% CI for the GMT ratio being 0.49 versus >0.50) (Table 6).

In supportive analyses, 77.8% of participants in the Prevnar 20 group achieved a ≥4-fold rise in serotype 8 OPA titers from before vaccination to 1 month post-vaccination.

Table 6. OPA GMTs 1 Month After Vaccination in Adults 60 Years of Age and Older Given Prevnar 20 Compared to Prevnar 13 for the 13 Matched Serotypes and PPSV23 for the 7 Additional Serotypes (Study 1)*,,,§
Prevnar 20
(N = 1157–1430)
Prevnar 13
(N = 1390–1419)
PPSV23
(N = 1201–1319)
Vaccine Comparison
GMTGMTGMTGMT Ratio
(95% CI)
Abbreviations: CI = confidence interval; GMT = geometric mean titer; LLOQ = lower limit of quantitation; N = number of participants; OPA = opsonophagocytic activity; PPSV23 = pneumococcal polysaccharide vaccine (23-valent).
*
Study 1 was conducted in the United States and in Sweden (NCT03760146).
Noninferiority for a serotype was met if the lower bound of the 2-sided 95% CI for the GMT ratio (ratio of Prevnar 20/comparator) was greater than 0.5 (2-fold criterion for noninferiority).
Assay results below the LLOQ were set to 0.5 × LLOQ in the analysis.
§
Evaluable immunogenicity population.
GMTs, GMT ratios, and the associated 2-sided CIs were based on analysis of log-transformed OPA titers using a regression model with vaccine group, sex, smoking status, age at vaccination in years, and baseline log-transformed OPA titers.
Serotype
11231540.80
(0.71, 0.90)
341480.85
(0.78, 0.93)
45096270.81
(0.71, 0.93)
5921100.83
(0.74, 0.94)
6A88911650.76
(0.66, 0.88)
6B111513410.83
(0.73, 0.95)
7F96911290.86
(0.77, 0.96)
9V145615680.93
(0.82, 1.05)
147477471.00
(0.89, 1.13)
18C125314820.85
(0.74, 0.97)
19A5186450.80
(0.71, 0.90)
19F2663330.80
(0.70, 0.91)
23F2773350.83
(0.70, 0.97)
Additional Serotypes
84668480.55
(0.49, 0.62)
10A200810801.86
(1.63, 2.12)
11A442725351.75
(1.52, 2.01)
12F253917171.48
(1.27, 1.72)
15B23987693.12
(2.62, 3.71)
22F366618461.99
(1.70, 2.32)
33F512637211.38
(1.21, 1.57)

Immunobridging in Pneumococcal Vaccine Naïve Adults 18 Through 59 Years of Age

In Study 1 (described above), the effectiveness of Prevnar 20 in adults 50 through 59 years of age and in adults 18 through 49 years of age was inferred following comparison of the immune response to each of the 20 vaccine serotypes in each of these age groups to the corresponding serotype-specific immune responses in adults 60 through 64 years of age following Prevnar 20 (immunobridging). In Study 1, pneumococcal vaccine-naïve participants 50 through 59 years of age and 18 through 49 years of age were randomly assigned (3:1 ratio) to receive 1 vaccination with Prevnar 20 or Prevnar 13. Serotype-specific OPA GMTs were measured before vaccination and 1 month after vaccination. A comparative analysis of Prevnar 20 in the younger age group versus Prevnar 20 in adults 60 through 64 years of age for each vaccine serotype was performed to support the indication in adults 18 through 49 years of age and 50 through 59 years of age. Immunobridging was to be declared successful if the lower bound of the 2-sided 95% CI for the GMT ratio (Prevnar 20 in participants 18 through 49 years of age/60 through 64 years of age and in participants 50 through 59 years of age/60 through 64 years of age) for the 20 serotypes was >0.5 (2-fold). Prevnar 20 elicited serotype-specific immune responses to each of the 20 vaccine serotypes in both of the younger age groups that were within 2-fold of the corresponding serotype-specific responses in adults 60 through 64 years of age, when measured 1 month after vaccination (Table 7).

Table 7. Comparisons of OPA GMTs 1 Month After Prevnar 20 in Adults 18 Through 49 or 50 Through 59 Years of Age to Adults 60 Through 64 Years of Age (Study 1)*,,,§
18–49 Years
(N = 251–317)
60–64 Years
(N = 765–941)
18–49 Years
Relative to 60–64 Years
50–59 Years
(N = 266–320)
60–64 Years
(N = 765–941)
50–59 Years
Relative to 60–64 Years
GMTGMTGMT Ratio
(95% CI)
GMTGMTGMT Ratio
(95% CI)
Abbreviations: CI = confidence interval; GMT = geometric mean titer; LLOQ = lower limit of quantitation; N = number of participants; OPA = opsonophagocytic activity; PPSV23 = pneumococcal polysaccharide vaccine 23-valent vaccine.
*
Study 1 was conducted in the United States and in Sweden (NCT03760146).
Immunobridging for a serotype was met if the lower bound of the 2-sided 95% CI for the GMT ratio (ratio of younger age group/60 through 64 years of age group) was greater than 0.5 (2-fold success criterion).
Assay results below the LLOQ were set to 0.5 × LLOQ in the analysis.
§
Evaluable immunogenicity population.
GMTs, GMT ratios, and the associated 2-sided CIs were based on analysis of log-transformed OPA titers using a regression model with age group, sex, smoking status, and baseline log-transformed OPA titers. The comparisons between adults 18 through 49 years of age and adults 60 through 64 years of age and between adults 50 through 59 years of age and adults 60 through 64 years of age were based on separate regression models.
Serotype
11631321.23
(1.01, 1.50)
1361321.03
(0.84, 1.26)
342421.00
(0.87, 1.16)
43411.06
(0.92, 1.22)
419675943.31
(2.65, 4.13)
6335781.10
(0.87, 1.38)
5108971.11
(0.91, 1.36)
85970.88
(0.72, 1.07)
6A393110233.84
(3.06, 4.83)
12049971.21
(0.95, 1.53)
6B426012503.41
(2.73, 4.26)
150311991.25
(1.00, 1.56)
7F187311871.58
(1.30, 1.91)
104711730.89
(0.74, 1.07)
9V604117273.50
(2.83, 4.33)
172616881.02
(0.83, 1.26)
1418487732.39
(1.93, 2.96)
9267421.25
(1.01, 1.54)
18C446013953.20
(2.53, 4.04)
180513551.33
(1.06, 1.68)
19A14156112.31
(1.91, 2.81)
6186001.03
(0.85, 1.25)
19F6553012.17
(1.76, 2.68)
2872900.99
(0.80, 1.22)
23F15593254.80
(3.65, 6.32)
5493281.68
(1.27, 2.22)
Additional Serotypes
88675081.71
(1.38, 2.12)
4875020.97
(0.78, 1.20)
10A415725701.62
(1.31, 2.00)
252024371.03
(0.84, 1.28)
11A716954201.32
(1.04, 1.68)
641752491.22
(0.96, 1.56)
12F587530751.91
(1.51, 2.41)
344531051.11
(0.88, 1.39)
15B460130191.52
(1.13, 2.05)
335628741.17
(0.88, 1.56)
22F756844821.69
(1.30, 2.20)
380842280.90
(0.69, 1.17)
33F797756931.40
(1.10, 1.79)
557154451.02
(0.81, 1.30)

Immunogenicity of Prevnar 20 in Adults Previously Vaccinated With Pneumococcal Vaccine

A randomized, open-label clinical trial (Study 6) described immune responses to Prevnar 20 in adults 65 years of age and older previously vaccinated with PPSV23 (≥1 to ≤5 years prior to enrollment), previously vaccinated with Prevnar 13 (≥6 months prior to enrollment), or previously vaccinated with Prevnar 13 followed by PPSV23 (with PPSV23 vaccination ≥1 year prior to enrollment). Participants in this clinical trial previously vaccinated with Prevnar 13 (Prevnar 13 only or followed by PPSV23) were enrolled at sites in the United States and participants previously vaccinated with PPSV23 only were also enrolled from Swedish sites (35.5% in that category). Immune responses elicited by Prevnar 20 were measured by an OPA assay.

OPA GMTs in participants who received PPSV23 1 to 5 years prior to Prevnar 20 were diminished compared to OPA GMTs in participants who received Prevnar 13 at least 6 months previously and compared to OPA GMTs in participants who received Prevnar 13 followed by PPSV23, with the last PPSV23 dose given at least 1 year prior to Prevnar 20.

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