Document text
20-valent Pneumococcal
Conjugate Vaccine
(PCV20) Phase 3
in Pediatrics
Wendy Watson, MD
Global Clinical Program Lead
ACIP February 22, 2023
1
PCV20 is Built on the Established Platforms of PCV7 and PCV13
• PCV20 builds on the 20 -year legacy of PCVs and contains PCV13 components + conjugates for 7 additional PCV20
Composition serotypes to broaden disease coverage for pneumococcal disease in children
• The 7 additional conjugates were modelled on the PCV13 Pfizer platform
• Licensure based on satisfactory safety and immunogenicity compared to PCV13
• Totality of data to support comparability per regulatory agreement Licensure and • Seeking same indications as PCV13 Indications
• PCV20 in the pediatric program is the same vaccine currently approved, recommended, and administered in
adults
PCV13 PCV20
PCV7
4 6B 9V 14 18C 19F 23F 1 3 5 6A 7F 19A 8 10A 11A 12F 15B 22F 33F
CRM197
PCV7
Immunogenicity & Safety
Clinical Efficacy
Real -World Effectiveness
Real -World Impact
2 PCV13
Immunogenicity & Safety
Efficacy from immunobridging
Real -World Effectiveness
Real -World Impact
Data available after vaccine implementation PCV20
Immunogenicity & Safety
Efficacy from Immunobridging
Real -World Effectiveness
Real -World Impact
Phase 2Senders
et al. 2021 2, 4, 6 and
12 months
of age 460
Participants Demonstrate safety, tolerability, and immunogenicity of PCV20
•Concomitant administration with Pediarix
•United States
Pivotal Infant
Study 2, 4, 6 and
12–15 months
of age 1997
Participants Demonstrate noninferiority of immune response of PCV20 vs PCV13
•Concomitant administration with Pediarix , Hiberix , M-M-R II, Varivax
•United States, Puerto RicoPhase 3 Pediatric
Single Dose
Study Single dose
(15 months –
<18 years
of age) 831
Participants Characterize safety and immunogenicity in children 15 months to
17 years of age
•United States
Safety
Study 2, 4, 6 and
12–15 months
of age 1511
Participants Further characterize safety profile of PCV20
•Concomitant standard vaccines allowed
•United States, Puerto Rico, Canada, Chile, Argentina, European UnionPCV20 Clinical Development Program
SAFETY
IMMUNOGENICITY
3
PCV20
N*=1001PCV13
N*=987
Sex n†(%) n†(%)
Male 518 (51.7) 505 (51.2)
Race
White 754 (75.3) 742 (75.2)
Black or African
American110 (11.0) 108 (10.9)
Asian 16 (1.6) 16 (1.6)
American Indian or
Alaska Native4 (0.4) 3 (0.3)
Native Hawaiian or
other Pacific
Islander2 (0.2) 2 (0.2)
Multiracial 68 (6.8) 73 (7.4)
Ethnicity
Hispanic/Latino 312 (31.2) 293 (29.7)
Non Hispanic/
nonLatino661 (66.0) 659 (66.8)-
-
Pivotal Infant Study
Study Design of Phase 3 Pivotal Study in Infants
Multicenter, Randomized, Double -blind Study in the Similar Demographics of PCV20
US/Puerto Rico Study in Infants (92 sites, n=1997) and PCV13 Groups
2 4 6 7 12-15 13- 16 18- 21 Age months months months months months months months PCV20 PCV13
N*=1001 N*=987
Sex n† (%) n† (%)PCV20 Group
Male 518 (51.7) 505 (51.2)
Race
White 754 (75.3) 742 (75.2)+ + + + PCV20 PCV20
PCV20 PCV20
Pediarix, Pediarix, Pediarix, MMR and
Hib Hib Hib Varicella
Control Group
+ + + + PCV13 PCV13 PCV13 PCV13
Black or African
American 110 (11.0) 108 (10.9)
Asian 16 (1.6) 16 (1.6)
American Indian or
Alaska Native 4 (0.4) 3 (0.3)
Native Hawaiian or
other Pacific 2 (0.2) 2 (0.2)
Islander
Multiracial 68 (6.8) 73 (7.4)
Ethnicity
Hispanic/Latino 312 (31.2) 293 (29.7)
Non-Hispanic/
non-Latino 661 (66.0) 659 (66.8) Pediarix,
Hib Pediarix,
Hib Pediarix,
Hib MMR and
Varicella
Blood draws Safety follow -up call • Concomitant Influen
any time during trial za and rotavirus vaccines permitted at
*N=number of participants in the specified age cohort. This value is the denominator for the percentage calculations.
†n=number of participants with the specified characteristic.
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Primary
Objectives
Key
Secondary
Objective Pre-specified Immunogenicity Analyses
Importance of Multiple Immunologic Assessments to Infer Effectiveness Pivotal Infant Study
Co-primary : Noninferiority of IgG GMCs after
toddler dose Noninferiority of IgG GMC after infant series Co-primary Noninferiority of % of participants with
IgG above predefined levels after infant series
Circulating IgG Antibody Functional Response Memory Response
• % above prespecified IgG level after
toddler dose • OPA GMTs after infant series and
toddler dose • Geometric fold -rises (GMFR) of IgG
from after infant series to after the
• IgG GMCs and % above prespecified
IgG for the 7 additional serotypes
relative to the PCV13 group •
• % with OPA titers ≥ LLOQ after infant
series and toddler dose
OPA titer RCDC after infant series and • toddler dose
GMFR of IgG from before to after the
toddler dose
• IgG Reverse Cumulative Distribution
Curve ( RCDC ) after infant series and
toddler dose toddler dose •
• GMFR of OPA from after infant series to
after the toddler dose
% with ≤ 4-fold rise in OPA titers from
before to after the toddler dose Additional Data
• Concomitant Vaccine Antigen GMCs
and GMRs
• Comparison of % With Prespecified
Antibody Levels for Concomitant
Vaccine Antigens
• Explore cross protection to 6C and 15C
NI for GMC ratio (GMR) = the lower bound of 2 -sided 95% CI for GMR (PCV20/PCV13) >0.5.
NI for difference in percentages of participants = the lower bound of 2 -sided 95% CI for percent difference (PCV20 -PCV13) > -10%.
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Pivotal Infant Study Co-Primary Objective
Post Dose 3 : Percentage with Predefined IgG Concentrations
14 Serotypes Met Noninferiority (Difference in %)
Serotype
PCV13 PCV20
(%) PCV13
(%) Difference (% )
(95% CI)
1 79.8 88.4 -8.6 (-12.1, -5.1)
3 52.1 67.6 -15.5 ( -20.1, -10.8)
4 79.7 88.2 -8.4 (-12.0, -4.9)
5 82.5 86.8 -4.3 (-7.8, -0.8)
6A 93.5 95.9 -2.4 (-4.6, -0.2)
6B 88.3 92.4 -4.1 (-7.0, -1.2)
7F 96.6 97.6 -1.0 (-2.7, 0.7)
9V 81.9 89.8 -7.9 (-11.3, -4.6)
14 93.4 94.1 -0.8 (-3.1, 1.6)
18C 92.6 93.1 -0.6 (-3.1, 1.9)
19A 97.1 98.1 -1.0 (-2.6, 0.5)
19F 96.9 96.6 0.2 (-1.5, 2.0)
23F 77.9 85.5* -7.6 (-11.4, -3.9)
7 Addition al
8 96.8 85.5 11.2 (8.6, 14.0)
10A 82.2 85.5 -3.3 (-6.9, 0.3)
11A 92.7 85.5 7.1 (4.2, 10.2)
12F 67.5 85.5 -18.1 ( -22.1, -14.0)
15B 98.2 85.5 12.7 (10.2, 15.4)
22F 98.3 85.5 12.8 (10.3, 15.5)
33F 86.7 85.5 1.1 (-2.2, 4.5)
-30 -20 -10 0 10 20 30
Difference in Percentage (PCV20 –PCV13)
*The 7 additional serotypes are compared to the percentage for serotype 23F after Dose 3 (lowest in PCV13 group, excluding serotype 3).
Predefined IgG concentration – ≥0.35 µg/mL for all serotypes except ≥ 0.23 µg/mL, ≥0.10 µg/mL and ≥ 0.12 µg/mL for serotypes 5, 6B and 19A respectively.
6
Pivotal Infant Study Key Secondary Objective
Post Dose 3 : IgG Concentration and Geometric Mean Ratio
All 20 Vaccine Serotypes Met Noninferiority
Serotype
PCV13 PCV20
GMC PCV13
GMC GMR
(95% CI)
1 0.74 1.14 0.65 (0.59, 0.72)
3 0.36 0.51 0.70 (0.64, 0.76)
4 0.75 1.08 0.70 (0.63, 0.78)
5 0.66 0.96 0.69 (0.61, 0.77)
6A 1.95 2.69 0.72 (0.65, 0.81)
6B 0.61 1.02 0.60 (0.51, 0.70)
7F 1.71 2.29 0.75 (0.69, 0.81)
9V 0.87 1.21 0.72 (0.65, 0.80)
14 2.16 2.72 0.79 (0.71, 0.89)
18C 1.31 1.71 0.77 (0.70, 0.84)
19A 0.72 0.91* 0.79 (0.72, 0.86)
19F 1.59 2.00 0.79 (0.73, 0.86)
23F 0.82 1.25 0.66 (0.58, 0.75)
7 Additional
8 1.80 0.91 1.98 (1.81, 2.16)
10A 1.21 0.91 1.32 (1.18, 1.49)
11A 1.39 0.91 1.52 (1.39, 1.67)
12F 0.55 0.91 0.60 (0.54, 0.67)
15B 4.40 0.91 4.82 (4.39, 5.30)
22F 3.71 0.91 4.06 (3.68, 4.48)
33F 1.49 0.91 1.64 (1.46, 1.83)
0.25 0.5 1 2 4 8
GMR
* The 7 additional serotypes are compared to the GMC after Dose 3 for serotype 19A (lowest in PCV13 group, excluding serotype 3).
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Pivotal Infant Study
Post Dose 3 : IgG Concentration and Geometric Mean Ratio
Statistically Significantly Higher Response when compared to actual PCV13 Response
Comparison of additional 7 serotypes to actual PCV13 IgG GMC, not lowest in PCV20 group
Serotype
7 Additional PCV20
GMC PCV13
GMC GMR
(95% CI)
8 1.80 0.02 100.54 (91.58, 110.38)
10A 1.21 0.01 99.64 (88.87, 111.70)
11A 1.39 0.02 91.03 (82.79, 100.09)
12F 0.55 0.01 68.42 (62.47, 74.94)
15B 4.40 0.03 169.40 (154.01, 186.33)
22F 3.71 0.01 730.84 (651.36, 820.01)
33F 1.49 0.02 97.45 (86.96, 109.21)
0.25 0.5 1 2 4 8 16 32 64 128 256 512 1024
GMR
8
Pivotal Infant Study
Post Dose 3: Comparison of PCV20 and PCV13 OPA GMTs
Functional Antibody Responses Were Similar Between PCV20 and PCV13 for
Shared Serotypes
Post Dose 3
1 10 100 1000 10000
1 3 4 5 6A 6B 7F 9V 14 18C 19A 19F 23F 8 10A 11A 12F 15B 22F 33F OPA GMTs PCV20 PCV13
PCV20 (n= 80 –105); PCV13 (n=77 –113).
9
Pivotal Infant Study Co-Primary Objective
Post Dose 4 : IgG Concentration and Geometric Mean Ratio
All 20 Vaccine Serotypes Met Noninferiority
Serotype
PCV13 PCV20
GMC PCV13
GMC GMR Ratio
(95% CI)
1 1.47 2.12* 0.69 (0.63, 0.76)
3 0.56 0.85 0.66 (0.61, 0.73)
4 3.77 4.84 0.78 (0.70, 0.86)
5 1.87 2.51 0.74 (0.67, 0.82)
6A 9.01 11.69 0.77 (0.70, 0.85)
6B 4.01 5.74 0.70 (0.62, 0.79)
7F 3.91 5.18 0.76 (0.70, 0.82)
9V 3.44 4.30 0.80 (0.73, 0.88)
14 5.68 6.34 0.90 (0.81, 1.00)
18C 3.46 4.69 0.74 (0.67, 0.82)
19A 3.53 4.13 0.85 (0.77, 0.94)
19F 5.01 5.79 0.86 (0.78, 0.96)
23F 3.95 6.18 0.64 (0.57, 0.72)
7 Additional
8 3.97 2.12 1.87 (1.71, 2.06)
10A 6.22 2.12 2.94 (2.64, 3.26)
11A 3.53 2.12 1.67 (1.51, 1.84)
12F 1.85 2.12 0.88 (0.79, 0.97)
15B 12.59 2.12 5.95 (5.39, 6.55)
22F 10.60 2.12 5.01 (4.54, 5.52)
33F 9.31 2.12 4.40 (3.99, 4.85)
0.25 0.5 1 2 4 8
GMR
* The 7 additional serotypes were compared to serotype 1 in the PCV13 group (lowest IgG GMC after Dose 4, excluding serotype 3).
10
Pivotal Infant Study
PD3 Compared to PD4: IgG and OPA Response to PCV20
Boosting Observed Across All 20 Serotypes Indicating Anamnestic Response/Memory
11 Post Dose 3 and Post Dose 4 IgG GMCs
Post Dose 3 and Pose Dose 4 O PA GMTs 0.01 0.1 1 10 100
1 3 4 5 6A 6B 7F 9V 14 18C 19A 19F 23F 8 10A 11A 12F 15B 22F 33F IgG GMCs PCV20 PD3 PCV20 PD4
1 10 100 1000 10000 100000
1 3 4 5 6A 6B 7F 9V 14 18C 19A 19F 23F 8 10A 11A 12F 15B 22F 33F OPA GMTs PCV20 PD3 PCV20 PD4
Pivotal Infant Study
Concomitant Use : Responses to the Vaccines Were Similar When Given
with PCV20 or PCV13 in the Infant Immunization Series
All Responses Met Noninferiority
Post Dose 3: Pediarix and Hiberix®
Concomitant
Vaccine Antigen PCV20
(%) PCV13
(%) Difference (%)
(95% CI)
Diphtheria 93.5 97.8 -4.3 (-7.5, -1.4)
Tetanus 99.7 99.4 0.3 (- 1.0, 1.7)
Pertussis
PT 94.9 95.0 -0.2 (-3.5, 3.1)
FHA 95.7 95.0 0.6 (-2.5, 3.9)
PRN 93.8 95.0 -1.3 (-4.7, 2.2)
HBsAg 100.0 100.0 0.0 (-3.2, 2.9)
Poliovirus
Type 1 100.0 100.0 0.0 (- 3.4, 3.2)
Type 2 100.0 99.2 0.8 (- 2.4, 4.6)
Type 3 100.0 100.0 0.0 (- 3.2, 3.1)
Hib 100.0 100.0 0.0 (- 3.0, 3.0)
-15.0 -5.0 0.0 5.0 15.0
% Difference (PCV20 –PCV13)
Post Dose 4: MMR ®II and Varivax®
Antigen
(Units) PCV20
GM PCV13
GM GMR
(95% CI)
277.74
36.96
49.63
233.05
0.25 0.50 1.00 2.00
GMR (PCV20:PCV13)
Measles 215.41 1.29 (1.05, 1.58) (AU/mL)
Mumps 34.19 1.08 (0.85, 1.38) (AU/mL)
Rubella 40.44 1.23 (1.02, 1.48) (IU/mL)
Varicella 234.78 0.99 (0.84, 1.17) (mIU/mL)
HBsAg = hepatitis B surface antigen; PT = pertussis toxoid, FHA =filamentous hemagglutinin (of Bordetella pertussis ), PRN = pertactin (of Bordetella pertussis )
12
Pivotal Infant Study
Solicited Reactions within 7 Days of Vaccination
Reactions Were Similar in Rate and Severity Across All 4 Doses
Local Reactions
100
80
60
%
40
25.5 24.6 26.4 25.4 27.2 26.6 23.2 23.5
16.4 18.8 15.5 17.3 17.1 17.6 14.9 17.3 49.1 45.3 44.1 41.7 38.6 39.0 35.7 35.8
Dose 1 Dose 2 Dose 3 Dose 4 Dose 1 Dose 2 Dose 3 Dose 4 Dose 1 Dose 2 Dose 3 Dose 4 Redness Swelling Injection Site Pain
PCV20 PCV13
Severe
20 Moderate
Mild
0
Systemic Reactions
100
Fever Decreased Appetite Drowsiness Irritability
80 70.9 71.7 71.6 68.8 67.2 66.0 64.4 63.0 61.1 61.0
60
%
10.3 7.5 17.3 16.3 12.6 13.7 14.5 14.0 24.4 23.9 26.4 23.5 20.6 22.4 24.8 25.2 54.7 55.6
44.1 44.1 39.5 39.5 PCV20 PCV13
>40.0 °C
Severe >38.9 –40.0°C
20 40
Moderate >38.4 –38.9°C
Mild ≥38.0 –38.4°C
0
Dose 1 Dose 2 Dose 3 Dose 4 Dose 1 Dose 2 Dose 3 Dose 4 Dose 1 Dose 2 Dose 3 Dose 4 Dose 1 Dose 2 Dose 3 Dose 4
PCV20: Dose 1=993, Dose 2=940, Dose 3=914, Dose 4=826. PCV13: Dose 1=974, Dose 2=924, Dose 3=901, Dose 4 =814.
13
1523 mos
N†=2092 4 yrs
N†=2165 9 yrs
N†=2011017 yrs
N†=216
Sex n‡(%) n‡(%) n‡(%) n‡(%)
Male 117 (56.0) 106 (49.1) 108 (53.7) 115 (56.1)
Race
White 168 (80.4) 173 (80.1) 174 (86.6) 178 (86.8)
Black or African
American26 (12.4) 26 (12.0) 22 (10.9) 17 (8.3)
Asian 3 (1.4) 0 0 0
American Indian or Alaska Native0 1 (0.5) 0 0
Native Hawaiian or
other Pacific Islander0 0 0 1 (0.5)
Multiracial 10 (4.8) 13 (6.0) 5 (2.5) 9 (4.4)
Ethnicity
Hispanic/Latino 35 (16.7) 45 (20.8) 31 (15.4) 43 (21.0)
Non Hispanic/Latino 172 (82.3) 171 (79.2) 168 (83.6) 161 (78.5)– – – –
-Demographic Characteristics –
Safety Population
15–23 mos 2 –4 yrs 5 –9 yrs 10–17 yrs
N†=209 N†=216 N†=201 N†=216
Sex n‡ (%) n‡ (%) n‡ (%) n‡ (%)
Male 117 (56.0) 106 (49.1) 108 (53.7) 115 (56.1)
Race
White 168 (80.4) 173 (80.1) 174 (86.6) 178 (86.8)
Black or African
American 26 (12.4) 26 (12.0) 22 (10.9) 17 (8.3)
Asian 3 (1.4) 0 0 0
American Indian or Alaska Native 0 1 (0.5) 0 0
Native Hawaiian or
other Pacific Islander 0 0 0 1 (0.5)
Multiracial 10 (4.8) 13 (6.0) 5 (2.5) 9 (4.4)
Ethnicity
Hispanic/Latino 35 (16.7) 45 (20.8) 31 (15.4) 43 (21.0)
Non-Hispanic/Latino 172 (82.3) 171 (79.2) 168 (83.6) 161 (78.5)
Phase 3 Study
Age Prior
Group Vaccination Status Day 1 1 month 6 months
PCV20 Group
Pediatric Single Dose Study Design and Demographics Single Dose Study
PCV20
≥3 doses of PCV13
15–23
months*
2–4
years*
5–9
years
10–17
years
Blood draws PCV20
≥3 doses of PCV13
PCV20
Not required
PCV20
Not required
Safety follow -up call
*Participants <5 years of age had confirmed receipt of >3 prior doses of PCV13.
† N=number of participants in the specified age cohort. This value is the denominator for the percentage calculations. ‡ n=nu mber of participants with the specified characteristic.
14
IgG GMC in Children Previously Vaccinated with PCV13
One Dose of PCV20 Elicited Responses to All Vaccine Serotypes Single Dose Study
15 15 to <24 Months
2 to <5 Years 0.01 0.1 1 10 100
1 3 4 5 6A 6B 7F 9V 14 18C 19A 19F 23F 8 10A 11A 12F 15B 22F 33F IgG GMCs
Before PCV20 1 Month After PCV20
0.01 0.1 1 10 100
1 3 4 5 6A 6B 7F 9V 14 18C 19A 19F 23F 8 10A 11A 12F 15B 22F 33F IgG GMCs
Before PCV20 1 Month After PCV20
Overall Safety
Overall Summary of Adverse Events in the US
PCV20 had no Related Serious Adverse Events or Deaths
Age < 15 months
16 *SAEs reported are in all sites, not just US (including Puerto Rico).
B7471003, B7471011, and B7471013 (all sites) : (PCV20 N=2232; PCV13 N=1717)
15 m -<18 yr
PCV20
(N=1567) PCV13
(N=1376) PCV20
(N=831)
AEs 43.8% 46.3% 10.7%
Immediate AEs 0.1–0.2% /dose 0.1% /dose 0%
Related AE 1.1% 1.1% 0.1%
Severe AEs 1.4% 1.1% 0.2%
Serious AEs* 4.5%* 3.7%* 0.6%
Related SAEs 0 0 0
Deaths 0 0 0
Summary of PCV20 Pediatric
PCV20 is well tolerated with a safety profile similar to PCV13
The totality of data shows PCV20 elicits immune responses to all 20 vaccine serotypes
A single dose of PCV20 elicited a robust immune response to all 20 serotypes and was well tolerated in
children 15 months to < 18 years of age, including those with prior PCV13
PCV20 is compatible with routine pediatric vaccines
PCV20 is currently under review by the FDA for use in pediatric population 6 weeks to <18 years of age
with a target action date in April 2023
PCV20 has the potential to address a substantial burden of pneumococcal disease in children
17
Questions?
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