Vaccines and Related Biological Products Advisory Committee (VRBPAC)May 21, 2002
Prevnar™, Pneumococcal Conjugate Vaccine 7-valent, for the Prevention of Acute Otitis Media
R. Douglas Pratt, M.D., M.P.H.
Review Team
Jingyee Kou, Ph.D.
Marion Gruber, Ph.D.
Carl Frasch, Ph.D.
Proposed Indication
For active immunization of infants and toddlers against invasive disease and otitis media caused by Streptococcus pneumoniae due to capsular serotypes included in the vaccine (4, 6B, 9V, 14, 18C, 19F, 23F)
Regulatory Background
November 1999
February 2000
June 2000
May 2001
October 2001
March 2002
May 2002
VRBPAC for invasive disease
Prevnar licensed for prevention of invasive disease
AOM license amendment submitted
FDA Letter to sponsor
Response to FDA letter received
Second FDA letter to sponsor; major amendment- Finnish follow-up data
VRBPAC for otitis media
Global Issues
• Efficacy estimates for AOM outcomes are comparatively low for preventive vaccines
• Possible increased risk of AOM (negative efficacy) for pneumococcal serotypes not included in Prevnar
• Potential for unrealistic public expectations regarding benefit in preventing AOM
Comments from Medical Community:Correspondence to New England Journal of Medicine
• Clinical significance of overall treatment effect questioned (Lavin A; Damoiseaux R; Cantekin E; Sauder K)
• Concern that limited benefit may be misunderstood by the public (Sauder K)
• Concern that credibility of existing recommendations may be compromised (Sauder K)
• Misunderstanding of FDA action taken regarding AOM (Cantekin E)
Clinical Studies ReviewedStudy Number
children enrolled
Control Vaccine
New Episode Interval
Case Definition
Regulatory Objective/ Other Information
Finnish OM 1,662† HBV 30 days Bacterial cultures
(myringotomy)
Demonstrate efficacy for prevention of AOM;
Kaiser
(NCKP)
34,146‡
MnCC 21 days Automated database search for AOM visits
Demonstrate efficacy for prevention of invasive disease, AOM, and pneumonia;
Large safety data base for assessing rates of adverse events;
Vaccines administered at 2, 4, 6, and 12-15 months of age in each study † Subjects distributed equally to PncCRM and HBV control vaccine; entire study was randomized 1:1:1,
PncCRM:PncOMP:HBV. ‡ Subjects randomized equally to 7VPnC or MnCC control vaccine.
Outline of FDA Presentation
• Introduction
• Efficacy data from Finnish OM study
• Supplementary analyses
• Finnish follow-up study
• Efficacy data from the NCKP study
• Safety data from Finnish OM study
• Considerations
• Questions to the Committee
Finnish OM Study—Primary Objective
Determine the protective efficacy of the
pneumococcal conjugate vaccine against
culture-confirmed pneumococcal acute
otitis media (AOM) due to vaccine
serotypes
Finnish OM Study—Secondary Objectives
Determine:
• Efficacy using different levels of etiologic diagnosis
• Efficacy in preventing nasopharyngeal carriage
• Antibody response
• Safety and tolerability
Finnish OM Study: Elements of the Study Design
• Randomized equally to one of 3 vaccines:
PncCRM (Wyeth-Lederle)
PncOMP (Merck)
HBV (Control)
Only data relating to PncCRM were provided in the application
• Double-blind
• Healthy 2 month old infants enrolled
Finnish OM Study: Vaccine Schedule and Concurrent Immunizations
Age of child (months) Vaccines Administered
2 4 6 7 12 18 24
PncCRM/HBV + + + +
DTP-Hib + + + +
IPV + +
MMR +
Finnish OM study
Case surveillance and ascertainment
• Free access to study clinics 7 days/week
• Children brought to study clinics for respiratory infections or symptoms suggesting AOM
• Myringotomy with aspiration of middle ear fluid for culture, if AOM diagnosed at the visit
• If S. pneumoniae found, the serotype was determined
• Follow-up of each child until age 2 years
Finnish OM Study:
Clinical Definition of Acute Otitis Media
• Visually abnormal tympanic membrane (in regard to color, position, and/or mobility) suggesting effusion in the middle ear cavity
• And at least one of:
fever, ear pain, irritability, diarrhea, vomiting, acute otorrhea not caused by external otitis, or other symptoms of respiratory infection.
Finnish OM Study: AOM Efficacy Endpoints
Primary: AOM episodes due to vaccine serotypes
Secondary: • First and Subsequent AOM episodes due to vaccine
serotypes
Other:• AOM due to vaccine serotypes by dose• All pneumococcal AOM, regardless of serotype
(culture and/or PCR)• All AOM episodes with MEF, regardless of etiology• All AOM episodes regardless of etiology• Children with recurrent AOM
Finnish OM Study-
Definition of Primary Endpoint
AOM episode due to vaccine serotypes
At least 30 days since beginning of previous AOM due to the same serotype
Or, any interval for different vaccine serotype
Culture confirmed
Finnish OM Study:Primary Endpoint Definition
Finnish OM Study-Analysis of Primary Endpoint
• Generalized Cox regression model with Anderson-Gill counting method
• Risk of AOM estimated “piecewise”, i.e., from event to event
• Assumes proportional hazards between groups over time
• Robust variance estimates used to compensate for interdependency of events within subjects
• Provides average vaccine effect on AOM episodes
Finnish OM Study-Definitions of Follow-up Periods
• Per protocol (PP) follow-up:
Begins 2 weeks after the 3rd vaccine dose
• Intent-to-treat (ITT) follow-up:
Begins at time of 1st vaccine dose
Finnish OM Study:Selected Population Characteristics
HBV PncCRM Population Characteristic
N (%) N (%)
Gestational Age < 37 weeks 53 (6.4) 41 (4.9)
Birth weight < 2.5 kg 42 (5.1) 25 (3.0)
Prior AOM episodes 39 (4.7) 27 (3.2)
Finnish OM Study-Primary Analysis, AOM due to Vaccine Serotypes
Number of Episodes
Vaccine Efficacy
Follow-up
Period HBV PncCRM Estimate 95% CI
PP 250 107 57% 44, 67
AOM due to vaccine serotypes
ITT 292 135 54% 41, 64
Finnish OM Study-AOM due to Individual Vaccine Serotypes, (Intent-to-treat)
Number of Episodes
Vaccine Efficacy AOM Episode due to Serotype HBV PncCRM Estimate
95% CI
4 4 2 50% -172, 91
6B 61 12 80% 60, 90
9V 11 6 45% -66, 82
14 31 8 74% 34, 90
18C 18 7 61% 2, 85
19F 67 60 10% -32, 39
23F 104 40 62% 41, 75
Finnish OM Study-Secondary Analyses, First and Subsequent AOM Episodes due to Vaccine Serotypes
Number of Episodes
Vaccine Efficacy
Follow-up
Period HBV PncCRM Estimate 95% CI
PP 177 89 52% 39, 63 First AOM Episode due to Vaccine Serotype
ITT 196 109 48% 34, 59
PP 73 18 45% 5, 69 Subsequent AOM Episode due to Vaccine Serotype
ITT 96 26 49% 20, 67
Finnish OM Study-Efficacy for All Culture-Confirmed Pneumococci, Regardless of Serotype
Number of Episodes
Vaccine Efficacy Follow-up
Period HBV PncCRM Estimate 95% CI
PP 414 271 34% 21, 45 Culture-confirmed pneumococcal AOM
ITT 467 322 32% 19, 42
Finnish OM Study-Efficacy for Vaccine-Related Serotypes
Number of Episodes Vaccine Efficacy
Follow-up
Period HBV PncCRM Estimate 95% CI
PP 84 41 51% 27, 67 AOM due to vaccine-related serotypes ITT 90 50 44% 20, 62
Finnish OM Study-AOM due to Individual Vaccine-Related Serotypes, (Intent-to-treat)
Number of Episodes
Vaccine Efficacy AOM Episode due to Serotype HBV PncCRM Estimate
95% CI
6A 48 23 52% 17, 72
9N 9 2 78% -6, 95
18B 1 2 -101% -2108, 82
19A 28 22 21% -40, 56
23A 4 1 75% -149, 97
Finnish Otitis Media Study-Efficacy for Vaccine-Unrelated Pneumococcal Serotypes
Number of Episodes Vaccine Efficacy
Follow-up
Period HBV PncCRM Estimate 95% CI
PP 95 126 -34 -81, 0 AOM due to other than vaccine related serotypes
ITT 101 140 -39 -86, -3
Serotypes 3, 11, 15, 35 were the most common vaccine-unrelated serotypes identified.
Finnish Otitis Media Study-Efficacy for Recurrent AOM *
Number of Children with Recurrent AOM
Vaccine Efficacy
Follow-up
Period HBV PncCRM Estimate 95% CI
PP 149 123 16% -6, 35 Children with Recurrent AOM ITT 174 158 9% -12, 27
All causes of AOM contribute to Recurrent AOM definition.
Finnish Otitis Media Study-Efficacy for Other Planned Analyses
Number of Episodes
Vaccine Efficacy
Follow-up
Period HBV PncCRM Estimate (95% CI)
PP 1267 1177 7% -5, 17 AOM with MEF
ITT 1445 1390 4% -7, 14
PP 1345 1251 6% -4, 16 AOM regardless of etiology ITT 1532 1474 4% -7, 14
MEF= Middle Ear Fluid
Finnish OM Study-Efficacy for Nasopharyngeal Carriage of Vaccine Serotypes (per protocol)
No. Children % Carriage % Reduction
HBV PncCRM HBV PncCRM Estimate 95% CI
12 mos 809 801 12.2 10.1 17% -9, 37
18 mos 797 787 16.2 9.5 41% 23, 55
Finnish OM Study—Serum Geometric Mean Antibody Concentration (GMC) After 3rd and 4th Doses
Serotype
Post Dose 3 GMC(mcg/mL)
Post Dose 4 GMC(mcg/mL)
HBVN=52
PncCRMN=54
HBVN=54
PncCRMN=55
4 0.05 1.70 0.11 2.56
6B 0.09 2.00 0.16 9.05
9V 0.10 2.48 0.21 3.97
14 0.21 6.28 0.21 10.82
18C 0.08 3.55 0.10 6.51
19F 0.22 3.28 0.41 4.96
23F 0.10 2.51 0.15 6.25
Finnish OM Study—Serum Antibody Concentrations (GMC)
and Serotype-Specific Efficacy
GMC (mcg/mL)
Serotype
Serotype-specific efficacy estimate
(Per Protocol) Post dose 3 Post dose 4
4 49% 1.70 2.56
6B 84% 2.00 9.05
9V 54% 2.48 3.97
14 69% 6.28 10.82
18C 58% 3.55 6.51
19F 25% 3.28 4.96
23F 59% 2.51 6.25
Finnish Otitis Media Study—Invasive Disease Due to Pneumococcus
Study group
Serotype Clinical syndrome
Age
(months)
PncCRM 7* Bacteremia 19
HBV 15* 23F 19F
Meningitis Meningitis Bacteremia
8 14 9
* Non-vaccine serotypes
Finnish Otitis Media Study: Review Issues and Supplementary Analyses
Finnish OM Study: Analysis of CovariatesEfficacy Estimates Adjusted for Gender, AOM Prior to Enrollment, Gestational Age, Birth Weight, Daycare, Breast-feeding, and Household Smoking
Vaccine Efficacy (95% CI) Outcomes Analyzed under Intent-to-treat
Un-adjusted for Covariates
Adjusted for Covariates
AOM due to Vaccine Serotypes 54% (41, 64) 54% (41, 64)
Culture-confirmed Pneumo. AOM 32% (19, 42) 32% (20, 43)
AOM Regardless of Etiology 4% (-7, 14) 5% (-6, 14)
Finnish OM Study: Example from the Data, Multiple Episodes Due to Same Serotype
Subject ID Vaccine Group Culture Age at AOM
23F 335
23F 347
1680
HBV 23F 355
23F 374
23F 462
23F 677
Finnish OM Study: Examples from the Data, Multiple Episodes Due to Same Serotype
Subject ID Vaccine Group Culture AOM Age
1450 PncCRM 23F 268
23F 344
23F 665 15 163
2241 PncCRM 15 227
15 267
Finnish OM Study—Supplementary Analysis: Subsequent AOM Episodes due to Same Serotype Excluded, Vaccine Serotypes (PP)
Number of Episodes
Vaccine Efficacy Inclusion/ Exclusion of Multiple Episodes of Same Serotype HBV PncCRM Estim. 95% CI
Per Analysis Plan 250 107 57% 44, 67
Exclude subsequent episode due to same serotype
216 95 55% 43, 65
Finnish OM Study—Supplementary Analysis: Subsequent AOM Episodes due to Same Serotype Excluded, All Pneumococcal Serotypes (Per Protocol)
Number of Episodes
Vaccine Efficacy Inclusion/ Exclusion of Multiple Episodes of Same Serotype HBV PncCRM Estim. 95% CI
Per Analysis Plan 414 271 34% 21, 45
Exclude subsequent episode due to same serotype
374 245 34% 21, 44
Finnish OM Study—Supplementary Analysis: Pneumococcal AOM by PCR/Culture
Number of Episodes Vaccine Efficacy Method of Diagnosis
Follow-up
Period HBV PncCRM Estimate 95%CI
PP 414 271 34% 21, 45 Culture
ITT 467 322 32% 19, 42
PP 678 541 20% 7, 31 PCR
ITT 764 635 18% 5, 29
PP 687 548 20% 7, 31 Culture or PCR ITT 775 642 18% 5, 29 PCR based on pneumolysin gene.
Finnish OM Study—Supplementary Analysis*: Antibiotic Use
Number (%) of Subjects Who Had Antibiotics During ITT Follow-up
HBV (N=831)
PncCRM (N=831)
P-Value
AOM Treatment**
589 (71%) 551 (66%) 0.051
AOM Prevention**
143 (17%) 132 (16%) 0.509
Other Purposes
147 (18%) 157 (19%) 0.568
Regardless of Purpose
605 (73%) 578 (70%) 0.159
P-value based on Fisher’s exact test. * Analysis requested by FDA post-unblinding. ** All etiologies of AOM.
Finnish OM Study-Supplementary Analysis: First Tympanostomy Tube Placement
HBV PncCRM
Number of Randomized Subjects 831 831
Number of Subjects with Events 161 153
Incidence of First Tube Placement 0.12 0.11
Finnish OM Follow-up Study—Tympanostomy Tube Placement
• To assess long-term effect of vaccine on procedures for ear tube placement
• Children evaluated at 4-5 years of age
• Unblinded
• Two populations evaluated:
Volunteers in follow-up study, N= 756
Original randomized population, N= 1662
Finnish OM Follow-up Study—Primary Analysis, Rate of Ear Tube Placement among Children Enrolled in Follow-up Study
Vaccine Efficacy
HBV
PncCRM Estimate 95% CI
Number of children enrolled 353 403
Rate of events (/100 child years)
ITT Follow-up 2 months- 2 years 14.8 12.9 12% -17, 34
Long-term Follow-up, 2 years-4 to 5 years 5.7 3.5 39% 4, 61
Finnish OM Follow-up Study—Secondary Analysis, Rate of Ear Tube Placement among All Children Followed to 4-5 years of Age
Vaccine Efficacy HBV PncCRM
Estimate 95% CI
Number of children enrolled 831 831
Rate of events,
ITT Follow-up, 2months-2years
12.7 12.0 4% -19, 23
Number of children available for follow-up 744 746
Rate of events,
Long-term Follow-up, 2 years- 4 to 5 year
4.1 2.4 44% 19, 62
Rate as per 100 child years.
Northern California Kaiser Permanente (NCKP) Otitis Media Efficacy Results
Northern California Kaiser Permanente (NCKP) Study: Elements of Study Design• Randomized, double-blind• Investigational meningococcal C conjugate vaccine
control• AOM a secondary endpoint• No standardized AOM clinical case definition• No tympanocentesis or routine culture of MEF• Automated database searches to identify OM
diagnoses
NCKP Study: Case Definitions
AOM Diagnosis: Based on clinical practice
AOM Episode: A clinic visit at which AOM was diagnosed, and at least 21 days had elapsed since any previous visit for AOM
Frequent AOM: 3 AOM episodes within 6 months, or 4 episodes within 12 months
NCKP Study: Prospectively Defined AOM Endpoints
Primary: All AOM episodes
Secondary:
• First AOM episode• Frequent AOM • First tympanostomy tube • All OM clinic visits• Ruptured ear drums
NCKP Study: Primary Analysis,Overall Reduction in AOM Episodes
Number of Episodes
Vaccine efficacy Reduction in All AOM Episodes
7VPnC MnCC % Reduction
95% CI
Per protocol 16,124 17,405 7.0% 4.1, 9.7
Intent-to-treat 25,590 27,199 6.4% 3.9, 8.7
Estimates of relative risk based on Andersen-Gill counting process over time with treatment as the only covariate.
NCKP Study: Secondary Analysis,Reduction in Risk of at Least 1 Episode
Number of Children with 1 Episode
Vaccine efficacy Reduction in Risk of 1 AOM Episode 7VPnC MnCC %
Reduction 95% CI
Per protocol 7,126 7,411 5.4% 2.3, 8.4
Intent-to-treat 10,112 10,394 4.9% 2.3, 7.5
Estimates of relative risk and confidence intervals based on Cox-regression model of hazard over time, with gender as covariate.
NCKP Study: Frequent Acute Otitis Media
Number of Children with Frequent AOM
Vaccine Efficacy
Frequent AOM 7VPnC MnCC % Reduction
95% CI
Per protocol 1,647 1,809 9.5% 3.2, 15.3
Intent-to-treat 2,612 2,839 9.2% 4.3, 13.9
Estimates of relative risk and confidence intervals based on Cox-regression model of hazard over time, with gender as covariate.
NCKP Study: First Tympanostomy Tube Placement
Number of Children with Tube Placement
Vaccine Efficacy Reduction in First Tympanostomy Tube Placement 7VPnC MnCC %
Reduction 95% CI
Per protocol 157 198 20% 2, 35
Intent-to-treat 192 240 21% 4, 34
Estimates of relative risk and confidence intervals were based on Cox regression model of hazard over time.
NCKP Study: Ruptured Ear Drums with Pneumococcus Isolated
Number of Ruptured Ear
Drums
Vaccine efficacy Ruptured Ear Drums
7VPnC MnCC Estimate 95% CI
Vaccine Serotypes
Per Protocol 4 9 56% -59, 90
Intent-to-treat 6 14 57% -19, 86
All Pneumococcal Serotypes
Per Protocol 5 13 62% -15, 89
Intent-to-treat 7 18 61% 24, 86
Confidence limits based on exact binomial distributions.
NCKP Study: Serotype Distribution of Ruptured Ear Drums with Pneumococcus Isolated (ITT)
Number of cases due to each serotype
Serotype
7VPnC MnCC
19F 6 7
14 0 4
9V 0 1
23F 0 2 Total of Vaccine Serotypes
6 14
Total of All Pneumococcal Serotypes
7 18
One non-vaccine serotype isolated (19A).
NCKP Study: Efficacy Through Extended Follow-up (ITT)
Efficacy Estimates (95% CI)
April 30, 1998 April 20, 1999
All AOM Episodes
6.4% (3.9%, 8.7%)
5.9% (3.8%, 7.9%)
First AOM Episode
4.9% (2.3%, 7.5%)
4.4% (2.1%, 6.7%)
First Ear Tube Placement
20.6% (4.0%, 34.3%)
23.2% (11.3%, 33.5%)
Frequent AOM 9.2% (4.3%, 13.9%)
10.2% (6.3%, 13.9%)
Ruptured Ear, Vaccine Serotype
57.1% (-18.7%, 86.5%)
66.7% (12.3%, 89.2%)
Summary of Efficacy Estimates (ITT)
Outcome Finnish NCKP
Vaccine Serotypes 54% NA
First Episode Vaccine Serotypes
48% NA
All S. pneumo, Culture- Confirmed
32% NA
Recurrent OM* 9%** 9%
Tympanostomy Tube 4%** 21%
All Cause OM 4%** 6%
First Episode All Cause AOM NA 5%
* All cause otitis media
** Not statistically significant at p=0.05
NA = Not available
Finnish Otitis Media Study: Safety Analysis
Finnish OM Study: Safety Analysis
Relevance of safety data to US population is limited:
Use of concurrent DTwP-Hib combination vaccines for first 3 doses, rather than DTaP, complicates assessments of systemic reactions
Homogeneous study population
Study not large enough to detect uncommon adverse events
Finnish OM Study: Safety Analysis, Local and Systemic Reactions, First 3 Doses
Dose 1 Dose 2 Dose 3
PncCRM
N=825
%
HBV
N=825
%
p-
value1
PncCRM
N=818
%
HBV
N=826
%
p-
value1
PncCRM
N=817
%
HBV
N=816
%
p-
value1
Fever 38C 14.3 9.3 0.01 18.4 12.7 <0.01 23.5 13.3 <0.01
Fever 39C 0.4 0.2 1 1.0 0.5 0.38 2.0 0.5 0.01
Crying increased
41.6 36.4 0.03 42.0 32.9 <0.01 39.6 30.6 <0.01
Crying > 4 hrs 0.6 0.4 0.72 0.5 0.1 0.37 0.4 0.1 0.62
Pain 3.4 1.9 0.09 3.7 0.7 0.02 5.1 2.8 0.02
Redness (Any) 14.2 9.3 <0.01 16.0 12.6 0.06 20.0 15.9 0.02
2.5 cm 0 0.1 1 0.2 0.2 0.62 0.4 0.0 0.25
Swelling (Any) 4.7 1.7 <0.01 4.0 3.0 0.16 4.8 3.6 0.19
2.5 cm 1.0 0.1 1 0.9 0.4 0.33 0.5 0.2 0.68
Number of subjects may vary slightly depending on reports received.
1 P-value based on Chi square test.
Finnish OM Study: Safety Analysis, Local and Systemic Reactions, 4th Dose
Dose 4 (12 months)
PncCRM N=798
%
HBV N=798
%
p-value1
11.5 6.9 <0.01 Fever 38C 39C 1.6 1.7 0.97
28.2 19.3 <0.01 Crying increased Crying > 4 hours 0 0 NA Pain 7.5 2.3 <0.01
14.7 14.4 0.60 Redness (Any) 2.5 cm 0.8 0.0 0.04
4.9 5.4 0.83 Swelling (Any) 2.5 cm 1.3 0.4 0.09
1 p-valus derived from Ch-square test.
Total number monitored varied from 771-798, depending on number of completed
reports received.
Finnish OM Study: Safety Analysis, Conclusions
• Safety data are consistent with earlier observations regarding the safety of Prevnar
• Increased rate of low-grade fever
• Complications of post-vaccination fever were uncommon
• No new safety concerns were identified
Considerations
Required Level of Efficacy
The minimum level of efficacy required for
licensure of a preventive vaccine is not
specifically addressed by FDA regulations
or published guidance.
Considerations: Licensure of Other Pneumococcal Vaccines for Otitis Media
• AOM indication should stand on its own.
• License applications for new pneumococcal vaccines for prevention of AOM may not include evidence of efficacy for prevention of invasive disease.
• If approved, a level of efficacy, preferred endpoints, and type of data (number of trials) sufficient for approval for AOM would be established.
• Prevention of more AOM episodes with less vaccine- serotype-specific efficacy is a possible scenario.
Considerations: Description of the treatment effect
• Primary outcomes in NCKP study and Finnish OM study differ
• Prevention of AOM due to vaccine serotypes does not capture:
Positive treatment effect on vaccine-related pneumococcal serotypes
Negative efficacy for unrelated pneumococcal serotypes
• Efficacy estimates relatively low for some outcomes• Confidence intervals wide for some outcomes
Considerations:
Clinical benefit vs. economic benefit
• Substantial evidence of clinical benefit must be provided from adequate and well-controlled studies.
• Economic benefit is not considered in the
efficacy evaluation by FDA.
Considerations: Marketing Implications
• Promotional materials based on approved labeling
• Potential for unrealistic expectations
• FDA is empowered to restrict marketing claims:
Advertisements and promotional labeling are reviewed by CBER
Advertisements that are misleading (defined in 21 CFR 202.1) can result in a product being misbranded. If a company fails to correct such violations, CBER is empowered to take multiple corrective actions (21 CFR 601.5 and 601.6).
Questions to the Committee
1. Are the data adequate to support the efficacy of Prevnar in infants and toddlers for prevention of otitis media caused by Streptococcus pneumoniae due to capsular serotypes included in the vaccine (4, 6B, 9V, 14, 18C, 19F, 23F)?
If not, would additional analyses from the Finnish otitis media study, the Northern California Kaiser Permanente efficacy study, or additional clinical trials be useful in establishing efficacy?
Questions to the Committee (cont.)
2. Please discuss the strength of the data with respect to secondary otitis media outcomes:
a. Acute otitis media episodes caused by S. pneumoniae, regardless of serotype
b. Overall reduction in acute otitis media episodes
c. Frequent otitis media
d. Tympanostomy tube placement