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