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Epidemiology of Pneumococcal Disease in the U.S. in the Conjugate Vaccine Era

Food and Drug AdministrationCenter for Biologics Evaluation and Research

Vaccines and Related Biological Products Advisory CommitteeNovember 18, 2009Bethesda, Maryland

Matthew R. Moore, MD, MPHCDR, USPHS

Respiratory Diseases BranchNational Center for Immunization & Respiratory Diseases

Centers for Disease Control and Prevention

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Questions

• How has the epidemiology of pneumococcal disease in the U.S. changed since PCV7 introduction?

• What opportunities for prevention remain?

• If PCV13 is licensed, how will CDC evaluate its effectiveness?

• What role, if any, might PCV13 play during the current influenza pandemic?

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How has the epidemiology of pneumococcal disease in the U.S. changed since PCV7 introduction?

• Nasopharyngeal colonization

– Effects of PCV7 on colonization, including serotype replacement

– Population-level trends since PCV7 introduction

• Acute otitis media

– Trends in pneumococcal serotypes since PCV7 introduction

– Trends in otitis media visits & antibiotic prescriptions

• Invasive pneumococcal disease

– Trends since PCV7 introduction

– Post-marketing study of vaccine effectiveness

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Colonization & Acute Otitis Media

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Challenges of Evaluating Effects of PCV7 on Acute Otitis Media caused by Streptococcus pneumoniae

• Precise diagnosis of acute otitis media

• Distinguishing colonization from infection

• Rates vs. proportions

• Assumption of stable clinical practices

• Care-seeking as confounder between vaccine exposure & diagnosis of acute otitis media

• Paucity of clinical isolates

• Limited serotyping capacity at state, local, national levels

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Changes in Visits for Acute Otitis Media among Children <2 years old Pre- & Post-PCV7

• Administrative data TN & NY 1998-2002– Outpatient AOM visits: 62 & 396 fewer per 1,000 children– Frequent OM visits: 17% & 28% reductions– Pressure-equalizing tube insertions: 16% & 23% reductions

• NAMCS/NHAMCS, 2002-03 vs. 1994-99 – Ambulatory visits: 20% reduction (95% CI 2-38)– No change in rates of other acute respiratory infections

• MarketScan Database, 2004 vs. 1997-99,– Ambulatory visits: 43% reduction– Antibiotic prescriptions: 42% reduction– Direct medical expenditures: 32% reduction

Poehling, Pediatrics 2004;114:755-6. Grijalva, Pediatrics 2006;118:865-73. Poehling, Pediatrics 2007;119:707-115. Zhou, Pediatrics 2008;121:253-60.

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Summary of findings: Acute Otitis Media

• Studies evaluating serotypes causing AOM consistently show reductions in PCV7-type AOM following PCV7 introduction

• Non-PCV7 serotypes have increased modestly in some studies, including one in the absence of PCV7

• Overall visits for AOM lower since PCV7 introduction– Potential role of change in treatment guidelines?– Potential role of appropriate antibiotic use programs?

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Invasive Pneumococcal Disease

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Case-control study of PCV7 using ABCs: Methods

Cases:• Identified between Jan 2001 and May 2004• Pneumococcus isolated from a normally sterile site• Resident of ABCs area on culture date• 3-59 months old on culture date• Pneumococcal isolate available for serotyping

Controls:• Identified through birth certificate records• 3 controls for each case matched by

age (DOB within 14 days of the case) zip code (mother’s zip code of residence at the time of birth

matched to zip code of case on culture date)

Whitney et al., Lancet 2006;368:1495-1502

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Effectiveness by serotype and presence of underlying medical conditions

Serotype

Vaccinated (>1 dose) vs. unvaccinated

VE (95%CI)

All Underlying medical

condition*

No medical condition

All 72 (65,78) 77 (62, 87) 71 (63, 78)

Vaccine type a - 81 (57, 92) 96 (93, 98)

Vaccine related 43 (6, 66) 35 (-151, 83) 44 (5, 67)

Non-Vaccine b - 77 (32, 92) -36 (-122, 17)

N=782 cases and N=2512 controls*Case/control sets with chronic or immunocompromising medical condition presenta p=0.0014 and b p=0.002 for interaction b/w vaccination and underlying conditions; overall estimates not reported

Whitney et al., Lancet 2006;368:1495-1502

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Effectiveness of different infant schedules

Schedule, by months of age at time of doses

Effectiveness, %

95% confidence

interval

1 dose ≤7 months 73 43, 87

2 doses ≤7 months 96 88, 99

3 doses ≤7 months 95 88, 98

1 dose ≤7 months, 1 dose 8-11 months, 1 dose 12-16 months

100 88, 100

2 doses ≤7 months, 1 dose 12-16 months 98 75, 100

3 doses ≤7 months, 1 dose 12-16 months 100 94, 100

1 dose 7-11 months, 2 doses 12-16 months 98 83, 100

Whitney et al., Lancet 2006;368:1495-1502

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Serotype-specific effectiveness of >1 dose PCV7 against invasive pneumococcal disease

Vaccine effectiveness / efficacy, % (95%CI)

Serotype CDC / ABCs NCKP Trial 2000

All PCV7 types

Healthy: 96 (93-98)

Underlying illness: 81 (57-92)

94 (80-98)

4 93 (65-99) --

6B 94 (77-98) 86 (-11,100)

9V 100 (88-100) 100 (-142,100)

14 94 (81-98) 100 (60,100)

18C 97 (85-99) 100 (49,100)

19F 87 (65-95) 85 (32,98)

23F 98 (80-100) 100 (15,100)

Whitney et al., Lancet 2006;368:1495-1502 & Black PIDJ 2000

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Summary of findings: Invasive Disease

• Rates of invasive pneumococcal disease among young children in the U.S. have declined dramatically since PCV7 introduction.

• Rates of non-PCV7 type IPD (especially serotype 19A) have increased modestly compared to reductions in PCV7-type IPD.

• Substantial reductions also observed among persons too old to receive PCV7 indirect effects.

• Post-licensure vaccine effectiveness studies suggest robust individual level protection, even with reduced-dose schedules.

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What opportunities for prevention remain?

• Population still at risk of pneumococcal disease

• Invasive pneumococcal disease caused by 6 serotypes unique to PCV13

• Other manifestations of pneumococcal disease

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Key epidemiologic features of 6 serotypes unique to PCV13

• Serotype 1: Classic epidemic serotype; now rare in U.S.; exquisitely susceptible to antibiotics

• Serotype 3: Strongly associated with mucosal disease, though also causes IPD

• Serotype 5: Another epidemic serotype; rare in U.S. but very important in developing countries

• Serotype 6A: Common cause of IPD globally• Serotype 7F: Common in carriage & IPD; outbreak type• Serotype 19A: Equally good at causing colonization vs.

IPD; diverse genetic background, especially since 2000; antibiotic resistance highly prevalent; most common serotype in U.S. IPD cases

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Conclusions regarding remaining opportunities for prevention

• Most children still at risk of IPD are healthy & bacteremia (with or without another source) is still the most common manifestation of IPD.

• Serotypes 19A, 7F, and 3 make up majority of IPD caused by PCV13 types.

• Disease & economic burden greatest among adults: How much can be prevented through herd immunity?

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If PCV13 is licensed, how will CDC evaluate its effectiveness?

• Routine surveillance through ABCs– Trends over time, by age & serotype– Cases of PCV13 type IPD among vaccinees

• Case-control study– Estimate vaccine effectiveness– Risk factors for IPD among remaining cases

• Carriage study: Atlanta Metro Area only

• Routine surveillance among Alaska Natives through the Arctic Investigations Program

• Assessment of administrative databases for otitis visits & pneumonia visits & admissions

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Post-licensure study of PCV13 effectiveness

• Objective: Estimate effectiveness of >1 doses of PCV13 against IPD caused by serotypes included in PCV13

• Design: Matched case-control study following routine introduction in the U.S.

• Participants: Children identified as having IPD through routine surveillance in ABCs sites, LA County, & Utah. Controls identified from birth certificates.

• Secondary objectives: – Serotype-specific effectiveness: types 19A, 7F, & 3 – Effectiveness of different schedules– Effectiveness in healthy children & children with

underlying conditions

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Evidence for Bacterial Co-infection among Fatal Cases of Pandemic Influenza A(H1N1)

• Autopsy specimens from 77 patients May 1-August 20, 2009

• All confirmed pandemic H1N1 infection

• 22* (29%) with bacterial co-infection

– 10 S. pneumoniae

– 6 S. pyogenes

– 7 S. aureus

• Ages 2 months-56 years

MMWR 2009;58(38):1071-1074 *Some with >1 bacterial pathogen

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Policy Options for Use of Pneumococcal Vaccines during the Influenza Pandemic

• Expand use of PCV7– Very little PCV7-type disease remaining– Off-label

• Expand use of PPV23– Intensive efforts underway– Already recommended for high-risk 2-64 year-olds– 16% coverage among 18-49 year-olds with ACIP indications Unclear

extent to which coverage can be increased– Questions about effectiveness among high-risk populations– http://www.cdc.gov/h1n1flu/guidance/ppsv_h1n1.htm

• PCV13 depending on– Licensure– ACIP Recommendations: being drafted– Supply

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AcknowledgementsABCs Surveillance

The views expressed in this presentation are those of the presenter and do not necessarily reflect the views of the Centers for Disease Control & Prevention or the Department of Health &

Human Services.

ABCs sites Joan Baumbach CDC

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