1. Epidemiology of Pneumococcal Disease in the U.S. in the Conjugate Vaccine Era Food and Drug Administration Center for Biologics Evaluation and Research Vaccines and Related Biological Products Advisory Committee November 18, 2009 Bethesda, Maryland Matthew R. Moore, MD, MPH CDR, USPHS Respiratory Diseases Branch National Center for Immunization & Respiratory Diseases Centers for Disease Control and Prevention

2. 22 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?

3. 3 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

4. 44 Colonization & Acute Otitis Media

5. 5 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

6. 6 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.

7. 7 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?

8. 88 Invasive Pneumococcal Disease

9. 9 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

10. 10 Effectiveness by serotype and presence of underlying medical conditions Serotype Vaccinated (>1 dose) vs. unvaccinated VE (95%CI) AllUnderlying medical condition* No medical condition All72 (65,78)77 (62, 87)71 (63, 78) Vaccine type a -81 (57, 92)96 (93, 98) Vaccine related43 (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 present a 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

11. 11 Effectiveness of different infant schedules Schedule, by months of age at time of doses Effectiveness, % 95% confidence interval 1 dose ≤7 months7343, 87 2 doses ≤7 months9688, 99 3 doses ≤7 months9588, 98 1 dose ≤7 months, 1 dose 8-11 months, 1 dose 12-16 months 10088, 100 2 doses ≤7 months, 1 dose 12-16 months9875, 100 3 doses ≤7 months, 1 dose 12-16 months10094, 100 1 dose 7-11 months, 2 doses 12-16 months9883, 100 Whitney et al., Lancet 2006;368:1495-1502

12. 12 Serotype-specific effectiveness of >1 dose PCV7 against invasive pneumococcal disease Vaccine effectiveness / efficacy, % (95%CI) SerotypeCDC / ABCsNCKP Trial 2000 All PCV7 types Healthy: 96 (93-98) Underlying illness: 81 (57-92) 94 (80-98) 493 (65-99)-- 6B94 (77-98)86 (-11,100) 9V100 (88-100)100 (-142,100) 1494 (81-98)100 (60,100) 18C97 (85-99)100 (49,100) 19F87 (65-95)85 (32,98) 23F98 (80-100)100 (15,100) Whitney et al., Lancet 2006;368:1495-1502 & Black PIDJ 2000

13. 13 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.

14. 14 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

15. 15 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

16. 16 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?

17. 17 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

18. 18 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

19. 19 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

20. 20 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.htmhttp://www.cdc.gov/h1n1flu/guidance/ppsv_h1n1.htm PCV13 depending on –Licensure –ACIP Recommendations: being drafted –Supply

21. 21 Acknowledgements ABCs 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 sitesJoan BaumbachCDC Monica FarleySue JohnsonCynthia Whitney Wendy BaughmanBill SchaffnerChris Van Beneden Nana BennettBrenda BarnesBernard Beall Shelley ZanskyKen GershmanElizabeth Zell Matt CartterB. KoziolTamara Pilishvili Lee HarrisonB. JuniCarolyn Wright Ann ThomasLesley McGee Art ReingoldUTHSC San AntonioKarrie-Ann Toews Pam DailyJim JorgensenEmily Weston Ruth LynfieldLettie McElmeelDee Jackson Catherine LexauSharon Crawford John Besser