1. New Vaccines for Preventing Bacterial Respiratory Infections Cynthia Whitney Centers for Disease Control and Prevention Atlanta, GA National Immunization Conference March 2007

2. Bacterial Respiratory Pathogens Targeted by New Vaccines Haemophilus influenzae type b (Hib) –New pediatric combination (Pentacel®) Pertussis –New pediatric combination (Pentacel®) –Tdap for adolescents and adults Streptococcus pneumoniae (pneumococcus) –Conjugate vaccine for children

3. Hi Incidence* in Children <5 Years, By Year and Serotype *From CDC’s Active Bacterial Core surveillance (ABCs)

4. Pentacel ® Introduction DTaP-IPV-Hib sanofi pasteur submitted a Biological License Application for 4-dose primary series in children 2, 4, 6, and 15-18 months Thanks to Pat Joyce

5. Pentacel ® in 2007 Childhood Schedule

6. Next Steps Form ACIP combination vaccines working group Review data on immunogenicity and safety Consider need to update combination vaccines statement

7. Global status of countries using Hib vaccine in their national immunization system, 2006 YesNo Routine Hib implementation status GAVI Fund Supported Introduced or plan to introduce in 2006 Source: WHO/IVB database Data as of April 2006 92 countries are using Hib vaccine

8. Reported Pertussis Cases – United States, 1922-2005* DTP 11-18 yrs > 18 yrs < 11 yrs *1950-2005, National Notifiable Diseases Surveillance System and 1922-1949, passive reports to the Public Health Service, courtesy of Kristin Brown Tdap DTaP

9. Tdap Products Licensed in the United States BOOSTRIX ® (GlaxoSmithKline Biologicals) * ADACEL ® (sanofi pasteur) † Date of FDA licensure May 3, 2005June 10, 2005 Age Indication (years) 10–1811–64 UsageActive booster immunization for prevention of tetanus, diphtheria, and pertussis as a single dose † Product label available at http://www.vaccineplace.com/products/http://www.vaccineplace.com/products/ * Product label available at http://us.gsk.com/products/assets/us_boostrix.pdf http://us.gsk.com/products/assets/us_boostrix.pdf

10. Objectives of Adolescent and Adult Pertussis Vaccination Policy Primary objective - Protect vaccinated adolescent/adult against pertussis Secondary objective - Reduce the reservoir of pertussis in population –Decrease exposure of persons at increased risk for complicated infection –Reduce the cost and disruption of pertussis in health-care settings

11. Tdap Target Groups Adolescents Adults 18-64 years Pregnant women/new mothers Healthcare workers Licensed for single dose only Not yet licensed for adults 65+ years

12. Pneumococcal Conjugate Vaccine Introduction in the U.S. Feb 20007-valent vaccine (Prevnar TM ) licensed Mid-late 2000Recommendations for vaccine use in all children <2 + high risk 2-4 years Government purchasing Rapid increase in use Aug 2001-May 2003, 2004 Shortages 200583% of children 19-35 months had received 3 or 4 doses

13. Areas OR (3 counties) CA (1 county) MN (7 counties) GA (20 counties) MD (6 counties) CT (entire state) NY (7 counties) TN (10 counties) CO (8 counties) NM (entire state) Active Bacterial Core Surveillance (ABCs) Emerging Infections Program Network Established

14. Effect in Target Age Group Invasive Pneumococcal Disease Rates in Children <5 Years, ABCs, 1998-2005 <1 yr 2 yrs 3 yrs 4 yrs 1 yr - 77% (<1 yr) - 82% (1 yr) - 75% (2 yr) 2005 vs baseline - 61% (3 yr) - 26% (4 yr) PCV7

15. Vaccine-Type Invasive Disease in Children <5 Years ABCs 1998-2005 CDC unpublished data and MMWR Sep 16, 2005 98% reduction

16. What is Herd Immunity?

17. Susceptible Population

18. Herd immunity: Partially Vaccinated Population x xx

19. Evidence of herd immunity reducing disease among children Drop in VT disease in children outside vaccinated age group (~50% reduction in infants <2 mos and children 5-17 years) Observed reduction in VT disease in children > expected (77%) –Expected reduction = vaccine coverage (83% 3+ doses) X vaccine efficacy (92%) Poehling K et al, JAMA 2006

20. Replacement (ri‘ pleys munt) 1.[n] a person or thing that takes or can take the place of another 2.[n] an event in which one thing is substituted for another www.hyperdictionary.com

21. Relative Magnitude of Changes by Serotype in <2 year olds, ABCs 1998/1999 (Baseline) vs. 2005 TypeCases/100,000 pop% change 95% CI Rate Diff. Baseline2005 Vaccine1602-99-99, -98-158 VR* w/o 19A 131-93-96, -77-12 19A515+180+95, +303+10 Other non- vaccine 1321+66+28,+116+8 *Same serogroup as vaccine type

22. V T Transmission from Children to Adults +

23. Herd Effect in Adults Invasive Pneumococcal Disease Rates over Time ABCs, 1998-2005 65+ years 18-39 yrs 40-64 yrs - 34% - 16% - 48% 2005 vs. baseline PCV7 Lexau et al. JAMA 2004 and unpublished data

24. Herd Effect in Adults 65+ Years PCV7 types vs. nonvaccine types ABCs 1998/99 average vs. 2005 SerotypeCases/100,000 popPercent change 95% CI Baseline2005 Vaccine346-82-85, -78 Nonvaccine2633+26+14, +39 Lexau et al. JAMA 2005 and unpublished data

25. Next steps Improve coverage in the U.S. Continue to track replacement disease Introduction of conjugate vaccines in more countries Evaluate how results in other settings compare to the U.S.

26. Multi- national Launched Clinical trial Phase III Clinical trial Phase II Clinical trial Phase I 9-valent 11-valent GSK 1 10- valent Prevnar (7-valent) 13-valent 7-valent Pre-clinical stage >5 mulit-valent conjugate vaccine projects Emerging suppliers Expected launch 2008 ~20 vaccines in research/ Pre-clinical stage (includes conjugate & protein-based vaccines) Discontinued 1 Completed first Phase III trial; results announced in Jun05 Development Stage Vaccine Supply Environment Pneumococcal vaccine pipeline Source: BCG Global Supply Strategy 2005 PneumoADIP team analysis

27. Acknowledgements ABCs Surveillance CDC Chris Van Beneden Anne Schuchat Elizabeth Zell Tamara Pilishvili Moe Kyaw Katherine Robinson Tami Skoff Carolyn Wright Brendan Noggle John Walls Dick Facklam LaShondra Shealey Dee Jackson ABCs sites Monica Farley Wendy Baughman David Stephens Nana Bennett Shelley Zansky Nancy Barrett Jim Hadler Lee Harrison Lauri Thompson Sanza Karen Stefonek Paul Cieslak Art Reingold Pam Daily Ruth Lynfield Catherine Lexau John Besser Sue Johnson Pam Gahr Allen Craig Bill Schaffner Brenda Barnes Matt Finke Ken Gershman B. Koziol B. Juni UTHSC San Antonio Jim Jorgensen Lettie McElmeel Sharon Crawford Emory University Keith Klugman

28. Pneumococcal Conjugate Vaccine Effectiveness Study Primary objective: Effectiveness against invasive disease caused by vaccine serotypes Secondary objectives –Effectiveness against individual types –Effectiveness of various schedules Whitney et al Lancet 2006

29. Results Enrollment: 782 cases (70% of eligible cases with isolates) 2512 matched controls (60% of eligible controls located for enrollment) 90 cases had 1-2 controls enrolled per case 693 cases had ≥ 3 controls per case Whitney et al Lancet 2006

30. 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

31. Effectiveness by Serotype Serotype Vaccinated (>=1 dose) vs. unvaccinated Discordant sets, N VE (95%CI )* Vaccine Types 41993 (65,99) 6B3294 (77,98) 9V20100 (88,100) 144794 (81,98) 18C3097 (85,99) 19F3487 (65,95) 23F1898 (80,100) Vaccine related 6A2676 (39,90) 19A4626 (-45,62) N=782 cases and N=2512 controls *Adjusted for underlying conditions

32. Effectiveness against Vaccine Types by Number and Timing of Doses Schedule, by months of age at time of doses Effectiveness, %95% confidence interval, % Infant schedules 1 dose ≤7 months7343, 87 2 doses ≤7 months9688, 99 3 doses ≤7 months9588, 98 1 dose ≤7 months, 1 dose 7-11 months, 1 dose 12-16 months* 10088, 100 2 doses ≤7 months, 1 dose 12-16 months 9986, 100 3 doses ≤7 months, 1 dose 12-16 months* 10094, 100 * ACIP recommended schedules Whitney et al Lancet 2006

33. Summary Vaccine highly effective in preventing IPD due to vaccine serotypes Vaccine effective against IPD due to vaccine-related serotype 6A but not 19A Different schedules also highly effective Some evidence of an added benefit from a booster dose at >12 months

34. Indirect Effects in Adults with HIV/AIDS Between 1999 and 2004, decline in invasive disease of 37% in those with HIV/AIDS 18-64 years Drop in vaccine-type disease in those with HIV/AIDS (-71%) same as in those without (-73%) Large increase in nonvaccine types in HIV/AIDS (+43%) vs no change in others (-7%) Flannery et al Annals Int Med 2005; CDC unpublished data

35. Penicillin Resistance in S. pneumoniae United States 1979-1999 1979-1994: CDC Sentinel Surveillance Network 1995-1999: CDC Active Bacterial Core Surveillance (ABCs) /Emerging Infections Program

36. Distribution of Pneumococcal Serotypes by Frequency and Penicillin Resistance Children <2 years, ABCs, 1999 Conjugate vaccine Not in vaccine

37. Invasive Disease in Children <2 years by Susceptibility to Penicillin Kyaw M et al, ABCs 2006 New Engl J Med Pen S Pen NS Vaccine introduced

38. Impact of Conjugate Vaccine on Pneumococcal Epidemiology Large declines in invasive disease rates in young children Shift in circulating serotypes has led to herd benefit in unvaccinated children and adults Indirect benefit in highly susceptible adults (HIV/AIDS) Fewer resistant infections But…. Replacement disease reduces benefit in some highly susceptible groups (HIV/AIDS)

39. Pertussis and Adults Pertussis (whooping cough) – a poorly controlled vaccine-preventable disease –Incidence increasing –In 2005, 25,616 US cases reported (40 year high) Adults vulnerable to pertussis –27% reported cases among adults –Pertussis immunity wanes 5 to 10 years after childhood DTaP* series First pertussis vaccines (Tdap) † for adolescents and adults licensed in 2005 *Diphtheria and tetanus toxoids and acellular pertussis vaccine † Tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine Slides thanks to Katrina Kretsinger

40. Pertussis Transmission to Infants Infants <12 months of age greatest risk for death and complications from pertussis –From 2000-2004 Accounted for 92 / 100 U.S. pertussis deaths Risk of death highest among youngest infants Over 60% infants with pertussis hospitalized Adults transmit to infants* –Among 264 known source-cases 55% identified as mother, father or grandparent 51% were adults >19 years of age * Bisgard KM, Pascual FB, Ehresmann KR, Miller CA, Cianfrini C, Jennings CE et al. Infant pertussis: who was the source? Pediatr Infect Dis J 2004; 23(11):985-989.

41. Pertussis in Health-Care Settings Health-care personnel (HCP) at increased risk of pertussis exposure and infection HCP can transmit to vulnerable patients, including infants Pertussis outbreaks reported in pediatric and adult inpatient wards, maternity units and obstetric units Infection control activities are resource- intensive, disruptive and costly

42. Clinical Pertussis Upper respiratory illness x 1-2 weeks, followed by cough illness –Median duration of cough illness >2 months Antimicrobials do not modify the course of illness after cough established –Will decrease infectivity of patients if given early Can result in repeated medical visits and time lost from work High risk groups for pertussis not well defined

43. Why Serotype 19A? Relatively common cause of disease before vaccine use Commonly carried Vaccine provides no cross protection Frequently antibiotic resistant Clonal expansion and possible capsular switching (Pai R et al J Infect Dis 2005)

44. Cost Effectiveness of PCV7 Before and After Incorporating Herd Effects G. Thomas Ray PIDJ 2006