1. Prevention of pneumococcal disease – What are the prospects? Allison McGeer, MSc, MD, FRCPC Mount Sinai Hospital University of Toronto Allison McGeer, MSc, MD, FRCPC Mount Sinai Hospital University of Toronto

2. ObjectivesObjectives l Review the benefits and limitations of current pneumococcal vaccines l Discuss the anticipated impact of newer conjugate vaccines, and future options l Review the benefits and limitations of current pneumococcal vaccines l Discuss the anticipated impact of newer conjugate vaccines, and future options

3. -Gram positive cocci - normal resident of human oropharynx - polysaccharide coat to evade phagocytosis ->90 serotypes - multiple other virulence factors

4. Annual rates of pneumococcal infection, developed world

5. 01,0002,0003,0004,0005,0006,0007,0008,0009,00010,000 Gonorrhea Adenovirus Chlamydia Legionella Tuberculosis Haemophilus influenzae Group A streptococcus Group B streptococcus Parainfluenza virus Respiratory syncytial virus Rhinovirus Clostridium difficile Influenza Staphylococcus aureus HIV/AIDS Escherichia coli Hepatitis B virus Human papillomavirus Streptococcus pneumoniae Hepatitis C virus HALYs YLL YERF

6. Age-Specific Incidence of Invasive Pneumococcal Disease, TIBDN, 1995

7. Introduction of pneumococcal vaccines Canada l 1983 – PPV23 licensed l 1996-9 – PPV23 programs for adults l 1983 – PPV23 licensed l 1996-9 – PPV23 programs for adults

10. How effective is pneumococcal vaccine? l Against pneumococcal pneumonia –Not effective (or effect <20% and not detectable) l Against invasive pneumococcal disease –CONTROVERSIAL –7 meta-analyses; 2 Cochrane reviews l Against pneumococcal pneumonia –Not effective (or effect <20% and not detectable) l Against invasive pneumococcal disease –CONTROVERSIAL –7 meta-analyses; 2 Cochrane reviews

11. PPV23 efficacy against IPD Indirect cohort analysis, TIBDN Vaccine efficacy Healthy adults >=65 years51% (33, 64) Immunocompromised patients 38% (5, 59) Against lab-confirmed pneumococcal pneumonia 31% (-18,60) 1. Butler JC JAMA 1993; 270(15):1826-31. 2. Andrews Vaccine. 2004 Nov 25;23(2):132-8. 3. Mooney JD BMC Infect Dis. 2008 Apr 23;8:53. 4. Lui, CIC 2006

12. Duration of effect Butler et al. Interval since Efficacy vaccine: <2 yrs 51% 2-4 yrs 54% 5-8 yrs 71% 9+ yrs 80% Butler et al. Interval since Efficacy vaccine: <2 yrs 51% 2-4 yrs 54% 5-8 yrs 71% 9+ yrs 80% Liu et al. Interval since Efficacy vaccine <3 yrs52% 3-5 yrs 47% >5 yrs 46%

13. Is hyporesponsiveness clinically significant? l Polysaccharide antigens can induce tolerance –Good evidence for meningococcal polysaccharide, some evidence for pneumococcal polysaccharide l BUT –Data not as convincing in adults –Some evidence that hyporesponsiveness may be time-limited –Likely to be different for different serotypes l Polysaccharide antigens can induce tolerance –Good evidence for meningococcal polysaccharide, some evidence for pneumococcal polysaccharide l BUT –Data not as convincing in adults –Some evidence that hyporesponsiveness may be time-limited –Likely to be different for different serotypes O’Brien K, Lancet Inf Dis 2007;7:597

14. Pneumococcal vaccination rates Eligible adults, Canada Risk GroupPercent ever vaccinated Canada 2001 Toronto 2002 BC 2008 >=65 years of age42%35-40%34% 15-64 years of age with chronic condition 15%12%10% Squires SG, CCDR 2001;27(10), Al-Sukhni, Vaccine 2007; NCS, 2008

15. Introduction of pneumococcal vaccines Canada l 1983 – PPV23 licensed l 1996-9 – PPV23 programs for adults l Dec 2001 – PCV7 licensed l Sep 2002-Jan 2005 – PCV7infant programs l 1983 – PPV23 licensed l 1996-9 – PPV23 programs for adults l Dec 2001 – PCV7 licensed l Sep 2002-Jan 2005 – PCV7infant programs

16. Serotype coverage Conjugate vs. polysaccharide vaccines PCV 46B9V1418C19F23F157F319A6A PPV 46B9V1418C19F23F157F319A 289N10A11A12F15B17F2022F33F

17. Vaccine Serotype Invasive Pneumococcal Disease Calgary 1998-2006 75.1% decrease p-value <0.001 27.8% decrease p-value =0.03

19. Invasive pneumococcal disease in adults Metropolitan Toronto/Peel region, 1995-2010

20. Pediatric IPD (<5yrs) post PCV7 introduction, Toronto

21. Invasive pneumococcal disease in adults Metropolitan Toronto/Peel region, 1995-2010

22. Age group Decline in rate of hospital admission for pneumonia (95% CL) <2 years39% (22,52) 18-39 years28% (4, 43) 40-64 years19% (-3, 35) >=65 years15% (-2, 30) Decline in pneumonia admissions after routine childhood immunization with PCV7 in USA Grijalva, Nuorti et al. Lancet 2007;369:1179

23. What are the future issues? l Will PCV13 serotypes be eradicated? –Will PCV13 be as successful as PCV7 has been for the additional serotypes? l How much serotype replacement will there be? –Likely to be greater in children then adults –Likely to be greater in pneumonia than IPD –What is the risk of emergence of virulent serotypes? l Will PCV13 serotypes be eradicated? –Will PCV13 be as successful as PCV7 has been for the additional serotypes? l How much serotype replacement will there be? –Likely to be greater in children then adults –Likely to be greater in pneumonia than IPD –What is the risk of emergence of virulent serotypes?

24. Where do we go from here? l Should we be recommending PPV23 and/or PCV13 in adults? –Awaiting PCV13 trial efficacy results –Re-assess efficacy/cost-effectiveness for PPV23 l Should we be recommending PPV23 and/or PCV13 in adults? –Awaiting PCV13 trial efficacy results –Re-assess efficacy/cost-effectiveness for PPV23

25. Opsonophagocytic antibodies Without Ab and C’ Pnc are not being engulfed With Ab and C’

26. Where do we go from here? l Should we be recommending PPV23 and/or PCV13 in adults? –Awaiting PCV13 trial efficacy results –Re-assess efficacy/cost-effectiveness for PPV23 l What can we do to more efffectively prevent all pneumococcal disease? l Should we be recommending PPV23 and/or PCV13 in adults? –Awaiting PCV13 trial efficacy results –Re-assess efficacy/cost-effectiveness for PPV23 l What can we do to more efffectively prevent all pneumococcal disease?

27. Invasive pneumococcal disease in adults Metropolitan Toronto/Peel region, 1995-2010

28. 01,0002,0003,0004,0005,0006,0007,0008,0009,00010,000 Gonorrhea Adenovirus Chlamydia Legionella Tuberculosis Haemophilus influenzae Group A streptococcus Group B streptococcus Parainfluenza virus Respiratory syncytial virus Rhinovirus Clostridium difficile Influenza Staphylococcus aureus HIV/AIDS Escherichia coli Hepatitis B virus Human papillomavirus Streptococcus pneumoniae Hepatitis C virus HALYs YLL YERF

29. Invasive pneumococcal disease in adults Metropolitan Toronto/Peel region, 1995-2010 30 different serotypes

30. New vaccines l Polyvalent conjugate vaccines, other serotypes –GAVI/Unicef, for developing world countries l Non-serotype-based vaccines –conjugate+protein vaccine –polyvalent protein vaccines –whole cell vaccines l Polyvalent conjugate vaccines, other serotypes –GAVI/Unicef, for developing world countries l Non-serotype-based vaccines –conjugate+protein vaccine –polyvalent protein vaccines –whole cell vaccines

31. Last question l Increasing recognition that a significant fraction of serious respiratory disease, especially in children, is illness due to two pathogens simultaneously

32. Outcome Effect pneumococcal vaccine Effect influenza vaccine Effect both vaccines Hospital admission for pneumonia 0.91 (.82, 1.0).94 (.86, 1.0)0.71 (.65,.75) In-hospital mortality due to pneumonia 0.92 (.73, 1.19).88 (.69,1,1)0.65 (.54,.78) Preventive effect of pneumococcal and influenza vaccine in older adults (Christenson, Eur Resp J 2004;23:363)

33. Questions?

34. PPV23 efficacy against IPD Indirect cohort analyses Vaccine efficacy, eligible adults US 1978-1992 (1)57% (45,66) Australia 1995-2002 (2)79% (-14, 96) Scotland 2003-4 (3)51% (-278,94) Ontario 1995-2006 (4)49% (34,60) 1. Butler JC JAMA 1993; 270(15):1826-31. 2. Andrews Vaccine. 2004 Nov 25;23(2):132-8. 3. Mooney JD BMC Infect Dis. 2008 Apr 23;8:53. 4. Lui, CIC 2006