prevention of pneumococcal disease – what are the prospects? allison mcgeer, msc, md, frcpc mount...

Prevention of pneumococcal disease – What are the prospects?

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

ObjectivesObjectivesObjectivesObjectives

Review the benefits and limitations of current pneumococcal vaccines

Discuss the anticipated impact of newer conjugate vaccines, and future options

Review the benefits and limitations of current pneumococcal vaccines

Discuss the anticipated impact of newer conjugate vaccines, and future options

-Gram positive cocci- normal resident of human oropharynx

- polysaccharide coat to evade phagocytosis->90 serotypes- multiple other virulence factors

Annual rates of pneumococcal infection, Annual rates of pneumococcal infection, developed worlddeveloped worldAnnual rates of pneumococcal infection, Annual rates of pneumococcal infection, developed worlddeveloped world

Disease Annual Rate Case fatality

Pneumonia 15 per 10,000 5%

Bacteremia 1.5 per 10,000 15%

Meningitis 0.2 per 10,000 25%

Disease Annual Rate Case fatality

Pneumonia 15 per 10,000 5%

Bacteremia 1.5 per 10,000 15%

Meningitis 0.2 per 10,000 25%

0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000 9,000 10,000

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

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

0

20

40

60

80

1000-

4

5 to

9

10 to

14

15-1

9

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

55-5

9

60-6

4

65-7

4

>75

Age Group (years)

Rat

e p

er 1

00,0

00 p

er y

ear

Introduction of pneumococcal vaccinesIntroduction of pneumococcal vaccinesCanadaCanadaIntroduction of pneumococcal vaccinesIntroduction of pneumococcal vaccinesCanadaCanada

1983 – PPV23 licensed 1996-9 – PPV23 programs for adults

1983 – PPV23 licensed 1996-9 – PPV23 programs for adults

How effective is pneumococcal vaccine?How effective is pneumococcal vaccine?How effective is pneumococcal vaccine?How effective is pneumococcal vaccine?

Against pneumococcal pneumonia– Not effective (or effect <20% and not detectable)

Against invasive pneumococcal disease– CONTROVERSIAL– 7 meta-analyses; 2 Cochrane reviews

Against pneumococcal pneumonia– Not effective (or effect <20% and not detectable)

Against invasive pneumococcal disease– CONTROVERSIAL– 7 meta-analyses; 2 Cochrane reviews

PPV23 efficacy against IPDPPV23 efficacy against IPDIndirect cohort analysis, TIBDNIndirect cohort analysis, TIBDNPPV23 efficacy against IPDPPV23 efficacy against IPDIndirect cohort analysis, TIBDNIndirect cohort analysis, TIBDN

Vaccine efficacy

Healthy adults >=65 years 51% (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

Duration of effectDuration of effectDuration of effectDuration of effect

Butler et al.

Interval since Efficacyvaccine: <2 yrs 51% 2-4 yrs 54% 5-8 yrs 71% 9+ yrs 80%

Butler et al.

Interval since Efficacyvaccine: <2 yrs 51% 2-4 yrs 54% 5-8 yrs 71% 9+ yrs 80%

Liu et al.

Interval since Efficacy vaccine <3 yrs 52% 3-5 yrs 47% >5 yrs 46%

Liu et al.

Interval since Efficacy vaccine <3 yrs 52% 3-5 yrs 47% >5 yrs 46%

Is hyporesponsiveness clinically Is hyporesponsiveness clinically significant?significant?Is hyporesponsiveness clinically Is hyporesponsiveness clinically significant?significant?

Polysaccharide antigens can induce tolerance– Good evidence for meningococcal polysaccharide,

some evidence for pneumococcal polysaccharide BUT

– Data not as convincing in adults– Some evidence that hyporesponsiveness may be

time-limited– Likely to be different for different serotypes

Polysaccharide antigens can induce tolerance– Good evidence for meningococcal polysaccharide,

some evidence for pneumococcal polysaccharide 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

Pneumococcal vaccination ratesPneumococcal vaccination ratesEligible adults, CanadaEligible adults, CanadaPneumococcal vaccination ratesPneumococcal vaccination ratesEligible adults, CanadaEligible adults, Canada

Risk Group Percent ever vaccinated

Canada 2001

Toronto

2002

BC

2008

>=65 years of age 42% 35-40% 34%

15-64 years of age

with chronic condition15% 12% 10%

Squires SG, CCDR 2001;27(10), Al-Sukhni, Vaccine 2007; NCS, 2008

Introduction of pneumococcal vaccinesIntroduction of pneumococcal vaccinesCanadaCanadaIntroduction of pneumococcal vaccinesIntroduction of pneumococcal vaccinesCanadaCanada

1983 – PPV23 licensed 1996-9 – PPV23 programs for adults Dec 2001 – PCV7 licensed Sep 2002-Jan 2005 – PCV7infant programs

1983 – PPV23 licensed 1996-9 – PPV23 programs for adults Dec 2001 – PCV7 licensed Sep 2002-Jan 2005 – PCV7infant programs

Serotype coverageSerotype coverageConjugate vs. polysaccharide vaccinesConjugate vs. polysaccharide vaccinesSerotype coverageSerotype coverageConjugate vs. polysaccharide vaccinesConjugate vs. polysaccharide vaccines

PCV 4 6B 9V 14 18C 19F 23F 1 5 7F 3 19A 6A

PPV 4 6B 9V 14 18C 19F 23F 1 5 7F 3 19A

2 8 9N 10A 11A 12F 15B 17F 20 22F 33F

Vaccine Serotype Vaccine Serotype

Invasive Pneumococcal DiseaseInvasive Pneumococcal Disease Calgary 1998-2006Calgary 1998-2006

Vaccine Serotype Vaccine Serotype

Invasive Pneumococcal DiseaseInvasive Pneumococcal Disease Calgary 1998-2006Calgary 1998-2006

0

10

20

30

40

50

60

70

0- 5 m 6- 23 m 2- 4 y 5- 15 y 16- 64 y 65- 84 y* 85+ y

1998- 2001 2002 2003- 2006

0

10

20

30

40

50

60

70

0- 5 m 6- 23 m 2- 4 y 5- 15 y 16- 64 y 65- 84 y* 85+ y

1998- 2001 2002 2003- 2006

75.1% decrease

p-value <0.001

27.8% decrease

p-value =0.03

Invasive pneumococcal disease in adultsInvasive pneumococcal disease in adultsMetropolitan Toronto/Peel region, 1995-2010Metropolitan Toronto/Peel region, 1995-2010Invasive pneumococcal disease in adultsInvasive pneumococcal disease in adultsMetropolitan Toronto/Peel region, 1995-2010Metropolitan Toronto/Peel region, 1995-2010

0

2

4

6

8

10

12

14

16

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Rate

per

100

,000

per

yea

r

NonePPV23PCV13PCV10PCV7

0

2

4

6

8

10

12

14

16

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Rate

per

100

,000

per

yea

r


Pediatric IPD (<5yrs) post PCV7 Pediatric IPD (<5yrs) post PCV7 introduction, Torontointroduction, TorontoPediatric IPD (<5yrs) post PCV7 Pediatric IPD (<5yrs) post PCV7 introduction, Torontointroduction, Toronto

RATE OF IPD IN TO/PEEL 1995-2010 <5YRS

0

5

10

15

20

25

30

35

40

45

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

RA

TE

/100000 P

OP

/YR

RATE_NPCV_UNDER5

RATE_PCV13_UNDER5

RATE_PCV10_UNDER5

RATE_PCV7_UNDER5


0

2

4

6

8

10

12

14

16

1995 2000 2005 2010 2015 (projected)

Rate

per

100

,000

per

yea

r


0

2

4

6

8

10

12

14

16

1995 2000 2005 2010 2015 (projected)

Rate

per

100

,000

per

yea

r


Age groupDecline in rate of hospital admission

for pneumonia (95% CL)

<2 years 39% (22,52)

18-39 years 28% (4, 43)

40-64 years 19% (-3, 35)

>=65 years 15% (-2, 30)

Decline in pneumonia admissions after routine Decline in pneumonia admissions after routine childhood immunization with PCV7 in USAchildhood immunization with PCV7 in USAGrijalva, Nuorti et al. Grijalva, Nuorti et al. Lancet 2007;369:1179Lancet 2007;369:1179

Decline in pneumonia admissions after routine Decline in pneumonia admissions after routine childhood immunization with PCV7 in USAchildhood immunization with PCV7 in USAGrijalva, Nuorti et al. Grijalva, Nuorti et al. Lancet 2007;369:1179Lancet 2007;369:1179

What are the future issues?What are the future issues?What are the future issues?What are the future issues?

Will PCV13 serotypes be eradicated?– Will PCV13 be as successful as PCV7 has been

for the additional serotypes? 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?

Will PCV13 serotypes be eradicated?– Will PCV13 be as successful as PCV7 has been

for the additional serotypes? 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?

Where do we go from here?Where do we go from here?Where do we go from here?Where do we go from here?

Should we be recommending PPV23 and/or PCV13 in adults?– Awaiting PCV13 trial efficacy results– Re-assess efficacy/cost-effectiveness for PPV23


Opsonophagocytic antibodies Opsonophagocytic antibodies Opsonophagocytic antibodies Opsonophagocytic antibodies

Without Ab and C’

Pnc are not beingengulfed

With Ab and C’

Where do we go from here?Where do we go from here?Where do we go from here?Where do we go from here?


What can we do to more efffectively prevent all pneumococcal disease?


What can we do to more efffectively prevent all pneumococcal disease?


0

2

4

6

8

10

12

14

16

1995 2000 2005 2010 2015 (projected)

Rate

per

100

,000

per

yea

r


0

2

4

6

8

10

12

14

16

1995 2000 2005 2010 2015 (projected)

Rate

per

100

,000

per

yea

r


0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000 9,000 10,000

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


0

2

4

6

8

10

12

14

16

1995 2000 2005 2010 2015 projected

Rate

per

100

,000

per

yea

r


0

2

4

6

8

10

12

14

16

1995 2000 2005 2010 2015 projected

Rate

per

100

,000

per

yea

r


30 different serotypes

New vaccinesNew vaccinesNew vaccinesNew vaccines

Polyvalent conjugate vaccines, other serotypes– GAVI/Unicef, for developing world countries

Non-serotype-based vaccines– conjugate+protein vaccine– polyvalent protein vaccines– whole cell vaccines

Polyvalent conjugate vaccines, other serotypes– GAVI/Unicef, for developing world countries

Non-serotype-based vaccines– conjugate+protein vaccine– polyvalent protein vaccines– whole cell vaccines

Last questionLast questionLast questionLast question Increasing recognition that a significant

fraction of serious respiratory disease, especially in children, is illness due to two pathogens simultaneously

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

OutcomeEffect

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 Preventive effect of pneumococcal and influenza vaccine in older adultsvaccine in older adults (Christenson, Eur Resp J 2004;23:363)(Christenson, Eur Resp J 2004;23:363)

Preventive effect of pneumococcal and influenza Preventive effect of pneumococcal and influenza vaccine in older adultsvaccine in older adults (Christenson, Eur Resp J 2004;23:363)(Christenson, Eur Resp J 2004;23:363)

Questions?Questions?

PPV23 efficacy against IPDPPV23 efficacy against IPDIndirect cohort analysesIndirect cohort analysesPPV23 efficacy against IPDPPV23 efficacy against IPDIndirect cohort analysesIndirect 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

prevention of pneumococcal disease – what are the prospects? allison mcgeer, msc, md, frcpc mount...

Documents

pneumococcal pneumonia

world slide

ppv23 licensed

ppv23 programs

future options slide

pcv7 licensed

effect ppv23 efficacy

efficacy vaccine