pneumococccal disease: an overview - sabin.org harrison.pdf · •peritonitis •septic arthritis...

Pneumococccal Disease: An Overview

Lee H. Harrison, M.D.

Infectious Diseases Epidemiology Research Unit

University of Pittsburgh

Fifth Regional Pneumococcal Symposium

São Paulo, Brazil

March 5, 2013

1

Disclosures Previous relationships*

Research Funding (to Univ. of Pittsburgh): Sanofi Pasteur SA

Consulting Agreements: GlaxoSmithKline, Merck, Novartis Vaccines, Pfizer, Sanofi Pasteur

Speakers’ Bureau/Honorarium Agreements: Sanofi Pasteur and Novartis Vaccines

Financial Interests/Stock Ownership: None

Discussion of Off-Label or Investigational Drug Use

Investigational vaccines

*All financial/consulting relationships terminated before July 1, 2012 (Advisory Committee on Immunization Practices membership)

Pneumococcal Disease: An Overview

• The organism

• The diseases

• Carriage and herd protection

• Epidemiology

• Pneumococcal vaccines

• Conclusions

Streptococcus pneumoniae

• Gram-positive bacterium

• Human pathogen but can colonize other species

• 90+ polysaccharide capsular types

• Polysaccharide capsule virulence factor for invasive

disease, prevents phagocytosis

• Protection and vaccines serotype specific, some cross

protection within serogroups

Lynch J, Zhanel G. Sem Respir Crit Care Med 2009;30:189

van der Linden M et al. PLoS ONE 2009;4:e8286. doi:10.1371/journal.pone.00082

Serotype 19F Streptococcus pneumoniae

Photograph by Rob Smith

Polysaccharide capsule


• The organism

• The diseases


• Epidemiology


• Conclusions

Pneumococcal disease: Clinical syndromes

• Pneumonia

• Bacteremia/sepsis

• Meningitis

• Otitis media

• Endocarditis

• Epidural abscess

• Peritonitis

• Septic arthritis

• Osteomyelitis

• Cellulitis/soft

tissue infection

• Endocarditis

Invasive pneumococcal disease (IPD)

• Definition: Isolation of

pneumococcus from normally

sterile site (e.g., blood or CSF)

• IPD can range from: – mild, transient, occult bacteremia without

focus

– severe disease with a focus such as

pneumonia or meningitis

– fulminant sepsis with cardiovascular

compromise

Pneumococcal sepsis

Pneumococcal meningitis:

Purulence beneath reflected dura

Photo: CDC/Dr. Edwin P. Ewing, Jr.

Pneumococcal pneumonia

Pneumococcal otitis media

Otoscopic exam showing red, bulging, immobile

tympanic membrane with purulence behind it


• The organism

• The diseases


• Epidemiology


• Conclusions

S. pneumoniae colonization and transmission

• Nasopharyngeal carriage of S. pneumoniae necessary for

transmission and invasive disease

• Person-to-person contact, respiratory droplets

• Some episodes of colonization lead to disease

Importance of nasopharyngeal carriage of

S. pneumoniae

Nose

Lung

Sinus

Tympanic

Membrane

Blood

Vessel

Meninges

Bone

Lung

Nasopharyngeal carriage and transmission

of S. pneumoniae

otitis media

pneumonia

meningitis

carrier carrier

carrier

carrier

carrier

carrier

Pediatric carriage prevalence of S. pneumoniae

10

20

30

40

50

Preschool Grammar school High school

Carr

iag

e r

ate

(%

)

60

38

29

9

0

Hendley JO et al. J Infect Dis 1975;132:55

Adult carriage prevalence of S. pneumoniae, by

age of children in the home

0

10

20

30

40

<6 years 6-12 years

Carr

iag

e r

ate

(%

)

25

6

Hendley JO et al. J Infect Dis 1975;132:55

Age of youngest child

Pneumococcal nasopharyngeal colonization, by age in

months, selected countries

0

10

20

30

40

50

60

70

80

90

100

Pro

port

ion

colo

niz

ed (

%)

Age (months)

O’Brien et al. Pediatr Infect Dis J 2003; 22: e1

Papua New Guinea Australian Aborigines

India Costa

Rica

Sweden & Finland

Israeli Jews

What is herd protection?

Courtesy of Dr. C. Whitney

Herd protection:

Unvaccinated population


Herd protection: Partially vaccinated

population (conjugate vaccine)

x

x x



• The organism

• The diseases


• Epidemiology


• Conclusions

Leading infectious causes of mortality, 2000 D

eath

s (m

illi

on

s)

< 5 years old > 5 years old

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Pneumonia AIDS Diarrhoea TB Malaria Measles

3.5

2.7

2.2

1.7

1.1 0.9

Source: WHO

S. pneumoniae:

~1.6 million deaths,

including ~800,000 in

older children/adults

Invasive pneumococcal disease incidence and

mortality, U.S. ABCs sites, 2008

www.cdc.gov/abcs/survreports/spneu08.htm

0

5

10

15

20

25

30

35

40

45

< 1 1 2-4 5-17 18-34 35-49 50-64 ≥ 65

Cases P

er

100,0

00 P

op

ula

tio

n

0

1

2

3

4

5

6

7

Death

s p

er

100,0

00 P

op

ula

tio

n

Age (years)

Cases

Deaths

Invasive pneumococcal disease incidence

much higher in low-income countries

0

100

200

300

400

500

600

700

Kenya(1) Gambia (2)

US rate3 IPD

rate

per

100,0

00

pers

on

-yrs

for

ch

ild

ren

<5 y

rs

1Brent AJ et al. Lancet 2006;367:482, 2Cutts FT et al. Lancet 2005;365:1139, 3CDC. MMWR 2005; 54(36): 893

Risk factors for pneumococcal disease

• Age <2 years, ≥65 years

• Exposure to cigarette smoke,

multiple children in household

• Comorbidities – Alcohol abuse

– Congestive heart failure

– Chronic lung disease

– Cigarette smoking

– Asthma

– Influenza

– Diabetes mellitus

– Neurological disorders

• Certain ethnic groups – American Indians, Alaska Natives,

African Americans (U.S.)

• Immune deficiencies – B cell defects

– Deficiencies of early components

of classical pathway of

complement

– Asplenia

– Sickle cell disease

– Hematological or solid

malignancies

– Organ transplant recipients

– HIV infection

– Immunosuppressive drugs

Lynch J, Zhanel G. Sem Respir Crit Care Med. 2009;30(2):189-209.

Histochemical and immunohistochemical diagnosis of S. pneumoniae infection

A: Lillie-Twort Gram stain of lung tissue

B: Immunohistochemical staining of multiple S. pneumoniae organisms

Bacterial infections in lung tissue of 22 (29%) of 77

fatal U.S. cases of H1N1 pandemic influenza

CDC. MMWR 2009;58:1071

A B Bacteria # cases

S. pneumoniae 10

S. aureus 7

S. pyogenes 6

S. mitis 2

H. influenzae 1

Multiple

pathogens 4

Risk factors for invasive pneumococcal disease,

adults 18-64 years old, United States

Factor Odds Ratio (95% CI)

Male sex 2.7 (1.7–4.3)

Black race 3.4 (2.0–5.6)

Chronic illness 2.6 (1.4–5.1)

Current smoker 4.1 (2.4–7.3)

Children in daycare <6 yrs old 3.0 (1.5–6.2)

Nuorti JP et al. N Engl J Med. 2000;342:681

Risk factors for death from community-acquired

invasive pneumococcal pneumonia, United States

Disease Relative Risk (95% CI)

Cirrhosis 5.8 (3.7, 9.2)

Congestive heart failure 4.7 (3.3, 6.7)

Diabetes 2.9 (2.0, 4.3)

Chronic lung disease 2.8 (1.9, 4.0)

Asplenia 3.2 (1.1, 9.3)

AIDS 2.3 (1.5, 3.6)

Solid organ malignancy 3.7 (2.5, 5.4)

Hematologic malignancy 2.2 (1.2, 4.3)

Feikin DR et al. Am J Public Health 2000;90:223

Penicillin resistance, selected countries, 1990s

www.who.int/infectious-disease-report/2000/index.html

Association of recent antibiotic use and invasive

disease caused by antibiotic-resistant S. pneumoniae

% Recent antibiotic use

Study Disease Nonsusc SP Susc SP Odds

ratio

P value

Jackson Invasive 56% 14% 9.3 0.009

Pallares Invasive 65% 17% 9.3 <0.001

Tan Invasive 70% 39% 3.7 0.02

Nava Invasive 30% 11% 3.5 <0.001

Moreno Bacteremia 57% 4% 3.6 <0.001

Block Otitis media 69% 25% 6.7 <0.001

Dowell SF, Schwartz B. Am Fam Phys 1997;55:1647

Shaler Giant Eagle, January 2012, Pittsburgh, U.S.A.


• The organism

• The diseases


• Epidemiology


• Conclusions

Licensed pneumococcal vaccines

Vaccine Year

Licensed

Protein

Carrier Manufacturer

23-valent

polysaccharide 1983 Pneumovax, Merck

7-valent

conjugate 2000 Prev(e)nar-7, Pfizer

10-valent

conjugate 2009 Synflorix, GSK

13-valent

conjugate 2010 Prev(e)nar-13, Pfizer

__

CRM197

Hi prot D

CRM197

PCV7: 4, 6B, 9V, 14, 18C, 19F, and 23F

PCV10: PCV7 + 1, 5, 7F

PCV13: PCV10 + 3, 6A, 19A

Proportion of pediatric pneumococcal disease

prevented by PCV-7

38%

73%

86%

60%

71%

62%


prevented by PCV-10

88%

81%

84%

81%

66%

81%


prevented by PCV-13

92%

87%

89%

87%

73%

86%

Property Polysaccharide Conjugate

T-cell-dependent

immune response No Yes

Efficacy in infants No Yes

Persistence of protection No Yes

Booster effect No Yes

Reduction of carriage No Yes

Herd effect No Yes

Lack of hyporesponsiveness No Yes

Why are conjugate vaccines better than

polysaccharide vaccines?

Granoff DM, Pelton SI, Harrison LH. Vaccines. 6th ed, in press

Polysaccharide vaccine versus

conjugate vaccine

Bröker M et al. Vaccine 2009;27:5574

Conjugation process

Effectiveness of 23-valent pneumococcal

polysaccharide vaccine against invasive disease

Overall, 5+ years old 57% (45%–66%)1

Patients with:

Diabetes 84% (50%–95%)1

Cardiovascular disease 73% (23%–90%)1

Congestive heart failure 69% (17%–88%)1

Chron. obstr. lung disease 65% (26%–83%)1

Anatomic asplenia 77% (14%–95%)1

Immunocompetent elderly 75% (57%–85%)1

HIV 49% (12%-70%)2

1Butler JC et al. JAMA 1993;270:1826 2Breiman RF et al. Arch Intern Med 2000;160:2633

Vaccine Efficacy (95% CI)

Effectiveness of 23-valent pneumococcal

polysaccharide vaccine (PPV23) in elderly

– Retrospective cohort study

– >47,000 subjects

– Persons ≥ 65 yrs

– Effectiveness of PPV23:

• Pneumococcal bacteremia: 44% (95% CI: 7%, 67%)

• All cause pneumonia: No effect

Jackson LA et al. N Engl J Med 2003; 348:1747

Summary of adult pneumococcal conjugate vaccine

efficacy data for prevention of pneumonia in adults

Investigation of pneumococcal conjugate

vaccine for adults: CAPITA

• Randomized, placebo-controlled clinical trial of PCV13

• 85,000 Dutch adults ≥65 years without prior pneumococcal

vaccine

• Primary endpoint: First episode vaccine-serotype

pneumococcal community-acquired pneumonia

• Secondary outcomes: Vaccine-serotype invasive

pneumococcal disease, safety

• Advisory Committee on Immunization Practices (U.S.A.) to

consider results to determine recommendations for PCV13

in healthy adults

www.clinicaltrials.gov/ct2/show/NCT0074426

Pneumococcal conjugate vaccine efficacy

Vaccine Phase 3 Efficacy

OM IPD Pneumonia Mortality

7-valent Wyeth

7-valent Merck

9-valent Wyeth

10-valent GSK

11-valent Aventis

11-valent GSK

• Significant protective efficacy

Reduction in invasive pneumococcal disease following

introduction of conjugate vaccines, vaccine serotypes

Fitzwater SP et al. P Infect Dis J 2012;31:501

Reduction in invasive pneumococcal disease following

introduction of conjugate vaccines, all serotypes


Reduction in all cause pneumonia hospitalization

following introduction of conjugate vaccines


0 1,700 3,400850 Kilometers

Countries that have introduced pneumococcal

conjugate vaccine in children as of September 2012

Not available

Not applicable

Not Introduced (77 countries or 40%)

Planned introduction in 2013 (24 countries or 12%)

Planned introduction in 2012 (15 countries or 8%)

Introduced* (78 countries or 40%)

www.who.int/nuvi/pneumococcus/decision_implementation/en/index1.html

Changes in incidence of invasive pneumococcal

disease, 1998–2007

Pilishvili T et al. J Infect Dis. 2010;201:32.

Cas

es

/100,0

00 p

op

ula

tio

n

0

20

40

60

100

80

120

1998 1999 2001 2000 2002 2003 2004 2005 2006 2007

Year

PCV7 introduced in children Age Group 2007 vs baseline

(years) (% reduction)

< 5

5–17

18–49

50–64

≥ 65

76

43 40

18

37

Invasive pneumococcal disease among adults ≥65

years, 1998–2007

Cas

es

/100,0

00 p

op

ula

tio

n

0

5

10

15

20

25

30

35

40

1998 1999 2001 2000 2002 2003 2004 2005 2006 2007

Year

Serotype group

PCV7 type

Non-PCV7 type

19A

*92% reduction in PCV7 serotypes, 2007 vs baseline

*

PCV7 introduced in children

Pilishvili T et al. J Infect Dis. 2010;201:32

Pediatric conjugate vaccine effect

on nasopharyngeal carriage

+

V T

V T V T

V T V T

V T

V T

V T

V T V T

Transmission from children to adults

+

0

5,000

10,000

15,000

20,000

25,000

Direct effect Herd effect

20,459

9,140

Cas

es

pre

ve

nte

d

Estimated annual cases of PCV7-type invasive

pneumococcal disease prevented in the U.S., 2003

CDC. MMWR 2005;54:893

0

5

10

15

20

25

30

35

40

45

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Cases p

er

100,0

00 p

op

ula

tio

n

Antibiotic Nonsusceptible Invasive Pneumococcal Disease, Children 0-4 Years Old

Not susceptible to 1 or more antibiotics

Not susceptible to 3 or more antibiotics

Source: Matt Moore, CDC

Antibiotic-nonsusceptible S. pneumoniae Isolates,

pneumococcal meningitis cases, ABCs sites, 1998-2005

Penicillin Chloramphenicol Meropenem Cefotaxime

0

5

10

15

20

25

30

35

No

nsu

scep

tib

le I

so

late

s (

%)

Intermediate

Resistant

-39%

+55%

-41%

-47%

Hsu H et al. N Engl J Med 2009;360:244


• The organism

• The diseases


• Epidemiology


• Conclusions

Conclusions

• Pneumococcal disease major cause of morbidity and

mortality in older children and adults

• Pneumococcal colonization common

• Polysaccharide vaccine effective for invasive disease

• Conjugate vaccines effective in preventing invasive and

non-invasive disease in children

• Immunization of children with pneumococcal conjugate

vaccines prevents pneumococccal disease in adults

• Need data on direct effects of pneumcoccal conjugate

vaccines on adult pneumonia

• Increased global utilization of pneumococcal conjugate

vaccines will have huge public health impact

pneumococccal disease: an overview - sabin.org harrison.pdf · •peritonitis •septic arthritis...

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