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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
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
Pneumococcal Disease: An Overview
• The organism
• The diseases
• Carriage and herd protection
• Epidemiology
• Pneumococcal vaccines
• Conclusions
Pneumococcal disease: Clinical syndromes
• Pneumonia
• Bacteremia/sepsis
• Meningitis
• Otitis media
• Endocarditis
• Epidural abscess
• Peritonitis
• Septic arthritis
• Osteomyelitis
• Cellulitis/soft
tissue infection
• Endocarditis
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
Pneumococcal Disease: An Overview
• The organism
• The diseases
• Carriage and herd protection
• Epidemiology
• Pneumococcal vaccines
• 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
Courtesy of Dr. C. Whitney
Herd protection: Partially vaccinated
population (conjugate vaccine)
x
x x
Courtesy of Dr. C. Whitney
Pneumococcal Disease: An Overview
• The organism
• The diseases
• Carriage and herd protection
• Epidemiology
• Pneumococcal vaccines
• 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.
Pneumococcal Disease: An Overview
• The organism
• The diseases
• Carriage and herd protection
• Epidemiology
• Pneumococcal vaccines
• 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%
Proportion of pediatric pneumococcal disease
prevented by PCV-10
88%
81%
84%
81%
66%
81%
Proportion of pediatric pneumococcal disease
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
Fitzwater SP et al. P Infect Dis J 2012;31:501
Reduction in all cause pneumonia hospitalization
following introduction of conjugate vaccines
Fitzwater SP et al. P Infect Dis J 2012;31:501
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
Pneumococcal Disease: An Overview
• The organism
• The diseases
• Carriage and herd protection
• Epidemiology
• Pneumococcal vaccines
• 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