Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Ron DaganThe Pediatric Infectious Disease Unit
Soroka University Medical Center
Ben-Gurion University
Beer-Sheva, Israel
Introduction of New Vaccines into
Vaccination Programs
Pneumococcal Conjugate Vaccines
(PCVs) - Overview
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Pneumococcal Disease Endpoints
6A 6B 9V 14 19A 19F 23F
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Pneumonia/LRI
Otitis media
Invasive Pneumococcal
disease
Meningitis
Bacteremia/sepsis
Bacteremic pneumonia
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
PCV7 4 6B 9V 14 18C 19F 23F
PCV13 4 6B 9V 14 18C 19F 23F 1 5 7F 3 6A 19A
PCV10 4 6B 9V 14 18C 19F 23F 1 5 7F
CRM197
conjugate
H. Influenzae Protein D (4, 6B, 9V, 14, 23F, 1, 5, 7F); Tetanus toxoid (18C); Diphtheria toxoid (19F)
Licensed PCVs
CRM197
conjugate
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Goldblatt, Proceedings of the Ninth Global Vaccine Research Forum and Parallel Satellite Symposia, WHO. Bamako, Mali, 6-9
December 2009
IPD
Pneumonia
Otitis media
NP carriage
Vaccine efficacy
PCV Efficacy Against Various
Disease Endpoints (PCV Serotypes)
This image is courtesy of Prof. David Goldblatt
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Perceived Efficacy of PCVs against IPD vs. Overall
Mucosal End-points
All-Cause
IPD
Alveolar
pneumonia
All-cause
pneumonia
All-cause
otitis media
Pe
rc
eive
d e
ffic
ac
y
10
20
30
40
50
60
70
80
90
100
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Impact
of PCV
What Does Determine Impact?
Efficacy/effectiveness
against disease
Dependent on
- end-point measured (IPD vs mucosal disease)
- Specific vaccine (i.e. different carrier)
Local epidemiologic characteristics
- Serotype distribution before PCV introduction
- Immunodeficient population (i.e. HIV prevalence)
Vaccination
uptake
Efficacy/effectivenes
s against carriage
- Specific vaccine efficacy (i.e. effect of
carrier)
Indirect protection
(herd; societal protection)
Especially important for the unvaccinated including
prevention of early exposure to VT strains
Serotype coverage
of the vaccine
(PCV7, 10, 13)
Time after vaccine
introduction
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Ra
te
ra
tio
re
la
tive
to
p
re
-P
CV
7 im
ple
me
nta
tio
n
PC
V7
typ
es
No
n-P
CV
7 typ
es*
All se
ro
typ
es
Years post PCV introduction
Feikin et al, PLOS Medicine, 9:e1001517, 2013
Post-PCV7 Introduction IPD -
Summary Rate Ratios
* Including PCV13 serotypes not in PCV7
6-7 yrs 6-7 yrs 6-7 yrs
Dagan/Pnc/2015Slides prepared by Ron Dagan MD
Antibiotics
1 3 4 5
6B 6C 7F 9V 11A
12F 14 15 18C 19A
19F 22F 23F 33F
6A
35B
PCV7
1 3 4 5
6B 6C 7F 9V 11A
12F 14 15 18C 19A
19F 22F 23F 33F
6A
35B
15 19A
35B
11A
33F
Antibiotics + PCV7
Susceptible
Resistant
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
IPD Incidence After PCV7 Introduction in US Population
Pilishvili et al, J Infect Dis, 201:32-41, 2010
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
0,0
10,0
20,0
30,0
40,0
50,0
60,0
90-91 92-93 94-95 96-97 98-99 00-01 02-03 04-05 06-07 08-09 10-11 12-1314-15
7VT 6A 1, 3, 5, 7F, 19A Non13VT
IPD Incidence in Children <24 Months,
Israel, 1989-2015
PCV7
NIP
PCV13
NIP
Ben-Shimol et al, Vaccine, 32:3452–3459, 2014 (updated)
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Number of Invasive Pneumococcal Isolates in Children Among 8 Children
Hospitals by Study Years, 1994–2011
Kaplan et al, PIDJ; 32: 203–207, 20013
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Incidence of IPD by Age Group,
Denmark, 2000–2013
Barrella Harboe et al, CID, 59:1066–73, 2014
<2 years
≥65 years
PCV7
Start PCV13
PCV7
Start PCV13
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
11-12/09 1-6/10 7-12/10 1-6/11 7-12/11 1-6/12 7-12/12 1-6/13 7-12/13 1-6/14 7-12/14 1-6/15 7-12/15
VT7 6A 19A 1 3 5 7F Others Cx(-)
Pneumococcal Carriage in Children <5 Yrs Attending
Pediatric Emergency Room, Southern Israel
* For the period of 07-12/09, data for Jewish children are from Nov-Dec only and for Bedouin children for Dec only
713
8 children <5 yrs old seen each working day at the medical Pediatric ER since Nov 09
Ben Shimol et al, Human Vaccine and Immunotherapeutic http://dx.doi.org/10.1080/21645515.2015.1095414, 2015, updated
Dis
trib
uti
on
b
y s
ero
typ
e g
rou
p
n=635 n=694 n=708 n=762 n=599 n=740 n=754n=890n=176 n=875 n=779 n=919 n=650
PCV13 serotype carriage 2014-2015 vs 2009-2010: -72%
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
0
0,5
1
1,5
2
Pre-PCV PCV7 PCV13
<4m 4-11m 12-23m
0
5
10
15
20
25
30
Pre-PCV PCV7 PCV13
<4m 4-11m 12-23m
0
1
2
3
4
5
6
Pre-PCV PCV7 PCV13
<4m 4-11m 12-23m
PCV7 serotypes + 6A 5 additional PCV13 serotypes
0
2
4
6
8
10
Pre-PCV PCV7 PCV13
<4m 4-11m 12-23m
All pneumococcal OM
All-cause OM
In
cid
en
ce
(p
er 1
00
0 p
op
ula
tio
n)
98% (74-100)
88% (55-93)
90% (81-95)
79%% (73-84)
Incidence and Incidence Rate Reductions of Pneumococcal
and All-cause OM, Children <4, 4-11 and 12-23m,
in the pre-PCV7, PCV7 and PCV13 Periods
Pre-PCV: 2004-2008
PCV7: 2010-2011
PCV13: 2013-2015
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
9.1
10.2
7.2
-25%
Regev-Yochay, Dagan et al, data from the prospective surveillance on carriage in Southern Israel last (updated Jan/2016)
-68%
IPD Incidence among Individuals ≥18 yrs,
Israel July 2009 through June 2015
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
0
5
10
15
20
25
30
35
2009-10 2010-11 2011-12 2012-13 2013-14 2014-15
5-17 18-44 45-64 65+
Ra
te
IP
D p
er 1
00
,0
00
po
pu
latio
n
All Pneumococcal IPD Incidence Rates
in Individuals ≥5 Yrs in Israel: 2009-2015
Year
-69%
-55%
-19%
-18%
PCV7
PCV`13
Dagan et al, data from the prospective surveillance on carriage in Southern Israel last (updated 08/06/2015)
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Annual Counts of Serotype-specific IPD in The Gambia
Mackenzie al, Lancet ID, http://dx.doi.org/10.1016/S1473-3099(16)00054-2, 2016
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Serotype 19A IPD Cases in Individuals <5 and ≥5 Yrs Old
in 6 Countries
1. Moore et Al, Lancet Infect Dis, 15:301-09, 2015 2. Dagan et al (data from the nationwide prospective surveillance on IPD in Israel)\
3. Finland Institute for Health and W elfare (THL) : http://www.thl.fi/en/web/thlfi-en/topics/information-packages/incid ence-of-invasive-pneumococcal-disease-in-finland
4. New Zealand Public Health Surveillance: institute of Environmental Science and Research Ltd (ESR); Accessed 13Feb2015 from https://surv.esr.cri.nz/surveillance/IPD.php5. www.ispch.cl/sites/default/files/Bolet%C3%ADn%20de%20Vigilancia%20de%20Laboratorio%20de%20Streptococcus%20pneumoniae.pdf accessed Oct 29, 30, 2015
6. For the UK: Prof Liz Miller, Personal Communication
- Some studies a year = Jan – Dec; in others July – June- In Chile – Individuals ≥2 years of age
<5 years old
≥5 years old
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
1. Moore et Al, Lancet Infect Dis, 15:301-09, 2015 2. Dagan et al (data from the nationwide prospective surveillance on IPD in Israel)\
3. Finland Institute for Health and W elfare (THL) : http://www.thl.fi/en/web/thlfi-en/topics/information-packages/incid ence-of-invasive-pneumococcal-disease-in-finland
4. New Zealand Public Health Surveillance: institute of Environmental Science and Research Ltd (ESR); Accessed 13Feb2015 from https://surv.esr.cri.nz/surveillance/IPD.php5. www.ispch.cl/sites/default/files/Bolet%C3%ADn%20de%20Vigilancia%20de%20Laboratorio%20de%20Streptococcus%20pneumoniae.pdf accessed Oct 29, 30, 2015
6. For the UK: Prof Liz Miller, Personal Communication
- In New Zeeland, serotypes 6A and 6C were only distinguished from 2010 onwards; they have been combined for this analysis- Some studies a year = Jan – Dec; in others July – June
- In Chile – Individuals ≥2 years of age
Serotype 6A IPD Cases in Individuals <5 and ≥5 Yrs Old
in 6 Countries
<5 years old <5 years old
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Mucosal infections –
the probe studies re-discovered
Pneumonia
Otitis
Media
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Clinical diagnosis (WHO fast breathing? Febrile? Other clinical signs?)
Any severe pneumonia
Modified from a slide prepared by Dr Thomas Cherian, WHO
Any Chest X-ray
abnormality
Lobar consolidation/
pleural effusion
Defining Pneumococcal Pneumonia
Lobar consolidation/pleural
effusion or CRP >40 mg/L
Culture-positive
Pneumococcal pneumonia
Vaccine probe
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
All-Cause IPD Alveolar
pneumonia
All-cause
pneumonia
Pe
rc
eive
d e
ffic
ac
y
10
20
30
40
50
60
70
80
90
100
Perceived Efficacy of PCVs against Overall
Pneumonia /LRIs
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
0,0
5,0
10,0
15,0
20,0
25,0
0,0
1,0
2,0
3,0
4,0
5,0
6,0
7,0
8,0
7/0
2
9/0
2
11/
02
1/0
3
3/0
3
5/0
3
7/0
3
9/0
3
11/
03
1/0
4
3/0
4
5/0
4
7/0
4
9/0
4
11/
04
1/0
5
3/0
5
5/0
5
7/0
5
9/0
5
11/
05
1/0
6
3/0
6
5/0
6
7/0
6
9/0
6
11/
06
1/0
7
3/0
7
5/0
7
7/0
7
9/0
7
11/
07
1/0
8
3/0
8
5/0
8
7/0
8
9/0
8
11/
08
1/0
9
3/0
9
5/0
9
7/0
9
9/0
9
11/
09
1/1
0
3/1
0
5/1
0
7/1
0
9/1
0
11/
10
1/1
1
3/1
1
5/1
1
7/1
1
9/1
1
11/
11
1/1
2
3/1
2
5/1
2
7/1
2
9/1
2
11/
12
1/1
3
3/1
3
5/1
3
7/1
3
9/1
3
11/
13
1/1
4
3/1
4
5/1
4
7/1
4
9/1
4
11/
14
1/1
5
3/1
5
5/1
5
7/1
5
9/1
5
11/
15
1/1
6
3/1
6
5/1
6
Monthly Hospital Visits for Alveolar Pneumonia, Children <2 Years,
Southern Israel, Since July 2002
Year
Mo
nth
ly in
cid
en
ce
s p
er 1
,0
00
p
op
ula
tio
n
n=362n=631n=585 n=673 n=674 n=660 n=593n=576 n=386 n=351 n=390n=648 n=705
22.8
24.0
19.8
20.5
23.322.8
21.9
20.4
19.0
12.2
11.210.7
09-1004-05 05-06 06-07 07-08 08-09 10-11 11-12 12-13 13-1403-0402-03 14-15
An
nu
al in
cid
en
ce
p
er 1
,00
0 p
op
ula
tio
n
PCV7
Private market
PCV7
NIP
PCV7
PCV13
11.7
n=345
15-16
Updated 28-02-2016
A prospective population-based study to document hospital use for alveolar pneumonia in young children
-50%
Vs. 2002-2008
Greenberg et al, Vaccine, 33:4623–4629, 2015 (updated)Each study year is July through June
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
0
20
40
60
80
100
120
0
500
1000
1500
2000
2500
3000
Alveolar pneumonia, southern Israel IPD, nationwide incidence
In
cid
en
ce
, c
hild
re
n <
2 yrs p
er
10
0,0
00
PCV7
NIP PCV7
PCV13
PCV7
Private market
* Pediatric Emergency Room ambulatory visits and hospitalizations
Greenberg et al, Vaccine, 33:4623–4629, 2015 (updated)
-50%
Vs. 2002-2008
Each study year is July through June
Alveolar Pneumonia Hospital Visits* and IPD
Incidence Reduction in Children <2 Yrs Old,
2012-14 vs 2004-8
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
0
20
40
60
80
100
120
0
500
1000
1500
2000
2500
3000
Alveolar pneumonia, southern Israel IPD, nationwide incidence
In
cid
en
ce
, c
hild
re
n <
2 yrs p
er
10
0,0
00
PCV7
NIP PCV7
PCV13
Alveolar Pneumonia Hospital Visits* and IPD
Incidence Reduction in Children <2 Yrs Old,
2012-14 vs 2004-8
PCV7
Private market
-64%
Vs. 2004-2008
-1100
-61
x18
Greenberg et al, Vaccine, 33:4623–4629, 2015 (updated)
Ben-Shimol et al, Vaccine, 32:3452–3459, 2014 (updated)
-50%
Vs. 2002-2008
* Pediatric Emergency Room ambulatory visits and hospitalizations
Each study year is July through June
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
The Viral-Bacterial Interaction and Pneumonia
ColonizationViral URI
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Virus PCV Placebo Efficacy 95% CI p value
Influenza A/B 31 56 45 14-64 0.01
PIV1-3 24 43 44 8-66 0.02
hMPV 26 62 58 34-73 0.001
RSV 90 115 22 -3-41 0.08
PCV Efficacy Against Viral-associated Pneumonia
Hospitalization in Children
Madhi & Klugman, Nature Med, 10:811-13, 2004
Madhi et al, J Infect Dis, 193:1236-43, 2006
• >1/3 of children hospitalized for pneumonia in whom a virus is identified
have concurrent infection due to pneumococcus included in the PCV
• Study provides a minimal estimate of contribution of pneumococcal co-
infection (role of serotypes not included in the PCV)
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
0
1000
2000
3000
4000
5000
6000
7000
2006-07 2007-08 2008-09 2009-10 2010-11 2011-12 2012-13 2013-14 2014-15
Alveolar Other LRIs All-cause LRIs
In
cide
nce
p
er 1
00,0
00 c
hild
re
n <2
yrs PCV7
Private marketPCV7
NIP
PCV7
PCV13
-40%
-21%
-25
-603
-905
-1508
Hospitalizations for Alveolar Pneumonia and
All-cause LRIs in Children <2 Years Old, Southern Israel:
Incidence Reduction 2012-15 vs 2006-8
Dagan et al, 55th
ICAAC, San Diego, CA, USA, Sept 2015 (Abst. # I-292).LRI = low er respiratory infections
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Griffin et al, MMWR, 63:995-8, 2014
-72%
An
nu
alized
mo
nth
ly h
osp
ita
lizatio
ns p
er
1,0
00
Annualized Monthly All-cause Pneumonia Hospitalizations
Children <2 Yrs During Pre-PCV, PCV7, and PCV13 Years
Tennessee, USA
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Evolution of Community-acquired Pneumonia Cases:
8 Pediatric Pediatric Emergency Department Visit, France
Pleuropneumonia
1, 3, 5, 7F, 14, 19A
- Pre-PCV13 (June 2009 - May 2010)
- Transitional (June 2010 – May 2011)
- Post PCV13 (June 2011 – May 2012)
Angoulvant et al, Clin Infect Dis, 58:918-24, 2014
8 Pediatric Emergency Departments, France
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Involvement of S. pneumoniae and NTHi in Otitis Media Evolution:
the Disease Continuum Model of Pathogenesis
Dagan et al et al, Lancet Infect Dis, 16:480-92, 2016
Complex otitis media: any cases of recurrent, non responsive, and spontaneously
draining infections, and chronic disease with effusion (which is a long-term and recurrent infection and inflammation of the middle ear)
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
The Paradoxical Efficacy of PCVs Against Otitis Media
Dagan et al et al, Lancet Infect Dis, 16:480-92, 2016
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Impact of PCV7/PCV13 Post Implementation on
OM-Associated Burden
Recurrence/
Complexity/
Chronicity
Chronicity
Ventilation tube
insertion
<12m
23%
(16–29)
Ventilation tube
insertion2
12-23m
16%
(13–19)
Hospitalization with
OM1
<24m
36.4%
(24.1–46.7)
<24m
42.7%
(42.4–43.1)
All OM-related
ambulatory
visits3
Presenting to ER with
OM complicated by
otorrhea5
<15yrs*
38%
P<0.001
* 75%
<36m
<24m
17%
(14-19)
<24m
28%
(23-33)
<24m
8%
(6-11)
<24m
33%
(28-38)
Development of Frequent
OM by age 2 yrs4
2000-2001 birth
cohort
2001-2002 birth
cohort
Tennesse
e
New
-Y
ork
<24m
16%
(11-21)
<24m
23%
(10-35)
<24m
3%
(-3-8)
<24m
21%
(6-33)
Ventilation tube insertion
by age 2 yrs4
2000-2001 birth
cohort
2001-2002 birth
cohortTennessee
New
-Y
ork
1Durando et al, Vaccine 27:3459–3462 2009
2Jardine et al, Pediatr Infect Dis J, 28:761–765, 2009
3Zhou et al, Pediatr. 121;253-260, 2008
4Poehling et al, Pediatrics, 119:707-15, 2007
5Stamboulidis et al, Pediatr Infect Dis J, 30: 551–555, 2011
6Marom et al, JAMA Pediatr, 168:68-75, 2014
37%
PCV7
PCV13
Recurrent-OM
USA 2001-20136
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
0,0
1,0
2,0
3,0
4,0
5,0
6,0
7,0
8,0
9,0
10,0
2004-2005 2005-2006 2006-2007 2007-2008 2008-2009 2009-2010 2010-2011 2011-2012 2012-2013 2013-2014 2014-2015
4 6B 9V 14 18C 23F 1 3 5 7F 6A 19F 19A
inc
ide
nc
ep
er
10
00
po
pu
lati
on
at
ris
k
Year
Serotype-specific Incidence (PCV7 and PCV13 Serotypes)
in Children <24m with MEF Culture, Southern Israel,
2004-2015*
* Each year is July 1st through June 30th
7.8 7.8
7.3
8.1
5.7
3.7 4.4
1.7
0.6
0.2
Ben-Shimol et al, CID, DOI 10.1093/cid/CIW347, 2016
0.4
-96%
Vaccination
HMO subsidized
Initiation of PCV7
NIP + catch-up
Initiation,
substitution
PCV7 by PCV13
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
9,8
8,7
9,3 9,4
7,2
5,6
6,7
4,4
2,5
1,9
1,2
0,0
1,0
2,0
3,0
4,0
5,0
6,0
7,0
8,0
9,0
10,0
All Pneumococcal OM
PCV7 in NIP*
An
nu
al
inc
ide
nc
e p
er
10
00
po
pu
lati
on
at
ris
kImpact of the Sequential PCV7/PCV13 Introduction to the NIP
on Pneumococcal OM, Children <24m
Initiation,
substitution
PCV7 by PCV13
87% (82 – 90%)
11,8
6,9
7,9
8,8
6,7
7,5 7,57,0
5,3
4,04,2
0,0
1,0
2,0
3,0
4,0
5,0
6,0
7,0
8,0
9,0
10,0
11,0
12,0
13,0PCV7 in Private
practice
Rate Reduction
2014-2015 vs. 2004-2008
12,0
10,0
12,1
10,9
9,5
8,7
10,4
8,8
4,7
3,12,4
0,0
1,0
2,0
3,0
4,0
5,0
6,0
7,0
8,0
9,0
10,0
11,0
12,0
13,0PCV7 in NIP*
Initiation,
substitution
PCV7 by PCV13
PCV7 in Private
practice
NTHi
78% (73 – 82%)
PCV7 in NIP*
Initiation,
substitution
PCV7 by PCV13
PCV7 in Private
practice
Culture-negative
53% ( 44 – 60%)
* Each study year is July 1st through June 30th Ben-Shimol et al, CID, DOI 10.1093/cid/CIW347, 2016
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Overall OM (Pneumococcal and Non-pneumococcal) Incidence
in Children <24m with MEF Culture, Southern Israel, 2004-2015*
30,6
23,2
26,127,1
21,2 20,5
22,9
19,6
12,0
8,5
7,8
0,0
5,0
10,0
15,0
20,0
25,0
30,0
35,0
2004-05 2005-06 2006-07 2007-08 2008-09 2009-10 2010-11 2011-12 2012-13 2013-14 2014-15
PCV7 in Private
practice
PCV7 in NIP*
Initiation,
substitution
PCV7 by PCV13
An
nu
al in
cid
en
ce
pe
r 1
00
0 p
op
ula
tio
n a
t risk
* Each study year is July 1st through June 30th
Year
71% (59 – 74%)
Rate Reduction
2014-2015 vs. 2004-2008
- 1895
cases/100,000
Ben-Shimol et al, CID, DOI 10.1093/cid/CIW347, 2016
Dagan/Pnc/2015Slides prepared by Ron Dagan MD
Children vs. Adults…
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Antipneumococcal Polysaccharide Binding Antibody Responses
Elicited During the Immunization Series
de Roux A et al. Clin Infect Dis. 2008;46:1015-1023
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Antipneumococcal OPA Responses
Elicited During the Immunization Series
de Roux A et al. Clin Infect Dis. 2008;46:1015-1023
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
OutcomeEfficacy
%95% CI
Primary outcome
• First episode of confirmed VT-CAP 45.6 21.8 – 62.5
Secondary outcomes
• First episode of non-bacteremic/non-invasive VT-CAP
• First episode of VT-IPD
• All-cause CAP
45.0
75.0
5.1
14.2 – 65.3
41.3 – 90.8
−5.1 – 14.2
CAPITA Study – Main Study Outcome Efficacies
Study group PCV13 Placebo
Death 3,006 (7.1%) 3,005 (7.1%)
Rapidly decreasing efficacy with age, especially after 75 years
Bonten et al. N Engl J Med, 372:1114-25, 2015
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Should PCV13 Be Implemented in Adults
Beyond High Risk Indications?
• The study was conducted on relatively fit elderlies
– Many of the CAP cases in debilitated, compromised, high risk and institutionalized
• Population did not receive PPV23 (no reduced response to PCV13)
• Effect on all-cause pneumonia ~5% and not statistically significant
• No overall reduction of mortality
• No PCV13 in children – Most cases in Bonten’ s study were PCV13 serotypes
• Implemenation to the entire population will take years, meanwhile PCV13
serotypes may continue to decrease
However:
• Still a considerable number of elderly with pneumonia have urine
molecular tests suggesting PCV7/13 serotypes
• what about populations with− Low (or no) vaccination rate in infants?
− Started national campaigns only recently?
− Does it depend on which vaccine is used (PCV10, PCV13) in infants?
Dagan/Pnc/2016Slides prepared by Ron Dagan MD
Nasopharyngeal and Otitis media Connection
and PCV Effect
PCV
Antibiotic resistance
Reduction in disease
caused by most
resistant serotypes
6B, 9V, 14, 19F, 23F, 6A, 19A
Reduction in
carriage most
resistant serotypes
Reduction in
antibiotic use