BH Presentation

Report
Challenges and opportunities in
development of new vaccines against
bacterial pneumonia
Lessons learned—and yet to be learned
William Hausdorff, PhD
Vaccine Development Leader, Pneumococcal Vaccines
GlaxoSmithKline Biologicals, Wavre, Belgium
Pneumonia is the major manifestation of
serious pneumococcal disease in children, even in Europe
Outline
• Pneumococcal conjugate vaccine candidates and their
impact on pneumonia
– What have we learned?
• Is non-typable H. influenzae a pathogen to target in
addition to pneumococcus?
• Future vaccine possibilities
PCV vaccine candidates tested in pneumonia efficacy
studies to date
Serotypes
PCV7-CRM
4, 6B, 9V, 14, 18C, 19F, 23F
CRM197 diphtheria variant carrier protein
PCV9-CRM
4, 6B, 9V, 14, 18C, 19F, 23F
1, 5
CRM197 diphtheria variant carrier protein
Serotypes
PCV11-D,T
4(T),6B(D),9V(T),14(D),18C(D),19F(T),23F(T) 1(T), 5(T), 7F(T)
3(D)
Tetatnus and diphtheria toxoid carriers
Prevnar™ and Prevenar13TM SPCs; Park IH, et al. J Infect Dis. 2008;198(12):1818-22; http://www.who.int/immunization/sage/target_product_profile.pdf; Synflorix™ SPC, 2009; PIDJ supplement volume 28, Number
4, April 2009; Vesikari T, et al. Pediatr Infect Dis J 2009;28(4 Suppl):S66-76; Prymula R, et al. Lancet 2006;367:740-748; Lucero et al PIDJ 2009
Synflorix™ is a trademark of the GlaxoSmithKline group of companies; PCV7-CRM: Prevenar™/Prevnar™ and PCV13-CRM: Prevenar 13 are trademark of Pfizer/Wyeth
Lesson #1: 3 different pneumococcal conjugate vaccines demonstrated
similar efficacy against consolidated pneumonia (children < 2 years of age)
WHO alveolar consolidated pneumonia (confirmed radiologically)
Vaccine
% VE
(95% CI)
Per protocol analysis
PCV7-CRM197
21 (4-34)
N. California Kaiser Permanente.1,5
30 (11-46)
PCV9-CRM197
25
(4, 40)
South-Africa2
PCV9-CRM197
37 (27-45)
The Gambia3
PCV11-TT&DT
23 ( -1, 41)
The Phillipines-ARIVAC4
Despite different immunogenicity, study settings, vaccine formulations, etc
1. Black et al., Ped Infect Dis J, 2002; 2. Klugman et al., New Engl J Med, 2003; 3. Cutts et al., Lancet, 2005; 5. Hansen et al., Ped Infect Dis J,
2006; 4. Lucero et al., Ped Infect Dis J 2009
Why is effect of PCV7/9 on alveolar consolidated
pneumonias limited to 23-37%?
Is pneumococcus not as important as we thought?
• Results likely underestimate importance of pneumococcus:
– Vaccine efficacy undoubtedly <100%
– There are other pneumococcal serotypes besides those covered by vaccine formulations
– Replacement disease by NVT or other pathogens?
• Age-related effect: in ¾ studies*, efficacy waned after 1st year (PP analyses)
Age Group (mos)
VE %
95% CI
(Booster given in NCKP).
NCKP (Black PIDJ 2002)
<12
32.2
(3.3-52.5)
<24
23.4
(5.2-38.1)
24
9.1
(-30.9-36.8)
3-11
34.0
(4.8-54.3)
12-23
2.7
(-43.5-34.0)
3-11
35
(19 -48)
12-23
38
(25-49)
24-29
32
(-10-58)
Philippines (Lucero PIDJ 2009)
The Gambia (Cutts Lancet 2005)
*Not shown: waning
pneumonia efficacy in
South Africa study though
prolonged IPD efficacy
through age 5
(pers. comm. S. Madhi)
Lesson #2: Pneumococcal Conjugate Vaccines (PCV9-CRM) can prevent
virus-associated pneumonia
pp.811-813
Lesson #3: Pneumococcal conjugate vaccines prevent more than
just consolidated alveolar pneumonias as defined by WHO
Madhi et al Vaccine 2007
LRTI = lower respiratory tract infection
VAR = vaccine attributable reduction (cases preventable/100,000)
CRP= c-reactive protein
Status of PCV vaccine candidates tested in
pneumonia efficacy studies to date
Serotypes
PCV7-CRM
4, 6B, 9V, 14, 18C, 19F, 23F
CRM197 diphtheria variant carrier protein
PCV9-CRM
4, 6B, 9V, 14, 18C, 19F, 23F
1, 5
CRM197 diphtheria variant carrier protein
NEVER
LICENSED
Serotypes
PCV11-D,T
4(T),6B(D),9V(T),14(D),18C(D),19F(T),23F(T) 1(T), 5(T), 7F(T)
3(D)
Tetatnus and diphtheria toxoid carriers
Prevnar™ and Prevenar13TM SPCs; Park IH, et al. J Infect Dis. 2008;198(12):1818-22; http://www.who.int/immunization/sage/target_product_profile.pdf; Synflorix™ SPC, 2009; PIDJ supplement volume 28, Number
4, April 2009; Vesikari T, et al. Pediatr Infect Dis J 2009;28(4 Suppl):S66-76; Prymula R, et al. Lancet 2006;367:740-748
Synflorix™ is a trademark of the GlaxoSmithKline group of companies; PCV7-CRM: Prevenar™/Prevnar™ and PCV13-CRM: Prevenar 13 are trademark of Pfizer/Wyeth
The licensed PCV vaccines
Serotypes
Likely Cross protection
PCV7-CRM
4, 6B, 9V, 14, 18C, 19F, 23F
6A
CRM197 Diphtheria variant carrier protein
Cross reactivity
Serotypes
4, 6B, 9V, 14, 18C, 19F, 23F
1, 5, 7F
6A, 19A
Synflorix™
NTHi protein D
T
D
NTHi protein D
Serotypes
PCV13-CRM
4, 6B, 9V, 14, 18C, 19F, 23F
1, 5, 7F
3, 6A, 19A
CRM197 Diphtheria variant carrier protein
Prevnar™ and Prevenar13TM SPCs; Park IH, et al. J Infect Dis. 2008;198(12):1818-22; http://www.who.int/immunization/sage/target_product_profile.pdf; Synflorix™ SPC, 2009; PIDJ supplement volume 28, Number
4, April 2009; Vesikari T, et al. Pediatr Infect Dis J 2009;28(4 Suppl):S66-76; Prymula R, et al. Lancet 2006;367:740-748
Synflorix™ is a trademark of the GlaxoSmithKline group of companies; PCV7-CRM: Prevenar™/Prevnar™ and PCV13-CRM: Prevenar 13 are trademark of Pfizer/Wyeth
Synflorix™ Status, November 2010
• First registered Dec 2008; approved in 83 countries
Countries & Regions with Synflorix™ in universal mass vaccination
3+1
2+1
• Sweden (3 Provinces)
 Bulgaria
• Finland
 The Netherlands
• Canada – Quebec
 Cyprus (Risk Groups)
• Colombia (Bogotá)
 Austria (Risk Groups)
• Mexico
 Brasil
• Taiwan (Taipei)
 Chile
 Australia (Northern Territories)
 Hong Kong
• Prequalified by WHO October 2009; GSK participating in AMC (Advanced Market
Commitment) to expedite pneumococcal vaccine access to GAVI countries
What is efficacy of Synflorix™ against pneumonia?
Panama
c lin ic a l o titis m e d ia
& p n e u m o n ia s tu d y
Colombia
Argentina
- Mendoza
- Santiago del Estero
- San Juan
Study 10PN-PD-DIT-028 (COMPAS)
COMPAS study design & objectives
• Double-blind, individually randomized (n=24,000), placebo controlled (Hepatitis)
• 3 primary doses of PHiD-CV (@ 2,4,6 mos) plus one booster (@ 15-18 mos) alongside
other routinely administered infant vaccines
• Started 2007; results expected in 2011
Primary objective:
• Demonstrate efficacy against “likely bacterial CAP”
Definitions:
• Likely bacterial CAP: alveolar consolidation (WHO) or abnormal CXR plus CRP > 40 mg/L.
Chosen to provide a better description of the true public health benefit of vaccination.
COMPAS “Likely bacterial CAP” endpoint
Clinical suspicion of pneumonia …
with abnormal chest X-ray (CXR)
showing alveolar consolidation
(=WHO case definition)
“Likely bacterial
pneumonia”
CRP ≥ 40 mg/L
with abnormal CXR
but without alveolar
consolidation
CRP < 40 mg/L
Design of Synflorix™: Why use a novel carrier protein?
Synflorix™ designed to:
• protect against 10 pneumococcal serotypes (1, 5 and 7F added to the 7 of Prevenar™)
• minimize risk of interference with co-administered vaccines
• provide protection against NTHi disease
S.pneumoniae
Polysaccharides
(10 serotypes*)
* 2 polysaccharides conjugated on tetanus and diphtheria toxoid respectively
Non-Typeable
H. influenzae
protein D
[carrier protein]
15
Can Protein D prevent NTHi disease?
Pneumococcal Otitis Media Efficacy Trial (POET)
• Czech Republic and Slovakia
• October 2000 – June 2004
• Double blind, randomised (1:1) study:
11Pn-PD versus hepatitis A control vaccine
– 11Pn-PD: prototype vaccine formulation with serotypes 1,3,4,5,6B,7F,9V,14,18C,19F,23F
all conjugated to NTHi protein D
• Co-administration: acellular pertussis combination vaccine (Infanrix hexa™)
Efficacy follow-up period
3
4
5
NTHi, non-typeable Haemophilius influenzae
Prymula, et al. Lancet 2006; 367: 740–8
12–15
24–27 months
Synflorix and Infanrix hexa are trademarks of the
GlaxoSmithKline group of companies
POET study indicates that a Protein D-containing vaccine can induce protection
against H. influenzae disease (AOM)
Acute Otitis Media Endpoint
Any (confirmed by presence of middle-ear fluid)
Vaccine pneumococcal serotypes
Non-vaccine pneumococcal serotype
Haemophilus influenzae
Recurrent AOM
Placement of grommets
(pressure-equalization tubes)
Vaccine Efficacy
(95% CI)
POET
% 33.6
(20.8 to 44.3)
% 57
(41.4 to 69.3)
%8
(-64.2 to 49)
% 35.6*
(3.8 - 57.0)
% 55
(-1.9 to 80.7)
% 60
(-26.7 to 87.5)
*Non-Typeable Haemophilus influenzae % 35.3 (1.8 to 57.4)
Prymula R, et al. Lancet 2006; 367:740–748
Is NTHi an important pathogen in paediatric lower
respiratory tract infections?
• In adults, NTHi generally accepted as an important lower respiratory
pathogen, at least in COPD exacerbations
• In children, NTHi is
– a major naso/oropharyngeal colonizer
– well recognized as a major cause of acute and recurrent otitis media, and otitis media with
effusion
• unlike non-encapsulated pneumococcus, and M. catarrhalis
NTHi : a major cause of mucosal infections in young
children
Major Bacterial Causes of Acute Otitis Media
US Post-PCV7 (9)
S. pneumoniae
&
H. influenzae
=
the 2 major
bacterial AOM
pathogens
US pre-PCV7 (9)
Japan (8)
Costa Rica (7)
Chile (6)
Spain (5)
Czech & Slovak (4)
Vast majority of H.
influenzae causing
AOM are nontypeable
(NTHi)
France (3)
Finland (2)
Israel (1)
0%
Spn
20%
Spn + Hi
40%
60%
% of cases
Hi
Mcat
80%
100%
S. pyog
Others
1. Leibovitz PIDJ 2007; 2. Eskola New Engl J Med 2001; 3. Gehanno PIDJ 2001; 4.Prymula Lancet 2006; 5. Del Catillo et al., PIDJ 1996
6.Rosenblut PIDJ 2001; 7. Guevara PIDJ 2008; 8.Suzuki PIDJ 2005; 9.Block PIDJ 2004
Is NTHi an important pathogen in paediatric lower
respiratory tract infections? - II
• In children, definitive etiological identification of pneumonias is
restricted to alveolar consolidation
– Pneumococcus likely not the whole story there, but role of NTHi appears limited
Lung puncture studies of alveolar consolidations in children
Country
Reference
Sample
% NTHi
Comment
Gambia
Morris, ISPPD, 2010
Lung puncture
5/50 (10%)
S. pneumoniae coinfection
Utilizing “gold standard” diagnostic techniques, NTHi has been detected
in pediatric alveolar consolidated pneumonias, but appears limited
Is NTHi an important pathogen in paediatric lower
respiratory tract infections? - III
• In children, bronchoalveolar lavages in immunologically “normal”
children yield significant proportions of NTHi in chronic cough, recurrent,
and treatment failure pneumonias
Studies with bronchoalveolar lavage in non-CF children
Country
Reference
Cases
% NTHi
France
Le Bourgeois, Chest, 2002
Recurrent Wheezing
50%
US
Saito, Ped Pulm, 2006
Recurrent Wheezing
26%
Spain
Romero, ERS, 2009
Persistent bacterial bronchitis
28%
Belgium
De Schutter, ESPID, 2009
Refractory bronchopneumonia
Recurrent bronchopneumonia
Persistent radiological abnormalities
Persistent Wheezing
43%
UK
Marguet, Am J Resp, 1999
Chronic cough
43%
Davidson, ERS, 2010
Persistent respiratory symptoms
30%
Australia
Hare, J Ped, 2010
Bronchiectasis
47%
Grecia
Mammas, ERS, 2010
Prolonged purulent bronchitis
61%
GSK Internal literature review, M. Van Dyke
NTHi in non-responding and recurrent community acquired
lower respiratory tract infection (LRTI)
• Retrospective analyses of bronchoalveolar lavage fluid (BALF) in Belgian children
(1-172 months; median = 33 months)
- 128 acute non-responding (broncho)-pneumonia
- 123 recurrent (broncho)-pneumonia
- 92 persistent X-ray abnormalities
- 41 persistent wheezers.
Pathogen
% Culture-positive (N = 227)
H. influenzae*
72 (164)
M. catarrhalis
24 (55)
S. pneumoniae
14 (33)
Adapted from De Schutter et al 2009
* 90.2% of Hi strains were non-typeable
• Non-typeable H. influenzae was the most commonly isolated pathogen in nonresponding or recurrent community acquired LRTI
De Schutter I et al. Abstract P445 (ESPID 2009)
Unmet medical need: improved and broader
protection against IPD, pneumonia, AOM
Streptococcus pneumoniae
Non-vaccine serotype (NVT) disease
 High PCV7/13 effectiveness against vaccine
serotype IPD but...
...NVT IPD (replacement?) considered major
problem, especially in Europe
•
...PCV7 effectiveness against AOM and
pneumonia limited
As a result, several vaccine developers are studying common-protein antigens
The future of anti-pneumonia vaccines: common proteins and conjugates?
One example
Study sponsors: GSK in collaboration with the Medical Research Council (The
Gambia), the London School of Tropical Medicine and Hygiene, with support
from PATH US
Design: infant vaccination comparing PCV vs PCV + pneumococcal proteins
A major endpoint: impact on NVT nasopharyngeal colonization
Conclusions
• Pneumococcal conjugate vaccines have proven highly
effective in preventing pneumonia, even some thought to
be caused by viruses
– Nonetheless, there is room for improvement
• Other bacteria such as NTHi may be important causes of
pediatric lower respiratory tract infections
– Data from COMPAS may help us understand its importance
• Next generation vaccines will likely be targeted at more
pneumococcal serotypes and possibly additional
pathogens
BACK-UPS

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