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Pneumoccocal vaccines in the elderly
(conjugated vs polysaccharides)
Paolo BonanniDepartment of Public HealthUniversity of Florence, Italy
Aging and Immunity II
Campus Novartis, Siena
April 24, 2012
Millions of people worldwide are at risk for pneumococcal diseaseRisk factor Global prevalence
Smoking 1 billion1
Age ≥65 years 518 million2
Asthma 300 million3
Diabetes 230 million4
COPD 210 million5
Alcohol use disorders 125 million6
HIV 33 million7
1. WHO. Tobacco key facts. http://www.who.int/topics/tobacco/facts/en/index.html. Accessed June 23, 2009. 2. US Census Bureau. Table 094. Midyear population by age
and sex. 2009. http://www.census.gov/ipc/www/idb/worldpopinfo.html. Accessed June 23, 2009. 3. WHO. Asthma. Fact sheet.
http://www.who.int/mediacentre/factsheets/fs307/en/index.html. Accessed June 18, 2009.4. World Diabetes Foundation. Diabetes facts.
http://www.worlddiabetesfoundation.org/composite-35.htm. Accessed June 18, 2009. 5. WHO. Chronic obstructive pulmonary disease (COPD). Fact sheet.
http://www.who.int/mediacentre/factsheets/fs315/en/index.html. Accessed June 18, 2009. 6. WHO. The global burden of disease: 2004 update.
http://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf. Accessed May 5, 2009 7. WHO. World health statistics 2009.
http://www.who.int/whosis/whostat/EN_WHS09_Full.pdf. Accessed June 23, 2009.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
≥5 diagnoses
2-4 diagnoses
1 diagnosis
Co-morbidities are commonly present in patients with pneumococcal disease, England and Wales
Melegaro A et al. J Infect. 2006;52(1):37–48.
Proportion of hospital admissions with 1, 2-4, and ≥5 diagnoses reported during a hospital stay (England and Wales, HES, 1995-2000)a
Age group
aHospitalizations including an occurrence of one of the pneumococcal-related ICD-10 codes; HES=hospital episode statistics
Age is an independent risk factor for CAP, Italy
Viegi G et al. Resp Med 2006;100:46–55
In patients >40 years, case-fatality rates for CAP increase with age, Germany
Ewig S et al. Thorax 2009;64:1062 –1069
M2
Diapositive 5
M2 Synergy to redrawMarie; 15/11/2010
Mixed patient populations in different settings and countries
*CAP=Community acquired pneumonia
# average of 30-day and 90-day mortality in ICU vs ward patients, with average of 2 rates ~ 12%
1. Austrian R et al. Ann Intern Med. 1964;60:759-776;
2. Fine MJ et al. JAMA. 1996;274:134-141;
3. Feikin DR et al. Am J Pub Health. 2000;90:223-229
4. Restrepo MI et al. Chest. 2008;133:610-617.
Case-fatality rates for hospitalised patients with IPD and CAP have remained constant over time1-4
LETHALITY1 LETHALITY2 LETHALITY3 LETHALITY4
US, 2009 : high incidence of IPD in subjectsaged >50 years
Incidence < 5yrs: 21.1/100 000, ≥ 65+: 38.7 /100 0001
Nb of cases and deaths per 100 000 related to Invasive Pneumococcal Diseases (IPD) in 2009 in the US in surveillance areas representing 29 million persons all ages.
1.CDC, Active Bacterial Core Surveillance (ABCs) Report Emerging Infections Program Network Streptococcus pneumoniae, 2009http://www.cdc.gov/abcs/reports-findings/survreports/spneu09.pdf accessed on 5-04-2011
Ra
tes
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ath
s p
er
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The polysaccharide capsule
� The bacterial polysaccharide capsule is highly antigenic� It is the virulence factor, and defines the serotype
� Capsular polysaccharide inhibits complement and interferes with opsonisation by phagocytes
� Different serotypes have different invasive, carriage and disease potentials
Jones C. An Acad Bras Cienc 2005;77:293-324.
Pneumococcal polysaccharide 23-valent vaccine (PPV23):
antigenic composition
PPV23 contains 25 µµµµg x 23 capsular polysaccharides of S. pneumoniae 1
• 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A,11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F
Serotype coverage2,3
• 85-90% of serotypes responsible of invasive pneumococcal diseases
Cross-protection 1
• Serotype 6B is partially protective against serotype 6A (not included in the vaccine)
1. CDC, MMWR, 19892. Fedson, Musher, in Vaccines, 19943. Geslin et al., Méd Mal Infect, 1992
PPV23 in IPD preventionCochrane metanalysis 2008
Invasive pneumococcal infections
Moberley Cochrane Database Syst. Rev. 3, CD000422 (2007).
Favours vaccine Favours control
Efficacy in IPD*: Results of 9 differentmeta-analyses
Studies show efficacy in adults without risk factors, in elderlypatients (to a lesser extent), but not in high-risk patients
Range RR (IC 95%) Range VE %
All serotypes
All population
High-risk population
0.17 (0.0–90.31) to 0.37 (0.08–1.45)
1.56 (0.35–6.94) to 0.58 (0.18–1.0)
83 to 63
0 to 42
Vaccine serotypes
All population
High-risk population
0.17 (0.09–0.34) to 0.27 (0.13–0.49)
0.53 (0.14–1.94) to 0.98 (0.51–1.89)
83 to 73
47 to 2%
Gaillat J. Exp Rev Resp Med 2009 *IPD is mainly CAP with positive blood culture
Efficacy in pneumonia: Synthesis of 9 meta-analyses
Range RR (IC 95%) Range VE %
Pneumonia all-cause
High-risk population
0.71 (0.56–0.94) to 0.89 (0.76–1.05)
0.89 (0.69–1.14) to 1.08 (0.92–1.27)
11 to 29
11 to 0
Suspected Sp
pneumonia
All population
High-risk
Vaccine serotypes
0.47 (0.23–0.94) to 0.64 (0.56–0.94)
0.68 (0.72–1.07) to 1.20 (0.75–1.92)
0.27 (0.08–0.87) to 0.39 (0.26–0.59)
53 to 36
32 to 0
61 to 73%
There is heterogeneity within controlled studies; no meta analysis supports efficacy against all-cause pneumonia
*Pneumonia is either all-cause pneumonia or suspected pneumococcalpneumonia mainly from sputumGaillat J. Exp Rev Resp Med 2009
PPV23 in mortality prevention (IPD* or pneumonia**): Synthesis of 9 meta-analyses
Range RR (IC 95%) Range VE %
Death all-cause
High-risk population
0.84 (0.7–1.01) to 1.01 (0.91–1.12)
> 1
16 to 0
0
Death and pneumonia
High-risk
0.69 (0.28–1.27) to 0.88 (0.62–1.25)
0.51 (0.09–2.92) to 1.10 (0.92–1.34)
31 to 12
49 to 0
Effect on mortality very limited, if any
There is heterogeneity within controlled studies
*CAP with positive blood culture**Pneumonia is either all-cause pneumonia or suspected
pneumococcal pneumonia based mainly from sputumGaillat J. Exp Rev Resp Med 2009
Summary of evidence and controversy on PPV23 efficacy
� PPV23 is effective in preventing invasive infections in healthy adults and, to a lesser extent, in the elderly
� No definitive conclusion possible for high risk subjects (very heterogeneous)
� Inconsistent data on efficacy against CAP (heterogeneous studies, insufficient statistical weight), evidence of effectiveness from some observational studies
� Most studies conclude there is no impact on mortality
WHO position paper on PPV23
“Despite multiple studies conducted during > 30 years, the efficacy and effectiveness of PPV in children and adults remain poorly defined and the subject of controversy.”
“ There is a need for more efficacious conjugate vaccine covering the majority of pneumococcal serotypes that cause serious diseases in older children and adults worldwide and that are responsible for resistance to commonly used antimicrobial drugs”
“ WHO supports the ongoing efforts to develop such products”
WHO position paper on 23-valent pneumococcal polysaccharide vaccine, 2008
The main principles of vaccine conjugation
� Conjugation covalently links capsular polysaccharides from encapsulated pathogens to carrier protein antigens
� Transforms T-cell independent antigens into T-cell dependent antigens to:� Elicits a stronger T-cell dependent response� Activates helper T cells to assist B cells in
humoral response and producing IgGantibodies
� Activates T cells to assist B cells in priming memory cells
� Induces a booster responseSiber GR, et al (Ed). Pneumoccocal Vaccines. The impact of conjugated vaccines. ASM Press. 2008
Conjugated vaccines induce
immunological memory by activating
B cells and T cells3
•Carrier protein conjugate antigen
helps B cells to differentiate both
into memory B cells and plasma
cells
Plain polysaccharide vs conjugated vaccines
Plain polysaccharide vaccines activate
B cells but do not induce
immunological memory1,2
•Short-lasting immune response, no
booster effects on re-challenge
•No reduction in carriage
1. Overturf GD, Committee on Infectious Diseases. Pediatrics. 2000;106:367-376.
2. Ada G. N Engl J Med. 2001;345:1042-1053. 3. Pollard et al. Nature Reviews Immunology. 2009;9:213
PCV7* N = 110; PPV23 N = 104
*
*
ELISA OPA
De Roux C I D. 46, 1015–1023 (2008)
*
**
** *
*p < 0.01
*PCV7 is not approved for adults
Immunogenicity one dose PCV7* vs PPV23
GM
T
*
* *
Pneumococcal Conjugate Vaccine
(PCV13) in adults > 50 years:
immunogenicity studies
20Pfizer property – Do not distribute EU-PREV-2011/10/0024. Subject to local review.
Pivotal non-inferiority comparisons of immune responses
• Definitions for the 12 serotypes in common− Noninferiority (primary endpoint)
• Lower limit of the 95% CI for the GMT ratio is > 0.5,
− Statistically significantly higher (secondary endpoint)• Lower limit of the 95% CI for the GMT ratio is > 1
CI: confidence intervalGMT: geometric mean titre
PPV HIGHER ANTIBODY RESPONSES N
ON
-
INF
ER
IOR
ITY
PCV 13 HIGHER ANTIBODY RESPONSES
0.0 0.5 1.0 2.0 3.0 4.0 5.0 8.0 12.0
Geometric Mean Ratio (GMR)
PPV HIGHER ANTIBODY RESPONSES N
ON
-
INF
ER
IOR
ITY
PCV 13 HIGHER ANTIBODY RESPONSES
0.0 0.5 1.0 2.0 3.0 4.0 5.0 8.0 12.0
Geometric Mean Ratio (GMR)
21
PCV13 impact on functional antibody responses in adults aged 60-64 years not previously vaccinated with PPV23
“The response to serotype 6A, which is unique to Prevenar 13, was assessed by demonstration of a 4-fold increase in the specific OPA titer
above previously vaccinated levels.” (Prevenar 13 Summary of Product Characteristics , Dec 2011)
Geometric Mean Ratio (GMR)1 month after dose
Trial 004: OPA responses elicited by PCV13 for the 12 serotypes in common:
• Non-inferior to PPV23 for all of the serotypes in common*
• Statistically significantly superior to PPV23 for 10 of the serotypes in common** and for serotype 6A*
* Primary endpoints
** Secondary endpoints
PPV HIGHER ANTIBODY
RESPONSES
NO
N-
INF
ER
IOR
ITY
PCV 13 HIGHER ANTIBODY RESPONSES
0.0 0.5 1.0 2.0 3.0 4.0 5.0 8.0 12.0
1
3
4
5
6B
7F
9V
14
18C
19A
19F
23F
22
CV, cardiovascular diseases; CPD, chronic pulmonary diseases; Diab, diabetes mellitus; GMT, geometric mean titre.
OPA response to PCV13 in adults aged 50-64 years not previously vaccinated with PPV23
*ad-hoc analysis
Responses to PCV13 in all subjects were similar, regardless of comorbidities*
23
PCV13 impact on functional antibody response in adults ≥≥≥≥70 years of age previously vaccinated with PPV
1 month after dose* Primary endpoint
** Secondary endpoint
“The response to serotype 6A, which is unique to Prevenar 13, was assessed by demonstration of a 4-fold increase in the specific OPA titer
above previously vaccinated levels.” (Prevenar 13 Summary of Product Characteristics , Dec 2011)
Trial 3005, OPA responses elicited by Prevenar 13 for the 12 serotypes in common:
•Non-inferior to PPV for all of the serotypes in common*
•Statistically significantly superior to PPV for 10 of the serotypes in common** and for serotype 6A*
PPV HIGHER ANTIBODY
RESPONSES
NO
N-
INF
ER
IOR
ITY
PCV 13 HIGHER ANTIBODY RESPONSES
0.0 0.5 1.0 2.0 3.0 4.0 5.0 8.0 12.0
1
3
4
5
6B
7F
9V
14
18C
19A
19F
23F
Geometric Mean Ratio (GMR)
24
Jackson L et al IDSA 2011
Trial type: Phase 3, randomized, active-controlled, modified double-blind
Trial population: Adults 50–64 years old, not previously vaccinated with PPV
004 Extension: Evaluation of the Immunogenicity and Safety of PCV 13 Compared with PPV upon Revaccination at 3.5−4 Years
25
004 Extension: secondary comparisons of antibody responses (OPA GMT), PPV / PPV vs PPV, adults aged 60-64 years
SerotypePPV / PPV
(na=157-181)GMTb
PPV(na=157-181)
GMTbGMT Ratioc
(95% CI)
1 95 115 0.8 (0.68-1.02)
3 53 103 0.5 (0.44-0.59)
4 725 1437 0.5 (0.40-0.64)
5 71 152 0.5 (0.39-0.56)
6Ad 133 286 0.5 (0.35-0.62)
6B 915 1133 0.8 (0.62-1.04)
7F 466 440 1.1 (0.81-1.37)
9V 181 669 0.3 (0.18-0.41)
14 619 823 0.8 (0.60-0.95)
18C 822 1096 0.8 (0.60-0.94)
19A 361 374 1.0 (0.83-1.12)
19F 405 596 0.7 (0.57-0.81)
23F 56 91 0.6 (0.50-0.76)
a: Adults with determinate antibody titer for the specified serotype; b: GMTs calculated using all evaluable subjects with data for a given
blood draw; c: Ratio of GMTs calculated by back transformation of the mean difference between vaccine groups on the logarithmic scale; d:
Serotype 6A is not included in PPV
• Revaccination with PPV resulted in OPA GMTs statistically significantly lower for 8 of
the 12 serotypes common to both vaccines compared with the first dose of PPV
Jackson L et al IDSA 2011
26
004 Extension: Primary comparisons of antibody responses (OPA GMT),
PCV 13 / PPV vs PPV / PPV, adults aged 60-64 years
• Administration of PPV after PCV 13 resulted in OPA GMTs statistically significantly
greater for the 12 serotypes in common to both vaccines compared with OPA GMTs
after revaccination with PPV
SerotypePrevenar 13 / PPV
(na=99-107)GMTb
PPV / PPV(na=174 -168)
GMTb GMT Ratioc (95% CI)
1 398 95 4.2 (2.87-6.08)
3 164 53 3.1 (2.26-4.30)
4 1875 733 2.6 (1.72-3.80)
5 476 74 6.5 (4.09-10.19)
6Ad 832 123 6.8 (3.72-12.33)
6B 2670 916 2.9 (1.83-4.63)
7F 1895 497 3.8 (2.41-6.03)
9V 1089 187 5.8 (3.13-10.82)
14 1268 661 1.9 (1.30-2.84)
18C 2489 802 3.1 (2.02-4.78)
19A 966 364 2.7 (1.87-3.76)
19F 1653 374 4.4 (2.97-6.58)
23F 299 54 5.5 (3.20-9.41)
Jackson L et al IDSA 2011
a: Adults with determinate antibody titer for the specified serotype; b: GMTs calculated using all evaluable subjects with data for a given blood draw; c:
Ratio of GMTs calculated by back transformation of the mean difference between vaccine groups on the logarithmic scale; d: Serotype 6A is not included in
PPV
27Pfizer property – Do not distribute EU-PREV-2011/10/0024. Subject to local review.
Immunogenicity studies PCV7-13 / PPV23 in adult subjects
Coverage of invasive pneumococcaldisease serotypes by PPV23 versus PCV13
Country (Region)
Lead Author,Journal, Year
Age Group (y) Interval Analyzed
Proportion of Isolates Corresponding to Types in:
PPV23 PCV13 Δ
UKMiller, Lancet Infect Dis,
201165+5-64
2008-201081%91%
58%63%
23%28%
France Grall, Eur J Clin Microbiol Inf Dis, 2011
≥16 2009 89% 70% 19%
GermanyImöhl, Int J Med Microbiol, 2010
>16 2008 85% 71% 14%
Spain (Tarragona)
Vila-Córcoles, Vaccine, 2011
65+ 2008 69% 63% 6%
Portugal Horacio, Vaccine, 2011 18+ 2006-2008 84% 68% 16%
29Pfizer property – Do not distribute EU-PREV-2011/10/0024. Subject to local review.
Main results to date with PCV13 and remaining issues
Registered in Europe for the prevention of invasive
pneumococcal diseases based on immunogenicity data.
It elicits higher levels of functional antibodies both in
naive subjects and in individuals already vaccinated
with PPV23
If a sequential vaccination is recommended, PCV13
should be always administered as first vaccine
The incremental serotype coverage of PPV23 vs PCV13
ranges from 6 to 28% in different countries (average
around 15%)
No efficacy data available up to now (awaited 2013)
30Pfizer property – Do not distribute EU-PREV-2011/10/0024. Subject to local review. 30
R
Placebo
PCV13
Screening/Recruitment
Start of enrollmentSept 2008
Results available~ I Quarter 2013
Tim
elin
e
End of Recruitment Jan.2010
84,496 Healthy, > 65 years
31Pfizer property – Do not distribute EU-PREV-2011/10/0024. Subject to local review.
� Primary
� Efficacy of PCV13* for prevention of first episode ofvaccine-type (VT) Community-Acquired Pneumonia (CAP)
� Secondary
� Efficacy of PCV13 for prevention of first episode ofnon-bacteremic VT- Community-Acquired Pneumonia (CAP)
� Efficacy of PCV13 for prevention of first episode of VT-Invasive Pneumococcal Disease (IPD)
� Additional exploratory objectives
� Efficacy of PCV13 for the prevention of all episodes of CAP
� Efficacy of PCV13 for the prevention of death• Investigate trends in efficacy by age• Assess economic effect of PCV13
31
CAPiTA: Study Objectives
32Pfizer property – Do not distribute EU-PREV-2011/10/0024. Subject to local review.
PCV13 ongoing studies
• Age expansion (6 - 49 years) (1Q2012)
• HIV infected (4Q2012)
− ≥6 years in PS naive subjects
− ≥18 years PS pre-immunized subjects
• Sickle cell disease (≥6 years) (2Q2012)
• Bone marrow transplant recipients (≥2 years) (2Q2014)
• Antibody persistence and re-vaccination at 5y (4Q2013)
33Pfizer property – Do not distribute EU-PREV-2011/10/0024. Subject to local review.
PCV
7 g 1 m
PCV
7 g 1 m
PPV
7 g 1 m6 m 6 m
PPV PCV PCV
34Pfizer property – Do not distribute EU-PREV-2011/10/0024. Subject to local review.
Effetto di una dose di PCV o di PPV sulle Cellule B di Memoriaad un mese dalla vaccinazione
Clutterbuck E at al, J Infect Dis, Access 28 Mar 2012
28 days after vaccination in
those receiving PCV7
Those who received PPV23
showed a decreasing trend
of memory B cells
compared to basal levels
PPV
PCV
Before any vaccinaion, 86% of subjects had some basal level of antibody-secreting MBC to at
leaast 1 of 7 serotypes, although being naive
Memory B cells
35Pfizer property – Do not distribute EU-PREV-2011/10/0024. Subject to local review.
Clutterbuck E at al, J Infect Dis, Access 28 Mar 2012
Effect of a dose of PCV or PPV on memory B cells 6 months after
immunization
6 months after vaccination, memory B cells (MBC):
Decrease to basal levels in
those receiving PCV7Further decrease in those
receiving PPV23
PPV
PCV
Age-based vs at-risk recommendations
Age-based At-risk
Easy access to target group High-risk people relatively inaccessible
(e.g. socially disadvantaged); Many at-risk
patients are missed
Exiiting infrastructure to administer
vaccines
At-risk recommendations may not cover
all possible situations
Establishment of community protection
(Herd effect)
Vaccination responsibility lies with
different professionals
Overall higher levels of immunity
achieved
� Target: subjects aged > 64 years (one or more cohorts by age)
� Vaccination with PCV13 (priming) + PPV23 , 1 year apart (to be discussed)
� Opportunistic vaccination?: co-administration with influenza vaccine
� Possible extension of vaccination offer in all seasons (single injection)
Conclusions
� Plain polysaccharide vaccines showed 50-80% efficacy against IPD in healthy adults, with a downward trend in the elderly, no definitive demonstration of efficacy in high risk groups
� They do not generate helper T cells or induce lasting and adequate immune memory
� Conjugate vaccines may induce a stronger immune response and memory compared with polysaccharide vaccines
� They had a dramatic impact on IPD and pneumonia in children
� Their efficacy/effectiveness in adults has not yet been demonstrated
� A recent study shows a depletion of memory B cells after PPV vaccination compared with PCV vaccination
� The best vaccination scheme and schedule needs to be investigated in the near future
Recommended