Pneumoccocal vaccines in the elderly - GLOBE Network · US, 2009 : high incidence of IPD in...

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

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s p

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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


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


Pneumonia all-cause


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


Death all-cause


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


0.0 0.5 1.0 2.0 3.0 4.0 5.0 8.0 12.0


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


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


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


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


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)


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


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%


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


� 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


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)


PCV

7 g 1 m

PCV

7 g 1 m

PPV

7 g 1 m6 m 6 m

PPV PCV PCV


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


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

Pneumoccocal vaccines in the elderly - GLOBE Network · US, 2009 : high incidence of IPD in...

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