Outline Background - PowerPoint Presentation

Slide1

Slide2

Outline

Background

Licensed pneumococcal conjugate vaccines

Effectiveness of PCV 13

Reduction in Nasopharyngeal carriage

Slide3

Major clinical syndromes are pneumonia, meningitis and bacteremia

1

Organism has an outer polysaccharide layer

1, 2

Defines the serotype

Functions as virulence factor

Is a vaccine target

More than

90 serotypes of S. pneumoniae have been identified.1, 2Serotypes are not equally pathogenicLast serotypes reported are 6C, 6D and 11EAntibiotic resistance in S. pneumoniae is a global concern.1, 2Exclusively human pathogen commonly carried in the nasopharynx1

Streptococcus pneumoniae

: The bacterium responsible for pneumococcal disease

Streptococcus pneumoniae

: The bacterium responsible for pneumococcal disease

1. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. In: Hamborsky J, Kroger A, Wolfe S, eds. 13th ed. Washington D.C. Public Health Foundation, 2015. 2. World Health Organization. Initiative for Vaccine Research. Acute respiratory infections. Updated September 2009. Available from: http://apps.who.int/vaccine_research/diseases/ari/en/index3.html. Accessed July 21, 2015.

Serotype 19F; Photograph courtesy of Robert P. Smith MS, MS Senior Research Scientist, Wyeth Vaccines.

3

Slide4

Pneumococcal disease can be broadly grouped into categories of invasive and non-invasive (mucosal) disease

1. World Health Organization (WHO).

Wkly

Epidemiol Rec

. 2012;87(14):129-144. 2. Said MA, et al.

PLoS

One. 2013;8:e60273. 3. Jansen AG, et al. Clin Infect Dis. 2009;49(2):e23-e29.

Non-invasive forms may become invasive (e.g. pneumonia when accompanied by bacteremia)

1Disease severity and invasiveness differ based on serotype3Pneumococcaldisease1MeningitisInvasiveBacteraemiaNoninvasive(mucosal)Sinusitis

Acute otitis media

~25% invasive

2

~75% non-invasive

Pneumonia

4

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5

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Pneumonia is a leading killer of children worldwide

3

Deaths from vaccine-preventable diseases in children worldwide

1−3

Hib,

Haemophilus influenzae

Type b.

1. World Health Organization. Global immunization data. July 2014. Available from: http://www.who.int/immunization/monitoring_surveillance/Global_Immunization_Data.pdf. Accessed July 21, 2015. 2. World Health Organization.

Wkly Epidemiol Rec. 2012;87(14):129-144; 3. UNICEF/World Health Organization. Pneumonia: The forgotten killer of children, 2006. Available from: http://www.childinfo.org/files/Pneumonia_The_Forgotten_Killer_of_Children.pdf. Last Accessed July 21, 2015.6

Slide7

CRM

4

6B

9V

14

18C

19F

23F

PCV71PCV134 CRM

4

6B9V1418C

19F

23F

1

5

7F

3

6A

19A

PCV10

2

Protein D

4

6B

9V

14

18C

19F

23F

1

5

7F

TT

DT

Protein D

PCV10 is conjugated to a

Haemophilus influenzae

‒derived protein D, carrier for all serotypes except 18C (tetanus toxoid) and 19F (diphtheria toxoid).

2

Development and licensure of expanded-valent vaccines were based on serology of the expanded-valent vaccine compared with PCV7.

1

−

3

PCV7 and PCV13 are conjugated to CRM

197.

1,4

Licensed pneumococcal conjugate vaccines

DT, diphtheria toxoid; PCV, pneumococcal conjugate vaccine (7-valent [PCV7], 10-valent [PCV10] or 13-valent [PCV13]); TT, tetanus toxoid.

1.

Prevenar13 vaccine NEAR Local Product Document (LPD) version 4 effective September 2017

. 2.

Vesikari

T, et al.

Pediatr Infect Dis J

. 2009;28(4

suppl

):S66-S76. 3. World Health Organization. Recommendations for the production and control of pneumococcal conjugate vaccines. WHO Technical Report Series, No. 927, 2005, Annex. Available from: http://

www.who.int

/biologicals/publications/

trs

/areas/vaccines/

pneumo

/ANNEX%202%20PneumococcalP64-98.pdf. Last Accessed July 22,2015. 4.

Prevenar 13 [abbreviated summary of product characteristics]. GLM ex Iraq: Pfizer Limited

.

7

Slide8

Clinical relevance of the 6 additional serotypes in Prevenar 13

Serotype

Clinical implications

Serotype 1

Associated with many IPD cases in children worldwide

1

One of the most common serotypes causing pediatric IPD

2

Associated with complicated pneumonia2 Serotype 3An important cause of invasive disease and is associated with complicated 2-4Among the most common isolates in AOM globally5,6Serotype 5Associated with many IPD cases in children worldwide1Serotype 6AIs multidrug-resistant7Among the most common isolates in AOM globally5Commonly found in nasopharyngeal isolates7,8Serotype 7FOne of the most common serotypes causing IPD and pneumonia in children

2-4High case-fatality rate compared with other serotypes9

Serotype 19AA leading cause of serious pneumococcal disease worldwide (including complicated pneumonia (empyema)2−4The most common serotype in pneumococcal carriage7,8Among the most common isolates in AOM globally4-6,10Multidrug resistance2,7,10

−12

Complicated pneumonia

Common cause of AOM

Very multidrug resistant

Is common in AOM

Common in NPC

Multidrug resistant

Global cause of IPD and complicated pneumonias

Clinical relevance of the 6 additional serotypes in PCV 13

1.

Hausdorff

WP.

Vaccine

. 2007;25(13):2406-2412. 2. Weil-Olivier C, et al.

BMC Infect Dis

. 2012;12:207. 3.

Pilishvili

T, et al.

J Infect Dis

. 2010;201(1):32-41. 4. Kaplan SL.

Pediatrics

. 2010;125(3):429-436. 5. Rodgers GL, et al.

Vaccine

. 2009;27(29):3802-3810. 6. Alonso M, et al.

PLoS ONE

. 2013;8(1):e54333. 7. Cho EY, et al.

J Korean Med Sc

i. 2012;27(7):716-722. 8.

Chappuy

H, et al.

BMC Infect Dis

. 2013;13:357. 9.

Ruckinger

S, et al.

Pediatr

Infect Dis J

. 2009;28(2):118-122. 10.

Pichichero

ME, Casey JR.

JAMA

. 2007;298(15):1772-1778. 11. Ma X, et al.

PLoS ONE

. 2013;8(6):e67507. 12.

Wroe

PC et al.

Pediatr Infect Dis J

. 2012;31(3):249-254.

8

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Serotype

PCV13

PCV7

Ratio

*

4

1573

1861

0.856B74411610.649V493853800.92142140

3345

0.6418C151017800.85

19F

150

166

0.90

23F

1090

1071

1.02

Serotype

PCV13

PCV7

Ratio

*

1

50

4

12.50

3

251

6

41.83

5

162

5

32.40

6A

1228

122

10.07

7F

11,545

115

100.39

19A

442

7

63.14

10- to 100-fold higher functional activity for the 6 additional serotypes in the PCV13 group:

Comparable functional activity

for the 7 shared serotypes:

Pivotal non-inferiority study (2, 3, 4 and 11–12 months),

post-infant series OPA GMTs

1

*GMT of PCV13 versus PCV7.

GMT, geometric mean titer; OPA,

opsonophagocytosis

assay

1. Adapted from:

Kieninger

DM, et al.

Vaccine

. 2010;28(25):4192-4203.

9

Slide10

Immunogenicity of licensed PCVs against serotype 19A

functional antibody activity (OPA)

Comparison of studies with different vaccines, with immunologic assays performed at different laboratories

OPA,

opsonophagocytosis

assay

1. Vesikari T, et al. Pediatr Infect Dis J. 2009;28(4 Suppl):S66-S76. 2. Kieninger DM et al. Vaccine 2010;28(25):4192-4203. 3. Pilishvili T, et al. J Infect Dis. 2010;201(1):32-41. 4.

Prevenar13 [Summary of Product Characteristics]. GLM ex Iraq: Pfizer Limited. 5. Synflorix [Summary of Product Characteristics]. Belgium: GlaxoSmithKline Biologicals

10Functional antibody levels (OPA)Serotype 19A(potentially cross-reactive)Serotype 19A (contained in the vaccine) PCV71PCV101PCV132Geometric mean titers*4.5 (3.9–5.3)8.6 (7.1–10.5)

442

(361–543)% Achieving >1:8*3.4 (0.7–9.5)19.6 (15.0–25.0)

100 (96.2–100)

*

Po

st-primary dosing in a 3+1 schedule

PCV7 did not have any impact on serotype 19A IPD.

3

The % of subjects achieving a ≥1:8 functional antibody response is at least 5x greater in PCV13 recipients than that of PCV7 or PCV10.

1, 2

Slide11

PCV13 effectiveness

11

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United Kingdom: Incidence of IPD in children <2 years

1

*Corrected for proportion of samples serotyped, missing age, denominator compared with 2009–2010, and trend in total IPD up to 2009–2010 (after which no trend correction was applied).

NVT, non-vaccine serotypes; PCV13 only, serotypes in the PCV13 vaccine but not in the PCV7 vaccine.

1. Adapted from: Waight PA, et al.

Lancet Infect Dis

.

2015;15(5):535-543.

12Serotype % change 2008‒2010 vs. 2013‒201446%All type76%PCV7 type89%PCV13 type only28%NVT

IPD incidence

* in children <2 years of age,

from epidemiological year 2000–2001 to 2013–2014, United Kingdom

60

50

40

30

20

10

0

Corrected Incidence per 100,000

2000/2001

2001/2002

2002/2003

2003/2004

2004/2005

2005/2006

2006/2007

2007/2008

2008/2009

2009/2010

2010/2011

2011/2012

2012/2013

2013/2014

Year

All

PCV7

PCV13 only

NVT

PCV7

PCV13

Slide13

85%

(37–96)

PCV13 2+1

92%

(40–99)

74%

( -183–98)

Effectiveness of 2 or more doses of PCV13 versus no doses against IPD during PCV13 period†52%(-12%–79%)

PCV13 serotypes (all)§

PCV13 serotypes (additional)‖PCV7 serotypesAll serotypes

Vaccine effectiveness* (%)

87%

(38–97)

82%

(44–94)

90%

(53–98)

77%

(17–94)

Exposed

to HIV

Not exposed

to HIV

Malnourished

Not malnourished

Vaccine effectiveness* (%)

Effectiveness of 2 or more doses of PCV7 or PCV13 versus no doses against PCV7-type IPD over full study period

‡

%

(95% CI)

%

(95% CI)

The overall effectiveness of 2 or more doses of PCV7 or PCV13 against PCV7-type IPD in children aged ≥16 weeks not infected with HIV over the full study period was

78%

[95% CI: 46%–91%].

South Africa: Vaccine effectiveness* of PCV13 against IPD in children not infected with HIV aged ≥16 weeks in a case-control study

1

*Vaccine effectiveness was adjusted for malnutrition, for diphtheria, tetanus, and pertussis vaccination status at 16 weeks (3 doses received or not), and for maternal education level.

†

Enrolled children born during or after August 2011.

‡

Children born from February 2009 through July 2011.

§

PCV13 serotypes included: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F.

‖

Serotypes included in PCV13 but not in PCV7 were 1, 3, 5, 6A, 7F, and 19A.

CI, confidence interval

1. Adapted from: Cohen C, et al.

Lancet Glob Health

. 2017;5(3):e359-e369.

13

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South Africa: Age-specific incidence rates* for laboratory-confirmed IPD reported to GERMS-SA, 2009–2015

1

*Incidence rates were determined based on population figures obtained from Statistics South Africa.

2009: N=4,765, age unknown for n=163; 2010: N=4,199, age unknown for n=142; 2011: N=3,804, age unknown for n=219; 2012: N=3,222, age unknown for n=253; 2013: N=2,866, age unknown for n=142; 2014: N=2,734, age unknown for n=162; 2015: N=2,640, age unknown for n=158.

GERMS-SA, Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa.

1

1. GERMS-SA Annual Report 2015. Available from: http://www.nicd.ac.za/assets/files/2015%20GERMS-SA%20AR.pdf. Accessed March 28, 2017.

14

Following the introduction of PCV7/PCV13 in South Africa, the incidence of IPD was significantly reduced between 2009 and 2015 in infants <1 year of age (p<0.001).Age category (years)Incidence (cases per 100,000 population)PCV7 introduced April 2009PCV13 introduced June 2011

Slide15

Number of cases

England and Wales: IPD cases due to Serotype 3 in children <5 years of age

1

*Not statistically significant.

1. Adapted from: Waight PA, et al.

Lancet Infect Dis

. 2015;15(5):535-543.

15

68% reduction* (vs. 2008–2010)PCV13

Slide16

United States: Cases of IPD due to Serotype 6A in children ≤5 years of age

1

1. Adapted from: Richter SS, et al.

Emerg Infect Dis

. 2013;19(7):1074-1083.

16

Number of cases

PCV7

PCV1397% reduction (vs. 1999–2000)

Slide17

England and Wales: IPD incidence due to serotype 19A in children <15 years of age

1

1.

Adapted from:

Waight PA, et al.

Lancet Infect Dis

. 2015;15(5):535-543.

17

Serotype 19ACorrected incidence per 100,000

<2 years of age

2–4 years of age

5–14 years of age

PCV7

PCV13

0.0

1.0

2.0

3.0

4.0

5.0

6.0

2000/2001

2001/2002

2002/2003

2003/2004

2004/2005

2005/2006

2006/2007

2007/2008

2008/2009

2009/2010

2010/2011

2011/2012

2012/2013

2013/2014

91%

reduction

in children

<5 years of age

(vs. 2008–2010)

Slide18

No overall change in 19A IPD was observed in vaccinated children (children <5 years) in New Zealand while PCV10 was in the NIP.

New Zealand: 19A IPD cases in children <5 years of age

1

1. Adapted from: Institute of Environmental Science and Research Limited Surveillance Report. Invasive pneumococcal disease in New Zealand 2015. Available from: https://surv.esr.cri.nz/PDF_surveillance/IPD/2015/2015IPDAnnualReport.pdf. Accessed 1 March 2018.

18

19A IPD cases in New Zealand

Number of IPD cases

<5 years of age

PCV7

PCV10

PCV13

Slide19

France: Pneumococcal CAP

*†

cases in children 1 month–15 years of age in 8 pediatric hospitals

1

*X-ray confirmed; laboratory-confirmed P-CAP defined by positive blood or pleural culture, positive pleural PCR, or positive pneumococcal antigen detection in pleural sample. Microbiologically confirmed.

CAP, community-acquired pneumonia; P-CAP, pneumococcal CAP; PCR, polymerase chain reaction

1. Adapted from: Angoulvant F, et al. Clin Infect Dis. 2014;58(7):918-924.

19

Pre-PCV13 (June 2009–May 2010)Transition (June 2010–May 2011)Post-PCV13 (June 2011–May 2012)Pneumococcal CAP (children 1 month–15 years of age)Number of casesPneumococcal CAP

63% reduction

vs. pre-PCV13

Slide20

Madrid, Spain: Incidence of bacteremic pneumonia before and after withdrawal of PCV13 from public vaccination program

1

1. Tagarro A, et al.

J Pediatr

.

2016

;171:111-5.e1-3.

20

Introduction of universal PCV13Withdrawal of government subsidy of PCV13S. pneumoniae incidenceIncidence of bacteremic pneumonia in children <14 years of age, Madrid, Spain, January 1, 2009−June 1, 2014PCV 13 introduction in NIPPCV 13 withdrawal from NIP

Slide21

New Zealand: Frequency of

S. pneumoniae

serotypes from middle ear fluid (MEF) in children <3 years of age undergoing tube insertion

1

*Phase 1 conducted from May to November 2011; Phase 2 conducted from May to November 2014.

†

PCV7 was introduced in the New Zealand national immunization schedule in 2008 and replaced with PCV10 in late 2011.1. Adapted from: Best EJ, et al. Vaccine. 2016;34(33):3840-3847.

21

30

25

20

15

10

5

0

Percent

11A

10A

23A

33F

22F

6C

16F

15B

19A

23B

15C

9N

35B

3

35F

19F

31

38

23F

Serotypes

Phase 1* (PCV7

†

); N=25

Phase 2* (PCV10

†

); N=25

Compared with Phase 1,

S. pneumoniae

serotype 19A became the most commonly isolated serotype from MEF during phase 2.

Slide22

United States: Rates of otitis media in children <2 years of age

1

1. Marom TM, et al.

JAMA Pediatr. 2014;168(1):68-75.

22

Otitis media visit rate/child-year, <2 years of age

51%

reduction

PCV13

Slide23

Introduction of PCV13 in pediatric populations has had an indirect impact on IPD in adults

IPD, invasive pneumococcal disease; PCV, pneumococcal polysaccharide vaccine

1. Dagan R, et al.

J Infect Dis

. 2002;185(7):927-936;

2. Cohen R, et al.

Pediatr Infect Dis J

. 2012;31(3):297-301;

3. Davis SM, et al. Vaccine. 2014;32(1):133-145.23Children are a primary reservoir for pneumococci.1 Relationship of carriage to development of natural immunity is not clearly understood.Pneumococcal conjugate vaccines (PCVs) have been shown to reduce the carriage of vaccine-type strains in vaccinated children, thus reducing opportunities for transmission.1, 2Decreased transmission of pneumococci from children to adults has led to the observed reduction in rates of IPD in adults since the introduction of PCV.3

Slide24

Vaccine coverage: 96% in 2012

(≥1 dose, 6 months old).²

Adapted from Cohen et al. 2015.

1

NPC of

S. pneumoniae

(Sp) Serotypes, PCV7 Serotype (ST), and 6 Additional Plus 6C Serotypes as well as Antibiotic Resistance From 2001 to 2014

Period 1

(Oct 2001–Jun 2006)Period 2 (Oct 2006–Jun 2010)Period 3 (Oct 2010–Jun 2011)Period 4 (Oct 2011– Jun 2014)Sp

PCV7 ST

ST 6 additional* + 6CPenicillin intermediatePenicillin resistantPCV7

PCV7

0

80

50

20

60

40

10

70

30

Recommendation

for high-risk infants

Recommendation

for all infants

PCV13

Implementation

Proportion of nasopharyngeal

swabs (%)

From 2001 to 2010, carriage of 6 additional* PCV13 serotypes plus 6C increased from 17.2% to 24.3% (P<0.001) and decreased from 2011 to 2014 after PCV13 implementation from 21.4% to 3.5% (P<0.001).

Penicillin-intermediate-resistant pneumococcal strains decreased from 65.8% in 2001 to 32.2% in 2014.

†

Penicillin-resistant pneumococcal strains decreased from 1.3% in 2001 to 1% in 2014.

†

France: Carriage of overall six additional serotypes in children

6–24 months with acute otitis media

1,2

Between 2001 and 2014, 121 paediatricians obtained nasopharyngeal swabs from children with acute otitis media aged 6–24 months. The swabs were analysed by the French National Reference Centre for Pneumococci. A total of 7991 patients were enrolled.

*Serotypes 1, 3, 5, 6A, 7F, 19A

. † 95% CIs and p-values not available; no conclusion can be drawn regarding statistical significance.

NIP, National immunisation programme;

NPC, nasopharyngeal carriage, PCV7, 7-valent pneumococcal conjugate vaccine;

PCV13, 13-valent pneumococcal conjugate vaccine.

1. Adapted from: Cohen R, et al.

Vaccine

. 2015;33(39):5118-26. 2. INVS. Available from: http://www.invs.sante.fr/Dossiers-thematiques/Maladies-infectieuses/Maladies-a-prevention-vaccinale/Couverture-vaccinale/Donnees/Pneumocoque. Accessed February 25, 2016.

24

Slide25

Switzerland: Pneumococcal carriage and serotype Distribution in AOM patients pre- and post-PCV introduction

1

AOM, acute otitis media.

1. Allemann A, et al.

Vaccine

. 2017;35(15):1946-1953.

25

Variation of pneumococcal serotypes isolated from nasopharyngeal swabs of AOM patients during PCV vaccination periods

Proportions of pneumococcal serotypes/serogroups isolated (%)PCV7 (p<0.001)PCV13-PCV7-Serotype 3- Serotype 19A (p=0.002)Serotype 19A (p=0.001)Serotype 3 (p=0.013)PCV13

Time (Year)

A decrease in PCV13 serotypes was observed following PCV13 introduction, with the exception of serotype 3 increasing from 8.5% in 2004 to 11.1% in 2015 (2 test for trend: P=0.013).The proportion of serotype 19A isolates increased post-PCV7, then decreased significantly in the PCV13 era (2

test for trend: P

=0.001).

The proportion of non-PCV13 serotypes increased following PCV introduction, increasing from 26.1% in 2004 to 85.2% in 2015

(2 test for trend:

P

<0.001).

PCV13 serotypes

Slide26

Prevention

1. Vaccination

CDC recommends administering PCV13 as a four-dose series at 2, 4, 6, and 12 through 15 months of life

Research shows that this vaccine is very effective at preventing infection resulting from the serotypes contained in the vaccine

PCV13 should also be administered to all adults 65 years or older and to some adults 19 through 64 years of age with conditions that put them at increased risk for pneumococcal disease

Slide27

2. OTHER PREVENTIVE MEASURES.

Nutritional support

Chemoprophylaxis – oral Pen V for those at risk

e.g functional/anatomical asplenia.Rational use of antibiotics

Reduction of the Environmental risks- Air pollution, overcrowding.

Slide28

New vaccine in future?

A 72- valent pneumococcal vaccine is under development.

Hoped to offer ‘most comprehensive coverage’.

THANK YOU.