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Meningi&s(and(Sep&caemia(in(Children(and(Adults' Tuesday'5'&'Wednesday'6'November'2013'''Royal'Society'of'Medicine,'London,'UK' ''

Preven&ng(pneumococcal(disease( ( 11:20 (Current'epidemiology'and'summary'of'vaccines'in' development;'the'need'for'higher7valent'and'alterna8ve' vaccines'' ' Prof'David(Goldbla;(( ( UCL(Ins8tute'of'Child'Health' Great'Ormond'Street'Hospital' London('

'


Meningi&s(and(Sep&caemia(in(Children(and(Adults' Tuesday'5'&'Wednesday'6'November'2013'''Royal'Society'of'Medicine,'London,'UK' ''

Talk(Outline' !  !  !  !  !  ! 

Pneumococcal'Disease'and'Vaccine'Development' Impact'of'first'licensed'pneumo'conjugate'vaccine'(PCV7)' Development'of'10'and'13'valent'conjugates' Impact'of'13'valent'vaccine'in'E&W'and'the'USA' Future'serotype'replacement?' Pneumococcal'vaccines'for'2020' o  Conjugate'vaccines?' o  Pneumococcal'protein'vaccines?'


Invasive pneumococcal disease incidence rate per 100,000 population by age grouping England and Wales, 1996-2005 80

70

Rate per 100,000 population

60

1996/97

1997/98

1998/99

1999/00

2000/01

2001/02

2002/03

2003/04

2004/05

50

40

30

'

'''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''

20

10

0 <2m

2-5m

6-11 m

1 year

2-4 years 5-9 years

10-14 years

Age range

15-44 years

45-64 years

65-74 years

75-79 years

80+ years

Data$courtesy$of$the$Health$Protec1on$Agency$


1914'Whole'cell'vaccine'

1945:'Penicillin'licensed'

1946:'PPV'licensed'(Squibb),'withdrawn'1951'

1977:'14'valent'(50µg/PS)''

1983' 23'Valent'Pneumococcal'Polysaccharide'' Vaccine'(Pneumovax'23™)'25µg/PS'

PROTEIN

KEITH KLUGMAN MB CHB


4

6B

9V

23F

19F

14 18C


Published'PCV7'impact' n=14'countries'

PIDJ'In'Press'


Quindecimal 22F

33F

6A

1

4

6B

9V

23F

19F

19A

5

14 18C

3

7F

Prevnar13™

Synflorix™


PCV13'replaced'PCV7' in'the'infant'immunisa8on' programme'in'April'2010'

(licensed'on'immunogenicity'alone)'


Impact of PCV7 followed by PCV13 !  Dramatic Reduction in PCV7 IPD !  Impact on IPD in unvaccinated adults (herd/indirect effect) !  Increase in IPD due to non-PCV7 serotypes !  Rapid impact on PCV13 serotype IPD since 2010 !  Early signs of a herd effect in adults !  Slower replacement disease?


Carriage(preE(and(postEPCV7(introduc&on(in(England(and(Wales(

80'

All'<60'years' %'Carriage' %'IPD'

70' 60' 50' 40' 30' 20' 10' 0'

PCV7' 01/02'

PCV7' 08/09'

1,5,7F' 01/02'

1,5,7F' 08/09'

3,6A,19A' 3,6A,19A' 01/02' 08/09'

Rest' 01/02'

Rest' 08/09'

Flasche'et'al'Plos'Med'2011'


Future'Conjugate'Strategies:'

' 1)  Glyco7conjugates'containing'more'serotypes:'15'(Merck),'>'15??' i.  Physicochemical/immunological'constraints' ii.  Novel'technologies'to'overcome'these?' 2)  Glyco7conjugates'containing'different'serotypes?' i.  Conjugate'Mk'II:'Next'most'important'X'serotypes' ii.  Adult'use?''

Which'Serotypes?'


S.$Pneumoniae'Capsule,'Cell'Wall'and'Membrane' Pneumolysin:$Cytoly1c,$ligand$for$TLR4,$ac1vates$complement,$s1mulates$proinflammatory$cytokines'' Pneumococcal$Surface$Protein$A:$binds$to$epithelial$membranes,$blocks$complement' Pneumococcal$iron$acquisi1on$A$and$iron$uptake$A:$ABC$transporters$that$acquire$iron$for$bacterial$growth$and$virulence' PspA

Pneumococcal$Surface$Protein$C,$also$known$as$choline$binding$protein$A:$binds$factor$H$and$blocks$C3b$fixa1on,$$ binds$to$human$polymeric$immunoglobulin$receptor$during$invasion$

(

PspC

Pneumococcal$choline$binding$protein$A:$Low$manganeseKinduced$protein,$unknown$func1on$but$$ Important$in$lungs$and$blood$

(

Pneumococcal$surface$an1gen$A:$mediates$metal$ion$uptake$(Zn$and$Mn),$protects$$ against$oxidant$stress,$binds$to$GlcNacKGal' IgA$protease:$degrades$human$IgA1$ Hyaluronate$lyase:$degrades$hyaluronan$in$the$extracellular$matrix$

PnaA(

Phosphorylcholine:$binds$to$PAFR$on$human$epithelial$cells$ Autolysin:$releases$pep1doglycan,$teichoic$acid,$$ pneumolysin$other$intracellular$contents' Pneumococcal(choline( binding(protein(A( PspC/CbpA( Pneumolysin(

IgA1(protease( PsaA(

Neuraminidase:$contributes$to$adherence,$$ removes$sialic$acids$on$host$glycopep1des$$ and$mucin$to$expose$binding$sites'

Hyaluronate(lyase(

Neuraminidase(

Phosporylcholine

Enolase:$binds$to$fibronec1n$in$host$1ssues'

(

Sortase$A:$links$surface$proteins$to$cell$wall'

Autolysin( Enolase( Sortase(A( Cell(membrane

Pili

(

Cell'wall

'

'

Polysaccharide'Capsule

(

Pili:on$cell$surface$inhibits$ phagocytosis,$promotes$ invasion'

Adapted'from:'Goldblam'and'O’Brien.'Pneumococcal''

Infec8ons,'Harrisons'Principles'of'Internal'Medicine'18th'ed'


Otcyzk'and'Cripps' Pneumonia'2013'


How'to'licence'non7conjugate'based' pneumococcal'vaccines?'


How'to'licence'non7conjugate'based' pneumococcal'vaccines?' •  •  •  •  • 

Efficacy'trial?'' Endpoint?' Design?'Conjugate'or'placebo'control??' Correlates'of'protec8on' Sample'Size'Calcula8ons' Carriage?'

Invasive'Disease'Efficacy'Trial'in'50764'year'olds'

Required Number of Subjects Per Group– 2 year Follow Up Event Rates VE 25/100,000 15/100,000 7.5/100,000 90 30,007 50,007 85,341 93,347 154,681 80 56,041 163,357 261,357 70 98,024


Sample'Size'Calcula8ons' Invasive'Disease'Efficacy'Trial'in'50764'year'olds' Required Number of Subjects Per Group– 2 year Follow Up Event Rates VE 25/100,000 15/100,000 7.5/100,000 90 30,007 50,007 85,341 93,347 154,681 80 56,041 163,357 261,357 70 98,024

Colonisa8on'Efficacy'Trial'in'50764'year'olds' “VT”'coloniza8on'rate'in'controls:''5%' “VT”'coloniza8on'rate'in'vaccinated:'1%''(i.e.'80%'reduc8on)' 'P=0.05,'80%'power'' The'sample'size'for'each'arm'≥'284'(568'total).'


Public'delivery'of'the'PneumoCarr'output:' Case'for'Carriage'(C4C)'' and'its'key'components'

Vaccine$2013'August'6th' $

WHO'Mee8ng'27728'March'2012,'' Genève,'Switzerland'


Summary' •  Profound'direct'and'indirect'impact'of'PCV7'and'now' PCV10/13'when'used'in'developed'country'sevngs' •  Serotype'Replacement'has'impacted'on'PCV7' effec8veness'in'developed'country'sevngs' •  Unclear'what'scale'this'will'reach'for'PCV13'as'“less' fit”'serotypes'may'predominate' •  Could'we'maintain'control'of'S.$Pneumoniae'disease' with'a'second'genera8on'conjugate'vaccine'or'will' replacement'con8nue'ad7infinitum?' •  Non'capsule'based'vaccines'are'amrac8ng'much' amen8on'but'the'pathway'to'licensure'for'protein'only' vaccines'remains'unclear' •  Glyco7conjugates'using'pneumococcal'proteins'as' carriers'are'a'highly'amrac8ve'op8on'


ACKNOWLEDGEMENTS:' ' ' Professor'Elizabeth'Miller'and'team'' ' ' Mam'Moore'CDC,'Atlanta' ' ' ' Mark'Alderson,'Seamle'


Current epidemiology and summary of vaccines in development; the need for higher-valent and alternat