Vaccines - RCP London

Vaccines

Robert Read University of Southampton

University Hospital Southampton

Disclosures

• Non personal, non specific; Novartis-GSK • Member, JCVI • Editor in Chief, Journal of Infection, and

Current Opinion in Infectious Diseases

Question

• In the under 5s, since 2013 there has been `replacement` invasive pneumococcal disease caused by

• A – serotype 4 • B – serotype 6 • C – serotype 9V • D – serotype 14 • E – serotype 22F

Question

• Since september 2015, adolescents have been receiving routinely the following meningococcal vaccine for the given reason

• A – rMenB to cover serogroup B • B – rMen B to cover serogroup Y • C – MenC to cover serogroup C • D – conjACWY to cover serogroup W • E – conjACWY to cover serogroup Y

Routine Immunisation Schedule 2015

Selective immunisation programmes 2015

NIHR Southampton Respiratory Biomedical Research Unit

The nasopharynx…the root of all…..

• Pneumonia • Otitis Media • Sinusitis • Chronic Bronchial

Sepsis • Meningitis



Pneumococcal carriage

Meningococcal carriage

Ifedayo et al 2012

Christensen et al 2010

Pneumococcal vaccines Vaccine Name acronym nature serotypes

23-valent pneumococcal polysaccharide vaccine

pneumovax PPV23 Plain polysaccharide

1, 2, 3, 4, 5, 6b, 7F, 8,9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F

7-valent pneumococcal glyco-conjugate vaccine

Prevnar PCV7 Conjugated to diphtheria protein (CRM197)

4, 6B, 9V, 14, 18C, 19F and 23F


Synflorix PCV10 Conjugated to NTHi protein D, or tetanus/diphtheria proteins

1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F


Prevnar 13 PCV13 Conjugated to diphtheria protein (CRM197)

1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F

Figure 1. Corrected* invasive pneumococcal disease incidence from epidemiological year 2000/01 to 2013/14, by serotype grouping and agePCV7=seven-valent pneumococcal conjugate vaccine. PCV13=13-valent pneumococcal conjugate vaccine. NVT=non-vaccine type. *Corr... Waight PA Lancet Infect Dis 2015



Pneumococcal carriage

Meningococcal carriage

Ifedayo et al 2012

Christensen et al 2010

Pneumococcal Carriage Rates in Children Decline 3 Years After Implementation of

PCV7 Vaccination1

1. Spijkerman J, et al. Emerg Infect Dis. 2011;17:765-767.

• Cross-sectional observation study, healthy Dutch 11- and 24-month-olds prior to and post-PCV7 introduction

0%

20%

40%

Pre-vaccination Post-vaccination

11 months24 months

*Streptococcus pneumoniae serotypes included in 7-valent pneumococcal conjugate vaccine. 11-month-olds: Pre-PCV7 n=319, Post-PCV7 n=329; 24-month-olds: Pre-PCV7 n=321, Post-PCV7 n=330.

16

Stre

ptoc

occu

s pn

eum

onia

e*

Carr

iage

in C

hild

ren

(%)

Time period nasopharyngeal swabs collected

Changes in ranked serotype distribution in overall carriage in our findings from 2001/2002, 2008/2009 and 2012/2013. Van Hoek AJ, Vaccine 2014

Pneumococcal carriage in children and adults two years after introduction of the thirteen valent pneumococcal conjugate vaccine in England

Van Hoek AJ, Vaccine 2014

Figure 3. Number of invasive pneumococcal disease cases due to non-PCV13 serotypes in children younger than 5 years from July, 2012, to June, 2013, and from July, 2013, to June, 2014Serotypes 15B and 15C were combined because they are considered to be one rapi...

Pauline A Waight, Nicholas J Andrews, Shamez N Ladhani, Carmen L Sheppard, Mary P E Slack, Elizabeth Miller

Effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study

null, Volume 15, Issue 5, 2015, 535–543

http://dx.doi.org/10.1016/S1473-3099(15)70044-7

Fig 3. Forest Plot of PPV23 efficacy to prevent all-cause CAP by study setting.

Schiffner-Rohe J, Witt A, Hemmerling J, von Eiff C, Leverkus FW (2016) Efficacy of PPV23 in Preventing Pneumococcal Pneumonia in Adults at Increased Risk – A Systematic Review and Meta-Analysis. PLoS ONE 11(1): e0146338. doi:10.1371/journal.pone.0146338 http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0146338

http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0146338

Bonten MJ et al. N Engl J Med 2015;372:1114-1125.

Post Hoc Analysis of the Cumulative Episodes of the Primary and Secondary Efficacy End Points in the Per-

Protocol Population.

Figure 1. Corrected* invasive pneumococcal disease incidence from epidemiological year 2000/01 to 2013/14, by serotype grouping and agePCV7=seven-valent pneumococcal conjugate vaccine. PCV13=13-valent pneumococcal conjugate vaccine. NVT=non-vaccine type. *Corr... Waight PA Lancet Infect Dis 2015

Neisseria meningitidis - groups

Neisseria meningitidis strains are classified into 12 groups.

The polysaccharide capsule is used to identify the different groups.

B

Polysaccharide Capsule

A

W Y

C Five main groups cause the majority

(95%) of all meningococcal disease around the world – A, B, C, W and Y.

MenB is responsible for ~85% of meningococcal disease in the England & Wales.

MEN-BEX-P-S-574-2742012

Meningococcal disease- global epidemiology

Generated from multiple refrences

Represents serogroups not defined for each individual country Y W-

135 B C A X

23% 59%

48%

14%

RUSSIA10

BRAZIL3

21%

71%

COLOMBIA3

CANADA1

USA2

ARGENTINA4

48% 43%

EUROPE5

71% 13%

AFRICAN MENINGITIS BELT8

17%

78%

SOUTH AFRICA9

47% 10%

11%

SAUDI ARABIA7

JAPAN11

TAIWAN12

50% 35%

57% 21%

AUSTRALIA13

NEW ZEALAND14

57%

25%

26%

40%

36%

32% 36%

28%

38%

29%

TURKEY6

29%

27% 83%

35%

18%

Structure of Meningococcal Outer Membrane, Showing Variability of Outer-Membrane Proteins and Capsule Used in Vaccines and Interaction with Complement.

Tan LK et al. N Engl J Med 2010;362:1511-1520.

Invasive meningococcal disease in England and Wales by capsular group 2002/03 to 2011/12 (data provided by Public Health England)

Meningococcal conjugate vaccine production

Vaccine

Polysaccharide capsule B

A W Y C

C

A

1999

2010

2010

?

MenB polysaccharide is polysialic acid, a compound identical to that found on the surface of human neuronal cells.

Consequently: (i) Poorly immunogenic.

(ii) Potential to induce an autoimmune response.

Serogroup C Conjugate Vaccine Successfully Reduced Carriage of Serogroup C

Meningococci (UK)1

1. Maiden MC, et al. J Infect Dis. 2008;197:737-743.

Immunised adolescents 15–19 years of age Serogroup C

0

1

2

3

71% 81%

05

10152025

Serogroup B

02468

10 Serogroup W-135

0

2

4

6

8

10Serogroup Y

Men

ingo

cocc

i (%

of i

sola

tes)

1999 2000 2001

Men

ingo

cocc

i (%

of i

sola

tes)

28

Figure 2 Areas of Chad vaccinated with PsA–TT in 2011, or in epidemic or alert situation during Jan–June 2012 Green shading shows the districts where mass vaccination of people aged 1–29 years was undertaken at the end of 2011, before the 2012 meningitis ...

DM Daugla , JP Gami , K Gamougam , N Naibei , L Mbainadji , M Narbé , J Toralta , B Kodbesse , C Ngadoua , ME ... Effect of a serogroup A meningococcal conjugate vaccine (PsA–TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study

The Lancet null 2013 null

http://dx.doi.org/10.1016/S0140-6736(13)61612-8

Figure 3 Incidence of reported cases of meningitis in Chad, 2009–12 Vaccination with PsA–TT was undertaken in patients aged 1–29 years at the end of 2011 (arrow). PsA–TT=serogroup A meningococcal polysaccharide–tetanus toxoid conjugate vaccine.

DM Daugla , JP Gami , K Gamougam , N Naibei , L Mbainadji , M Narbé , J Toralta , B Kodbesse , C Ngadoua , ME ...

Effect of a serogroup A meningococcal conjugate vaccine (PsA–TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study

The Lancet null 2013 null

http://dx.doi.org/10.1016/S0140-6736(13)61612-8

serogroup A carriers 32/4278 pre Serogroup A carriers 1/2001 post

Novel antigens discovered by reverse vaccinology

expression and

purification

purified proteins

immunisations

~350 proteins successfully expressed in E. coli, purified, and used to immunise mice

Based on the genome sequence of MC58, 570 ORFs that potentially encoded novel surface

exposed or exported proteins were identified 100,000

200,000

300,000

400,000

500,000

600,000

700,000

800,000

900,000

1,000,000 1,100,000 1,200,000

1,300,000

1,400,000

1,500,000

1,600,000

1,700,000

1,800,000

1,900,000

2,000,000

2,100,000

2,200,000 IHT-A

IHT-B

IHT-C

1

28 novel protein

antigens identified

Sera used to confirm surface exposure of novel

proteins

Slide provided by Novartis Vaccines

Bexsero®

Novartis MenB vaccine, Bexsero

http://www.inpharm.com/news/101223/novartis-meningococcal-vaccine-bexsero

Previously known as 4CMenB or rMenB+OMV. Contains 4 main antigens.

NadA fHBP (Variant 1)

NHBA

OMVs from the New Zealand outbreak strain

(NZ 98/254).

Three recombinant proteins discovered by reverse vaccinology.

+

PorA

• Phase III, multi-centre, RCT

• 2,968 students from universities at 10 different UK sites

• 3 month enrolment (Sep–Dec 2010)

• Subjects received either:

– 2 doses of 4CMenB (BEXSERO)

– 1 dose of MenACWY-CRM (MENVEO)/1 dose of saline placebo

– 2 doses of Japanese encephalitis (IXIARO) (control)

• Nasopharyngeal swabs taken at baseline, and at Months 1, 2, 4, 6 and 12

• Carriage isolate characterisation performed at HPA (PHE) and Oxford University

Study Methods Pre-licensure study to assess effect on carriage at an individual level

Carriage Study Design

Group Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6

Day 1 Month 1 Month 2 Month 4 Month 6 Month 12 4CMenB

(BEXSERO) (974 subjects)*

Swab 4CMenB

(BEXSERO)

Swab 4CMenB

(BEXSERO)

Swab Swab Swab Swab MenACWY (MENVEO)

Control (985 subjects)*

Swab IXIARO (JEV)

Swab IXIARO (JEV)

Swab Swab Swab Swab MenACWY (MENVEO)

MenACWY (MENVEO)

(984 subjects)*

Swab MenACWY (MENVEO)

Swab Placebo

Swab Swab Swab Swab

*Subset (~600 subjects) evaluated for immunogenicity

Primary Analysis at 1 Month After the Vaccination Series (Read et al Lancet 2015)

Vaccine Groups Efficacy % (95% CI) MenACWY-CRM Control

Visit 2 [Month 1]

Number 56 58 16.0%

(-27.3 – 44.5) % 5.87% 6.12%

N 954 947

MenACWY-CRM co-primary Carriage prevalence of N. meningitidis combined serogroups A, C, W and Y at 1 month following administration of a single dose of MenACWY-CRM

Vaccine Groups Efficacy % (95% CI) 4CMenB Control

Visit 3 [Month 2]

Number 87 75 -18.2%

(-73.3 – 19.4) % 9.50% 8.08%

N 916 928

4CMenB co-primary Carriage prevalence of virulent sequence types (ST)* of N. meningitidis capsular group B at 1 month following administration of 2 doses of 4CMenB

*Virulent ST types are those capsular group B ST types (or clonal complex members) causing disease in the UK (2006-2010).

Analyses adjusted for baseline carriage, treatment group, centre and significant risk factors as identified within the multivariate model.

Vaccine Groups Efficacy % (95% CI) MenACWY-

CRM Control

C, W, Y Serogroupable

Number 193 260 36.2%

(15.6 – 51.7)

% 5.5% 7.4%

N 3520 3504

MenACWY-CRM – Carriage at Cumulative Later Sampling Points

MenACWY-CRM secondary Carriage prevalence and calculated efficacy of combined serogroups CWY and serogroup Y across cumulative later timepoints (Visits 3–6)

MenACWY-CRM reduces nasopharyngeal carriage of N. meningitidis serogroup CWY strains

Y Serogroupable

Number 157 227 39.0%

(17.3 – 55.0)

% 4.5% 6.5%

N 3520 3504


4CMenB– Carriage at Cumulative Later Sampling Points 4CMenB secondary Carriage prevalence and calculated efficacy for carriage of combined capsular groups BCWY or all N. meningitidis strains across cumulative later timepoints (Visits 4–6)

Any N. meningitidis

Number 797 885 18.2%

(3.4 – 30.8) % 32.0% 34.4% N 2489 2576

Vaccine Groups Efficacy % (95% CI) 4CMenB Control

B, C, W, Y Capsular group

Number 449 539 26.6%

(10.5 – 39.9) % 18.0% 20.9% N 2489 2576

4CMenB reduces nasopharyngeal carriage of N. meningitidis capsular group BCWY strains

Non-significant trends for virulent B strains (12.6%; p=0.350) and all ST B strains (15.6%; p=0.225)


Serogroup W disease

Serogroup W disease, by age

Question

• In the under 5s, since 2013 there has been `replacement` invasive pneumococcal disease caused by

• A – serotype 4 • B – serotype 6 • C – serotype 9V • D – serotype 14 • E – serotype 22F

Question

• Since september 2015, adolescents have been receiving routinely the following meningococcal vaccine for the given reason

• A – rMenB to cover serogroup B • B – rMen B to cover serogroup Y • C – MenC to cover serogroup C • D – conjACWY to cover serogroup W • E – conjACWY to cover serogroup Y

Thankyou

Vaccines for Underlying medical conditions2015

Vaccines - RCP London

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