Helen Campbell

Meningcoccocal conjugate vaccines: epidemiological and

immunological perspective

Clinical Scientist (epidemiology)

Immunisation, Hepatitis and Blood Safety Department

HPA Centre

September 2010

o The contribution of high quality surveillance

to our understanding of how serogroup C

conjugate (MenC) vaccines work on an

individual and population basis.

MenC experience in England & Wales

In 1999, the UK introduced MenC vaccines into the primary

immunisation schedule at 2, 3 and 4 months of age.

A catch-up of all children <18 years of age was performed.

Age groups were prioritised to receive vaccine according the

risk profile for that cohort.

Three MenC vaccines were licensed.

Vaccine Manufacturer Carrier protein

Meningitec Wyeth (Pfizer) CRM197

Menjugate Chiron (Novartis) CRM197

NeisVac-C Baxter Tetanus toxoid

Miller E, Salisbury D, Ramsay M. Vaccine 2001;20 Suppl 1:S58-67.

At the time of introduction, immunological

response to MenC vaccines had been

measured by:

• production of protective levels of serum bactericidal

• antibodies (SBA )

• using baby rabbit complement (rSBA)

• Standardisation

• Ease of sourcing

• titre ≥ 8 and/or 4 fold rise 4 weeks after vaccination

• response to challenge dose of plain polysaccharide* vaccine

• greater than in unprimed individuals

• or response ≥ primary response

• Increase in antibody avidity

1

10

100

1000

Pre MCC Post MCC Pre-boost Post-boost

SB

A T

itre

0

20

40

60

80

100

120

GM

AI*

(m

M S

CN

)

10000

140

160

SBA titres (dotted lines) and antibody

avidity (solid lines) in UK toddlers.

The 3 vaccines used in the study were

Chiron/Novartis (blue), Wyeth/Pfizer (pink) and NAVA/Baxter (green).

Surveillance of MenC vaccines post introduction in E&W

• Post-marketing surveillance involved follow up for vaccination history of all laboratory confirmed MenC cases

–Vaccination status of >99% of all MenC cases ascertained

• Vaccine coverage data collected nationally against individual immunisation records

Effectiveness estimates using screening method.

Incidence of laboratory confirmed meningococcal

disease England & Wales 1998/99 to 2009/10

Health Protection Agency, Meningococcal Reference Unit, unpublished data

0

1

2

3

4

5

6

1998/1999 1999/2000 2000/2001 2001/2002 2002/2003 2003/2004 2004/2005 2005/2006 2006/2007 2007/2008 2008/2009 2009/2010

epidemiological year

rate

per

100,0

00 p

opula

tion

meningococcal B disease

meningococcal C disease

all meningococcal disease

MenC Vaccine Impact in Europe

0

1

2

3

4

5

Bel

gium

Icel

and

Irel

and

Net

herlan

ds

Spai

n UK

incid

en

ce p

er

100,0

00

1999

2000

2001

2002

2003

2004

50.0%

55.0%

60.0%

65.0%

70.0%

75.0%

80.0%

85.0%

90.0%

95.0%

100.0%

>= 1:4 >= 1:8 >= 1:16 >= 1:32 >= 1:64 >= 1:128

Protective threshold

Va

cc

ine

Eff

ica

cy

(%

)

Observed

VE (95% CI)

Andrews N, Borrow R, Miller E. Clin Diagn Lab Immunol 2003;10:780-6.

Efficacy predicted in toddlers by proportions of

unvaccinated and vaccinated with titres below different

rSBA cutoffs 1 month after MCC

rSBA titre 8 correlates closely with observed efficacy

rSBA titre 8 correlates closely with observed effectiveness

Calculated vaccine effectiveness (VE) 28-Feb-2010 (screening method)

-100

-50

0

50

100

Routine Toddlers catch-

up

Pre-school

catch-up to sixth

form

Secondary

school catch-up

immunised cohort

calc

ula

ted

eff

ecti

ven

ess

VE w ithin 1 year of vaccination VE > 1 year of vaccination

P<0.01 P=0.16 P=0.12 P=0.76

Richarda M. de Voer, PhD. Meningococcal C specific immune responses. Immunity in an era of immunization with

conjugate vaccine.

Also see Snape M et al. BMJ 2008.

Seroprevalence of rSBA, 4 to 5 years following a

catch-up campaign comprising a single dose of

MenC conjugate vaccine - the Netherlands.

Evidence that priming of immune memory did not protect against disease

• Compared SBA titres, IgG levels and avidity indices (AI) in acute and convalescent samples in vaccine failures (n=56) and non-vaccine failures (n=55)

• No evidence of immunodeficiency in vaccine failures.

• AIs in acute serum samples were significantly higher in subjects with vaccine failure than in unvaccinated subjects 3.2-fold higher for AIs [P=.001].

• SBA titers in convalescent serum samples were significantly higher in subjects with vaccine failure than in unvaccinated subjects 6.1-fold higher for SBA titers [P=.03]

Auckland C et al. The Journal of Infectious Disease 2006; 194:1745–52

CONCLUSION:

“The antibody response in the subjects with vaccine

failure was consistent with an anamnestic response,

suggesting that MenC disease occurred despite the

MCC vaccine priming for immune memory…”

Antibody decay post-booster

•UK changed the MenC

routine schedule on 4

September 2006 to 2

doses in infancy (at 3,4

months) and 1 dose at 12

months as MenC-Hib

(Menitorix)

•Meningococcal SBA decay pattern

post booster is very similar (-1.59) to

that post primary (-1.55).

•Thus as time doubles, SBA titres go

down by two thirds.

•MenC IgG decay pattern was -0.95,

thus as time doubles, IgG goes

down by half.

Borrow R, Andrews N, Findlow H, Waight P, Southern J, Crowley-Luke A, Stapley L, England A,

Findlow J, Miller E. Clin Vaccine Immunol. 2010;17:154-9.

Reduction in capsular group C carriage following introduction of MenC vaccines in

students aged 15-19 years

Meningococci(% of isolates)

1999 2000 2001

Maiden MC et al. J Infect Dis. 2008;197:737-43.

Serogroup C

Serogroup YSerogroup B

Serogroup W135

-71% -81%

Evidence of herd immunity:Rate per 105 of serogroup C disease in 15-17 year olds before and after campaign

Pre vaccine

5.28/100,000

Unvaccinated

1.79/100,000Vaccinated

All ages

0.09/100,000

66% reduction in rate in

unvaccinated cohort 2000/01

0

1

2

3

4

5

6

7

8

9

98/99 00/01 00/01

Ramsay ME et al. BMJ. 2003;326:365-6.

ca

se

s/1

00

,00

0 p

ers

on

s

0

100

200

300

400

500

600

700

800

1998/

1999

1999/

2000

2000/

2001

2001/

2002

2002/

2003

2003/

2004

2004/

2005

2005/

2006

2006/

2007

2007/

2008

2008/

2009

2009/

2010

<20 years 20+ years

Cases of laboratory confirmed meningococcal

disease England & Wales 1998/99 to 2009/10

Model predictions and observed cases of

laboratory confirmed serogroup C

disease in England & Wales

Campbell H et al. Clin Vaccine Immunol 2010;17:840-7.

0

10

20

30

40

50

60

70

80

90

100

% w

ith

SB

A t

itre

s ≥

8

Age

Predicted proportions of sera with

serogroup C SBA titres ≥8 by age in

England and Wales (2010).

Predicted data based upon Trotter CL et al., Clin Vaccine Immunol. 2008 and Borrow et al., Clin. Vaccine

Immunol . 2010.

Age and week of onset for 2008/9 and

2009/10 serogroup C cases

Conclusions - MenC

•Ongoing, high quality surveillance with timely analysis

and dissemination of data generated are key.

•Persistence of SBA is recognised as a more appropriate

correlate of long-term protection for MenC vaccines than

immune memory.

•Catch-up campaigns and herd immunity of paramount

importance.

• duration of protection against carriage is not known and

correlates of protection against carriage are lacking.

Acknowledgements

HPA Meningococcal Reference UnitRay Borrow

Steve Gray

Ed Kaczmarski

HPA Immunisation, Hepatitis and Blood Safety DepartmentMary Ramsay

Nick Andrews

Jessica Flood

Shamez Ladhani

University of BristolCaroline Trotter

Percentage of genogroup C meningococcal

carrier isolates expressing capsule in 15 to

19 year olds in the UK in 1999.

N 43 6 28

Maiden MC et al. J Infect Dis. 2008;197:737-43.

Increase in serogroup Y disease in

England & Wales, 2007 to 2009

Health Protection Agency, Meningococcal Reference Unit, unpublished data