Adolescent booster after single primary MenCC

vaccination at young age: the TIM-study

Fiona van der Klis

1RIVM-CIB6 november 2013

2

Introduction MenC conjugate vaccine in the Netherlands

● Implemented in Dutch NIP since september 2002– Single vaccination for all children

at 14 months of age– Vaccination coverage >95%

● Catch-up campaign 1-18 year olds in June-November 2002 – Vaccine uptake: 94%

● Vaccine: NeisVac, MenCC-TT

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Meningococci incidence since 1993

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Source: NRBM, AMC/RIVM

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PIENTER studies

● PIENTER: nation-wide, cross-sectional, serosurveillance studies to monitor immune status of the Dutch population

● Allows to investigate the effect of the MenCC-vaccine immunity pre- and post implementation

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95 02 07

Serum bankn=8539

Serum bankn=6377

Start MenC immunizationCatch-up campaign <19 years

96 97 98 99 00 01 03 04 05 06 08

5

MenC PS IgG GMCs pre- vs post-immunization

De Voer et al, PloS ONE, 2010, 5(8), e12144

0

0.5

1

1.5

2

2.5

3

3.5

0-7

mo

8-14

mo

15-2

4 m

o 2 3 4 5 6

7--8

9--1

0

11--1

2

13--1

4

15--1

6

17--1

8

19--2

0

21--2

2

23--2

5

25--3

0

31--3

9

40--4

9

50--5

9

60--6

9

70--7

9

Age at bloodsampling

Men

C-sp

ecifi

c Ig

G GM

C (μ

g/m

l)

Pre-immunization era (n=2305) Post-immunization era (n=6376)

0

0.5

1

1.5

2

2.5

3

3.5

0-7

mo

8-14

mo

15-2

4 m

o 2 3 4 5 6

7--8

9--1

0

11--1

2

13--1

4

15--1

6

17--1

8

19--2

0

21--2

2

23--2

5

25--3

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31--3

9

40--4

9

50--5

9

60--6

9

70--7

9

Age at bloodsampling

Men

C-sp

ecifi

c Ig

G GM

C (μ

g/m

l)

Pre-immunization era (n=2305) Post-immunization era (n=6376)

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MenC PS IgG prediction 2013 in NS

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Approaches● Shift in schedule

– Move dose from first year to second year of life– Recommend dose at later age, adolecence

3+1, 2+1, 1+1, 1+1+1

– The dutch situation

1

7

8

TIM-study

Tweede Immunisatie MenCC studie =Second Immunisation MenCC

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Set-up TIM study● 3 age groups (No interference with other vaccinations)

– 10 years – 12 years – 15 years

● Vaccination with NeisVac-CTM at T0– blood and saliva collection

● Follow-up 1 month (T1) and 1 year (T2)– blood and saliva collection

● Start: October 2011 – 9 years after introduction of MenCC vaccination into Dutch NIP

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Objectives● Primary

– Difference in serum bactericidal antibody titers and percentages above correlate of protection

● Secundary– MenC PS specific IgG and IgA in serum and saliva

› Quantity› Subclass distribution› Avidity

– Longitudinal kinetics of B- and T- cell memory immune responses – Effect on IgG antibody levels against tetanus– Antibody persistence 9 years after primary vaccination

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Methods

● Measurement MenC-PS specific IgG, IgG subclass and avidity levels: Fluorescent bead-based multiplex immunoassay

● Measurement functional antibody levels (SBA):– Baby rabbit complement– Meningococcal serogroup C strain C11

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Flow chart enrollment

56 dropped out during inclusion procedure:

- 40 ‘no’ after receiving additional information

- 16 fear for venapuncture

157 excluded:

- 83 study fully enrolled

- 31 medical history

- 21 immunisation history different

- 14 not available during study period

- 8 other reason

268 ENROLLED

10 year olds

N=91

12 year olds

N=91

15 year olds

N=86

4667 approached

705 responses 224 ‘no’

481 assessed for eligibility

T0

T1N=88

2 dropped out

1 no blood

N=90

1 no show

1 ‘no’blood

N=85

1 no show

N=89

2 dropped out

N=85

2 dropped out

2 no blood

N=83

3 dropped outT2

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Baseline characteristics

 10 year

olds12 year

olds15 year

olds

No. of enrolled participants 91 91 86

Female: No. (%) 53 (58) 44 (48) 41 (48)

Mean age at MenCC vaccine priming: years (±SD) 1.2 (0.2) 2.7 (0.3) 5.8 (0.4)

No. of priming doses of MenCC vaccine 1 1 1

Mean age at enrollment T0: years (±SD) 9.9 (0.3) 12.0 (0.3) 15.0 (0.3)

Interval since primary MenCC vaccine: years (±SD) 8.8 (0.3) 9.3 (0.1) 9.2 (0.2)

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Difference in SBA GMTs

14

10 12 1501

10

100

1,000

10,000

100,000

T0 T1

T2

Age (years)

Me

nC

sp

ec

ific

SB

A G

MT

***

* = P<0.01** = P<0.001

**

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Stoof et al, in preparation

SBA titers≥ correlate of protection

10 years 12 years 15 years

T0 Total 91 91 86

SBA ≥8: n (%) 17 (19)*‡ 31 (34)* 39 (45)‡

T1 Total 88 90 85

SBA ≥128: n (%) 85 (100) 89 (100) 85 (100)

T2 Total 85 89 83

SBA ≥128: n (%) 81 (100) 87 (100) 80 (100)

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* 10 vs. 12 years P=0.02‡ 10 vs. 15 years P<0.001

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Difference in MenC-PS specific IgG GMCs

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10 12 150.10

1.00

10.00

100.00

1000.00

T0

T1

T2

Age (years)

Me

nC

-PS

sp

ec

ific

GM

C (

µg

/mL

)

**

* = P<0.05** = P<0.001

**

**

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Stoof et al, in preparation

MenC-PS specific IgG decrease between T1 and T2

09-04-202317

T1GMC IgG μg/ml (95%CI)

T2GMC IgG μg/mL (95%CI)

% decreasemedian (IQR)

10 year olds 134 (117-153) 12 (10-14) 92 (85-94)*‡

12 year olds 194 (168-222) 23 (19-28) 86 (81-92)*#

15 year olds 174 (147-206) 33 (28-40) 81 (69-86)‡#

* 10 vs. 12 years: P<0.001 ‡ 10 vs. 15 years: P<0.001# 12 vs. 15 years: P<0.001

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Conclusions● 9 years after the single MenCC vaccination, 45% of the 15 year-olds

had protective antibody levels, versus 34% in the 12 year-olds and 19% in the 10 year-olds

● All age groups developed extremely high antibody levels 1 month after the study MenCC vaccination– 1 year after the booster vaccination 100% of the participants had

protective antibody levels

● 1 year after the study vaccination the 15 year-olds remained the highest antibody levels and showed the lowest decay rate potential age for vaccination

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Discussion

● 15 years seems a good age for second MenCC vaccination based on these immunological data

● Another sample after 3-5 years to follow-up decrease (2014-2016)

● Role of the age at priming. Another booster study including same age groups with similar priming ages and with MenACWY tetravalent vaccine

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Acknowledgements● RIVM-CIb

– Susanne Stoof– Debbie van Rooijen– Nelleke Bakker– Pieter van Gageldonk– Mirjam Knol– Guy Berbers

● WKZ-UMC Utrecht– Lieke Sanders– Tom Wolfs

● All participants TIM-study and their parents!

● Baxter for vaccines

20RIVM-CIB

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SBA seroprevalence pre- vs post-immunization in NS

0

10

20

30

40

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60

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100

0-7

mo

8-14

mo

15-2

4 m

o 2

3--4

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9--1

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11--

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13--

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15--

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19--

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25

25--

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49

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60--

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70--

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Age at bloodsampling

Prev

alen

ce S

BA ≥

8 (%

)

Pre-immunization era (95/96) Post-immunization era (06/07)

De Voer et al, PloS ONE, 2010, 5(8), e12144RIVM-CIB

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0

10

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mo

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o 2

3--4

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9--1

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11--

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13--

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15--

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17--

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19--

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22--

25

25--

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39

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49

50--

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Age at bloodsampling

Prev

alen

ce S

BA ≥

8 (%

)

Pre-immunization era (95/96) Post-immunization era (06/07)

SBA seroprevalence pre- vs post-immunization in NS

De Voer et al, PloS ONE, 2010; 5(8), e12144RIVM-CIB