Fiona van der Kliss' presentation at the 2013 Meningitis Research Foundation conference Meningitis & Septicaemia in Children & Adults

1. Adolescent booster after single
primary MenCC vaccination at
young age:
the TIM-study
Fiona van der Klis
1
RIVM-CIB
6 november 2013

2. 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
RIVM-CIB

3. Meningococci incidence since 1993
3
Source: NRBM, AMC/RIVM
RIVM-CIB

4. 4
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
RIVM-CIB
95 02 07
Serum bank
n=8539
Serum bank
n=6377
Start MenC immunization
Catch-up campaign <19 years
96 97 98 99 00 01 03 04 05 06 08

5. 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
15-24
mo
2
3
4
5
6
7--8
9--10
11--12
13--14
15--16
17--18
19--20
21--22
23--25
25--30
31--39
40--49
50--59
60--69
70--79
Age at bloodsampling
MenC-specific
IgG
GMC
(μg/ml)
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
15-24
mo
2
3
4
5
6
7--8
9--10
11--12
13--14
15--16
17--18
19--20
21--22
23--25
25--30
31--39
40--49
50--59
60--69
70--79
Age at bloodsampling
MenC-specific
IgG
GMC
(μg/ml)
Pre-immunization era (n=2305) Post-immunization era (n=6376)
RIVM-CIB

6. 6
MenC PS IgG prediction 2013 in NS
RIVM-CIB

7. 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. 8
TIM-study
Tweede Immunisatie MenCC studie =
Second Immunisation MenCC
RIVM-CIB

9. 9
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
RIVM-CIB

10. 10
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
RIVM-CIB

11. 11
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
RIVM-CIB

12. 12
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
T1
N=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 out
T2
RIVM-CIB

13. 13
Baseline characteristics
10 year olds 12 year olds 15 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)
RIVM-CIB

14. Difference in SBA GMTs
14
01
10
100
1,000
10,000
100,000
10 12 15
MenC
specific
SBA
GMT
Age (years)
T0
T1
T2
**
*
* = P<0.01
** = P<0.001
**
RIVM-CIB
Stoof et al, in preparation

15. 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)
18-3-2022
15
* 10 vs. 12 years P=0.02
‡ 10 vs. 15 years P<0.001
RIVM-CIB

16. Difference in MenC-PS specific IgG GMCs
18-3-2022
16
0.10
1.00
10.00
100.00
1000.00
10 12 15
MenC-PS
specific
GMC
(µg/mL)
Age (years)
T0
T1
T2
**
* = P<0.05
** = P<0.001
**
**
RIVM-CIB
Stoof et al, in preparation

17. MenC-PS specific IgG decrease between T1 and T2
18-3-2022
17
T1
GMC IgG μg/ml (95%CI)
T2
GMC IgG μg/mL (95%CI)
% decrease
median (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
RIVM-CIB

18. 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
18-3-2022
18
RIVM-CIB

19. 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
18-3-2022
19
RIVM-CIB

20. 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
20
RIVM-CIB

21. 21
SBA seroprevalence pre- vs post-immunization in NS
0
10
20
30
40
50
60
70
80
90
100
0-7
mo
8-14
mo
15-24
mo
2
3--4
5--6
7--8
9--10
11--12
13--14
15--16
17--18
19--21
22--25
25--30
31--39
40--49
50--59
60--69
70--79
Age at bloodsampling
Prevalence
SBA
≥
8
(%)
Pre-immunization era (95/96) Post-immunization era (06/07)
De Voer et al, PloS ONE, 2010, 5(8), e12144
RIVM-CIB

22. 22
0
10
20
30
40
50
60
70
80
90
100
0-7
mo
8-14
mo
15-24
mo
2
3--4
5--6
7--8
9--10
11--12
13--14
15--16
17--18
19--21
22--25
25--30
31--39
40--49
50--59
60--69
70--79
Age at bloodsampling
Prevalence
SBA
≥
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), e12144
RIVM-CIB