Immunogenicity of combined vaccines in infants Helena Käyhty, PhD National Public Health Institute...
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Transcript of Immunogenicity of combined vaccines in infants Helena Käyhty, PhD National Public Health Institute...
Immunogenicity of combined vaccines in infants
Helena Käyhty, PhDNational Public Health InstituteDept of VaccinesHelsinki, Finland
Combined vs. reference administrationhexavalent vaccines
• Gylca et al. Vaccine 2001: DTaP-HBV-IPV / Hib vs. DTwP-IPV mixed with Hib +HBV at 6, 10, 14 weeks
• Schmitt et al. J Ped 2000: mixed vs. separate DTaP-HBV-IPV / Hib at 2, 3, 4 months
• Mallet et al. PIDJ 2000: DTaP-HBV-IPV-Hib vs. DTaP-IPV-Hib / HBV at 2, 4 and 6 months
Combined vs. reference administration
0 1 2
D
T
HB
Polio 1
Polio 2
Polio 3
PTA
FHA
PRN
Hib Mallet ea
Schmitt ea
Gylca ea
fold difference
Eskola et al. Lancet 1996Vaccinations at 4 and 6 mo
DTaP / Hib/ IPV
DTaP-IPV/ Hib
DTaP-Hib/ IPV
DTaP-Hib-IPV
GMC, g/ml 3.9 3.1 0.4 0.6
%>0.15 g/ml 93 93 78 79
% >1.0 g/ml 87 77 19 48
Three doses, combined vs. separate administration in different studies
0
2
4
6
8
10
12
14
16
18combined
separate
Anti-Hib
Mechanisms???
• Missing adjuvant effect of wP• Epitopic supression - antigenic competition• Physicochemical interference
Immunogenicity trials in Sweden (3,5,12 mo) and Finland (4,6,14 mo)
0,9
9,8
2
15
1
12
5
35
0
5
10
15
20
25
30
35
40
6/7 mo 13/15 mo
An
ti-H
ibPRP-T/DT+IPV
PRP-T/DT/IPV
PRP-T/DT/IPV/aP
PRP-T+DTP, FIN
T
B
B
B
B
HELP
Anti-CHO Ab
Anti-Tetanus Ab
CHO
Tet
B
HELP
Anti-CHO Ab
Anti-Tetanus Ab
PncT, PRP-T and T simultaneouslyDose of PncT and response to PRP-T and
Tetanus toxoid (Dagan et al. 1998)
0
2
4
6
8
10
12
Placebo PncT01 PncT03 PncT10
Hib
0
1
2
3
4
5
Placebo PncT01 PncT03 PncT10
Tetanus
Concomitant administration 2 cm apart in the same leg at 2, 4 and 6 mo
Eskola et al.
0
2
4
6
8
10
12
mixed separate differentlegs
separate sameleg
2 mo
6 mo
7 mo
anti-Hib
Clinical implications?
• Are the induced anti-Hib responses high enough for protection?
• Experience from Finland, Sweden, the UK and Germany
Protective efficacy vs. antibody response
Study 1: PRP-D at 3, 4, 6 and 14 months
Anti-Hib 7 mo 14 moGMC, µg/ml 0.53 0.37% > 1 µg/ml 40 22% > 0.15 µg/ml 68 67% >0.06 µg /ml 85 85
Protection 90 (70-96) %
Eskola et al, 1990
Protective efficacy vs. antibody response
Study 2: PRP-D at 4, 6 and 14 months
Anti-Hib 7 mo 14 moGMC, µg/ml 0.63 0.38% > 1 µg /ml 32 24% > 0.15 µg /ml 77 72% >0.06 µg/ml 86 90
Protection 87 (69-96) %
Peltola et al, 1994
Immunogenicity trials in Sweden (3,5,12 mo) and Finland (4,6,14 mo)
0,9
9,8
2
15
1
12
5
35
0
5
10
15
20
25
30
35
40
6/7 mo 13/15 mo
An
ti-H
ibPRP-T/DT+IPV
PRP-T/DT/IPV
PRP-T/DT/IPV/aP
PRP-T+DTP, FIN
Three doses, combined vs. separate administration in different studies
0
2
4
6
8
10
12
14
16
18combined
separate
Anti-Hib
DTaP/Hib/(IPV) combinations in Germany Schmitt et al 2001
• 2 year follow up after the introduction of combined vaccines
• Overall VE 97.5 % (96.3-98.4)• 1 dose 88.6 % (76.1-94.3)• 2 doses 95.1 % (92.2-97.0)• 3 doses 98.8 % (98.2-99.3)
Measurement of the immune response to vaccination
Vaccine Sample Antibody
Capsular polysaccharides (PS)
• Antibodies protective• Poor and short lasting immune response in infants
and children• Long lasting antibody response in older children
and adults• TI-antigens -> no memory -> protection is based on
existing antibodies
Conjugate vaccines????
• immunogenicity improved by conjugating PS to carrier proteins -> TD properties -> antibody response even in infancy
• development of memory• protection may last longer than detectable antibody• memory B cells triggered upon challenge -> high and
quick antibody response• increase in avidity -> antibodies may function better
How to test development of memory
• Memory B cells• Priming with conjugate and booster with PS
– PS mimics contact with bacteria– more memory B cells to be triggered by PS– high antibody response of IgG isotype
• Avidity maturation
Increasing Affinity / Avidity
104 108 1012
Geometric mean titer (GMT) and GM avidity index (GMAI)
Goldblatt et al., JID 177, 1998, 1112-5
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
10.0
100.0
0.1
1.0
14121086420
Avi
dit
y In
dex
(G
MA
I)
An
ti-P
RP
Igg
(G
MT
µg
/ml)
Age (months)
AvidityTitre
Poolman et al Vaccine 2001
Avidity of anti-6B Pnc PS- primary seria at 2,4,6 mo with a conjugate - booster at 14 mo with conjugate or PS
30
35
40
45
50
55
60
65
70
75
80
5 10 15 20
Age, mo
AI
PncCRM
PncD
30
35
40
45
50
55
60
65
70
75
80
5 10 15 20
Age, mo
AI
PncCRM
PncD
PncT
Laboratory surrogates for evaluation of new conjugates, modified from Frasch 1995
• antibody response in infancy• persistence of antibodies (up to booster dose)• induction of immunologic memory
• PS-vaccine• avidity
• isotype/subclass distribution and avidity of antibodies• functional activity of antibodies
(opsonic or bactericidal activity)
Mucosal immune response
• is or may be important when• local mucosal infection• colonization precedes disease
• the role as a surrogate test unknown