Download Is there a scientific question to answer?

Global Advisory Committee
on Vaccine Safety
6 - 7 June 2006
Potential immunogenic overload
resulting from concomitant
vaccination with too many antigens
David Goldblatt
Professor of Vaccinology and Immunology/
Consultant Paediatric Immunologist
Director of Clinical R&D
Institute of Child Health, UCL
And Great Ormond Street Children’s Hospital
Director, WHO Pneumococcal Serology Reference Laboratory
Is there a scientific question
to answer?
• What is “injection overload” or “immune
overload”?
• How is it identified?
• What would the symptoms of overload be?
– reduced responses to multiple vaccines given
at the same time?
– increased risk of other infections after
vaccination?
1946
1946 Pneumococcal
PneumococcalHexavalent
Hexavalent
1955
1955 Tetanus
Tetanusand
andDiphtheria
DiphtheriaToxoids
Toxoids(Td)
(Td)
1975
1975 Meningococcus
MeningococcusAACC
1977
1977 Pneumococcal
Pneumococcal14
14Valent
Valent
1981
1981 Meningococcus
MeningococcusAACCYYW135
W135
1983
1983 Pneumococcal
Pneumococcal23
23Valent
Valent
1960
1960 Smallpox
Smallpoxand
andYellow
YellowFever
Fever
1967
1967 Smallpox
Smallpoxand
andMeasles
Measles(Swz)
(Swz)
1977
1977 OPV
OPVand
andMMR
MMR
1983
1983 Hib
Hiband
andMMR
MMR
1989
1989YF
YFand
andMeasles
Measles(Swz)
(Swz)
1
Live Viral Vaccines
Multi-component
Combination Vaccines
FcγR
Simultaneous Administration
Of Childhood Vaccines
È
È IL12
IL12production
production
Ç
Ç IL10
IL10production
production
Ç
Lymphocyte
Ç Lymphocyteapoptosis
apoptosis
APC
CD46
È
ÈAntigen
Antigenspecific
specific
TTcell
cellproliferation
proliferation
È
ÈHypersensitivity
Hypersensitivity
responses
responses
T
MV Proteins
J Infect Dis 1996
Does MMR
“overwhelm”
the immune
system?
% seroconversion
Measles
Mumps
Rubella
Single Measles
100
--
Single Mumps
--
92
---
Single Rubella
--
--
100
MMR Vaccine
96
90
100
Pediatrics 1981
2
Response of 12-23 month old children
receiving MMR and VZV vaccines alone or in
combination
1000
100
MMRV + Placebo
Hep A/B + DTaP-IPV/Hib
Hep A/B + MMR
MMR + VV
10
1
Measles
Mumps
Rubella
VZV
Vaccine 2005
Shinefield et al 2005
Live Viral Vaccines
Multi-component
Combination Vaccines
Simultaneous Administration
Of Childhood Vaccines
Co-administration of DTaP and Hib conjugate vaccine at
4 and 6 m of age following DTaP at 2 m.
Anti-Hib Polysaccharide Ab
4
What is the
mechanism?
3.5
3
A DTP-a, Hib, IPV
2.5
B DTP-a + IPV, Hib
2
C DTP-a + Hib, IPV
1.5
D DTP-a + Hib + IPV
1
0.5
0
4 months
6 months
7 months
Eskola et. al. 1996 Lancet;348:1688-92
Is this immune
overload?
3
Claesson et al J Pediatr 1988
DTaP
10.1
aP
Tetanus
Al(OH)3
11
Dip
aP
No PncT
PncT
12.5
+ 9 µg TT
+ 24 µg TT
+ 72 µg TT
2
Anti PRP
(µg/ml)
-T
PRP
Pn
cT
( 4va
len
t)
4.1
2, 4, 6 months
Dagan et al, Infect & Immun 66:266:2-9393-8, 1998
12
11
11.5
10
7.8
8
6
PncD
PncD1
(low dose)
PncD
PncD3
(medium dose)
PncD
PncD10
(high dose)
-T
P RP
7.2
4
No PncD
PncD
P = NS
PncT
PncT1
(low dose)
PncT
PncT3
(medium dose)
PncT
PncT10
(high dose)
/
Pw
DT
Geometric mean concentration
after dose 3
aP
Tetanus
6
0
Tet
aP
w/
8
Hib
DTP
10
Hib
Dip
aP
P = 0.0121
12
+
Tetanus
( 4va
l en
t)
Tet
aP
Al(OH)3
aP
aP
Pn
cD
aP
Al(OH)3
Dip
Geometric mean concentration
after dose 3
Tet
Hib
Hib
2, 4, 6 months
4
2
0
Anti PRP
(µg/ml)
Dagan et al, Infect & Immun 66:266:2-9393-8, 1998
4
*iC3b
* CR2
Protein
B
B7-1/-2
CD28
II
IL4
CD40
CD40L
CD4
IL2
Journal of Infectious Diseases 2005
Protein
*iC3b
* CR2
B
Polysaccharide
Specific Antibody
g
chin
swit
n
ype
atio
Isot
tur
ma
y
t
i
in
Aff
B
CD40
CD40L
Cytokines
Cytokines
II
II
CD4
Cytokines
Cytokines
II
B
II
B
Protein
CD4
CD4
CD4
Memory B Cells
BSI-99b
5
Protein
B
II
B
Cytokines
CD4
II
Cytokines
CD4
Tetanus conjugates
DTwP/IPV/PRPT
1
DTwP/IPV/PRPT
*
2
7
10
13
4
2
7
*
0.1
2
12
100
13
7
12
5
*
*
0.1
2
7
12
*
*
0.1
*
1
*
0.1
2
10
7F
1
13
7
12
Age (months)
13
7
12
13
23F
1
*
*
0.1
2
13
19F
10
1
10
*
*
*
0.1
10
9V
2
7
2
10
7
12
13
6B
1
0.1
2
10
7
12
14
13
*
1
0.1
2
10
7
12
13
18C
*
1
12
13
DTwP/IPV/PRPT
*
2
12
2
7
12
Age (months)
10
13
4
*
0.1
2
7
12
100
13
7
12
5
*
*
0.1
2
7
12
13
*
1
*
*
1
*
0.1
2
10
7F
7
12
Age (months)
13
7
12
13
23F
1
*
*
0.1
2
13
19F
10
1
13
*
*
*
0.1
10
9V
1
2
3
1
DTaP/IPV/PRP-T
0.1
7
1
10
10
*
0.1
0.1
Age (months)
1
0.1
10
Diphtheria conjugates
Concomitant Administration:
DTwP/IPV/PRPT
1
0.1
12
1
1
3
1
DTaP/IPV/PRP-T
*
0.1
Tetanus conjugates
10
Anti-capsular IgG concentrations (µg/ml)
Anti-capsular IgG concentrations (µg/ml)
1
10
10
Anti-capsular IgG concentrations (µg/ml)
10
Serotye specific Pneumococcal IgG following an 11-valent experimental Pneumo-Conjugate Vaccine
Diphtheria conjugates
Concomitant Administration:
2
7
Anti-capsular IgG concentrations (µg/ml)
Serotye specific Pneumococcal IgG following an 11-valent experimental Pneumo-Conjugate Vaccine
2
10
7
12
13
7
12
13
6B
1
0.1
2
10
14
*
1
0.1
2
10
7
12
13
18C
*
1
0.1
12
Age (months)
13
2
7
12
Age (months)
13
Dagan, Goldblatt, Maleckar et al Inf & Imm, In Press
Effect on Hib, tetanus and diphtheria responses to DTaP/Hib-TT
from co-administration of different MCC vaccines
7
6
GMC
(ug/ml)
Providing extra carrier mediated help (at a
separate site) can help overcome the attenuation
seen with DTaP/Hib-TT combinations
5
4
MCC-CRM +
PNC-CRM *
3
MCC-CRM *
2
MCC-TT **
1
0
Hib
tetanus
diphtheria
*Southern et al 2006
**Goldblatt et al 2006
6
• Responses to Measles, Mumps and Rubella
are similar irrespective if given singly or in
combination
• MMR does not interfere with responses to
concomitant vaccines
• MMR does not lead to susceptibility to
infections in the 90 days post infection
• Combined vaccines may display reduced
responses due to individual components
• These are due to physical degrading of
vaccine components or skewing of the
immune response to those components
present in high dosage
We conclude that although there is no scientific evidence that
supports parents’ fears about combined vaccines causing
“immune overload”, policy makers need to recognise these
concerns if they are to successfully persuade parents that
combined vaccines are safe.
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