Immune memory after hepatitis B vaccination et al 2002 break-through infections after successful Hep...
39
Viral Hepatitis Prevention Board Meeting Sevilla, Spain, March 11-12, 2004 Hepatitis B vaccine: long-term efficacy, booster policy, and impact of HBV mutants on hepatitis B vaccination programmes Viral Hepatitis Prevention Board Meeting Sevilla, Spain, March 11-12, 2004 Hepatitis B vaccine: long-term efficacy, booster policy, and impact of HBV mutants on hepatitis B vaccination programmes Immune memory after hepatitis B vaccination Immune memory after hepatitis B vaccination Wolfgang Jilg Institute for Medical Microbiology and Hygiene University of Regensburg Wolfgang Jilg Institute for Medical Microbiology and Hygiene University of Regensburg
Transcript of Immune memory after hepatitis B vaccination et al 2002 break-through infections after successful Hep...
Viral Hepatitis Prevention Board MeetingSevilla, Spain, March 11-12, 2004Hepatitis B vaccine: long-term efficacy, booster policy, and impact of HBV mutants on hepatitis B vaccination programmes
Viral Hepatitis Prevention Board MeetingSevilla, Spain, March 11-12, 2004Hepatitis B vaccine: long-term efficacy, booster policy, and impact of HBV mutants on hepatitis B vaccination programmes
Immune memory after hepatitis B vaccinationImmune memory after hepatitis B vaccination
Wolfgang JilgInstitute for Medical Microbiology and Hygiene University of Regensburg
Wolfgang JilgInstitute for Medical Microbiology and Hygiene University of Regensburg
what is memory?
immunologic memory
cardinal feature of the adaptive immune system
ability to respond again to an antigen with a more rapid, larger and qualitatively differentresponse (anamnestic response)
production of anti-HBs during Hep B vaccination
0 1 2 3 4 5 6 7 8 months
anti-
HB
s (
IU/l)
vaccinations
anamnestic response
booster
immunologic memory role for hepatitis B immunisation
responsible for height and persistence of anti-HBs after third (booster) dose
protects against disease after loss of anti-HBs in successfully vaccinated individuals
may play a role for protection against antibody-escape mutants (as long as T-cell epitopes are not involved)
persistence of anti-HBs
protection after Hep B vaccination
protection against infection bound to anti-HBs-concentrations ≥10 IU/l persistence depends on initial (peak) anti-HBs concentration
1
10
100
1 000
10 000
100 000
anti-
HB
s I
U/L
6 12 18 24 30 36 42 48 54months after third vaccination
0
decrease of anti-HBs in 4 individuals after 3rd dose
Jilg et al, Lancet 1990; 335:173
percentage decrease of anti-HBs
0
20
40
60
80
100
anti-
HB
s(%
of p
eak
valu
e
months after 3rd vaccination6 12 18 24 30 36 420
202 healthy young adults after three doses of recombinant hepatitis B vaccine
Jilg et al, Infection 1989;17:70
kinetics of anti-HBs after hepatitis B vaccination
very similar in every vaccinee irrespective of the peak antibody level after the third vaccinationhalf-life of anti-HBs is function of time, being very short initially and becoming longer with time after last vaccinationinfluenced by disturbances to the immune system, specific disorders (e.g. Down-Syndrome), certain drugs (e.g. antiepileptics)
Jilg et al, J Hepatol 1988;6:201; Coursaget et al, Lancet 1991;337:1180; Gesemann et al, Vaccine 1995;13:443; Vellinga et al, J Med Virol 1999; 57:100
how long does anti-HBs persist?
persistence of anti-HBs after hep.B vaccination
Population time after anti-HBs first vacc. ≥10 IU/l (%)
Alaskan natives (n=959) 10 yrs 76Wainwright et al 1997
Taiwanese children (n=539) 10 yrs 85Wu et al 1999
Italian children (n=223) 11-14 yrs 75Mele et al 1999
Chinese children (n=52) 15 yrs 50Liao et al 1999
in 10 - 50% of all succesfully vaccinated individuals the anti-HBs concentration decreases below 10 IU/l within 10 years
as protection against infection is bound to anti HBs concentrations above 10 IU/l these individuals are again susceptible to infection
break-through infections
10-year follow-up afterHep B vaccination in high-risk infants
972 Taiwanese children of HBsAg-positive mothersHBIG at birth + vaccine at month 0,1, 6
4 different doses of plasma-derived vaccine tested(2.5 / 5 / 10 / 20 µg)
month 12: 805 children anti-HBs pos., HBsAg and anti-HBc neg.
after 10 years: 539 available for analysis
Wu et al JID 1999; 179: 1319
anti-HBs 10 years after HB vaccination according to anti-HBs level at 12 months (Wu et al 1999)
54 85 960
20
40
60
80
100
ant
i-HBs
pos
. va
ccin
ees
(%)
<100 100-999 1000+anti-HBs at month 12 (IU/L)
Wu et al JID 1999; 179: 1319
infection rate 10 yrs after HB-vaccinationaccording to anti-HBs level at 12 months (Wu et al 1999)
28 17 90
10
20
30
inf
ectio
n ra
te (
%)
<100 100-999 1000+anti-HBs at month 12 (IU/L)
Wu et al JID 1999; 179: 1319
break-through infections in successfully vaccinated individuals
homosex. men (n=634) 7-9 yrs 46 (7)* 2 (0.3) **Hadler et al 1991
eskimos in Alasca (n=1630) 10 yrs 13 (0.8)* 0 Wainwright et al 1997
children in Taiwan (n=805) 10 yrs 109 (14)* 4 (0.5)Wu et al 1999
* clinically silent ** HIV-positive
population time after n (%) positive for1st vaccination anti-HBc HBsAg
children in Gambia (n=731) 14 yrs 79 (11)* 2 (0.3)Whittle et al 2002
break-through infections after successful Hep B vaccination
risk of hepatitis B infection is inversely related to the maximal antibody response to vaccinerisk of infection increases with declining anti-HBsvast majority of infections in successfully vaccinated individuals are clinically silentprotection against clinically important diseaseoutlasts the presence of detectable antibodies
Hadler et al, NEJM 1986; 315: 209; Wainwright et al, JID 1997; 175: 674; Wu et al JID 1999; 179: 1319 Whittle et al BMJ 2002; 325: 569
protection after Hep B vaccinationde
gree
of p
rote
ctio
nan
ti-H
Bs-
conc
entr
atio
n
time
protection against infection(anti-HBs >10 IU/l)
protection-limit
vaccination
?protection against disease
protection against infection
protection against disease(immunologic memory)
?
protection against disease due to presence of immunologic memory
vaccination induces B- and T-memory cellsrapid proliferation after contact with antigen,
production of cytokines and specific antibodies („anamnestic response“)
in case of infection the anamnestic response prevents its further spread, downregulates viral replication and finally eliminates the virus
prevents disease and chronic infection
how can we prove the presence of an immunologic memory ?
methods to demonstrate immunologicmemory after hepatitis B vaccination
anamnestic anti-HBs response after revaccination
anamnestic response 17 years after HepB vacc.
0 2 4 6 8anti-HBs-response
10
100
1000
10000
100000
anti-
HB
sIU
/L
days
within 8 days anti-HBs increases from 80 IU/l to 25 000 IU/l
>300 fold increase in anti-HBs
mean increase of 130 IU per hour or 2 IU per min
anamnestic response to revaccination of 203 individuals ≥10 years after first Hep B-vaccination
ital. children (n =147*) 10 years 96Da Villa et al 1996
group time after anamnesticfirst vaccination reponse at (%)
ital. children (n =17*) 10 years 100Resti et al 1997
US children (n =14) 12 years 100West et al 1994
US children/adults (n =25**) 13 years 100Watson et al 2001
** 5 anti-HBs neg. * all anti-HBs neg.
anamnestic response to booster doses with 2.5 or 10 µg HBsAg in previously immunized HCW (n=59)
633 3881920 1572
10
100
1000
10000
100000
Ant
i-HB
s IU
/l (G
MT)
2.5 µg 10 µg
baseline anti-HBs: <10 IU/l
day 10 day 30
2441 2122
1185013770
10
100
1000
10000
100000
Ant
i-HB
s IU
/l (G
MT)
2.5 µg 10 µg
baseline anti-HBs: 10-50 IU/l
Williams et al Vaccine 2001;19:4081
revaccination of 131 individuals 2-6 years after basic immuni-zation
anamnestic response to revaccination is correlated to primary responsebut on a higher level
Jilg et al in Coursaget, Progress in Hepatitis B immunization 1990;p 419
anamnestic response to administration of non-absorbed HBsAg in responders to HB vacc. after loss of anti-HBs
50 63 75 69 88 88 75 94 94 81 100 100
0
20
40
60
80
100
sero
conv
ersi
on (%
)
0.6 µg (16) 3.5 µg (16) 10 µg (16) 20 µg (16)dose of HBsAg (no. participants)
day 7 day 15 day 30
GMTs day 30: 23 30 262 1359 IU/l
Dentico et al Vaccine 2002;20:3725
anamnestic anti-HBs response after revaccination
present in >95% of vaccinees for at least 10 years after basic immunization
correlated with primary response
strength of response depends on antigen dose
methods to demonstrate immunologicmemory after hepatitis B vaccination
anamnestic anti-HBs response after revaccination
demonstration of anti-HBs-secreting B-cells in vitro (ELI-spot)
in vitro anti-HBs production by B cellsafter vaccination against hepatitis B (n=51)
0
2
4
6
8
10
12
spot
s / 1
04B
cel
ls
> 10 1-10 0 0 0responders
anti-HBsnon-resp. unvacc.
van Hattum et al in Hollinger, Viral Hepatitis and Liver disease;1990; p 774
methods to demonstrate immunologicmemory after hepatitis B vaccination
anamnestic anti-HBs response after revaccination
demonstration of anti-HBs-secreting B-cells in vitro (ELI-spot)
demonstration of HBsAg-specific T-cells
proliferation assayscytokine secreting cells (ELI-spot)intracellular cytokines (FACS-analysis)
T cell proliferative response to HBsAgin 31 HCW vaccinated 3-12 years before against hepatitis B T cell proliferation positive individuals
Wang et al World J Gastroenterol 2004;10:260
0
58
100 100
0
20
40
60
80
100
T ce
ll pr
olif.
pos
. (%
)
unvacc. (9) - 10 IU/l (12) 11-100 IU/l (6) > 100 IU/l (13)anti-HBs-titer at analysis (no. participants)
T cell proliferative response to HBsAgin 31 HCW vaccinated 3-12 years before against hepatitis B T cell proliferation: mean counts per minute
Wang et al World J Gastroenterol 2004;10:260
252 2819 4718
12167
02000400060008000
100001200014000
mea
n co
unts
per
min
unvacc. (9) - 10 IU/l (12) 11-100 IU/l (6) > 100 IU/l (13)anti-HBs-titer at analysis (no. participants)
T cell immunity of Hep B vaccineesbefore and after a booster 10 yrs after basic immunization
100 children (born to HBeAg pos. mothers) immunized at birth were tested after 10 years
21 (21%) were found to be negative for anti-HBs
a subgroup was tested for cellular immunity by stimulation of PBMCs with HBsAg
on revaccination all showed a clear anamnestic anti-HBs response
Huang et al Hepatology 1999;29:955
T cell immunity of Hep B vaccineesbefore and after a booster 10 yrs after basic immunization
T-cell proliferation 29/58 ( 50%) 27/46 ( 59%)
IL-2 production 42/52 ( 81%) 14/16 ( 87%)
IL-5 production 41/41 (100%) 13/13 (100%)
before booster after booster no. pos./no. tested no. pos./no. tested
Huang et al Hepatology 1999;29:955
Immunologic memory afterHep B vaccination
presence of HBsAg specific T- and B-cell memory in in succesfully vaccinated individuals documented for at least 10 yearsprimary immune response seems to be a good predictor for the quality of immunologic memory *question about long term protection can only be answered by future long term follow-up studies looking for break-through infections and investigating the humoral and cellular basis for immunologic memory
* Banatvala et al, Vaccine 2001: 19: 877
difficulties in determining the length of protection
follow-up studies with an observation time of >>10 years still rarenumber of vaccinees available for follow up decreases with time - data become less significantin low endemicity countries risk of hepatitis B very low - clinically significant break-through-infections (as sign of vaning immunity) will be rareimmunologic memory so far mainly demonstrated byanamnestic response to revaccination - reliable and sensitive cellular tests only seldom used
