Status of Zoster Vaccine for the Elderly
Myron Levin“Aging and Immunity”
Siena, September 23, 2009
Pathophysiology of HZ- begins with varicella-
• Almost all adults (>96%) have had varicella(chickenpox), usually in childhood.
• Adults have the complete varicella-zoster virus (VZV) genome (from childhood) present in approximately 5% of neurons in dorsal root and cranial sensory ganglia.
• This virus is latent, with 5 immediate-early/ early genes being transcribed and translated.
• But viral replication does not normally proceed - this activity is clinically silent.
Pathophysiology of HZ
• The mechanism that maintains the latency of VZV in neurons is not known – but it is dependent on adequate immune function
• Although people maintain VZV-specific antibody life-long, cell-mediated immunity(CMI) is the essential component in maintaining latency
• HZ is more frequent (age-specific) and more severe in immunocompromisedpatients
Role of Immunity in HZ-CMI is essential-
• Congenital agammaglobulinemia is not associated with HZ → VZV-CMI is sufficient
• Other diseases associated with defects in antibody synthesis – are not associated with HZ → VZV-CMI is sufficient
• VZV vaccine (heated) in HSCT recipients– HZ risk correlated with VZV CMI; no
significant change in antibody
Hata A et al. N Engl J Med 2002; 347: 26
Role of Immunity in HZ-CMI is essential-
• HZ correlated with decline in VZV-specific CMI in lymphoma patients– VZV antibody unaffected by disease or therapy, and
did not correlate with HZ → CMI is sufficient
• Hematopoietic stem cell transplantation– all immunity is ablated and humoral immunity is
maintained with IV immune globulin (which maintains a high serum titer of VZV antibody)
– Yet HZ is very common → CMI is necessary (and sufficient)
Arvin AM et al. J Clin Invest 1980; 65: 869
What happens if VZV-CMI declines?
Latent VZV in ganglia probably reactivates (sporadically) throughout life– When VZV-CMI is adequate, this event is less
likely to occur or is aborted (subclinical)
– When VZV-CMI is inadequate, the latent VZV will propagate in the affected ganglion, which explains the dermatomal nature of HZ
HZ Pathogenesis
• VZV growing in the ganglion causes an inflammatory response (ganglionitis) that explains the characteristic prodromaldermatomal (neuropathic) pain
• The virus then descends in the sensory nerve of the affected ganglion to the skin to cause the characteristic dermatomal vesicular rash(with added nociceptive pain)
• Persisting damage in the nerve and ganglion (and beyond) are the basis of dermatomalpost-herpetic neuralgia (PHN)
HZ is a common, often severe, disease of the
elderly
Herpes Zoster Incidence-Disease of the elderly-
0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Age
Annual Incidence
(per 10000 person-yrs)
Canada (Manitoba) - Brisson
UK - Hope-Simpson
UK (RCGP) - Brisson
Netherlands - de Melker
US (Olmstead) - Yawn
US (Medstat) - Insinga
From Marc Brisson
Kost R et al. N Engl J Med. 1996;355:32-42.
Pat
ien
ts r
epo
rtin
g p
ain
(%
)
Age (years)
0
100
80
60
40
20
0-19 20-29 30-39 40-49 50-59 60-69 ≥79
>1 yr
<1 mo
6 - 12 mo
1 - 6 mo
Prevalence of Pain and Duration of Pain Increases with Age
Complication rates by ageComplication rates by age
Yawn BP et al. Mayo Clinic Proc. 2008
22-29 30-39 40-49 50-59 60-69 70-79 80+
05
1015
perc
ent o
f cas
es w
ith c
ompl
icat
ions
eyeneuroskinother
HZ and Aging
• Frequency of HZ is greater• Severity of HZ is greater
– ↑Duration and extent – Post-herpetic neuralgia (PHN)
– Complications
• Implies that VZV-CMI declines with age
VZV-CMI Declines With Age
Burke et al, Arch Intern Med 1982; 142: 291
VZV-CMI and Age-CD4 Memory Cell Assay
Weinberg, Lazar, Zerbe, Levin et al. submitted to JID
Preventing (Attenuating) HZ
Preliminary experiments 1986-1996– Ability to boost VZV-CMI > 5-fold at 1 week;
>2-fold at 3 months– Safety of a life, attenuated VZV vaccine
– Suggested that disease was attenuated– Immunologic assessment methods and dose
determined
VZV-IFNγ ELISPOT-Zoster Vaccine-
20 (14;28)33 (29;65)Week 6
17 (12;25)50 (35;70)Week 2
30 (13;67)102 (38;275)Week1
18 (13;27)17 (12;25)Day 0
GMC (95% CI)GMC (95% CI)
PlaceboZoster VaccineInterval
JN Vermeulen et al, unpublished N= 70-90/category except 19-20 for week 1
Zoster Vaccine-Pivotal Trial-
• Same virus as varicella vaccine (live)• Potency = 18-fold greater• 38,500 subjects, ≥60 years old
– 45% ≥70 years old
• Monthly real-time clinical follow-up for HZ and PCR confirmation
• Average follow-up – 3.1 years
37.6%63.9%51.3%(44.2 - 57.6)
Efficacy(95% CI)
0
2
4
6
8
10
12
All 60-69 yr ≥70 yr
Incidence of H
Z
Vaccine
Placebo
Vaccine Efficacy for Incidence of Herpes Zoster
AUC of Worst Pain Scores Over TimeAUC of Worst Pain Scores Over Time--Severity of IllnessSeverity of Illness--
0 10 30 40 50 60 7020
10Worst pain score
9
8
7
6
5
4
3
2
1
0
Days since rash onset
Vaccine Efficacy forHerpes Zoster BOI
55.4%(39.9 – 66.9)
65.5%(51.5 – 69.1)
61.1%(51.1 – 69.1)
Efficacy(95% CI)
0
1
2
3
4
5
6
7
8
9
All 60-69 yr ≥70 yr
HZ burd
en of illness
Vaccine
Placebo
Vaccine Efficacy for Incidence of PHN
66.8%(43.3 - 81.3)
65.7%(20.4 - 86.7)
66.5%(47.5 - 79.2)
Efficacy(95% CI)
0.0
0.5
1.0
1.5
2.0
2.5
All Subjects 60-69 yr ≥70 yr
Incidence of PH
N
Vaccine
Placebo
HZ Severity of Illness Score >600
73%1140Total
68%1031≥70 years
89%1960-69 years
% Reduction
VaccinePlaceboAGE
HZ Severity of Illness Score >800
82%528Total
82%422≥70 years
83%1660-69 years
% Reduction
VaccinePlaceboAGE
Pivotal Vaccine Trial-Immunologic Assessment Substudy-
• ~1300 subjects• Randomized to vaccine or placebo• Evaluated at Days 0, 6 weeks; years 1,2,3• Measure VZV antibody and VZV-CMI
– gp-ELISA– Responder cell frequency (RCF)– ELISPOT
• Correlate with clinical events– Evaluate immune responses at 1, 3, 6 weeks after
HZ, and subsequently
10
15
20
25
30
35
40
45
50
55
ELIS
POT
Coun
t
220
240
260
280
300
320
340
360
380
60-64N=447
65-69N=376
70-74N=313
75-79N=197
>79N=62
Age at Randomization (Years)
gpEL
ISA
Tite
r2
3
4
5
6
7
8
RCF
Valu
e
VZV Immune Responses by Age-Baseline
Levin et al,JID 2007
0
20
40
60
80
100
120
Incr
ease
in R
CF fr
om P
lace
bo (%
)
0
20
40
60
80
100
120
140
160
Incr
ease
in E
LISP
OT fr
om P
lace
bo (%
)
0
20
40
60
80
Day 0 6 Weeks 1 Year 2 Years 3 years
Time Since Randomization
Incr
ease
in g
pELI
SA fr
om P
lace
bo (%
)
N =V/P 691/704 686/702 669/682 659/665 635/632
Increase in VZV-Specific immune responses to zostervaccine
Levin et al. JID, 2007
RC
F v
alue
12
9
6
3
0E
LIS
PO
T c
ount
100
60
40
20
0
gpE
LIS
Atit
re
600
400
200100
0
300
500
80
204/24060-64
186/18865-69
162/14970-74
103/9475-79
31/31>79
Age at randomization, years
N = V/P
Vaccine Placebo
Levin et al, JID 2007
Age and 6-week response
Vaccination Reduces Incidence of Postherpetic Neuralgia
Placebo
Zoster vaccine
P<0.001
0.0
0.2
0.4
0.6
0.8
1.0C
um
ula
tive
inci
den
ce o
f P
ost
her
pet
icN
eura
lgia
(%
)
Years of follow-up0 1 2 3 4 5
19247 18915 18422 9806 1856Placebo
No. at Risk
19254 18994 18626 9942 1906Vaccine
0
50
100
150
200
250
ELIS
POT C
ount
0
4
8
12
RCF V
alue
Vaccine Recipients without HZ
Placebo Recipients with HZ
0
500
1000
1500
2000
2500
6 Weeks 677/70
1 Year 660/58
2 Years 651/55
3 Years 633/24
Time since Exposure to VZV
gpEL
ISA
Titer
Response to zoster vaccine vs HZ
Weinberget al; JIDOct,2009
Immune Correlates-Risk of HZ-
• Baseline VZV-CMI correlated with magnitude of response to the vaccine
• VZV-CMI (both measurements) was higher in those who did not get HZ– Measured prior to vaccination
– Measured at 6 weeks post-vaccination– Measured at last time prior to HZ
Levin et al; JID 2007
0
1
2
3
4
5
Week 1 Week 3
Time since Rash Onset
RC
F V
alu
e
Not PHN PHN
0
10
20
30
40
50
60
70
Week 1 Week 3
Time since Rash Onset
EL
ISP
OT
Co
un
t
Not PHN PHN
0
1000
2000
3000
4000
5000
6000
7000
8000
Week 1 Week 3Time since Rash Onset
gp
EL
ISA
Tit
er
Not PHN PHN
Immune Correlates of Recovery-Severity of HZ-
• Higher RCF and ELISPOT at 1 week after HZ– correlated with less severe HZ and less PHN
– later measurements did not correlate with these
• Antibody response was inversely related to the severity of HZ
Weinberg et al; JID, Oct, 2009
VZV-CMI and Aging-Phenotypic Analysis-
• Compare 60-69 y/o with 35 y/o subjects• Give two doses of zoster vaccine• Determine lymphocyte phenotype at
baseline and frequent intervals after each dose
Patterson-Bartlett, Levin, Lang et al. Vaccine 2007; 25: 7087
VZV-CMI and Aging-Baseline Phenotypic Assessment-
• CD4 cells with activation marker (CD69+) were increased (2-fold) in the elderly
• CD4 cells that produce IFNγ or IL 4&5 were much less frequent (5-fold) in the elderly
• No differences were seen in CD8 cell pool• Significantly less CD4 early effectors
(CD45R0+62L-) in the elderly
• Significantly less CD8 effector memory (CD45RA+62L-) and early effectors in the elderly
VZV-CMI and Aging-Post-Vaccine Phenotype Changes-
– ↑ activation of CD4 cells
– ↑ number of CD4 and CD8 Th1 cells– ↑ number of CD4 and CD8 effector memory
and CD8 early effector– Increase in CD4 and CD8 INFγ+ cellsIncrease
(not quite significant) in CD4 IL 4&5+ cells
– These changes largely abolished the differences between the older and younger subjects
Patterson-Bartlett, Levin, Lang et al. Vaccine 2007; 25: 7087
Effector Memory
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