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