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Understanding Herpes Zoster
and the Herpes Zoster Vaccine
John W. Gnann, Jr. MD
University of Alabama at Birmingham
Birmingham, Alabama, USA
Pre-Test Questions
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Outline –
Herpes Zoster





VZV Infections
Epidemiology of Herpes Zoster
Natural History
Complications
Medical Management of Herpes Zoster and
Postherpetic Neuralgia
Varicella-Zoster Virus




alphaherpesvirus HHV-3
primary infection - varicella (chickenpox)
95% of U.S. adults are VZV-seropositive
varicella is now preventable by vaccine (since
1995 in the US) – dramatically declining incidence
 Viral latency in cranial nerve and dorsal root
ganglia
 reactivation of latent VZV results in dermatomal
herpes zoster (shingles)
VZV – Varicella and
Herpes Zoster
Viral Replication Results in Ganglionitis
Skin or mucous
membrane
Pain perceived
at skin or mucous
membrane
Descending noradrenergic and
serotoninergic inhibitory fibers
Ascending
spinothalamic fibers
Dorsal-root
ganglion
Modified from Kost R et al. N Engl J Med. 1996;335:32-42.
12
Herpes Zoster Lesions
Reprinted with permission form Gnann JW, Whitley RJ. N Engl J Med. 2002;347:340-346.
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Incidence of Herpes Zoster (Shingles)
• Approximately 1 million cases of zoster in the
United States annually1
• 3.2 to 3.7 cases of zoster per 1000 person-years
across the population (all ages)2-5
• Risk of developing zoster is strongly age-dependent6
• Zoster incidence by decade4,5:
–
–
–
–
50-59 years of age 4.2-4.6 cases per 1000 person-years
60-69 years of age 6.0-6.9 cases per 1000 person-years
70-79 years of age 8.6-9.5 cases per 1000 person-years
≥80 years of age 10.7-10.9 cases per 1000 person-years
1. Oxman MN et al. N Engl J Med. 2005;352:2271-2284; 2. Jumaan AO et al. J Infect Dis. 2005;191:2002-2007; 3. Mullooly JP
et al. Epidemiol Infect. 2005;133:245-253; 4. Yawn BP et al. Mayo Clin Proc. 2007;82:1341-1349; 5. Insinga RP et al.
J Gen Intern Med. 2005;20:748-753; 6. Schmader K et al. J Infect Dis. 2008; 197(suppl 2):S207-S215.
Incidence of Herpes Zoster
Incidence rates of herpes zoster (HZ) among Olmsted County, MN,
adults from 1996 to 2001, in 2-year increments
Incidence rate of HZ
per 1000 person-years
14
1996-1997
1998-1999
2000-2001
12
10
8
6
4
2
0
22-29
30-39
40-49
50-59
Age (years)
Yawn BP et al. Mayo Clin Proc. 2007;82:1341-1349.
60-69
70-79
≥80
Lifetime Risk of Herpes Zoster
• Lifetime risk of herpes zoster is
approximately 20% in the United States1
• 50% of individuals living until 85 years
of age will ultimately develop
herpes zoster2
• Risk of recurrent herpes zoster is low
in the immunocompetent host—
1.7% to 5.2%3
1. Gnann JW Jr, Whitley RJ. N Engl J Med. 2002;347:340-346; 2. Katz J et al. Clin Infect Dis. 2004;39:342-348;
3. Ragozzino MW et al. Medicine (Baltimore). 1982;61:310-316.
Risk Factors for Development
of Herpes Zoster
 Advancing age (with declining VZV-specific CMI)
 Malignancy, esp. lymphoproliferative cancers
(leukemia, lymphoma)
 Deficiencies in cell-mediated immunity,
esp. HIV infection
 Medical / Iatrogenic:
– Chemotherapy, radiation therapy
– Corticosteroids (high dose, systemic)
– Organ transplantation with anti-rejection
therapy
Acute Herpes Zoster – Evolution of the
Cutaneous Eruption
(prodromal pain)
Evolution of the Rash
Vesicles
(3-7 days)
Pustular lesions
(4-6 days)
Crusting of lesions
(7-10 days)
Resolution of rash
(2-4 weeks)
Pitfalls in Diagnosis of Herpes Zoster
• Prodrome of acute pain and paresthesias may be mistaken for other
painful conditions1
– Migraine, glaucoma, myocardial infarction, pleurisy, duodenal
ulcer, cholecystitis, appendicitis, and biliary or renal colic
• Skin manifestations can appear similar to other rashes
– Zosteriform herpes simplex is the most frequent error in diagnosis2
• Can be linear, but heals more rapidly, is likely to have less
pain, and may recur in same area2
• If indicated, only reliable way to distinguish between the two is
with laboratory testing (PCR, culture, IFA)2,3
– Occasional confusion with contact dermatitis
HSV = herpes simplex virus; IFA = immunofluorescent assay; PCR = polymerase chain reaction.
1Oxman MN. Clinical manifestations of herpes zoster. In: Arvin AM, Gershon AA, eds. Varicella-Zoster Virus: Virology and
Clinical Management. Cambridge, UK: Cambridge University Press; 2000:246-275; 2Rűbben A et al. Br J Dermatol. 1997;137:
256-261; 3Gershon AA et al. Varicella-zoster virus. In: Murray PR et al, eds. Manual of Clinical Microbiology. 6th ed.
Washington, DC: ASM Press; 1995:884-894.
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Acute Herpes Zoster Pain:
A Source of Significant Morbidity
• Pain is the critical symptom of herpes
zoster
• Characteristics include burning, stabbing,
stinging, and shooting pain1,2
• Patients report that acute zoster pain is
“horrible” or “excruciating”3
• 45% of patients report that they
experience pain every day3
• 23% of patients report that they
experience pain the entire day3
1. Goh CL, Khoo L. Int J Dermatol. 1997;36:667-672.
2. Stankus SJ et al. Am Fam Physician. 2000;61:2437-2444.
3. Katz J et al. Clin Infect Dis. 2004;39:342-348.
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Acute Herpes Zoster Pain Causes
Significant Morbidity in Older Adults
• Poorer physical, emotional, social,
and role functioning
• Interference with activities of daily living
• Impaired physical and mental health
• Lower vitality
• Insomnia
• Depression
Schmader KE et al. Clin J Pain. 2007;23:490-496; Chidiac C et al. Clin Infect Dis. 2001;33:62-69; Lydick E et al. Qual Life
Res. 1995;4:41-45; Katz J et al. Clin Infect Dis. 2004;39:342-348; Coplan PM et al. J Pain. 2004;5:344-356.
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Acute Herpes Zoster Pain Interferes
With Activities of Daily Living
Patients (%)
Prospective, observational US study of 102
outpatients ≥60 years of age with herpes zoster,
7 days after rash onset
80
ZBPI ADLI ≥5
70
ZIQ ADLI ≥5
60
50
40
30
20
10
0
None (0)
Mild (1-3)
Moderate (4-7)
Severe (8-10)
(n=10)
(n=25)
(n=48)
(n=19)
Pain category
ADLI=activities of daily living interference.
Schmader KE et al. Clin J Pain. 2007;23:490-496.
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Complications of Herpes Zoster
Neurologic
• Postherpetic neuralgia
(PHN)
• Motor neuropathy
• Cranial palsy
• Encephalitis
• Transverse myelitis
• Post-zoster stroke
syndromes
Cutaneous
• Bacterial superinfection
• Scarring
Ophthalmic
• Stromal keratitis
• Iritis
• Retinitis
• Visual impairment
• Episcleritis
• Keratopathy
Visceral
• Pneumonitis
• Hepatitis
• Encephalitis
Gnann JW Jr, Whitley RJ. N Engl J Med. 2002;347:340-346; Arvin AM. Clin Microbiol Rev. 1996;9:361-381.
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Herpes Zoster Ophthalmicus
• About 15% of zoster cases involve the
ophthalmic division of the trigeminal nerve
• Keratitis, conjunctivitis, scleritis, iritis,
anterior uveitis, retinitis
• Without antiviral therapy, 50%-70% of patients
with HZO develop ocular complications
• Can result in chronic ocular complications and
reduced vision, even blindness
• Refer patients with ocular involvement to an
ophthalmologist immediately
HZO=herpes zoster ophthalmicus.
McPherson RE. J Am Optom Assoc. 1997;68:527-538.
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Treatment of Acute Herpes Zoster
Symptomatic Measures
Treatment of skin:
– Wet compresses
– Non-occlusive dressings
– Protection with bandages
– Antibacterial drugs for superinfection
Treatment of acute neuritis:
– Pain – NSAIDs, opioid analgesics, nerve blocks
– Itching – antihistamines (hydroxyzine,
diphenhydramine)
1. Gnann JW, Whitley RJ. N Engl J Med. 2002;347:340–346. 2. Straus SE, Oxman MN. In: Freedberg IM,
Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. Vol 2. New York, NY:
McGraw-Hill; 1999:2427–2450.
Treatment of Acute Herpes Zoster
• Antivirals - acyclovir, famciclovir, valacyclovir
– Nucleoside analogues inhibit viral replication
– Promote healing and reduce duration of pain of
acute herpes zoster
– Therapy must be initiated within 72 hours of onset
of rash for maximal benefit
• Corticosteroids – limited role
–
–
–
–
Reduce inflammatory features of acute zoster
Possibly prevent injury to affected neurons
Used in combination with antivirals
Do not alter the risk of PHN
Kost R et al. N Engl J Med. 1996;355:32-42.
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Antiviral Therapy for Herpes Zoster
in Immunocompetent Patients
Benefits of acyclovir, valacyclovir, or famciclovir
therapy for herpes zoster proven in randomized,
controlled clinical trials:
• Shortened duration of new vesicle formation
• Shortened duration of virus shedding
• Accelerated lesion healing
• Reduced duration of pain
• For HZO, reduced risk of ocular complications
HZO=herpes zoster ophthalmicus.
Antiviral Therapy for Herpes Zoster
Medication
Typical Dosing
Acyclovir
(Zovirax®)
800 mg 5x/day, 7-10 days
Famciclovir
(Famvir®)
500 mg 3x/day, 7 days
Valacyclovir
(Valtrex®)
1000 mg 3x/day, 7 days
Zovirax Package Insert, GlaxoSmithKline.
Famvir Package Insert, Novartis Pharmaceuticals.
Valtrex Package Insert, GlaxoSmithKline.
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Circumstances That Favor the Use of
Antiviral Therapy in Immunocompetent
Patients With Herpes Zoster
• Early zoster (lesions <72 hours) or ongoing new
vesicle formation
• Older patients1
– Primary goal: to reduce the duration of pain
– However, this benefit is variable. Up to 20% of
patients who have pain at 30 days still report pain at
6 months despite antiviral therapy
• Extensive eruption or severe pain at
presentation (predictors of chronic pain)
• Herpes zoster ophthalmicus2
– Primary goal: to prevent ocular complications
1. Beutner K et al. Antimicrob Agents Chemother. 1995;39:1533-1546.
2. Gnann J et al. N Engl J Med. 2002;347:340-346.
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Postherpetic Neuralgia – A Chronic and
Disabling Neuropathic Pain Syndrome

Chronic neuropathic pain that persists or develops after herpes
zoster rash has healed1. Current definitions include pain persisting
90-120 days after rash onset1-3

Frequency is about 25% (range 10%-75%), depending upon age of the
population and definition used. Both frequency and severity
increase with advancing age4

Early antiviral therapy (within 72 hours of zoster lesion onset) is
indicated to minimize duration of pain, but not reliably effective
for preventing PHN

PHN usually requires adjunctive pain-management interventions
Dworkin and Schmader. CID 2003; 36:877-882; 1Oxman MN et al. N Engl J Med. 2005;352:2271-2284; 2Wood MJ, Easterbrook P.
Shingles, scourge of the elderly. In: Sacks SL et al, eds. Clinical Management of Herpes Viruses. Amsterdam: IOS Press; 1995:193-209;
3Jung BF. Neurology. 2004;62:1545-1551; 4 Levin MJ et al. J Infect Dis. 2008;197:825-835.
Incidence of Postherpetic Neuralgia
Duration of herpes zoster-related pain among Olmsted County, MN, adults
(≥22 years old), stratified by age
Adults with HZ (%)
35
Pain ≥30 days
Pain ≥60 days
Pain ≥90 days
30
25
20
15
10
5
0
22-29
30-39
40-49
50-59
60-69
70-79
≥80
Age (years)
Yawn BP et al. Mayo Clin Proc. 2007;82:1341-1349.
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Postherpetic Neuralgia
Primary Characteristics:
– Chronic pain – persistent or intermittent
– Burning, itching, aching
– Paroxysmal or lancinating pain
– Abnormal skin sensations – paresthesia,
hyperesthesia, allodynia
Secondary Characteristics:
– Sleep disturbance
– Anorexia
– Lassitude
– Depression
Factors Which Influence
Pain Outcomes in Herpes Zoster
Risk of Chronic Pain Increased if:




Prodromal pain is present
Age is >50 years old
Initial acute pain is severe
Involved skin surface area is extensive, with large
numbers of lesions
Whitley, R, et al. JID. 1998;178(S1): S71-S75.
Whitley, R et al. JID. 1999; 179: 9-15.
Severity of Acute Herpes Zoster Is a
Major Risk Factor for Chronic Pain
in Adults ≥50 Years of Age
Patients reporting pain (%)
1.0
0.9
0.8
0.7
0.6
0.5
Severe or incapacitating pain and 47 lesions
0.4
No or mild acute pain and <47 lesions
0.3
0.2
0.2
0
0
15
30
45
60
75
90
105 120 135 150 165 180
Study day
Modified from Whitley R et al. J Infec Dis. 1999;179:9-15;
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Pharmacologic Management of PHN
Interventions with benefits proven in controlled clinical trials:
• Anticonvulsants (eg, gabapentin, pregabalin)
– Better tolerated than other anticonvulsants; aid sleep
– Easier dosing with pregabalin
• Tricyclic antidepressants (eg, amitriptyline, nortriptyline)
• Lidocaine patch
– Safe, easy to use, rapid effect
• Opioids (eg, methadone, morphine, oxycodone)
• Topical capsaicin
Problems include polypharmacy and adverse effects in elderly patients.
Dubinsky RM et al. Neurology. 2004;63:959-965; Dworkin RH et al. Neurology. 2003;60:1274-1283; Stankus SJ et al. Am Fam
Physician. 2000;61:2437-2444; Christo PJ et al. Drugs Aging. 2007;24:1-19; Wu CL, Raja SN. J Pain. 2008;9(suppl 1):S19-S30.
Summary
• Increased age and suppressed immune status
are risk factors for reactivation of VZV
• Zoster can be associated with numerous
complications, including ocular injury,
bacterial superinfection, and especially PHN
• For maximal effectiveness, antivirals should
be administered within 72 hours of rash
onset
• Strategies to prevent zoster occurrence may
help reduce disease burden in susceptible
populations
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Outline – The Herpes
Zoster Vaccine





Rationale for the Vaccine
The Shingles Prevention Study
Vaccine Efficacy
Vaccine Safety
Recommendations for Use of the
Herpes Zoster Vaccine
Why Do We Need a Strategy
to Prevent Shingles?
• In immunocompetent persons, herpes zoster is a
common condition (esp. among elderly patients)
and is associated with substantial morbidity.
• Once herpes zoster develops, the available
treatments (including antiviral therapy) do not
prevent PHN in all patients.
• The treatments for PHN are complicated,
associated with frequent adverse effects, and
not always effective.
• Prevention is preferable to treatment
43
Why Would We Expect a
Zoster Vaccine to Work?
• Fact: Herpes zoster incidence and
severity increase with advancing age,
primarily due to declining VZV-specific
cell-mediated immunity (CMI)
• Hypothesis: Boosting VZV-specific CMI
with a vaccine before it reaches a critical
level could suppress VZV reactivation and
prevent or attenuate herpes zoster
Oxman MN et al. N Engl J Med. 2005;352:2271-2284.
44
RCF (per 100,000 PBMC)
CMI to VZV Decreases With Age
6
5
4
3
2
1
0
30
40
50
60
70
80
>85
Age (years)
CMI=cell-mediated immunity; PBMC=peripheral blood mononuclear cell; RCF=responder cell frequency;
VZV=varicella-zoster virus.
Adapted from Levin MJ et al. Unpublished results.
45
Shingles Prevention Study
• Efficacy trial to determine whether an attenuated livevirus “zoster vaccine” decreases the incidence and/or
severity of herpes zoster and its complications
• Placebo-controlled, randomized, double-blind study
• 22 U.S. sites (VA and university medical centers)
• Enrolled 38,456 adults >60 years
• Single subQ injection of vaccine (live VZVOka) or placebo
• Subjects followed for minimum of 3 years
after enrollment
• Monthly follow-up with automated telephone response
system (ATRS)
• Patients who developed zoster were offered appropriate
antiviral therapy and standard-of-care pain medications
Oxman M et al. N Engl J Med. 2005;352:2271-2284.
47
SPS - Inclusion and Exclusion Criteria
• Inclusion
– Adults >60 years old
– Ambulatory
– History of chickenpox (or >30 years residence in the
continental US)
• Exclusion
– Prior episode of herpes zoster
– Prior varicella vaccine
– Immunosuppression resulting from:
• Disease, malignancy
• Corticosteroids
• Other immunosuppressive/cytotoxic therapy
– Expected survival <5 years
Oxman M et al. N Engl J Med. 2005;352:2271-2284.
48
Shingles Prevention Study Endpoints
• Primary Endpoint
– Burden of illness of herpes zoster (a
composite measure affected by zoster
incidence plus the severity and duration of
the associated pain and discomfort)
• Secondary Endpoint
– Incidence of PHN (pain persisting at severity
>3/10 more than 90 days after rash onset)
• Additional Endpoint
– Incidence of herpes zoster
Oxman MN et al. N Engl J Med. 2005;352:2271-2284
49
Primary Outcome Measure
1. Burden of illness (BOI)
–
defined as the sum of the areas under worst pain-vstime curves in all subjects who develop HZ in the
vaccine vs the placebo group
2. Instrument: Zoster Brief Pain Inventory (ZBPI)
–
–
Validated self-reported assessment of severity and
impact of HZ-associated pain
administered weekly to each HZ patient until pain
was “≤3 out of 10” for two consecutive weeks
3. Measure the area-under-the-curve (AUC)
of pain-vs-time. Sum the areas for all subjects (for
patients without HZ, area = 0)
Oxman M et al. N Engl J Med. 2005;352:2271-2284; Coplan et al. Journal of Pain 5:344-356, 2004
50
AUC of Worst Pain Scores Over Time
10
Worst pain score
9
8
7
6
5
4
3
2
1
0
0
10
20
30
40
50
60
70
Days since rash onset
Oxman M et al. N Engl J Med. 2005;352:2271-2284.
51
SPS Randomization
Subjects enrolled
(n=38,546)
Adverse events substudy
(n=6616)
Cell-mediated immunity
substudy (n=1395)
Age 60 to 69 years
(n=20,747)
VZV vaccine
(n=10,378)
Placebo
(n=10,369)
Oxman M et al. N Engl J Med. 2005;352:2271-2284.
Age 70 years
(n=17,799)
VZV vaccine
(n=8892)
Placebo
(n=8907)
Disposition of SPS Subjects
Enrolled
38,546
Zoster vaccine
19,270
Terminated before study end
793 (4.1%) Died
57 (0.3%) Withdrew
61 (0.3%) Lost to follow-up
Completed study
18,359 (95.3%)
Oxman M et al. N Engl J Med. 2005;352:2271-2284.
Placebo
19,276
Terminated before study end
792 (4.1%) Died
75 (0.4%) Withdrew
52 (0.2%) Lost to follow-up
Completed study
18,357 (95.2%)
53
Herpes Zoster Case Determination
Suspected Cases of HZ
N=1308
481 Zoster Vaccine
315 Evaluable Cases of HZ
294 (93.3%) VZV+ by PCR*
2 (0.6%) VZV+ by local culture
19 (6.0%) HZ by CEC only
827 Placebo
642 Evaluable Cases of HZ
600 (93.5%) VZV+ by PCR*
8 (1.2%) VZV+ by local culture
34 (5.3%) HZ by CEC only
*VZV = varicella zoster virus. All VZV DNA was wild-type; no Oka detected. CEC = clinical
evaluation committee; HZ = herpes zoster; PCR = polymerase chain reaction.
Oxman M et al. N Engl J Med. 2005;352:2271-2284.
54
Vaccine Efficacy for
Herpes Zoster Burden of Illness (BOI)
61.1%
65.5%
55.4%
(95% CI)
(51.1 – 69.1)
(51.5 – 69.1)
(39.9 – 66.9)
HZ burden of illness
Efficacy
9
8
7
6
5
4
3
2
1
0
5.68
7.78
Vaccine
Placebo
4.33
3.47
2.21
1.50
All
60-69 yr
70 yr
(P<0.001)
Oxman M et al. N Engl J Med. 2005;352:2271-2284.
55
Vaccine Efficacy
for Incidence of Herpes Zoster
Efficacy
51.3%
(95% CI)
(44.2 - 57.6)
Incidence of HZ
(per 1000 person-years)
14
63.9%
37.6%
Vaccine
12
11.12
10.79
11.50
Placebo
10
8
6
7.18
5.42
3.90
4
2
0
N= 315
642
All
(P<0.001)
Oxman M et al. N Engl J Med. 2005;352:2271-2284.
122
334
193
308
60-69 yr
70 yr
(P<0.001)
(P<0.001)
56
Cumulative incidence of HZ (%)
Effects of Vaccine on
Incidence of HZ over Time
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Placebo
P<.001
Zoster vaccine
Placebo: n=19,247
Zoster vaccine: n=19,254
0
1
2
3
4
5
Years of follow-up
Oxman M et al. N Engl J Med. 2005;352:2271-2284.
57
Vaccine Efficacy
for Incidence of PHN
Efficacy
66.5%
65.7%
66.8%
(95% CI)
(47.5 - 79.2)
(20.4 - 86.7)
(43.3 - 81.3)
Incidence of PHN*
2.5
2.0
Placebo
1.38
1.5
1.0
0.5
0.0
2.13
Vaccine
0.74
0.71
0.46
0.26
N= 27
80
All Subjects
8
23
60-69 yr
19
57
70 yr
(P<0.001)
* Per 1000 person-years
Oxman M et al. N Engl J Med. 2005;352:2271-2284.
58
Cumulative incidence of PHN (%)
Effect of Zoster Vaccine
on Postherpetic Neuralgia
1.0
0.9
0.8
P<.001
0.7
Placebo
0.6
0.5
0.4
Zoster vaccine
0.3
0.2
Placebo: n=19,247
Zoster vaccine: n=19,254
0.1
0.0
0
1
2
3
4
5
Years of follow-up
Oxman M et al. N Engl J Med. 2005;352:2271-2284.
59
SPS - Adverse Events
(Day of Vaccination to Day 42*)
Event
Vaccine
No. (%)
N=3,345
Placebo
No. (%)
N=3,271
Difference in Risk
(95% CI)
Erythema
1,188 (35.8)
227 (7.0)
31.7 (28.3 to 32.6)
Pain or tenderness
1,147 (34.5)
278 (8.5)
28.8 (26.9 to 30.6)
Death
14 (0.1)
16 (0.1)
-0.01 (-0.1 to 0.1)
One or more SAEs
255 (1.4)
254 (1.4)
0.01 (-0.2 to 0.3)
7 (<0.1)
24 (0.1)
Confirmed case of HZ
-0.09 (-0.16 to -0.03)
* among AE substudy subjects who kept daily diaries
Oxman M et al. N Engl J Med. 2005;352:2271-2284.
62
Herpes Zoster Vaccine Trials: Summary
• Zoster vaccine efficacy1
– 61.1% reduction in the HZ burden of illness
(BOI)
– 66.5% reduction in the incidence of PHN
– 51.3% reduction in the incidence of HZ
• Zoster vaccine was safe and efficacious
in preventing HZ and PHN in adults 60 years of
age and over
• Most common AE was tenderness and erythema
at the injection site (36%)
Oxman M et al. N Engl J Med. 2005;352:2271-2284.
Hornberger J and Robertus K. Ann Int Med 2006; 145: 317-325.
63
Clinical Practice
Recommendation
• Practice Recommendation:
Zoster vaccine is recommended for all adults age 60 and
above.
• Evidence-Based Source:
National Guidelines Clearinghouse
• Web Site of Supporting Evidence:
http://www.guideline.gov/summary/summary.aspx?doc_id=120
93&nbr=006222&string=zoster+AND+vaccine
• Strength of Evidence:
Class A: Randomized, controlled trial; Class M: Meta-analysis,
Systemic review, Decision analysis, Cost-effective analysis; Class
R: Consensus statement, Consensus report, Narrative review
64
CDC Recommends
Herpes Zoster Vaccination for Adults
• October 2007 — CDC includes zoster vaccine
in adult immunization schedule for adults
≥60 years of age
• May 2008 — For the prevention of herpes zoster,
the CDC recommends that the zoster vaccine be
given to all people ≥60 years of age who have no
contraindications, including1:
– Patients who have had a previous episode
of herpes zoster
– Patients with chronic medical conditions
1. Centers for Disease Control and Prevention. MMWR. 2008;57:1-30.
65
Herpes Zoster Vaccine:
Dosage and Administration
• Zostavax® (Zoster Vaccine Live [Oka/Merck]) is a
lyophilized preparation of the Oka/Merck strain of live,
attenuated VZV.
• For subcutaneous administration
• Administered in a single dose of 0.65 mL
• Stored frozen
• Should be reconstituted immediately upon removal from
freezer
• Diluent should be stored separately
• Discard reconstituted vaccine if not used within
30 minutes
Zostavax [package insert]. Whitehouse Station, NJ: Merck & Co.; 2007.
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Contraindications
to Herpes Zoster Vaccine
• History of anaphylactic/anaphylactoid reaction to
neomycin (does not include contact dermatitis)
• Serious current illness (or temperature ≥38.5°C)
• History of immunodeficiency state, including
– Leukemia, lymphomas, or other malignant neoplasms
affecting bone marrow or lymphatic system
– AIDS or other clinical manifestations of HIV infection
• Immunosuppressive therapy, including high-dose
corticosteroids
• Active untreated tuberculosis
• Known or suspected pregnancy
Zostavax [package insert]. Whitehouse Station, NJ: Merck & Co.; 2007.
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Herpes Zoster Vaccine
Case #1
• A 52 y.o. woman comes to clinic for routine follow-up
• Active problems - type 2 diabetes mellitus and
hyperlipidemia, which are fairly well-controlled with
medication.
• Social history – successful corporate attorney,
unmarried, no children
• PMH – no prior zoster. Chickenpox history unknown
• Two of her co-workers have had shingles in the last
few months, both associated with severe pain and
protracted absence from work. She requests the
zoster vaccine.
• What do you recommend to her?
69
?
Can Zoster Vaccine be Given to
Patients <60 years of Age?
• Current FDA approval only for age >60 years (the
population studied in SPS)
• In one recent study, 50-60 years was the decade with the
highest absolute number of herpes zoster cases
(incidence 4.2 cases/1000 person-yrs)1
• In studies with high-potency zoster vaccine in subjects
50-59 y.o., the vaccine was safe and immunogenic, but
efficacy was not assessed2. Efficacy studies in this age
group are ongoing.
• Uncertainty regarding duration of protection when given
to younger patients. Will they “outlive” vaccine efficacy?
• In the absence of data, physicians and their patients
<60 y.o. who desire vaccination will have to discuss the
risk-benefit ratio. Unlikely to be covered by insurance.
1Yawn
et al, Mayo Clin Proc 82:1341, 2007
et al, Vaccine 25:1877, 2007
2Tyring
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Can Zoster Vaccine be Given to Patients
with Unknown Chickenpox History?
• VZV seropositivity rate among Americans >60 y.o.
is >95%1. Most patients who do not recall a history
of chickenpox are VZV seropositive.
• Serologic testing was not requirement for SPS.
• Limited data suggest no excess morbidity if VZV
seronegative patients are given zoster vaccine2.
• The efficacy of a single injection of zoster vaccine
for protecting against chickenpox is unknown.
• No recommendation that patients undergo VZV
serologic testing before receiving zoster vaccine
1Kilgore,
et al, J Med Virol 70 (suppl):S111, 2003
2Macalalad et al, Vaccine 25:2139, 2007.
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Herpes Zoster Vaccine Case #2
• A 78 y.o. retired physician comes to clinic in December for
a flu shot
• Active problems – chronic bronchitis, ischemic heart
disease, congestive heart failure, all adequately controlled
with medication
• Social history – previous heavy smoker, recently quit
• PMH – MI 3 years ago. Herpes zoster (V-1 dermatome with
ocular involvement and 18 months of PHN) 9 years ago.
• Because of his prior severe case of shingles, he has read
about the herpes zoster vaccine and wants to receive it
today
• What do you recommend to him?
74
?
Should Zoster Vaccine be Given to Patients
With a Previous Episode of Herpes Zoster?
• Use of zoster vaccine in those who have previously had
herpes zoster. Considerations:
–
–
–
–
–
>15% of target population (>60 y.o.) has had prior HZ;
Risk of a second case of HZ is small (2-5%);
The diagnosis of remote herpes zoster is imperfect;
No laboratory marker for prior herpes zoster or for zoster risk;
No data on rate of decay in boost of VZV-CMI that occurs following
naturally-occurring zoster.
• Vaccine is likely to add protection when the initial HZ was
in the “remote” past
• Vaccinating patients who have already had HZ is unlikely
to create safety concerns
• ACIP recommends vaccination “whether or not they report
a prior episode of herpes zoster.”
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Clinical Practice
Recommendation
• Practice Recommendation:
A history of prior shingles disease is not a contraindication to
immunizing patients over age 60 against zoster/shingles.
• Evidence-Based Source:
Institute for Clinical Systems Improvement
• Web Site of Supporting Evidence:
http://www.icsi.org/immunizations/immunizations__guideline_.
html
• Strength of Evidence:
Class A: Randomized, controlled trial; Class M: Meta-analysis,
Systemic review, Decision analysis, Cost-effective analysis; Class
R: Consensus statement, Consensus report, Narrative review
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Can Zostavax be Co-Administered
with Other Vaccines?
• Concomitant use:
– In general, live vaccine administration is acceptable
any time before or after an inactivated vaccine1
– Few other live vaccines are routinely used in adults
– Inactivated influenza and zoster vaccines can be
given at the same time
• Same immune response and safety when given
concomitantly (N=382) or sequentially (N=380)2
– Pneumococcal PS – studies ongoing
– Tdap – studies planned
1ACIP
General Recommendations on Immunization—December 2006
2Kerzner et al, J Am Geriatr Soc 55:1499, 2007
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Herpes Zoster Vaccine and Inactivated Influenza
Vaccine Can Be Administered Concomitantly
VZV antibody geometric
mean titer (GMT)
1000
900
800
700
Estimated GMT ratio 0.9 (P<.001)
Prevaccination
GMFR
Week 4 postvaccination
(95% CI)
2.0
2.3
(1.8-2.2)
(2.0-2.5)
600
500
400
300
200
100
0
Concomitant
Nonconcomitant
GMFR=geometric mean-fold rise; patients aged ≥60 years.
Kerzner B et al. J Am Geriatr Soc. 2007;55:1499-1507.
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Herpes Zoster Case #3
• A 61 y.o. woman comes to clinic for follow-up of breast
cancer
• Active problems – breast cancer, s/p lumpectomy and
chemotherapy (completed 4 months ago); hypertension
• PMH – hysterectomy for fibroids
• PE – hair is growing back, breast well-healed, no
adenopathy, no evidence of metastatic disease
• Lab – HCT 29; WBC 7600 (65 PMN, 25 lymphs, 10 monos);
PLT 180,000
• Both her mother and her father had severe cases of
shingles in their 70s. She asks you if she should receive
the zoster vaccine.
• What do you recommend to her?
81
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Can Zoster Vaccine be Given to
Immunocompromised Patients?
• Zoster vaccine contains replicating VZV. There is
theoretical potential for vaccine virus to cause disease in
immunocompromised patients.
• Per package insert, zoster vaccine is contraindicated in
immunocompromised patients
• Patients with impaired cell-mediated immune responses
likely to be at greatest risk include:
–
–
–
–
HIV seropositive patients
Organ transplant recipients on anti-rejection therapy
Cancer patients actively receiving chemotherapy or radiation
Patients receiving corticosteroids or other immunosuppressive
therapy for autoimmune diseases
However, many other “gray areas” remain where physicians must use
clinical judgment
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CDC Recommendations:
Immunocompromised Patients
• Corticosteroids: Patients ≥60 years of age receiving a dose
equivalent to 20 mg/d prednisone for >2 weeks should not receive
the zoster vaccine for at least 1 month after discontinuation of
such therapy
– Topical (e.g., skin, nasal, inhaled), intraarticular, bursal, or
tendon injections are not considered sufficiently
immunosuppressive to raise vaccine safety concerns
• Immunosuppressive therapy not considered sufficiently
immunosuppressive to raise vaccine safety
concerns includes:
• Methotrexate (≤0.4 mg/kg/week)
• Azathioprine (≤3.0 mg/kg/d)
• 6-Mercaptopurine (≤1.5 mg/kg/d)
Centers for Disease Control and Prevention. MMWR . 2008;57:1-30.
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CDC Recommendations:
Immunocompromised Patients (cont’d)
• Patients ≥60 years of age whose leukemia
is in remission and who have not received
chemotherapy or radiation therapy for at least
3 months can receive the zoster vaccine
• Patients ≥60 years of age undergoing hematopoietic
stem cell transplantation (HSCT) should be assessed on
a case-by-case basis
– Zoster vaccine should be given no sooner than
24 months after transplantation
Centers for Disease Control and Prevention. MMWR. 2008;57:1-30.
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CDC Recommendations:
Immunocompromised Patients (cont’d)
• Patients ≥60 years of age with impaired humoral
immunity (e.g., dys- or hypogammaglobulinemia) can
receive the zoster vaccine
• Patients ≥60 years of age receiving recombinant human
immune mediators or immune modulators should be
assessed on a case-by-case basis
– If it is not possible to administer zoster vaccine before
the initiation of therapy, it should be deferred until at
least 1 month after discontinuation of therapy
Centers for Disease Control and Prevention. MMWR. 2008;57:1-30.
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Herpes Zoster Vaccine Case #4
• An oncologist calls you to discuss a mutual patient, a 68
year old man with colon cancer
• Active problems – Adenocarcinoma of the colon, s/p
hemicolectomy 3 weeks ago. His post-op course was
complicated by a COPD exacerbation that required a 10
day tapering course of prednisone (now completed).
• PE – colostomy; abdominal wound healing well; lungs clear
• The oncologist plans to initiate chemotherapy in about 3
weeks. She wants to know whether it might be a good
idea to give the patient the zoster vaccine today.
• What advice do you give her?
88
?
Can the Zoster Vaccine be Given in
Advance of Immunosuppressive Therapy?
• The concept of vaccination prior to planned
immunosuppressive therapy is attractive, but
unstudied
• Potential situations:
– Chemotherapy or radiation therapy planned for solid
tumor malignancy (e.g., breast cancer)
– TNF-alpha inhibitor therapy planned for autoimmune
disease (e.g., rheumatoid arthritis)
• What is a safe interval between vaccination and
initiation of immunosuppressive therapy?
• Safety and efficacy of this approach are
unknown
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CDC Recommendations:
Special Groups and Circumstances
• Patients ≥60 years old who are anticipating
immunosuppression should receive zoster vaccine while
immunity is intact—at least 14 days before initiating
immunosuppressive therapy
• Patients ≥60 years of age taking chronic acyclovir,
famciclovir, or valacyclovir should not receive zoster
vaccine until at least >24 hours after drug
discontinuation
• Zoster vaccine can be administered at any time before,
concurrent with, or after receiving:
– Blood
– Antibody-containing blood products
Centers for Disease Control and Prevention. MMWR. 2008;57:1-30.
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Future of Herpes Zoster
in the U.S.
 Incidence likely rising among adults (DOB before 1995)
who had chickenpox.
- aging population
- more immunocompromised persons
- reduced exposure to chickenpox - ?
 More zoster in the elderly will mean more PHN.
 Acceptance of vaccination of adults to prevent zoster?
 Impact of childhood varicella vaccination?
- Dramatic decline in chickenpox. Will these
vaccinated children be at higher or lower risk for
shingles in 50 years?
Reducing the Public Health Burden of
Herpes Zoster and PHN Through Vaccination
• Herpes zoster is a cause of major morbidity
in older adults, significantly impacting their
quality of life
• Advancing age is the primary risk factor for
herpes zoster and its major complication, PHN
• Current treatment options for herpes zoster
and PHN have limitations
• Herpes zoster vaccine reduced the incidence
and severity of herpes zoster and PHN in adults
≥60 years
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Post-Test Questions
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