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Varicella Zoster Vaccine in Preventing Zoster in
Elderly People
Dr David Dai
Prince of Wales Hospital
21st July, 2007
Today’s Talk
• Clinical features of Herpes Zoster
• Post Herpetic Neuralgia (PHN)
• Treatment
• Prevention
Herpes Zoster (Shingles): Etymology1
herpesherpes =derived from Greek “herpeinderived from Greek “herpein” meaning “to creep”” meaning “to creep”
zosterzoster =a Greek word meaning a Greek word meaning “girdle”“girdle”
shinglesshingles = derived from Latin “cingere”derived from Latin “cingere”
1. Dorland’s Illustrated Medical Dictionary. 28th ed. Philadelphia: WB Saunders Company, 1994:759.
Human Herpesviruses (HHV)
HHV family1
Alpha-HHV Beta-HHV Gamma-HHV
VZV†
(HHV-3)HSV*
(HHV-1, -2)EBV‡ (HHV-4) CMV§ (HHV-5)
KSHV ׀׀ (HHV-8)
1. Roizman B et al. In: Fields Virology. 4th ed. Vol. 2. New York: Lippincott Williams & Wilkins, 2001:2381–2397. 2. Arvin AM. In: Fields Virology. 4th ed. Vol. 2. New York: Lippincott Williams & Wilkins, 2001:2731–2767.
Reactivation: herpes zoster (shingles)2
Primary infection: varicella (chickenpox)2
(HHV-6A, -6B)(HHV-7)
*HSV = herpes simplex virus†VZV = varicella-zoster virus‡EBV = Epstein-Barr virus§CMV = cytomegalovirusKSHV = Kaposi’s sarcoma-associated herpesvirus׀׀
A typical case (Clin Inf Disease 1999; 28: 736-9)
• 70 year old man
• Pain in RUQ, diagnosed as cholescystitis
• 4 days later, rash noted by nurse; diagnosis reviewed as “Shingles”
• Rash persisted in next 3 weeks
• No relief of pain
• 5 yrs afterwards, still severe pain
• Constant deep ache
• Sharp pains
• Involuntary muscle contractions
• Extremely sensitive skin
• Unable to wear clothes over the area
Medications• Codeine, oxycodone, morphine• Amitriptyline, topical lidocaine• Capsaicin, mexilitine, phenytoin• Carbamazepine, NSAID• TENS• Epidural anaesthetic/steroid injection• Intercostal nerve blocks
All without relief
• Falls 2 years after onset and hip fracture
• Forced retirement
Zoster: Clinical Features
• Usually limited to 1 or 2 adjacent, unilateral dermatomes1,2
• “Grape-like” lesions clustered on an erythematous base1,2
• Lesions usually heal within 4 weeks1
Courtesy of the American College of Physicians.www.acponline.org/shell-cgi/printhappy.pl/bioterro/smallpox_mimics.htm
1. Oxman MN. In: Varicella-Zoster Virus, Virology and Clinical Management. Cambridge: Cambridge University Press, 2000:246–275. 2. Lycka BAS et al. In: Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition. Vol. 11. Amsterdam: Elsevier Science B.V., 2001:97–106.
Zoster: Dermatomal Distribution
Image courtesy of Charles E. Crutchfield III, MD.
Zoster: Cranial Involvement1
Reproduced with permission.1 ©Diepgen TL, Yihune G et al. Dermatology Online Atlas (www.dermis.net) Reprinted with permission.
I ophthalmic
II maxillary
III mandibular
1. Stedman’s Medical Dictionary. 27th ed. Baltimore: Williams & Wilkens, 2000:1202.
Zoster Ophthalmicus
Image courtesy of Charles E. Crutchfield III, MD.
KO Studios, Pacifica, CA.©2002. Reprinted with permission.
Image courtesy of Dr. Dubin’s collection (www.skinatlas.com)
Establishment of VZV Latency in Sensory-Nerve Ganglia. After a primary VZV infection (chickenpox), latent VZV infection is established in the dorsal-root ganglia, and zoster occurs with subsequent reactivation of the virus
N Engl J Med Vol 356(13) P1338-1343
Incidence of Zoster and Postherpetic Neuralgia (PHN) in the UK
Ra
te p
er
10
00 p
er y
ear
0 10 20 30 40 50 60 70 80+
1110
9876543210
Zoster cases/1000/year
PHN/1000/ year
Age (years)
1. Hope-Simpson RE. J R Coll Gen Pract 1975;25:571–575.
Post Herpetic Neuralgia( J Infect Dis 2002; 186(Suppl): 983-90)
Herpes Zoster pain 3 Phases:1) Acute2) Subacute: 4-5 weeks 28.4%3) Chronic: > 3months 15% > 12 months: 5-10%
Spontaneous remission: limited
Effects of PHN on Patients
Pain• Tender
• Burning
• Throbbing
• Stabbing
• Shooting/stabbing
• Allodynia
• Disturbance in physical and psychological functioning
• Drug dependency
• Depression
• Suicide
Map of Sensory Disturbances of PHN
• Allodynia
• Postherpetic scarring
• Reduced sensation to pinprick, temperature (cold), and touch
Reprinted from Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition, Vol. 11, Watson CPN, Oaklander AL, Deck JH, The neuropathology of herpes zoster with particular reference to postherpetic neuralgia and its pathogenesis, pp167–182, 2001, with permission from Elsevier.
Map of Sensory Disturbances of PHN Following Zoster Ophthalmicus
Reprinted from Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition, Vol. 11, Watson CPN, Oaklander AL, Deck JH, The neuropathology of herpes zoster with particular reference to postherpetic neuralgia and its pathogenesis, pp 219–222, 2001, with permission from Elsevier.
Comparison of Pain Scores for Various Conditions
Acute Pain Conditions Chronic Pain Conditions
Less Pain
More Pain
0
10
20
30
40
50
Abdominal hysterectomy
Acute headache
ZosterLabor pain
Postsurgical painMucositis
Angioplasty sheath removal
Postherpetic neuralgia
Chronic cancer pain
Fibromyalgia
Rheumatoid arthritisOsteoarthritisArthritisMusculoskeletal painAtypical facial pain
Adapted from Surgical Clinics of North America, Vol 79, Katz J, Melzack R, Measurement of pain, pp 231–252. Copyright® 1999, with permission from Elsevier.
Financial Impact
• UK(1994)
• Life unit cost for managing PHN
•₤ 770 per patient
Treatment
Antiviral therapy within 72 hours of rash:
•↓duration (pain, rash healing)•↓eye complications• ? Incidence of PHN
Table 1. Proportions (%) of patients (aged 50 years) with persisting pain in controlled trials of antiviral therapies for herpes zoster [4 6, 36, 40].
PHN pain
Drugs compared
Acyclovir(800 mg 5×/day, 7
10 days)vs. placebo
Valacyclovir(1000 mg 3×/da
y, 7 days)vs. acyclovir
Valacyclovir(1000 mg 3×/day, 7 days)
vs. famciclovir(500 mg 3×/day, 7 days)
Famciclovir(500 mg 3×/da
y, 7 days)vs. placebo
At 3 months
25 vs. 54a 31 vs. 38b 32 vs. 34c 34.9 vs. 49.2
At 6 months
15 vs. 35a 19.9 vs. 25.7d 19 vs. 19c 19.5 vs. 40.3a
NOTE. PHN, postherpetic neuralgia. a P < .05 from 95% confidence interval (CI) for the relative risk (RR) for the difference between treatments. b GlaxoSmithKine data on file. c P = .84 from 95% CI for the RR for the difference between treatments. d P = .08 from 95% CI for the RR for the difference between treatments
J Infectious Dis 2002;186(Suppl 1):S83-90
The problem
• Diagnosis in prodromal period extremely difficult
• Majority of elderly patients with localised, unilateral pain does not develop herpes
Later therapy still has benefit
↓duration of illness• Immunocompromised
• Older
• Ophthalmic
• New lesions after 72 hours
At Risk of PHN
• Old age
• Prodromal pain
• Severe acute pain
• Rash
• ? Female
• Ophthalmic zoster
• Preexisting neurological disorder
Figure 1. Annual Incidence of Herpes Zoster and Proportion of Patients with Postherpetic Neuralgia. Panel A shows the annual incidence of herpes zoster per 1000 persons in a general medical practice.1 Panel B shows the percentage of patients with pain persisting after the onset of the zoster-associated rash. Data are from the placebo group in one large, double-blind treatment study.7 Panel C shows the proportion of patients with postherpetic neuralgia according to age.16
N Eng J Med 335(1);32-42, 1996
Duration of Zoster-Associated Pain According to Age1,2
0
20
40
60
80
100
0– 19 20– 29 30– 39 40– 49 50– 59 60– 69 ≥70
Age (years)
Pat
ient
s re
portin
g pa
in (%
)
>1 year6– 12 months1– 6 months<1 month
(n)2 (24) (53) (69) (136) (204) (270) (160)
Adapted with permission from Kost RG et al.1 © 1996 Massachusetts Medical Society.
1. Kost RG et al. N Engl J Med 1996;335:33–42. 2. de Moragas JM et al. AMA Arch Derm 1957;75:193–196.
Treatment of established illness
• Tricyclics
• Anti-convulsants
• Opiate analgesics
• Surgery: sympathectomy, dorsal root entry zone lesion, cordotomy, thalamotomy, cingulumotomy, spinal cord and deep brain stimulation
The Patient
Do anything to reduce the pain
Strategy
• Prevent or attenuate herpes zoster
• Pain programme ( drug and non-drug)
Prevention of PHN
• ? Antiviral therapy
• ? Oral steroids ( excessive side effects)
• Intervention to reduce acute inflammation and tissue damage (attenuate peripheral nocioceptive sensitisation and central hyperexcitability)
Shingles Prevention StudySPS
A vaccine to prevent Herpes Zoster and Post Herpetic Neuralgi
a in Older PatientsMN Oxman etal
NEJM 2005(352): 2271-84
The Question
In persons > 60 yrs, does a live attenuated zoster virus( VZV) vaccine decrease the burden of illness caused by herpes zoster and incidence of PHN?
ZOSTAVAX® [Zoster Vaccine Live (Oka/Merck)] Product Profile
• Live, attenuated varicella-zoster virus vaccine
• Minimum of 19,400 PFU* per dose• No preservative• Lyophilized product• Same excipients as VARIVAX® [Varicella
Virus Vaccine Live (Oka/Merck)]• Single subcutaneous dose
*PFU = plaque-forming units
Randomised placebo-controlled trial
• Follow up period: 3.13 yrs (median)
• Setting: 22 sites in US
• Participants: 38,546 persons > 60yrs
• Mean age: 69 yrs, 59% men, with a history of varicella or had resided in US > 30yrs
• Immunocompromised persons excluded
Randomization of Subjects
Subjects Enrolled38,546
Age 60 to 69 years20,747
Placebo10,369
Zoster vaccine10,378
Adverse Event (AE) Substudy: 6616
CMI Substudy1395
Age 70 years17,799
Placebo8907
Zoster vaccine8892
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
Zoster and PHN
• Zoster cases were confirmed by– Polymerase-chain-reaction (PCR) assay– Viral culture– Adjudication by a clinical evaluation committee
• PHN was defined as:Zoster-associated pain rated as 3 or more on a 10-point pain scale persisting or appearing at least 90 days after rash onset
Intervention
• Study group ( n= 19270): 1 subcut injection of 0.5mL Oka/Merck VZV vaccine
• Placebo group (n= 19276)
• Vaccine has median potency of 24600 plaque-forming units
Outcomes
Vaccine efficacy:• Relative reduction in burden-of- illness
sore(VEBOI): severity of and duration of herpes zoster pain
• Incidence of PHN: pain rated as >3/10
Patient follow-up: 95%( modified intention to- treat- analysis)
Definition and Measurement of the BOI
Zoster BOI: Population measure
Wor
st P
ain
Days
0
10
Main Results
Vaccine Efficacy
Reduction of Cumulative Incidence of Zoster
Cumulative Incidence Over Time*
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
0 1 2 3 4 5
Pe
rce
nt
of
Su
bje
cts
Wit
h Z
os
ter
Time Since the Start of Follow-Up (in Years)
Placebo
Zoster vaccine
Logrank P-value = <0.001
*A limited number of subjects were followed beyond Year 4.
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
Reduction of Cumulative Incidence of PHN
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0 1 2 3 4 5
PlaceboZoster vaccine
Logrank P-value = <0.001
Time Since the Start of Follow-Up (in Years)
Pe
rce
nt
of
Su
bje
cts
Wit
h P
HN
Cumulative Incidence Over Time*
*A limited number of subjects were followed beyond Year 4.
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
Overall Efficacy of the Zoster Vaccine
51.3%
66.5%
61.1%
25%=prespecified lower bound success criterion
0 25 50 75 100
Vaccine Efficacy (%)
V211.VEsummary1c Sept. 30, 2005
BOI
PHN
Zoster 95% CI
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
Efficacy of the Zoster Vaccine by Age Stratum
v211ACM.Vbar1a Dec. 6, 2005
0 20 40 60 80 100
Vaccine Efficacy (%)
BOI
PHN
Zoster
Ages 60 to 69
Ages 70
95% CI
Shingles Prevention Study: Summary of Efficacy
• The zoster vaccine was highly effective in reducing the incidence and morbidity from zoster and PHN– Reduced the incidence of zoster by 51%– Reduced the incidence of PHN by 67%– Reduced the BOI associated with zoster
by 61%
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
Vaccine Efficacy by Age Group
• The zoster vaccine benefited the 60- to 69-year-olds by reducing the incidence of zoster1:– 60-to-69-year-old group: 63.9% 70-year-old group: 37.6%
• The zoster vaccine benefited the 70-year-olds by decreasing disease severity1
– Efficacy for pain BOI was similar in both age groups
– Efficacy for PHN was similar in both age groups
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
The AE Monitoring Substudy
AE
Zoster Vaccine
(N=3345)%
Placebo(N=3271)
%Injection Site
Erythema*
Pain / tenderness*
Swelling*
Hematoma
Pruritus
Warmth
35.8
34.5
26.2
1.6
7.1
1.7
7.0
8.5
4.5
1.4
1.0
0.3
*Designates a solicited adverse experience. Injection-site adverse experiences solicited only from Days 0–4 postvaccination.
1. Oxman MN et al. N Engl J Med 2005;352:2271–2284.
Serious side effects
5 subjects:1) asthma on D2
2) PMR on D3
3) Anaphylactoid reaction 90minures
4) PMR on D15
5) Goodpasture syndrome D52
Shingles Prevention Study: Summary of Safety
• The zoster vaccine has demonstrated a favorable safety profile.
• Transient injection-site reactions occurred in approximately 50% of the vaccine recipients.
• There were clinically important differences between the zoster vaccine and placebo with respect to– SAEs (1.4% in each group)– Systemic clinical AEs
• Following a dose of zoster vaccine, vaccine-associated rashes were uncommon (0.1%)
Conclusion
In persons >60 yrs, a live attenuated varicella-zoster virus vaccine decreased the burden of illness caused herpes zoster and the incidence of PHN. The incidence of herpes zoster was also reduced to a greater extent in vaccine recipients
Figure 3. Host Factors in Latent VZV Infection and Reactivation. Varicella is the primary infection caused by VZV, and its resolution is associated with the induction of VZV-specific memory T cells (blue line). Memory immunity to VZV may be boosted periodically by exposure to varicella or silent reactivation from latency (red peaks). VZV-specific memory T cells decline with age. The decline below a threshold (dashed green line) correlates with an increased risk of zoster. The occurrence of zoster, in turn, is associated with an increase in VZV-specific T cells. The administration of zoster vaccine to older persons may prevent VZV-specific T cells from dropping below the threshold for the occurrence of zoster (dashed blue line). (Reprinted from Arvin.19)
N Engl J Med Vol 356(13) P1338-1343
Unresolved Issues(ACP Journal club 2005, 143(3): 61)
• Cost-effectiveness
• Optimal age at first administration
• Duration of protection
Additional Comments( MN Oxman , Human Vaccine 2007,3:2, 64-68)
• Efficacy persist for at least 4 years• Young subjects: prevent HZ• Older subjects: attenuate HZ• No use in PHN treatment or HZ• Transmission of vaccine virus no
risk
• 86% of SPS subjects who develop HZ received famcyclovir and analgesia, and 2/3 received anti-viral treatment within 72 hrs; therefore, severity and duration of HZ pain reduced and understimate efficacy of VZV vaccine
Cost -effectiveness
• QOL and functional of older persons with HZ comparable to CCF, MI, DM, major depression
(Neurol; 45 Suppl 8: S52-3)• PHN cause severe functional impairment, fa
tigue, anorexia, weight loss, insomnia, difficult concentration, depression, isolation, loss of independence and death
Figure 2. Cost per quality-adjusted life-year (QALY) gained as a function of duration of vaccine efficacy (from 3 to 30 years) and total vaccination costs (from $50 to $500). Total vaccination costs include unit vaccine cost, a public awareness campaign, administration costs, patient travel time and time receiving vaccine, and cost of treating adverse events. Ann Intern Med 2006;145:317-325
• Cost of vaccine US$150 per dose, assuming duration of efficacy 10 yrs:
• $ 2600 per HZ prevented
• $ 7500 per PHN prevented
• NNV to prevent a case of HZ: 18
• NNV to prevent a clinically significant case of PHN: 1009
Improved Zoster vaccine
• Increased potency ( ↑quantity of infective VZV and amount of VZV antigens)
• 5 times the current vaccine
• Likely to be well tolerated
• Effective inactivated zoster vaccine to protect immunodeficient population
ZOSTAVAQX®
Stored frozen at an average temperature of -15ºC or colder until it is reconstituted for injection.
Recommendations
The author has already been vaccinated and has purchased the vaccine and administrated to his wife
Preventive Dermatology(J Am Acad Derm 2007; 56:675-6)
Vaccination with live attenuated VZV vaccine should be made available to all immunocompetent persons aged 60yrs and older during routine office visits; and before immunosuppresive atherapy
ACIP Provisional Recommendations( October 25, 2006)
• A single dose of zoster vaccine is recommended for adults 60 years of age and older whether or not they report a prior episode of herpes zoster. Persons with chronic medical conditions may be vaccinated unless a contraindication or precaution exists for their condition.
• Contraindications and precautions to use of zoster vaccine are available at http://www.fda.gov/Cber/label/zosmer052506LB.htm
To give or not to give?
Give
Patient treatment experience
Storage
Cost
