1. Herpes Zoster Vaccine: Implementation Issues
Division of Viral Diseases
Herpes Zoster Vaccine: Implementation Issues
Rafael Harpaz, MD MPH
Medical Epidemiologist National Center for Immunizations and Respiratory Diseases
Centers for Disease Control and Prevention Atlanta, GA

2. Outline Background Recommendations & implementation of HZV
Clinical manifestations of herpes zoster (HZ)
Epidemiology of HZ
The pivotal HZ vaccine (HZV) study
Recommendations & implementation of HZV

3. Clinical Manifestations
of HZ

4. Definition:
HZ (zoster, shingles): reactivation of varicella zoster virus (VZV) leading to crop of blisters in a dermatomal pattern (an area of skin supplied by sensory nerves from 1 nerve root)
After initial infection (chickenpox), VZV establishes a latent infection in nerve cell bodies along the central nervous system
Years or decades later VZV reactivates
VZV virions reappear & spread to skin via peripheral nerves

5. Manifestations of HZ: Rash
Unilateral; 1-3 adjacent dermatomes
Typically resolves over ~5-25 d
Occasional complications: bacterial infections, scarring
VZV from rash can spread to susceptible persons and cause varicella (HZ is ~20% as contagious as varicella)

6. Classic HZ Rashes: Thoracic, Lumbar Distribution
T1-T2
T7-T8
L3-L4

7. Classic HZ Rashes: Cranial (Trigeminal) Distribution
Mandibular
Trigeminal:
Ophthalmic

8. Manifestation of HZ: Pain
Often precedes rash by days or weeks
Can be excruciating (e.g., like renal colic, childbirth)
Described as aching, burning, stabbing, shock-like
Continuous or paroxysmal
Often associated with:
Altered or painful sensitivity to touch
Provoked by trivial stimuli like bed sheets
Unbearable itching

9. Complications of HZ: Post Herpetic Neuralgia (PHN)
Prolonged, often severe, pain after resolution of the rash
Variable definitions of “prolonged”
May persist months or years; some experience recurrence
No consistently effective ways to prevent or treat PHN

10. Complications of HZ: PHN Impact on Quality of Life
Comparable to congestive heart failure, diabetes & depression
PHYSICAL
PSYCHOLOGICAL
Chronic fatigue
Anorexia & weight loss
Physical inactivity
Insomnia
Anxiety
Difficulty concentrating
Depression, suicidal ideation
SOCIAL
FUNCTIONAL
Fewer social gatherings
Change in social role
Interferes with activities of daily living: dressing, bathing, eating, travel, cooking, shopping
Schmader KE. Clin Infect Dis2001;32(10):1481-6

11. Complications of HZ: Herpes Zoster Ophthalmicus
Courtesy of MN Oxman UCSD/San Diego VAMC
Involvement of ophthalmic division of trigeminal nerve
~15% of HZ cases
Can lead to chronic ocular complications, reduced vision, even blindness
Keratitis, retinitis, scleritis, iritis, anterior uveitis, conjunctivitis

12. Uncommon HZ Complications
Neurologic:
Encephalitis, myelitis, optic neuritis, palsies
Hearing impairment, vertigo, loss of taste
Neurologic dysfunction of diaphragm, bladder, colon
Oral (destruction of alveolar bone with loss of teeth)
Immunocompromised:
Above complications can be much more agressive
Dissemination: generalized rash +/- visceral involvement (pneumonia, encephalitis, hepatitis)
Mortality: mostly in immunocompromised persons

13. Epidemiology of HZ
Zoster linguae

14. Epidemiology of HZ in U.S.
Annual rate 3-4 per 1000 population per year
~1 million cases in the U.S. annually
Age-adjusted rates appear to be increasing
Lifetime risk of developing HZ: ~30%

15. Risk Factors for HZ Age (detailed in next slide)
Dominant factor influencing incidence in population
Immunosuppression
Less common but influential due to magnitude of risk:
Following bone marrow transplant: 17-52%
Patients with hematological malignancies: 5-14%
HIV: risk  fold, recurrences common

16. Risk Factors for HZ: Age Hope-Simpson, UK (1975)
Rate of HZ per 1000 per year 10 20 30 40 50 60 70
80+ 11 9 8 7 6 5 4 3 2 1
Age (years)
N=321

17. Risk Factors for HZ: Unconfirmed or lower magnitude
Gender: most studies show risk  in females
Race: risk in blacks <1/2 that in whites (U.K., U.S.)
Local trauma: 30-day risk in affected area  12-fold
Stress: risk  ~40% following stressful life events
Certain illnesses: diabetes, Crohn’s, rheumatoid arthritis
Varicella exposure (“external boosting”): risk 
However, we don’t know why some immunocompetent persons get HZ and others do not!! 

18. Epidemiology of PHN in U.S.
Proportion of HZ patients that develop PHN:
10% of HZ patients will have ≥90 days of pain
18% of HZ patients will have ≥30 days of pain
100 to 200 thousand new PHN cases per year

19. Risk Factors for PHN
Of those with HZ, age is key risk factor for developing PHN
Risk of progression to PHN (≥90 days) in HZ patients:
Persons years of age: 6%
Persons at least 80 years of age: 20%
Since risk of HZ itself increases with age, PHN is ~20X more likely to occur in persons >80 y.o. vs. <40 y.o.

20. The Shingles Prevention Study
Mandibular

21. Shingles Prevention Study: Methods
Double-blind, placebo-controlled, multicenter trial
Enrolled 38,546 healthy subjects 60 years old
Randomized: HZV vs. placebo
Attenuated VZV; titer ≥14X higher than varicella vaccine
Follow up: median of ~3.1 years

23. Shingles Prevention Study: Vaccine Efficacy for HZ & PHN (≥90 days)
67% 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
>79
Age at Randomization (Years)
Vaccine Efficacy (%)
PHN HZ
ALL
51%
Note that while vaccine efficacy declines with age and that efficacy for preventing zoster is under 20% for persons 80 and over that the vaccine still retains substantial efficacy against PHN at all ages so that it is particularly important to reach persons 80 and over since they are at greatest risk of progressing to PHN and since the oldest patients are those that are most vulnerable to zoster and PHN due to difficulties in both seeking and tolerating medical management

24. PHN Defined by Varying Duration Vaccine Efficacy VEPHN (95% CI)
Shingles Prevention Study: Vaccine Efficacy for PHN of Varying Duration
PHN Defined by Varying Duration
(days)
Vaccine Efficacy VEPHN (95% CI) 30
59% (47, 69) 60
60% (44, 73) 90
67% (48, 79)
120
69% (45, 83)
180
73% (42, 89)

25. Shingles Prevention Study:
Adverse events: appears to be safe
No pattern suggesting causal link to serious adverse events
Vaccine rashes did not occur in the trial
Excess of local injection site reactions
Vaccinees: 48%
Placebo recipients: 17%
Durability of protection:
Vaccine efficacy against HZ & PHN declined during the 1st year of observation but remained stable at above 50% for the remaining 3 years of observation
A slight excess in serious adverse events in sub-study not noted in full study population nor did events follow temporal or organ system pattern to suggest causality

26. Recommendations and Implementation: HZV

27. ACIP (Oct. 2006)
ACIP recommends a dose of HZV for all adults ≥60 years of age unless they have contraindications

28. Implementation
HZV should be offered at the patient’s first available clinical encounter
▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲
The average adult ≥60 y.o. has 5-8 clinical encounters a year; HZV can be offered at the first available opportunity
It can also be given along w/ influenza vaccine (see next slide)
Residents of chronic care facilities should be included in vaccination activities if no contraindications exist

29. Implementation HZV can be administered with other vaccines
▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲
Simultaneous administration with live or inactivated vaccines is acceptable, as is non-simultaneous administration with inactivated vaccines
The only issue arises with non-simultaneous administration with other live vaccines
Not acceptable unless separated by >28 days
Persons ≥ 60 y.o. only rarely require other live vaccine (e.g., yellow fever) but this might occur if the patient was accidentally given varicella vaccine

30. Implementation
HZV is recommended whether or not the patient reports a prior episode of HZ
▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲
Patients (and less commonly, doctors) misdiagnose HZ, and there are no tools to confirm or rule-out a history of prior HZ
Validating an HZ history can thus be a real challenge for providers & introduce a major barrier to vaccination
Having >1 episode of HZ is not uncommon; the rate of HZ after a prior episode may be similar to the rate of a first episode
Following an episode of HZ, there is no specific minimal time interval before one can receive HZV

31. Implementation
It is not necessary to check varicella history or titers before administering HZV
▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲
Virtually all persons ≥60 years of age have serologic evidence of prior varicella, even if they do not recall having the illness
There is no evidence that HZV inadvertently given to persons without prior varicella raises safety concerns
Determining varicella history would introduce a major and unnecessary barrier to vaccination

32. Implementation
HZV should be offered to eligible persons including those >80 y.o., frail, or with chronic illnesses
▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲
While HZV is less effective at preventing HZ in persons >80 yrs of age, its effectiveness at preventing PHN is better
The oldest and frailest population
Experiences the largest burden of HZ and PHN, so even less effectiveness translates to more prevention
Least able to seek medical attention and access care
Least able to tolerate powerful meds used to control pain
Has least physical, social, psych reserve to handle HZ or PHN

33. Implementation HZV must be kept ≤5°F until reconstitution
▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲
Any freezer with separate sealed freezer door that can reliably maintain average temp of <5°F (-15°C) is acceptable (dorm-style units are not)
Caution: for some combined fridge/freezer models, setting the freezer to low temps for HZV can reduce fridge temps below freezing and ruin refrigerated vaccines
Unused HZV must be discarded 30 min after reconstitution

34. Implementation
Immunosuppression (high-dose steroids, biological response modifiers, chemotherapy, AIDS) is a contraindication for HZV
▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲
BUT there is neither contraindication nor recommendation to offer HZV to HIV infected persons without AIDS
Expert opinion: HZV is likely to be safe for HIV+ persons with less immunosuppression (as is varicella vaccine)
…but no safety & efficacy data for this population
Studies of HZV safety & efficacy among HIV+ persons are being initiated and will guide future recommendations

35. Implementation
Persons ≥60 y.o. anticipating immunodeficiency due to initiation of treatments or progression of illness should be offered HZV
▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲
Increasing numbers of diseases are now being treated with various immunosuppressive medications (rheumatoid arthritis, lupus, inflammatory bowel disease, psoriasis)
Patients should be screened for eligibility to get HZV before starting such treatments

36. Implementation
HZV is not recommended for persons ≥60 y.o. who have received the varicella vaccine
▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲
HZ risk in varicella vaccine recipients is not yet well known but appears much lower than for persons who had chickenpox
Very few persons who have received varicella vaccine are eligible for HZV (≥60 y.o.); this will be so for over a decade
As data on risk & severity of HZ following varicella vaccination accumulate we will re-evaluate this guidance

37. Implementation
Monitoring & reporting of adverse events following administration of HZV is emphasized
▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲
HZV is the 1st live attenuated vaccine targeted to the elderly & it presents special safety monitoring challenges in this population:
High level of “background noise”; i.e., incident medical events (heart attacks, Alzheimer’s diagnosis, falls, strokes)
Prevalent chronic disease may pose unexpected risks
Frequent use of multiple meds may pose unexpected risks
Adverse medical events may coincidently follow HZV but they may be caused by HZV
Significant adverse events should be reported to VAERS

38. Thank You!!!
…Questions??

39. Key remaining questions, activities & challenges

40. Key Remaining Questions
What is the duration of protection from HZ vaccine?
Is there a role for HZ vaccine among immunosuppressed persons (e.g. corticosteroids, chemotherapy, biological response modifiers, AIDS with CD4+ counts ≤200)?
What is appropriate vaccination policy for those with early HIV or treated AIDS (and CD4+ counts >200)?
What about vaccinating persons <60 yrs of age, especially if they anticipate becoming immunocompromised due to progression of illness or immunosuppressive treatment?
Why do HZ rates appear to be increasing in many settings?

41. Key activities and challenges
Disease surveillance: how to monitor impact of HZ vaccine
No disease reporting
No capacity to distinguish wild-type & vaccine strain HZ (i.e., vaccine failure from vaccine adverse events)
Key impact pain (how to track pain intensity/duration?)
How can we track vaccine impact given the changing baseline rates of HZ in absence of vaccine?
Medicare data as a key surveillance tool?
Assuring access and financing for those desiring vaccine
Medicare part D: depending on setting, beneficiaries may have to pay many hundreds of dollars up-front
Must be stored frozen: most adult providers not used to or equipped to handle such requirements

42. Key activities and challenges
How to monitor vaccine coverage and disparities
How to monitor adverse events?
This it the first live vaccine just for the elderly
The elderly have high rates of medical events (“noise”)
But the elderly also may be frail, have co-morbidities, and take multiple meds so unexpected adverse events can be plausible