Shingles Prevention. Dr. JS Reid March 2014

Transcription

1 Shingles Prevention Dr. JS Reid March

2 Conflict of interest In the past I have received support for vaccine work, clinical trials, presentation of papers and conference attendance from NZ Ministry of Health, US Government, Foundation Merieux, International Vaccine Institute, CSL, GSK, MSD, Novartis and Pfizer. MSD is paying me an honorarium for this talk 2

3 This talk covers Universality of varicella/chickenpox Clinical features of Shingles and post herpetic neuralgia (PHN) Epidemiology of Shingles and PHN Zoster vaccine efficacy, safety, contraindications and duration of protection 3

4 Key issues Epidemiology Am I really at risk of shingles? Effectiveness of vaccine Does it work? Duration of protection How long does it last? Vaccine safety 4

5 Epidemiology of Varicella Zoster Virus (VZV) Varicella occurs worldwide and equally affects both sexes and all races. 1,2 Varicella is highly contagious and infects at least 90% of the susceptible population. 1 In New Zealand 3 it is expected that 3% are infected during infancy 8-9% infected each year throughout childhood 90% by age 14 and 97% by age Whitley RJ. In: Harrison s Principles of Internal Medicine. 15th ed. New York: McGraw-Hill, 2001: Straus SE et al. In: Fitzpatrick s Dermatology in General Medicine. 5th ed. Vol. 2. New York: McGraw-Hill, 1999: NZ Imm Handbook

6 Nearly all adults are seropositive for VZV by age 40 putting them at risk of having shingles later in life 1 Seroprevalence of Varicella by Age Seroprevalence (%) >50 Age UK2 Canada (Manitoba)3 Mexico4 Australia5 Malaysia6 Italy7 Netherlands8 Philippines6 Thailand9 Regardless of the countries studied, there is high seroprevalence of the varicella zoster virus among adults 40 years of age and older, therefore putting them at risk for developing shingles (herpes zoster) References: 1. Fleming DM et al. Euro J Epidemiol :1113; 2. Kudesia G et al. J Clin Pathol. 2002, 55:154; 3. Brisson M et al. Epidemiol Infect. 2001, 127:305; 4. Alvarez y Munoz MT et al. Archives of Medical Research. 1999, 30:60; 5. O Grady KA et al. Tropical Medicine and International Health. 2000, 5:732; 6. Lee BW Tropical Medicine and International Health. 1998, 3:886; 7. Gabutti et al. Epidemiol Infect. 2001, 126:433; 8. de Melker et al. Vaccine :3946; 9. Migasena S et al. Int J Infect Dis :26. 6

7 VZV: Latency Spinal cord Dorsal root ganglion VZV moves along the sensory nerve to the dorsal root ganglion Varicella rash VZV establishes latency in the dorsal root ganglion Skin Viral latency is established during primary infection (varicella) Transport of virus up sensory nerve from infected dermal sites Dormant in dorsal root ganglion 7

8 VZV: Reactivation Spinal cord Dorsal root ganglion Skin Inflammation and necrosis of nerve cells VZV reactivates and moves along sensory nerve from dorsal root ganglion to skin VZV emerges from sensory nerve endings in the skin to cause the unilateral rash of zoster 8

9 Clinical Aspects of Shingles (Zoster) and Post Herpetic Neuralgia (PHN) 9

10 Typical rash Diepgen TL, Yihune G et al. Dermatology Online Atlas; Reprinted with permission i 9

11 Mrs JC aged 77 Lower thoracic shingles late presentation No antiviral Analgesia paracetamol, codeine, and Amitriptyline Duration around 3 months requiring analgesia 8 months later on going allodynia but no analgesia required

12 Image courtesy of Charles E. Crutchfield III, MD. Crutchfield Dermatology, Eagan, MN. 12

13 Mr CV age 60 Temporal arteritis on steroids ophthalmic shingles Acyclovir and saw ophthalmologist Analgesia - codeine, amitriptyline, epilim gabapentin Duration - off work 3 months - plumber Ongoing symptoms - remained on gabapentin for 6 years and still some pain and on amitriptyline 8 years later

14 Anatomic Distribution of Zoster Thoracic 50-70% Cervical 10-20% Ophthalmic 10-20% Dworkin RH et al In Herpes Zoster and PHN 2 nd edition Amstredam Elselvier 2001:

15 Effect of Zoster on Activities of Daily Living Lydick E et al. Neurology 1995;45:S52 S53. 15

16 Complications of Zoster Neurologic Acute neuropathic pain (>90% of patients over 60 yrs) PHN Limb weakness Sensory loss Peripheral palsies Meningitis Myelitis Encephalitis Hearing loss Ophthalmic Visual impairment Ptosis Cutaneous Scarring Bacterial superinfection Disseminated disease Pneumonia Hepatitis 1. Oxman MN. In: Varicella-Zoster Virus, Virology and Clinical Management. Cambridge: Cambridge Press, 2000:

17 Stroke and Zoster Risk of stroke increased in 6 months following zoster 1 Weeks 1-4 IR 1.63 ( ) Weeks 5-12 IR 1.42 ( ) Weeks IR 1.23 ( ) Taiwan studies - increased stroke risk 1.3 fold ( ) 2 in year following Zoster 4.5 fold ( ) 3 in year following HZ ophthalmicus 1. Langan SM et al CID april 2 nd Kang J et al. Stroke 2009; 40: Lin HC, et al. Neurology 2010; 74:792 7.

18 Zoster summary Reactivation of VZV results in zoster (shingles). 1 The zoster eruption occurs in a unilateral distribution. 1 Advancing age and decreased cell-mediated immunity (CMI) are defined risk factors. 1 Zoster is characterized by pain that can negatively affect quality of life. 2 Postherpetic neuralgia is the most common complication Straus SE et al. In: Fitzpatrick s Dermatology in General Medicine. 5th ed. Vol. 2. New York: McGraw-Hill, 1999: Schmader KE. Clin J Pain 2002;18:

19 Definition of PHN Zoster-associated pain rated as 3 on a 10-point pain scale and occurring or persisting at least 90 days after rash onset Oxman MN et al. N Engl J Med. 2005;352:

20 Risk Factors for PHN Older age More severe acute zoster pain Greater rash severity Greater sensory abnormalities during acute zoster Prodrome prior to zoster rash Dworkin RH et al. In: Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition. Vol. 11. Amsterdam: Elsevier Science B.V., 2001:

21 Impact of PHN Clinical observations include: Depression and other psychological distress Physical, occupational, and social impairments resulting from constant pain Schmader KE. Clin J Pain 2002;18:

22 Summary of PHN PHN is a chronic neuropathic pain syndrome that persists beyond healing of the zoster rash. 1 Risk factors include older age, greater severity of rash and zoster pain, sensory abnormalities, and the presence of a prodrome. 1 Common features of PHN include spontaneous pain and allodynia. 2 PHN can have a profound impact on activities of daily living Dworkin RH et al. Pain 1996;67: Bowsher D. In: Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition. Vol. 11. Amsterdam: Elsevier Science B.V., 2001: Schmader K. Vaccine 1998;16:

23 Comparison of Pain Scores for Various Conditions Acute Pain Conditions More Pain Chronic Pain Conditions Abdominal hysterectomy Acute headache Zoster Labor pain Postsurgical pain Mucositis Angioplasty sheath removal Less Pain Fibromyalgia Postherpetic neuralgia Atypical facial pain Musculoskeletal pain Arthritis Osteoarthritis Rheumatoid arthritis Chronic cancer pain Adapted from Surgical Clinics of North America, Vol 79, Katz J, Melzack R, Measurement of pain, pp Copyright 1999, with permission from Elsevier. 23

24 Duration of Zoster-Associated Pain According to Age 1,2 (n) 2 (24) (53) (69) (136) (204) (270) (160) Adapted with permission from Kost RG et al Massachusetts Medical Society. 1. Kost RG et al. N Engl J Med 1996;335: de Moragas JM et al. AMA Arch Derm 1957;75:

25 Treatments for Zoster and PHN Zoster Antiviral therapy 1 Acyclovir, famciclovir, valacyclovir Antiviral therapy should begin as soon as possible after onset of zoster lesions Analgesics 2 Non-narcotics TCA, Gabapentin, steroids Narcotics Supportive care TENS = Transcutaneous electric nerve stimulation PHN Analgesics 2 Non-narcotics Narcotics Topical agents 2 Anticonvulsants 2 Other Nerve blocks 2 TENS 2 Biofeedback 2 Spinal cord stimulation 3 Consultation with a pain specialist may be required 1 1. Gnann JW Jr et al. N Engl J Med 2002;347: Stankus SJ et al. Am Fam Physician 2000;61: Schmader K. Vaccine 1998;16:

26 Epidemiology 26

27 Rate per 1000 per year Incidence of Zoster and Postherpetic Neuralgia (PHN) in the United Kingdom Zoster cases/ 1000/year PHN/ 1000/ year Age (years) Hope-Simpson RE. J R Coll Gen Pract 1975;25:

28 Country-specific Zoster Rates Annual Incidence (per 1,000 person-years) Hope-Simpson (UK) Brisson (UK) Gonzalez (France) Ultsch (Germany) Insinga (US) Yawn (US) Stein (Australia) Brisson (Canada) Jih (Taiwan) Choi (South Korea) Age 28

29 Epidemiology of Herpes Zoster High global VZV seroprevalence VZV infection = risk for zoster About 1 in 3 persons will develop zoster during lifetime Incidence increases with advancing age By 85 years of age, ~ 50% will have had zoster Estimated 1,000,000 cases/year in the US approximately 70% occur in adults 50 years of age. Harpaz R et al. MMWR. 2008;57(RR 5):1 30. Oxman MN et al. N Engl J Med. 2005;352: Insinga RP et al. J Gen Intern Med. 2005;20: Pappagallo M et al. CNS Drugs. 2003;17: Schmader KE. Clin Infect Dis. 2001;32:

30 Hospitalisations (public and private) for zoster by age group, 2010/11 Number Courtesy Ministry of Health NZ Age group (years) 30

31 Incidence of Shingles at Ropata Medical Centre NZ 19,000 patients - 5 years shingles diagnoses Age 1 44 rate 2/1000/annum Age 45+ rate 8/1000/annum Age 85+ rate 14/1000/annum 75% cases occurred in those aged > 45 Risk of zoster between 45 and 85-40% These figures are broadly consistent with international data.

32 Incidence of PHN Incidence dependent on definition of PHN Definition Zoster patients (all ages) who develop PHN Pain at rash healing 9% 24% Pain persisting 1 month after rash onset 8% 19% Pain persisting 3 months after rash onset 8%* *Up to 50% of adults >50 years of age develop PHN. Schmader KE. Clin J Pain 2002;18:

33 Prevention 33

34 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 34

35 The Shingles Prevention Study: Study Design Double-blind, placebo-controlled, multicenter trial Collaboration between VA, Merck, and NIH Enrolled 38,546 subjects 60 years of age Age-stratified (60 to 69 years, 70 years) Randomized to receive zoster vaccine or placebo All subjects were followed for safety and efficacy Efficacy endpoints: Primary: Burden of illness (BOI), defined as total pain and discomfort associated with herpes zoster Secondary: Incidence of PHN Oxman MN et al. N Engl J Med 2005;352:

36 Zoster and PHN in the Shingles Prevention Study Zoster cases were confirmed by Polymerase-chain-reaction (PCR) assay Viral culture Adjudication by a clinical evaluation committee blinded to vaccination status 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 36

37 Worst Pain Definition and Measurement of the Severity by Duration Score and BOI 10 Zoster BOI: Population measure 0 Days 37

38 Disposition of Subjects in the Shingles Prevention Study Subjects Enrolled 38,546 Censored Before End of Study 793 (4.1%) Died 57 (0.3%) Withdrew 61 (0.3%) Lost to follow-up Zoster vaccine 19,270 Completed Study 18,359 (95.3%) Placebo 19,276 Censored Before End of Study 792 (4.1%) Died 75 (0.4%) Withdrew 52 (0.3%) Lost to follow-up Completed Study 18,357 (95.2%) Oxman MN et al. N Engl J Med 2005;352:

39 Efficacy Analysis Population Modified intention-to-treat (MITT) All enrolled subjects who did not develop evaluable zoster within 30 days postvaccination Analyses included only the first evaluable case Rationale for excluding cases in the first 30 days Cases may have been in development at the time of vaccination Vaccine-induced immune responses unlikely to be fully developed for some time after vaccination Potential confusion with vaccine-induced rash Oxman MN et al. N Engl J Med 2005;352:

40 Overall Efficacy of the Zoster Vaccine 25%=prespecified lower bound success criterion HZ 51.3% 95% CI 95% 66.5% PHN 61.1% BOI Vaccine Efficacy Efficacy (%) (%) 40

41 Efficacy of the Zoster Vaccine by Age Stratum Zoster PHN Ages 60 to 69 Ages 70 95% CI BOI Vaccine Efficacy (%) v211acm.vbar1a Dec. 6,

42 Incidence of Zoster and PHN in the Shingles Prevention Study Subjects Zoster Vaccine Group No. of cases (n=19,254) Incidence per 1000 Person-Yr.* No. of cases (n=19,247) Placebo Group Incidence per 1000 Person-Yr.* Zoster PHN * For the total population, incidence in each treatment group was the weighted average of the observed incidence stratified by age group, with weights proportional to the total number of person-years of follow up in each group. 1. Oxman MN et al. N Engl J Med 2005;352:

43 Rate per 1000 per year Incidence of Zoster and Postherpetic Neuralgia (PHN) in the United Kingdom Zoster cases/ 1000/year PHN/ 1000/ year Age (years) Hope-Simpson RE. J R Coll Gen Pract 1975;25:

44 Shingles Prevention Study: Summary of Efficacy The zoster vaccine was highly effective in reducing the incidence and morbidity from zoster and PHN 1 Reduced the incidence of zoster by 51% Reduced the incidence of PHN by 67% Reduced the BOI associated with zoster by 61% ZEST 2 study age similar (slightly higher) reduction in zoster 1. Oxman MN et al. N Engl J Med 2005;352: Medsafe data sheet - Zostavax 44

45 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 no 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, vaccineassociated rashes were uncommon (0.1%) 45

46 Additional issues Does more than one dose improve the response? NO (Vermeulen et al Vaccine 2012:30; ) Is prior zoster a contraindication to Zostavax? NO (Morrison V et al J Infect Dis 2013:208(4); ) What is duration of protection? What is the protection offered by a second dose some years after the first dose? 46

47 Duration of protection At least for burden of illness protection seems reasonably stable for 7 years By 10 years protection is waning and in long term persistence study protection had dropped to ~40% for BOI and rate of zoster was 10.3 /1000 person years (mean age at enrollment 74.3 years). 47

48 Second dose protection What is the protection offered by a second dose some years after the first dose? The VZV antibody response in those aged 70 or older, following a second dose 10 years or more after the first dose, was non inferior to the response to a first dose in those age 70 or older. The vaccine was well tolerated Levin MJ et al Poster presented at 20 th IAGG World Congress of Gerontology and Geriatrics Seoul, Korea, June

49 Indications Indicated for individuals 50 years of age and older irrespective of past history of chickenpox or shingles for Prevention of herpes zoster Prevention of PHN Reduction of acute and chronic zoster associated pain 49

50 Contraindications and precautions Hypersensitivity to any vaccine component and anaphylaxis to neomycin Primary and acquired immunodeficiency states Immunosuppressive therapy but not low dose systemic steroids or topical steroids Active untreated TB Pregnancy Can be given concommitantly with Influenza vaccine but not PCV23 50

51 How common is a second Scarce data episode of zoster? Small populations and short follow up periods Recent study: 6.2% recurrence over 8 years Recurrence more likely in women, the immune compromised and with prolonged pain at initial episode (Yawn et al. Mayo Clin Proc. 2011; 86) Episode of zoster does not ensure protection against recurrence 51

52 Summary Almost all adults are susceptible to Shingles Life time risk is 1 in 3 and 1 in 2 by 85 years Shingles is more severe and debilitating and PHN is more likely as one ages Zostavax offers approximately 60% efficacy against shingles, PHN and the burden of illness Zostavax has a favourable safety profile It is possible that a further dose(s) may be required several years after the initial dose. 52

53 Questions? 53

54 Back up slides 54

55 Vaccine efficacy by age HZ PHN % 67% % 66% % 74% >80 18% 42% % N/A Schmader KE et al, Clin Infect Dis 2012; 54: 922-8; Oxman et al. NEJM 352;

56 Effect of Zoster Vaccine on Preserving ADLs By Age -On total study population basis- Age Group Zoster Vaccine* Loss of Activity Placebo* Loss of Activity VE (95% CI) Prevention of Loss of Activity All ages (0.55, 0.74) 60 to (0.47, 0.86) 65 to (0.44, 0.81) 70 to (0.35, 0.76) 75 to (0.30, 0.80) (0.11, 0.81) *Vaccine n= 19254, HZ cases= 315; Placebo = 19247, HZ cases = 642 AUC ADLI Area-under-the-curve activities of daily living interference Schmader K et al. J Am Geriatr Soc 2010; 58:

57 Patients Experiencing PHN (%) Older Age is Associated With Increased Incidence of PHN (United States) 1,a % 20% 10 5% 5% 10% 0 n=538 n=314 n=284 n=287 n= Age (Years) PHN=postherpetic neuralgia. a This was a retrospective population-based study of 1,669 adult residents ( 22 years of age) of Olmsted County, Minnesota with a confirmed diagnosis of HZ between January 1, 1996 and December 31, PHN was defined as pain persisting for at least 90 days. 1. Yawn BP et al. Mayo Clin Proc. 2007;82:

58 Patients Reporting Moderate Severe Pain b (%) Older Age Is Associated With Increased Severity of PHN (United Kingdom) 1,a % 46% 56% 57% 61% 61% 65% 68% PHN=postherpetic neuralgia. a This was a retrospective study of data extracted from the United Kingdom General Practice Research Database. The study identified 25,002 immunocompetent patients aged 50 years with a diagnosis of herpes zoster occurring between January 1, 2000 and March 31, ,415 (13.7%) developed PHN, defined as pain persisting for at least 3 months after rash onset. b Severity of PHN pain was assessed on the basis of prescribed medications. 1. Gauthier A et al. Epidemiol Infect. 2009;137: Age (Years)

59 Higher risk groups Higher risk groups 144,569 cases in UK Median age 62 RR Rheumatoid arthritis 1.46 Inflammatory bowel disease 1.36 COPD 1.32 Asthma 1.21 Chronic Kidney Disease 1.14 Depression 1.15 Diabetes (Type 1 not Type 2) 1.27 Lymphoma 3.9 Myeloma 2.16 Forbes HJ et al BMJ 2014;348:g2911

60 P029 Safety Summary The safety profile observed in this study was consistent with that observed in individuals of similar ages in the ZOSTAVAX clinical development program and postmarketing experience The most frequently reported injection-site AEs were erythema, pain, and swelling Overall frequency of injection-site AEs was comparable between booster dose recipients and age-matched first time vaccinees Booster dose recipients had a significantly higher incidence of injection-site pain compared with age-matched first time vaccinees (23.4% vs. 14.1%, p=0.011) Injection site pain was rated by most subjects as mild in intensity The most common systemic AE was nasopharyngitis No event of nasopharyngitis was reported as vaccine related No subject discontinued due to an AE 60

61 Descriptors of Spontaneous Pain in PHN Patients using descriptor (%) 1 (n=80) Continuous Burning 49 Throbbing 40 Paroxysmal Stabbing 40 Shooting 37.5 Sharp Bowsher D. In: Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition. Vol. 11. Amsterdam: Elsevier Science B.V., 2001:

62 Statistical Analysis (Acceptability) of VZV gpelisa Antibody Responses at Week 6 Postvaccination with Zoster Vaccine Primary Immunogenicity Hypothesis and Results In subjects 70 years of age, a booster dose of ZV administered ~10 years following a first dose will elicit an acceptable GMFR in VZV antibody titers Statistical success criterion corresponds to lower bound of the 2-sided 95% CI on GMFR being >1.0 Group 1 (N=201) Endpoint Time Point n Estimated GMFR (95% CI) p-value GMFR from Day 1 Week (1.44, 1.66) <0.001 The hypothesis test performed using a longitudinal regression model adjusting for age GMFR = Geometric mean fold-rise from baseline. N = Number of subjects vaccinated in each vaccination group. n = Number of subjects contributing to the immunogenicity analysis. Group 1: 70 years of age, subjects who received ZV in the Shingles Prevention Study ~10 years previously 62

63 Recurrence More Frequent in Women proportion with recurrence female male p= Yawn B et al. Mayo Clin Proc. 2011;86(2): years after index For training purposes only; not to be used in discussion with healthcare professionals. 63

64 Recurrence More Frequent in Immunocompromised proportion with recurrence immunocompromised p=0.006 immunocompetent Yawn et al. Mayo Clin Proc. 2011; 86 years after index For training purposes only; not to be used in discussion with healthcare professionals. 64

65 Recurrence Associated with Duration proportion with recurrence of Pain of Initial Zoster Episode pain 30 >= 30 days days p< p<0.001 pain <30 < 30 days Yawn et al. Mayo Clin Proc. 2011; 86 years after index For training purposes only; not to be used in discussion with healthcare professionals. 65

66 SPS and extension studies SPS 22 sites ZOSTAVAX N=19,270 Placebo N=19,276 Short Term Persistence Substudy (STPS) - 12 sites ZOSTAVAX N=7,320 Placebo N=6,950 Long Term Persistence Substudy (LTPS) - 12 sites ZOSTAVAX N=6,867 Placebo N=0 66

67 ZOSTAVAX effect on incidence of HZ & BOI has been followed for 7 years in the Short-Term Persistence Study (STPS) Vaccine Efficacy on the Incidence of HZ Pooled SPS and STPS 48.7% (95% CI, ) Vaccine Efficacy on the Incidence of PHN Pooled SPS and STPS 64.9% (95% CI, ) Vaccine Efficacy on HZ BOI Pooled SPS and STPS 58.6% (95% CI, ) Participants were followed for up to a total of 7 years At present, the duration of protection after vaccination with ZOSTAVAX is unknown Reference: Schmader K, Oxman MN, Levin M et al. Persistence of the Efficacy of Zoster Vaccine in the Shingles Prevention Study and the Short-Term Persistence Substudy, Clin Infect Dis, 2012; /cid/cis638 67

68 After completion of the STPS, the LTPS evaluated the duration of protection of ZOSTAVAX against HZ, PHN and HZ BOI Vaccine Efficacy on the Incidence of HZ, Incidence of PHN and HZ BOI LTPS Follow-up Period Vaccine Efficacy (%) HZ PHN HZ BOI Reference: EMA Summary of Product Characteristics The LTPS (Long-term Persistence Substudy) followed 6,687 subjects previously vaccinated with ZOSTAVAX in the SPS Mean age at enrollment into LTPS was 74.5 years The LTPS analyses for vaccine efficacy are based on data collected primarily from Year 7 through Year 10 following vaccination in the SPS The median follow-up during the LTPS was ~3.9 years (range is one week to 4.75 years) There were 263 evaluable HZ cases reported among 261 patients [10.3/1000 personyears] during the 68 LTPS

69 P029 (Booster) Study Design Primary Objectives Determine whether ZOSTAVAX administered to adults 70 years of age as a booster dose 10 years following a first dose elicits a VZV antibody response that is noninferior to that of ZOSTAVAX administered as a first dose to subjects 70 years (Geometric Mean Titer [GMT and GMFR], 6 weeks postvaccination) Secondary Objective Describe safety and tolerability Exploratory Objectives Measures of cell-mediated immunity, health and functional status Data collection still ongoing for exploratory objectives and serious AE safety follow-up through Day 365 postvaccination 69

70 Booster Study Phase III, Randomized, Multi-Center, Open-Label, Single-Dose Study 70

71 Statistical Analysis (Noninferiority) of VZV gpelisa Antibody Responses at Week 6 Postvaccination with Zoster Vaccine Primary Immunogenicity Hypothesis and Results In subjects 70 years of age, GMT of VZV antibody responses at 6 weeks postvaccination for Group 1 will be noninferior to that in Group 2 71

72 Age group rates/1000 person years Age Group Rate/1000/annum F M Combined 9.5 F M Combined 19.4 F M Combined

73 Risk of Zoster Increased in the Immune compromised and on therapy resulting in reduced immunity Increased in rheumatoid arthritis 73

74 Incidence of Shingles Ropata Medical Centre 5 year period all patients diagnosed with shingles - accepted without notes review 19,000 patients stable register in terms of numbers Incidence up to age cases - 21 per year, 10,750 patients registered ~ 2/1000/annum Incidence age Cases - 65 per year, 8,300 patients registered ~ 8/1000/annum 74

75 Shingles Ropata Medical Centre Age No of cases Population annual rate /1000 1/ /1000 1/ /1000 1/ /1000 1/200 75% of cases occurred in those age 45+ and 45% occurred in those age 65+ Extrapolating annual Ropata Incidence to NZ results in estimate of 20,000 cases per annum And further extrapolation to population size of US results in ~1.4M cases per year 75

76 Shingles Ropata Medical Centre age band risk Age annual rate age band risk /200 20/200 = 1/ /100 10/100 = 1/ /50 10/50 = 2/10 Risk of shingles from these data from age is 40%. 76