Herpes zoster: The disease and the vaccines Tony Cunningham Centre for Virus Research The Westmead Institute for Medical Research Sydney, Australia

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1 Herpes zoster: The disease and the vaccines Tony Cunningham Centre for Virus Research The Westmead Institute for Medical Research Sydney, Australia Declarations Chair, Publications committee, GSK Shingrix ZoE50 and ZoE70 trials Member, Global Adult Vaccine Advisory Board, Merck Chair, Zostaxax Advisory Board, BioCSL 1

2 Herpes Zoster (shingles) Reactivation of latent varicella zoster virus Markedly increases after 50 years Usually unilateral, vesicular cutaneous eruption with a dermatomal distribution Acute pain accompanies the rash in >90% of individuals aged over 50 years The most common complication is post herpetic neuralgia (PHN), defined as pain persisting for 90 or more days after rash onset >50% of population >85 years will get zoster Gnann, Jr. & Whitley 2002 Dworkin et al Age dependent incidence of herpes zoster and PHN in Australia Stein A et al Vaccine

3 0 0 7/15/2016 Neurologic Cutaneous Ocular Involvement Rate of HZ Complications Sacral Dermatome Involvement Visceral Complications n 298 ZOSTAVAX N=19, Incidence Rate* n Placebo N=19, Incidence Rate* *Incidence rate= per 1000 person years (total population). Incidence of Herpes zoster is increasing globally Trend in zoster ED visits - NSW Non-Admitted Admitted NSW Admitted ED Visits per 100,000 population Year Year <25 <25 predicted predicted <25 <25 predicted predicted predicted predicted predicted predicted predicted predicted predicted predicted Rates of ED visits increased with age. Most ED visits are not admitted Increasing trend in non-admitted ED visits over time, most prominent in older population) MacIntyre R et al Plos One

4 RCF (per 100,000 PBMC) 7/15/2016 Types of vaccines Whole virus Live attenuated Inactivated Split Sub-unit Rationale for a HZ Vaccine The frequency and severity of zoster increase with age T cell responses to VZV decline with aging, while antibody does not The basis for two hypotheses: >8 Age (years) 5 1. the fall in T cell responses to VZV with age to below a threshold permits clinical reactivation of latent VZV 2. increasing the T cell responses to VZV in older people will prevent OR attenuate herpes zoster 4

5 Pilot studies of HZ Vaccine Pilot studies demonstrated that T cell responses to VZV could be safely boosted with a live attenuated Oka strain VZV These studies suggested that the booster effect was significantly increased for 6 years Levin M et al J.Infect Dis 2003 Shingles Prevention Study (SPS) A double-blind, placebo-controlled trial 22 Sites Live, attenuated VZV vaccine Oka/Merck strain (Median = 24,600 pfu) 14-fold greater titer than childhood vaccine Subjects = 38,500 Median age = 69 years years = 20, years = 17,800 (46%) years = ~2500 (>6.5%) Oxman al. NEJM 352; 2271:

6 Worst pain score 7/15/2016 SPS: Endpoints Herpes Zoster (incidence/1000/year) Mean follow-up = 3.13 years Burden of Illness (BOI) Sum of all severity of illness scores for each of two treatment groups - vaccinees and placebo recipients (No HZ = score of 0) Post-herpetic neuralgia (PHN) Significant pain ( 3 on ZBPI) 90 days after rash onset 95% of subjects completed the study AUC of Worst Pain Scores Over Time Days since rash onset 6

7 Incidence of HZ 7/15/2016 SPS: Efficacy HZ Incidence 51.3% ( %) Burden Of Illness 61.1% ( %) Post Herpetic Neuralgia 66.5% ( %) 13 Vaccine Efficacy for Incidence of Herpes Zoster Efficacy (95% CI) % ( ) 63.9% 37.6% Vaccine Placebo 0 All yr 70 yr 7

8 Incidence of PHN HZ burden of illness 7/15/2016 Vaccine Efficacy for Herpes Zoster BOI Efficacy (95% CI) 61.1% ( ) 65.5% ( ) 55.4% ( ) Vaccine Placebo All yr 70 yr Vaccine Efficacy for Incidence of PHN Efficacy (95% CI) 66.5% ( ) 65.7% ( ) 66.8% ( ) Vaccine Placebo All Subjects yr 70 yr 8

9 SPS: Conclusions In the full SPS population Zostavax significantly altered the natural history of zoster Prevented zoster in the younger group of vaccinees (60-69) Prevented OR attenuated zoster in the older group of vaccinees (>70) Efficacy and safety essentially replicated in several large postmarketing studies (Kaiser Permanente, CA etc) Low rates of severe injection site reactions (~1%) SPS ZEST Study in year olds: HZ incidence decreased by 70%, HZ pain by 73% (ie greater VE) Duration of protection of Zostavax Short term Persistence Substudy: Zostavax /6950 placebo recipients, 89% of which accepted the offer of Zostavax; all participants followed for 4-7 years - VE = 39.6% for zoster, 60% for phn and 50% for BOI Long term Persistence Substudy - Open label Multicentre study, followed up 6867 vaccine recipients for 7-12 years. No unvaccinated concurrent control group so original SPS placebo recipients used as controls. - VE = 21% for zoster, 35% for PHN and 37% for BOI - ie provides evidence for waning of efficacy but probably significant to 8 years when analysed annually Booster dose at 10 years: in >70 year old CMI responses were stimulated to levels similar to those of a first response in YO (Levin M et al JID 2016) 9

10 Effectiveness and 95% confidence interval of herpes zoster vaccine, by years after vaccination, Kaiser Permanente Southern California, Hung Fu Tseng et al. J Infect Dis. 2016;213: Zoster vaccines for Immunecompromised patients Zostavax, ACIP Recommendations: Live attenuated vaccines, such as Zostavax, contraindicated for severely immune-compromised - >20mg prednisone daily for >2 weeks, - Hemopoietic Stem Cell Tx - hematologic malignancies not in remission for >3 months, esp advanced Hodgkins disease, (ie cytotoxic therapy within past 3 months) - T cell immunodeficiency, including HIV+ pts with CD4<15% Zostavax probably safe with anti-tnf biologics but need more studies on the others (Zhang et al 2012) Heat killed zostavax effective in reducing zoster disease in transplant patients; (Hata A and Arvin A NEJM 2002); recent safety studies Immunize prior to chemotherapy (?14-30 days before) Tseng et al 2014 cf Shingrix GSK (Recombinant VZV ge + adjuvant ASO1B) not contraindicated and safe in immunecompromised (HSCT, HIV <15% CD4) 10

11 Licensure, availability and uptake worldwide USA: ACIP recommendation: immunize all immunocompetent persons>60 with one dose of Zostavax - over 25 million doses distributed since overall uptake: 10.0% in 2009, 14.4% in 2010, 2014:24% UK: Sept 2013: Funded immunization program: all people > 70 and catchup cohort >79 Australia: National Immunization Program funded for all i/c people >70 from Nov 2016; Catchup 71-79; Private market >50 since 2008 Zostavax: issues Low efficacy, especially in >80 Duration of efficacy -Need a booster, probably at 10 years Cost-effectiveness:? Commence age boosters OR at age 70 (cf France, Australia, UK) Safety in moderately immunecompromised pts needs better definition 11

12 Recombinant VZV/HSV glycoprotein + T cell adjuvant Pathogen Glycoprotein Antigen Adjuvants act as substitutes for natural T cell stimulants T cell stimulating adjuvant Systems Combinations of: - Classical adjuvants: aluminum salts, emulsion, liposomes - Immunostimulants: MPL, QS21, (CpG), dmpl QS21 12

13 Vaccines: recombinant proteins + T cell adjuvants Vaccine Antigen Adjuvant Antibody (neut) CD4 T cells Hepatitis B HBsAg ASO4 (dmpl) CD8 T cells HSV Glycoprotein D ASO4 (dmpl) Malaria RTS, S ASO1 (dmpl, QS21) Herpes zoster Glycoprotein E ASO1 (dmpl, QS21) ? CD4 T cell response to VZV ge Vaccine response rate 80+ YOA Vaccine response rates to HZ/su were also well-preserved with subject age. 13

14 ge-specific CD4 T cell responses after two doses of HZ/su Chlibek R. Heineman TC et al Vaccine, 2016, Phase III Trials of GSK Shingrix Placebo - RCT in Europe, USA, Australia Two doses IMI two months apart, 96% compliance ZoE-50: adults > 50 years, stratified in 10 year blocks, evaluable subjects -recently reported ZoE-70: adults >70 years to focus on PHN - headline results released by GSK 14

15 GSK Herpes Zoster (HZ/su) Vaccine Efficacy 100 Secondary Objectives Primary Objective % LL>25% >=70 >=60 OVERALL/>=50 15

16 ZoE-50 trial: reactogenicity and safety Overall: 84 % of vaccine recipients vs 38% of placebo recipients - severe: 17.0% of vaccine vs 3.2% of placebo recipients. Local/injection site Severe: 9.5% vs 0.5%, lasted on average 2 days Serious adverse events were similar in placebo and recipient No increased autoimmune diseases or exacerbations ZoE70 trial: efficacy against PHN 13,900 Adults >70: vaccine efficacy = 90% (95% CI 84-94) similar in and >80 efficacy against PHN: 89% (69-97) (Pooled) Adults>50 efficacy against PHN: 91% (76-98) Oct Data currently resubmitted to NEJM for publication (Cunningham, Lal..Heineman et al) 16

17 Shingrix: issues Two doses: likely compliance in real world setting (Hepatitis A: 65%) High reactogenicity Duration of efficacy to be determined (T cell immunogenicity plateaus for 2-6 years- promising) - long term followup trials about to commence Risk of auto-immunity with new adjuvants: needs long term post marketing surveillance Efficacy in severely immunecompromised: immunogenicity retained in patients undergoing allogeneic HSCT, phase III trial results available soon Conclusions Shingrix development and trialling confirms several scientific hypotheses: - vaccines consisting of a single pathogen protein and adjuvant(s) can be more efficacious than a live attenuated vaccine - such a combination may cut through immunosenescence = hope for other vaccines in older subjects - Pathogen/vaccine/adjuvant immunology is of increasing relevance for (rational) vaccine development 17

18 Acknowledgements Westmead Institute for Medical Research/ University of Sydney Herpesvirus Immunopathogenesis Min Kim Kirstie Bertram Allison Abendroth Kerrie J. Sandgren Naomi Truong David Booth Vaccine development & trials Janette Taylor Dominic Dwyer Paul Mac Seqirus Alicia Stein GSK Herpes zoster Trials: Tom Heineman (GSK) Himal Lal (GSK) Myron Levin (Denver) Adriana Weinberg International/Australian co-authors University of Melbourne David Jackson Weiguang Zeng Institut Cochin, Paris Anne Hosmalin UNSW Raina Macintyre Funded by; Australian National Health and Medical Research Council Vaccine trials: GSK Herpes zoster epidemiology: Seqirus SPARE SLIDES 18

19 Vaccine Efficacy (%) Subject- Years 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Estimated Vaccine Efficacy for 4 Years After Vaccination Vaccine= Placebo= Year 1 19,132 19,081 Year 2 18,827 18,679 Year 3 14,505 14,327 Year of Follow-up After Vaccination Year HZ BOI Incidence of PHN Incidence of HZ Comparison of durability of Zostavax in various models Li, X et al Vaccine, 2015,

20 Additional Effects on PHN (M Levin) Reduction in PHN even if Zoster developed Overall = 39% Age = 55% Age >80 = 26% Duration of pain shortened p = 0.03 Severity of pain decreased p = Is immune control of PHN (DRG) by Zostavax qualitatively different to that of Zoster rash (skin vs nerve)) Zostavax Concomitant use of Zostavax with: - influenza vaccine: Similar antibody responses and safety - pneumococcal vaccines: contradictory reports on risk of Zoster when immunized simultaneously 20

21 SPS Extension Study in year olds RDPC trial, USA, UK, Finland, 21,105 subjects HZ incidence decreased by 70% (54.1, 80.6) - HZ pain by 73% (52.7, 84.6) Similar efficacy to YOs, but lower incidence of of HZ and especially PHN in placebo group. Effect of second dose of Zostavax on VZV immune responses Three trials: 2 doses of Zostavax 6 wks apart vs placebo (n= 210. >60 years: Second dose did not boost VZV specific T cell (Elispot) or antibody (gp-elisa) responses> dose 1 (Vermeulen et al Vaccine 2011) - NB In SPS vaccine induced one log increase in antibody and T cell responses reduced zoster risk by 18% and 38% respectively Single vs 2 doses of vaccine either at 0,1 or 0,3 months (n=759, >70yo): No difference in antibody (gp-elisa GMT) responses up to 12 months later (Vesikari et al Hum Vacc 2013) Booster dose at age >70 (n=198): 1.5 geometric mean fold rise (GMFR) in antibody gp-elisa) from Day 1 to week 6 post immunization (Merck Clinical trials.gov 2013) Conclusions: Booster/second doses safe even if close together - Cannot overcome effect of age with two dose regime 21

22 Duration of protection of Zostavax Short term Persistence Substudy: Zostavax recipients; 6950 placebo recipients 89% of which accepted the offer of Zostavax; all participants followed for 4-7 years. Non significant decreases in VE for: zoster incidence (51 to 40%), PHN (67 to 60%) and BOI (61 to 50%). Limitations: subset (~50%) of original sites and gap in surveillance but no differences in subject characteristics to SPS Duration of protection of Zostavax Long term Persistence Substudy Open label Multicentre study, followed up 6867 vaccine recipients for 7-12 years. No unvaccinated concurrent control group so original SPS placebo recipients used as controls years post vaccination, VE = 21% for zoster, 35% for PHN and 37% for BOI - ie provides evidence for waning of efficacy but probably significant to 8 years when analysed annually. - Most experts viewing data believe a booster at 10 years will be necessary 22

23 Probability of Zoster 7/15/2016 Post-marketing studies of Zostavax efficacy 3 population based cohort studies: - Langan et al 2013: 5% of Medicare (>65yo) participants (n=29,785) : VE (zoster) = 48%; VE (PHN) = 59% Low vaccine uptake (3.9%) - Tseng et al 2011, Retrospective Kaiser Permanente study, Southern California: 303,044 members; VE= 55%, 63% for ophthalmic zoster and 65% for hospitalizations - Zhang et al 2012: Medicare beneficiaries with selected auto-immune diseases; VE= 39% Overall VE for incidence of zoster and PHN not significantly different to SPS Inactivated Zoster vaccine in Transplant patients Months 23

24 Zostavax in Immunecompromised Issues to Be Clarified Use in VZV+ Ill patients who expect immune suppression: Organ transplant Therapy for autoimmune disease (drugs or antibodies) Prior to chemotherapy Early HIV (>15% CD4) Post-licensure Zostavax vaccine safety studies 2 large post-licensure safety studies: Vaccine Safety Datalink Network (193,083 adults>50 yrs) and Kaiser- Permanente North California Study: Medically attended reactions 1-7 days post Zostavax were highest in the y.o age group (Tseng et al JIntern Med 2012; Baxter et al Vaccine 2012) - 83% local tenderness, swelling, erythema, 15% localised diffuse rash. No serious AEs early after vaccination - No serious AEs after a second dose of Zostavax within 1-3 months, nor as a 10 year booster (Levin et al, World Congress Geriatrics) - No increase in AEs when Zostavax administered to those with history of Zoster (15% of older adults) (Mills et al Vaccine 2010, Morrison et al JInfect Dis 2013) 24

25 Zostavax in Less Immunocompromised patients Post licensure studies: - Autoimmune diseases (arthritis and inflammatory bowel disease): 2 year followup VE (HZ) =39% (9,48%), safe - Population based cohort study of patients on immunosuppressive medication: VE (HZ) = 37% - Can use in asymptomatic HIV+ patients, but not if symptomatic or CD4 <15%; trial in progress (NB 6 fold decreased zoster risk on HAART) - Still inadequate data but Zostavax probably safe in mildmoderate immunecompromise: arthritis, SLE, IBD, chronic renal failure, diabetes, anti-tnf, prednisone <20mg daily Concomitant use of Zostavax with influenza and pneumococcal vaccines With Inactivated Influenza vaccine (n=380, >50 yo), sequential or simultaneous Similar antibody responses and safety (Kerzner et al, JAmGerSoc 2007) Pneumococcal Polysaccharide vaccine (23 valent) RDPC (n= 473); for immune response: simultaneous < sequential (McIntyre et al Hum Vacc 2010) - But Retrospective Cohort study (n=14,366) showed no increased risk of Zoster when immunized simultaneously (Tseng et al JAMA 2011) 25

26 RCF (per 100,000 PBMC) 7/15/2016 Tcell responses to VZV Decrease With Age >85 Age (years) CMI=cell-mediated immunity PBMC=peripheral blood mononuclear cell RCF=responder cell frequency Adapted from Levin M et al. Unpublished results. 26