04-Sep-17

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, Zostavax Advisory Board, BioCSL/Sequirus

Take home message

• From November 2016

• Management of herpes zoster demands immunization of all people between 70 and 79 with Zostavax

• To prevent: Herpes zostero Post-herpetic neuralgia

• Contraindications: Severely immune- compromised patients

• Vaccine efficacy 50-65% so breakthroughs may occur and require antiviral treatment, less severe though

• Duration ~ 10 years so a booster may be necessary

• A new competing vaccine with different characteristics may be available in 2018

Zoster: Latency and Reactivation

Herpes Zoster (shingles)

• 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. 2007

Risk factors for Herpes Zoster

• Increasing age

Less opportunity for boosting?– Less frequent exposure to varicella cases

– Less frequent contact with multiple ill children

• Decline in cell-mediated immunity– Immunosenescence

- Cell-mediated immunosuppressive disorders

Haematological malignancies

Immunosuppressive drugs

HIV: 12-17 fold increased risk

Thomas & Hall Lancet Infect Dis 2004;4(1):26-33; Liesegand Curr Opin Ophthalmol 2004;15:531-6: Donohue et al Arch Int Med 1995;155(15):1605-9

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Herpes zoster and PHN increase with age in

Australia

Stein A et al Vaccine 2009

0

1

2

3

4

5

6

30 40 50 60 70 80 >85Age (years)

RC

F (p

er

10

0,0

00

PB

MC

)

Rate of HZ Complications

Neurologic (incl PHN)

Cutaneous

Ocular Involvement

Sacral Dermatome Involvement

Visceral Complications

ZOSTAVAX™N=19,270

298

41

14

6

9

nIncidence

Rate*

5.0

0.7

0.2

0.1

0.2

PlaceboN=19,276

634

118

40

25

29

nIncidence

Rate*

10.7

2.0

0.7

0.4

0.5

*Birch C et al, Sex Transm Infect 2003;79:298-300

Zoster Diagnosis

• Clinical diagnosis alone

– ‘shingles’

• Laboratory diagnosis needed in

– immunosuppressed patients

– less common & atypical presentations

– (eg. genital*,HZ oticus)

– complicated presentations (eg. dissemination, CNS disease)

– Vesicle NAT or IF

*Birch C et al, Sex Transm Infect 2003;79:298-300

Five ‘ages’ of vaccines

• Infancy: multiple

• Adolescence: papillomavirus, HSV, EBV

• Pregnancy

• Older adults: influenza, pneumococcus, shingles

• Any, Epidemic: influenza, Ebola, Dengue, ?Zika

11

Adult immunization is not prioritized

PCV (3+ doses)

PCV (4 doses)

DTaP (4 doses)

DTaP (3+ doses)

Varicella (1 dose)

Hep B (3 doses)

Polio (3 doses)

Full ped schedule3

US Pediatric Coverage Rates %

Adult pneumo (65+, ever)

Flu (18+, per season)

Hepatitis B (19+, >3 doses)

Zoster (60+, ever)

US Adult Coverage Rates %

Tetanus/Tdap (50+, past 10 years)

1. CDC. MMWR. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6433a1.htm2. CDC. MMWR. https://www.cdc.gov/mmwr/volumes/65/ss/ss6501a1.htm.

Types of vaccines

● Whole virus

● Live attenuated

● Inactivated

● Split

● Sub-unit

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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

– 60-69 years = 20,750

– ≥ 70 years = 17,800 (46%)

– ≥ 80 years = ~2500 (>6.5%)

Oxman al. NEJM 352; 2271: 2005

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

• Post-herpetic neuralgia (PHN)– Significant pain (≥ 3 on ZBPI)

– ≥90 days after rash onset

– 95% of subjects completed the study

Efficacy(95% CI)

51.3%(44.2 - 57.6)

63.9% 37.6%

0

2

4

6

8

10

12

All 60-69 yr ≥70 yr

Incid

en

ce o

f H

Z

Vaccine

Placebo

Vaccine Efficacy for Incidence of Herpes Zoster

Vaccine Efficacy for Incidence of PHN

Efficacy(95% CI)

66.5%(47.5 - 79.2)

65.7%(20.4 - 86.7)

66.8%(43.3 - 81.3)

0.0

0.5

1.0

1.5

2.0

2.5

All Subjects 60-69 yr ≥70 yr

Incid

en

ce o

f P

HN

Vaccine

Placebo

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 50-59 year olds:

HZ incidence decreased by 70%, HZ pain by 73% (ie greater VE)

Duration of effectiveness of herpes zoster vaccine Kaiser Permanente Southern California, 2007–2015.

Hung Fu Tseng et al. J Infect Dis. 2016;213:1872-1875

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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), including CLL

- T cell immunodeficiency, including HIV+ pts with CD4<15%

• Cf HZ/su GSK (Recombinant VZV gE + adjuvant ASO1B) – not contraindicated and safe in immunecompromised (HSCT, HIV <15% CD4)

Zostavax: issues

• Moderate efficacy, lower in >80

• Duration of effectiveness ?8-10 years

-Need a booster, probably at 10 years

• Unsafe in severely immunecompromised

• Safety in moderately immunecompromised pts needs better definition

Zostavax in Australia

• Nov 2016: Approved for National Immunization program

• 70-79 yo with catchup (private 50 years)

• Now >50% vaccine dose distribution within a year

• Implications for new vaccine

Recombinant VZV glycoprotein E + T cell adjuvant

Pathogen

Glycoprotein Antigen

Adjuvants act as substitutes for natural T cell stimulants

• Viral proteins alone may be insufficiently immunogenic• Adjuvants act as substitutes for viral immune stimulants

enhancing and directing the immune response

T cell stimulating adjuvant Systems

• Combinations of:

- Classical adjuvants: aluminum salts, emulsion, liposomes

- Immunostimulants: MPL, QS21, (CpG),

(d)MPL QS21

0

20

40

60

80

100

1 2 3

50-59 YOA

60-69 YOA

70+ YOA

Vac

cin

e re

spo

nse

rat

e (%

)

gE/AS01B (HZ) gE/AS01E Post-dose 2 (M3) gE/Saline

Phase I/II: T cell responses to HZ/su (gE/AS01B) but not gE alone diminish little with advancing age

Chlibek et al 2015

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Phase III Trials of GSK HZ/su (Shingrix)

• Placebo - RCT in Europe, USA, Asia, Australia

• Two doses IMI two months apart, 96% compliance

• ZoE-50: 15,411 evaluable adults > 50 years, stratified in 10 year blocks, -

• ZoE-70: 13,900 adults >70 years focusing on PHN

- two papers published in NEJM,

- abstract on immunology presented to IHW

96.57 97.36 97.93 97.58 97.16

0

10

20

30

40

50

60

70

80

90

100

50-59 60-69 >=70 >=60 OVERALL/>=50

%

LL>25%

Secondary Objectives Primary Objective

ZOE-50: GSK Herpes Zoster (HZ/su) Vaccine Efficacy

Lal H, Cunningham AL et al, N Engl J Med, 2015

ZOE-70 trial: efficacy against HZ and PHN

13,900 Adults >70, average age 75.2 years • vaccine efficacy = 90% (95% CI 84-94)

- similar in 70-79 and >80

- efficacy against PHN: 89% (69-97)

- ie no additional efficacy against PHN cf HZ

• Efficacy against PHN in (Pooled) Adults>50 : 91% (76-98) - No cases <70 years

(Cunningham, Lal, Levin ..Heineman et al NEJM 2016)

Cunningham AL et al N Engl J Med 2016

ZOE-70: Risk of development of Herpes zoster after vaccination

Cunningham AL et al.N Engl J Med 2016

ZOE-70: Risk of development of post-herpetic neuralgia after vaccination

04-Sep-17

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Chlibek R. Heineman TC et al Vaccine,

2016,

gE-specific CD4 T cell responses after two

doses of HZ/su

>70 years ----

Baseline -----

ZoE-50 & 70: reactogenicity and safety

• Systemic: - Severe (grade III); 11.5% vs 2.5%

• Local/injection site

– Severe: 9.5/8.5% vs 0.4/0.2%: lasted on average 2 days

– 96% of all subjects received second dose

– 91% with severe reactions returned for second injection

– No increased reactogenicity after second dose

– IMI less reactogenic than s/c injection

Serious adverse events were similar in placebo and recipient

No increased autoimmune diseases or exacerbations

HZ/su in immunecompromised patients

• Phase I-II trials of HZ/su in autologous HSCT for HD, AML, Myeloma:

- comparable immunogenicity (antibody and CD4 T cells) and reactogenicityto immunocompetents; maintained for 1 year

- Phase III trial data soon to be submitted

• HIV: HZ markedly diminished by ART: still 3-5X risk if CD4<200

- Phase I-II trials HZ/su in 3 cohorts: good immunogenicity maintained for duration, 18 mo. No worsening of CD4 counts, safe

• Need to compare Zostavax vs HZ/su in mildly immuncompromisedpatients respectively (ie autoimmune diseases and Rx with biologics)

Shingrix, HZ/su: issues• Two doses: likely compliance in real world setting,

Efficacy after a single dose?

• Will high reactogenicity (severe local: 9%) reduce uptake?

• Duration of efficacy to be determined (T cell immunogenicity plateaus for 3-9 years- promising)

• - long term followup trials commenced

• Can it be used as a booster after Zostavax?

• Risk of auto-immunity with new adjuvants: needs long term post marketing surveillance

• Efficacy in severely immunecompromised: phase III trial results available soon

HZ/su:Implications

• HZ/su development and trialling confirms several scientific hypotheses:

- vaccines consisting of a single pathogen protein and adjuvant(s) can be efficacious -and more 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

Take home Message

• From November 2016

• Management of herpes zoster demands immunization of all people between 70 and 79 with Zostavax

• To prevent: Herpes zoster

– Post-herpetic neuralgia

• Contraindications: Severely immune- compromised patients

• Vaccine efficacy 50-65% so breakthroughs may occur and require antiviral treatment, less severe though

• Duration ~ 10 years so a booster may be necessary

• A new competing vaccine with different characteristics may be available in 2018

04-Sep-17

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HZ/su: Remaining Immunologic questions• Duration of humoral and CD4 T cell responses (>9 years)?

• Mechanisms:

- Relative importance of T cells in boosting antibodies vs other mechanisms

- Role and importance of polyfunctional CD4 T cells

- Is there a CD8 T cell response?

- Role of innate immune responses (NK, mono, DCs)

• Immune correlates of protection difficult to define because few breakthrough HZ cases

• However difference in protection against HZ in Zostavax and HZ/sucorrelates with CD4 T cell response: (2x vs 39x baseline)

• ? with CD8 T cell responses: available soon

• Will these responses be improved after HZ/su boosting of Zostavax?

Antiviral treatment of herpes zoster

• Oral famciclovir, valaciclovir or, if complications, IV aciclovir

• Treat up to 72 hpi or if new vesicles appearing, disseminated lesions, HZ opthalmicus/oticus

• Check renal function and modify dosage if necessary

• Treat pain with systemic analgesics, no topical LA, capsaicin

• If pain moderate/severe: add amitryptaline, pregabelin

• If pain prolonged > 4 weeks refer to pain specialist

• If ophthalmic zoster, refer to ophthalmologist

• Consider immunosuppression, pregnancy

• No evidence antivirals prevent PHN defined as pain >90 days

The Pivotal Phase 3 Program: ZOE-50 and ZOE-70

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ZOE 50/70 efficacy studies conducted at the same sites.Subjects ≥70 years of age were randomly assigned to ZOE-50 or ZOE-70.

Study Design and Objectives

ZOE-50(Zoster-006)

ZOE-70(Zoster-022)

Experimental designRandomized, observer-blind, placebo-controlled, multicenter,

multinational (North America, Europe, Latin America, Asia, Australia)

Primary objectives HZ efficacy in persons ≥50 YOA HZ efficacy in persons ≥70 YOA

Primary objectives in

pooled analysis

PHN efficacy in 70+

HZ efficacy in 70+

Actual enrollment 16,160 enrolled 14,816 enrolled

HZ, herpes zoster; PHN, postherpetic neuralgia; YOA,

years of age.

Laboratory diagnosis

• Antigen detection (IF etc)

• Nucleic acid testing (NAT)

– VZV

– Multiplex (eg HSV 1/2, VZV etc)

• Serology

– VZV-specific IgM

– ‘immune status’ (FAMA, gpELISA)

– (avidity)

95% of young Australian adults (~25 YO) immune

Heininger U et al Lancet 2006;9544:1365, Arvin AM, Clin Micro Rev 1996; 9,:361-81

Complications of Zoster

• Neurologic

– PHN

– Limb weakness

& Peripheral palsies

– Sensory loss

– Meningitis

– Myelitis

– Encephalitis

– Hearing loss

• Ophthalmic

– Visual impairment

– Ptosis

• Cutaneous

– Scarring

– Bacterial superinfection

• Disseminated disease

– Pneumonia

– Hepatitis

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VZV Pathogenesis

Courtesy C. Hood

Trials in Progress

• Co-administration with other ‘adult’ vaccines

- Tdap, influenza, pneumococcal conjugate vaccine

• Immunization of previous Zostavax recipients

• Safety and immunogenicity in other severe immunecompromising conditions

• - renal transplant

• - solid organ tumours

• - Hematologic malignancies

Duration of protection of Zostavax

• Short term Persistence Sub study:– 7320 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 Sub study:– 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 60-69 YO

(Levin M et al JID 2016)

Age dependent incidence of herpes zoster and PHN in Australia

Stein A et al Vaccine 2009

Immunosenescence

• Progressive decline in systemic immunity• Increased prevalence of cancer, autoimmune and chronic

diseases• Poor response to immunization• Increased vulnerability to common infectious diseases

(influenza etc)• Mechanism:

– decline in innate immunity: NK cells, DCs, PMNs– naïve T cells less diverse, more memory T cells, signalling

defects

• Role of late reactivation of CMV still controversial• Role of adjuvants (cf MF59 for influenza)

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Incidence of Herpes zoster is increasing globally.Trend in zoster ED visits - NSW

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Year

<25 <25 predicted 25-49 25-49 predicted

50-59 50-59 predicted 60-69 60-69 predicted

70-79 70-79 predicted 80+ 80+ predicted

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04

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Year

<25 <25 predicted 25-49 25-49 predicted

50-59 50-59 predicted 60-69 60-69 predicted

70-79 70-79 predicted 80+ 80+ 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 2015

Clinical Manifestation of Zoster

Acute pain

Characteristic dermatomal rash

May or may not occur; most

common is PHN

Prodromal Phase

Acute Phase

Complications

Resolves

1. Oxman MN. In: Varicella-Zoster Virus: Virology and Clinical Management. Cambridge: Cambridge University Press, 2000:246–275.

Nature of Pain in PHN

1. Bowsher D. In: Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition. Vol. 11. Amsterdam: Elsevier Science B.V., 2001:143–147.

CMI to VZV Decreases With Age

CMI=cell-mediated immunity

PBMC=peripheral blood mononuclear cell

RCF=responder cell frequency

Age group (years)

Shingrix group Placebo group Vaccine efficacy (95% CI)†

Shingles cases (N)* Shingles cases (N)*

≥50 6 (7344) 210 (7415)97.2%

(93.7-99.0)

≥60 3 (3852) 123 (3890)97.6%

(92.7-99.6)

≥70 1 (1711) 48 (1724)97.9%

(87.9-100)

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Efficacy in all age groups >50 years old (ZOE-50)1-3

*Included 7344 randomized subjects ≥50 years old without immunocompromise, who received a second dose of the vaccine and did not develop a confirmed case of shingles within 1 month after the second dose. N=number of subjects within each age group.

†P-value for all comparisons <0.001. Two-sided exact P-value conditional to number of cases.

CI, confidence interval.

1. Lal H, et al. N Engl J Med. 2015.2. Shingrix (prescribing information). Research Triangle Park, NC: GlaxoSmithKline; 2017.3. Data on file. 54

Efficacy in all age groups >70 years old

Age range (years)

Shingrix group Placebo group Vaccine efficacy(95% CI)†

Shingles cases (N)* Shingles cases (N)*

70-79* 19 (6468) 216 (6554)91.3%

(86.0-94.9)

≥80* 6 (1782) 68 (1792)91.4%

(80.2-97.0)

*Pooled data from ZOE-50 (subjects ≥ 50 years) and ZOE-70 (subjects ≥70 years). Included 16,596 randomized subjects ≥50 years old, without immunocompromise, who received a second dose of the vaccine and did not develop a confirmed case of shingles within one month after the second dose. N=number of subjects within each age group.

†P-value for all comparisons <0.0001.2

CI, confidence interval.

1. Shingrix (prescribing information). Research Triangle Park, NC: GlaxoSmithKline; 2017.

2. Data on file.

Pre-specified, Pooled Analyses from ZOE-50 and ZOE-70*

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Pathogenesis of Herpes zoster

• VZV

– latent within neurones mainly (2-5 copies/cell) reactivation

– Usually only once (5% second)

– Different to HSV but mechanism unknown

Necrosis and inflammation in nerve root, DRG and nerve

• VZV No apoptosis of infected neurones in vitro

Neurone/support cell lysis in DRG is probably immunopathologic

SPS: Efficacy

• HZ Incidence

–51.3% (44.2 – 57.6%)

• Burden Of Illness

–61.1% (51.1 – 69.1%)

• Post Herpetic Neuralgia

–66.5% (47.5 – 79%)

Licensure, availability and uptake worldwide

• USA: ACIP recommendation: immunize all immunocompetent persons>60 with one dose of Zostavax– over 25 million doses distributed since 2006

– 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

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Minimal decline in efficacy up to 4 years post initial vaccination1

Years*

Shingrix VACCINE GROUP PLACEBO GROUP

Vaccineefficacy

(95% CI)†

Shingles cases (N)

Rate of shingles

(cases per 1000 person-years)

Shingles cases (N)

Rate of shingles(cases per 1000 person-years)

Year 1 2 (8250) 0.2 83 (8346) 10.197.6%

(90.9-99.8)

Year 2 7 (8039) 0.9 87 (8024) 11.192.0%

(82.8-96.9)

Year 3 9 (7736) 1.2 58 (7661) 7.784.7%

(69.0-93.4)

Year 4 7 (7426) 1.0 56 (7267) 8.287.9%

(73.3-95.4)

Vac

cin

e e

ffic

acy

by

year

po

st v

acci

nat

ion

CI, confidence interval.

*Year 1: from 30 days to 395 days after the second vaccination. Year 2: from >396 days to 760 days after the second vaccination. Year 3: from >761 days to 1125 days after the second vaccination. Year 4: from >1125 days after the second vaccination to the last contact date. N=number of subjects within each age group.

†P-value for all efficacy comparisons with placebo <0.001.

1. Cunningham AL, NEJM. 2016.

To prevent 1 HZ case in the 60+ population, you would need to vaccinate 10 individuals with Shingrix or 32

individuals with Zostavax®

Assuming a 2nd dose compliance of 69% for Shingrix.

Shingrix

Zostavax®

Vaccinate 10 individuals

withVaccinate 32 individuals with

to prevent 1 HZ

Case

Assuming a 2nd dose compliance of 69% for Shingrix.

HZ/su as a booster following Zostavax?

• Important where high ZV coverage: data soon to be published

• HZ/su after natural herpes zoster (physician documented):

- no safety concerns but high reactogenicity as for ZOE 50/70

- good response rate antibody to vaccine for patients >50: - 90.2%

- similar across all age groups

Godeaux O et al Hum Vacc Immuno 2017

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• One month post-dose 2, 93.3% of HZ/su recipients ≥50 YOA met the

criteria for vaccine response.

VRR, vaccine response rate ≥2-fold increase in gE-specific CD42+ frequencies as compared to pre-vaccination levels; or

≥2-fold above the cut-off (320/106 gE-specific CD42+).

Anti-gE cell-mediated immune responses (in ZOE-50 CMI cohort)

Q3 (75th

percentile

Median (50th

percentile)

Q1 (25th

percentile)

Sustained CD4 T cell Response at 9 years

• Both cellular and humoral immune responses persisted through 9 years

• Immune responses were stable since year 4

• Immune response persistence above baseline was independent of age (60-69 and ≥70 YOA)