An Update on Herpes Zoster - s3.amazonaws.com · SPS: Study Design • RCT: double-blind, placebo-controlled • Subjects: – 38,546 subjects enrolled, ≥ 60 years of age – History

An Update on Herpes Zoster

HZ Burden and the Rationale for

Vaccination

Ian D.R. Landells, MD, FRCPC

Clinical Associate Professor

Memorial University

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Learning Objectives

• Discuss the pathogenesis & clinical consequences of

pain caused by herpes zoster (HZ)

• Answer questions from patients and their families

about the efficacy and safety of the HZ vaccine

• Identify patients in whom HZ vaccination should be

considered, based on recent clinical and

epidemiological studies

Definition of Shingles

• Shingles is a painful vesicular

eruption in a dermatomal

distribution

Dermatomes are areas on the skin supplied by sensory fibers of the spinal nerves

http://www.dermnet.com/image.cfm?passedArrayIndex=16&moduleID=21&moduleGroupID=308

Natural History of VZVIn

cre

asin

g im

mu

ne

eff

icie

nc

y

Days

Edgar Hope-Simpson

3 1596

Weeks Months

Critical immune efficiency

Neutralized reversionsNeutralized

reversions

Neutralized

reversions

Immune

stateC

onta

ct w

ith a

case o

f varicella

Zoste

r successfu

l revers

ion

Infe

cte

d w

ith

viru

s

Varicella

(la

tent virus

go

es to

se

nso

ry g

ang

lia)

VZV: Pathophysiology

of Reactivation

Posterior column

spinal cord

Dorsal root

ganglion

Site of VZV

replication

Incidence of HZA

nnual in

cid

ence

(per

10,0

00 p

ers

on

-ye

ars

)

80

0

40

120

60

20

100

0

Age (years)

10 20 30 40 50 60 70 80

Canada (Manitoba) – Brisson

U.K. – Hope-Simpson

U.K. (RCGP) – Brisson

Netherlands – de Melker

U.S. (Olmstead) – Yawn

U.S. (Medstat) – Insinga

Upward HZ Trend in Canada

12

10

Cases/1

,000 p

opula

tion

Fiascal year (April 1 – March 31)

75+ years

65-74 years

45-64 years

8

0

4

6

2

• Incidence of HZ

increases with age

• Baby boomer

population is now

51-71 years of age

• 35% increase from

1980 to 1997

• Increasing

incidence related to

childhood varicella

vaccination is

unclear

1980 1985 1990 1995

HZ Burden and Complications

• 1 out of 3 Canadians will experience an episode

of HZ in their lifetime

– 1 out of 2 for those aged 85 years and older

• Complications can severely affect the patient’s

quality of life

PHN (10-22%)

Ocular complications

Scarring

Super infections

Stroke

ACUTE

HZ PAIN• loss of work

• low quality of life

Estimated Annual Burden of

HZ in Canada

2005 Healthcare Cost: $69 Million

Number of HZ-related Events in Canada

Conclusion:

Vaccinating 65-year-old adults yields a $33,000 cost

per QALY gained (usual threshold is $50,000)

HZ Cases: 130,000

Consultations: 360,000

Hospitalizations: 2,000

Deaths: 20

PHN: 17,000Physician consultation

and prescriptions:

$49 million

(71%)

PHN: $5 million (8%)Hospitalization:

$14 million

(21%)

HZ: An Approach to

Classifying Complications

Common

• PHN

• Scarring

• Bacterial

superinfection

• Ocular complications

of HZ ophthalmicus

Less common

• Stroke

• Cutaneous dissemination

• Herpes gangrenosum

• Pneumonitis

• Hepatitis

• Encephalitis

• Motor neuropathies

• Myelitis

• Hemiparesis (granulomatous

central nervous system vasculitis)

Prevalence and Duration of PHN

(PHN: Pain for > 30 Days After Rash Onset)

Prevalence and duration of acute pain and PHN increase with age

0-19 20-29 30-39 40-49 50-59 60-69 ≥70

Age (years)

100

80

60

40

20

0

Perc

ent of

patie

nts

report

ing p

ain

> 1 year

6-12 months

1-6 months

< 1 month

Comparison of Pain Severity

HZ

PHN

50

40

30

20

10

0

Fibromyalgia

Atypical facial pain

Musculoskeletal pain

Arthritis

Osteoarthritis

Rheumatoid arthritis

Chronic cancer pain

Abdominal hysterectomy

Acute headache

Labour

Postsurgical pain

Mucositis

Angioplasty sheath removal

Incre

asin

g p

ain

Risk Factors for Developing PHN

Increased likelihood

• Age over 50 years

• Female

• Severity of prodrome

• Severe or disseminated rash > 1 dermatome

• Severe pain at presentation (visual analogue scale > 5)

Impact of HZ on HRQoL

A Prospective Study

% o

f patie

nts

report

ing p

roble

ms

80

0

60

40

20

100At recruitment

70

50

30

10

90

Mobility Self-care Usual

activities

Pain/

discomfort

Anxiety/

depression

After pain stopped

% o

f patie

nts

report

ing p

roble

ms

80

0

60

40

20

100At 90 days after rash onset

70

50

30

10

90

Mobility Self-care Usual

activities

Pain/

discomfort

Anxiety/

depression

After 180 days after rash onset

Impact of PHN on HRQoL

Pharmacologic Therapeutics & PHN

Agent NNT*

Lidocaine patch 2.0

Capsaicin cream 3.3

Tricyclic

antidepressants

2.6

Narcotics

Oxycodone

Morphine

2.5

2.8

Pregabalin 4.2

Gabapentin 4.6

Tramadol 4.0

•Johnson RW, Rice ASC. Postherpetic neuralgia. N Engl J Med 2014; 371:1526-33.

*Number needed to treat (NNT) to

have at least a 50% reduction in

baseline pain intensity

BUT:

• Pharmacologic therapeutics for

PHN are not consistently

efficacious

• Even the most effective

treatments result in clinically

significant analgesia in fewer than

half of patients

• PHN pain may persist for years or

life, but data for these therapies

do not extend beyond treatment

periods of a few weeks

Antivirals for Preventing PHN?

•Chen N, Li Q, Yang J, et al. Antiviral treatment for preventing postherpeticneuralgia. Cochrane Database of Systematic Reviews 2014; 2:CD006866.

• Must be given during time of rash (within 72 hours of

HZ onset in studies)

• In 6 RCTs with 1,211 eligible subjects:

– No significant difference between aciclovir and control

groups for PHN incidence

• 4 months after HZ rash onset: RR 0.75; 95% CI 0.51-1.11

• 6 months after HZ rash onset: RR 1.05; 95% CI 0.87-1.27

– No significant reduction in PHN incidence with famciclovir

vs. placebo

• Further research needed to investigate famciclovir and

other new antivirals for preventing PHN

The Shingles Prevention Study (SPS)

•Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005; 352:2271-84.

SPS: Study Design

• RCT: double-blind, placebo-controlled

• Subjects:– 38,546 subjects enrolled, ≥ 60 years of age

– History of chickenpox or U.S. resident ≥ 30 years

• Excluded– Immunocompromised

• One dose of live-attenuated vaccine or placebo

• 93% of HZ cases confirmed to be VZV by PCR

• Primary endpoint: Burden of Illness Score = severity-by-duration over 182 days after rash onset

• PHN: pain with severity ≥ 3 out of 10 max, present at ≥ 90 days after rash onset


SPS Results:

Live Vaccine Efficacy – HZ Incidence by AgeIn

cid

ence o

f H

Z

(per

1,0

00 p

ers

on

-years

)

0

12

8

4

14

10

6

2

All 60-69 years ≥ 70 years

11.12

5.42

10.79

3.90

11.50

7.18

p < 0.001

Efficacy:(95% CI):

51.3% (44.2-57.6)

63.9% (55.5-79.9)

37.6% (25.0-48.1)

Vaccine

Placebo


SPS Results:

Live Vaccine Efficacy – PHN Incidence by AgeIn

cid

ence o

f P

HN

(per

1,0

00 p

ers

on

-years

)

0.0

2.0

1.0

2.5

1.5

0.5

All 60-69 years ≥ 70 years

1.38

0.46

0.74

0.26

2.13

0.71

Efficacy(95% CI)

66.5% (47.5-79.2)

65.7% (20.4-86.7)

66.8% (43.3-81.3)

Vaccine

Placebo


SPS Results:

Live Vaccine Efficacy – BOI by Age

BOI = burden of illness (a severity-by-duration measure of the incidence, severity and duration of all HZ-associated pain and discomfort).

Oxman MN, et al. N Engl J Med 2005; 352:2271-84.

Efficacy(95% CI)

Vaccine

9

Placebo

61.1% (51.1-69.1)

All

65.5% (51.5-75.5)

60-69 years

55.4% (39.9-66.9)

≥ 70 years

HZ

BO

I

8

0

6

4

2

7

5

3

1

5.68

2.21

4.33

1.50

7.78

3.47


SPS Adverse Events

Vaccine

n = 19,270

Placebo

n = 19,276

Vaccine-related systemic events 6.3% 4.95%

Injection site reactions

Erythema

Pain or tenderness

Swelling

48.3%

35.8%

34.5%

26.2%

16.6%

7.0%

8.5%

4.5%

All were different with p < 0.05


Efficacy, Safety, and Tolerability of

Live HZ Vaccine in Persons Aged 50–59 Years

HZ vaccine

Placebo

Estim

ate

d

incid

ence r

ate

of

HZ

(per

1,0

00 p

ers

on

-years

)

0

6

4

2

7

5

3

1

1.99

6.57

n = 30 n = 99

ITT Population

Vaccine Efficacy (95% CI): 0.698 (0.541* - 0.806)

*A lower bound of > 25% indicates that the success criterion was met

•Schmader K, Levin MJ, Gnann JW Jr., et al. Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years. Clin Infect Dis 2012; 54(7):922-8.

Adverse Events with Live HZ Vaccine vs.

Placebo, Both Studies (50-59 and > 60

Years)

Vaccine Placebo

n = 19,270

Old

n = 11,211

Young

n = 19,276

Old

n = 11,228

Young

Vaccine-related

systemic events6.3% 6.7% 4.9% 4.7%

Injection-site reactions

• Erythema

• Pain or tenderness

• Swelling

48.3%

35.8%

34.5%

26.2%

63.9%

n/a

n/a

n/a

16.6%

7.0%

8.5%

4.5%

14.0%

n/a

n/a

n/a

Systemic events and injection-site reactions were significantly different between vaccine and placebo

groups in both studies.

One vaccine-related SAE: < 59-year-old subject developed anaphylaxis after vaccine.

Conclusions

• Immunization with Live HZ vaccine reduced:

– The PHN Burden of Illness score by 66% (aged

60-69 years) and 55% (aged ≥ 70 years)

– The incidence of HZ by 64% and 37% in the two

age cohorts

– The incidence of PHN by 66% and 67% in the

two age cohorts

• HZ vaccine was well tolerated and was not

accompanied by an increased risk of AEs

Live HZ Vaccine Duration of Protection

• HZ vaccine (1 dose) reduces the

risk of HZ for at least 8 years in

immunocompetent adults1

• No booster dose is currently

recommended2

1. Morrison VA, et al. Clin Infect Dis 2014; [epub ahead of print].2. National Advisory Committee on Immunization (NACI) 2014. PHAC Publication 130536.

NACI Recommendations – Live HZ

Vaccine

Immunization with Live HZ vaccine for

immunocompetent adults:

• Vaccine is recommended for adults ≥ 60 years of age

• Vaccine may be used in adults 50-59 years of age

• Vaccine may be administered to individuals ≥ 50 years old with

a prior history of HZ. Based on expert opinion, it is

recommended that the vaccine be given at least one year

following the last episode of HZ

– Annual recurrence rate in immunocompetent adults has varied

across studies/methods:

• Yawn et al 2011: 5.7% recurrence rate over 8 years (and 12% in

immunocompromised adults)

See supplementary slides for more detailed NACI recommendations.National Advisory Committee on Immunization (NACI) 2014. PHAC Publication 130536.

NACI Recommendations – Live HZ

Vaccine (cont’d)

Immunization with HZ vaccine for

immunosuppressed adults:

• Individuals on low-dose immunosuppressive therapy

– It is reasonable to consider HZ vaccine in patients on lower doses of

immunosuppressive agents: prednisone < 20 mg/day; methotrexate

≤ 0.4 mg/kg/week, azathioprine ≤ 3.0 mg/kg/day; 6-mercaptopurine ≤

1.5 mg/kg/day

• Individuals on anti-TNF biologics

– HZ vaccine may be used; on a case-by-case basis after review with

an expert in immunodeficiency

See supplementary slides for more detailed NACI recommendations.National Advisory Committee on Immunization (NACI) 2014. PHAC Publication 130536.

Updated NACI Recommendations:

Live HZ Vaccine Recommended Use –

Administration with Other Vaccines

Recommendation Comments

• PneumovaxTM23 may be

administered concomitantly

with HZ vaccine at a different

body injection site

• NACI recommendation

A, good.

• This is a change from the

previous NACI

recommendation.

National Advisory Committee on Immunization (NACI) 2014. PHAC Publication 130536.

Updated NACI RecommendationsLive HZ Vaccine Recommended Use –Immunosuppressed Patients (cont’d)

Group Recommendation Comments

Individuals on anti-TNF

biologics

• May be used

• NACI

recommendation

B, fair.

On a case-by-case basis

after review with an

expert in

immunodeficiency

National Advisory Committee on Immunization (NACI) 2014. PHAC Publication 130536.

Adjuvanted subunit vaccine:

Adjuvanted subunit vaccine product profile

Administered as two doses IM, 2‒6 months apart3

Indicated for the prevention of HZ in adults ≥50 years of age3

Non-live glycoprotein E subunit vaccine1

– Uses the AS01B adjuvant system2

Approved for use in Canada on October 13, 20173

1. Haumont M, et al. Virus Res 1996;40:199‒204; 2. Chlibek R, et al. J Infect Dis 2013;208:1953‒61; 3. SHINGRIX Product Monograph. GSK Canada: October 13, 2017

Adjuvanted subunit vaccine composition

SHINGRIX vaccineNon-live

Adjuvant SystemAS01B: QS-21* and MPL - 50 µg

each

AntigengE - 50 µg

*QS-21 adjuvant licensed from Antigenics Inc, a wholly owned subsidiary of Agenus Inc. a Delaware USA corporation; gE,

glycoprotein; MPL, 3-O-desacyl-4’-monophosphoryl lipid A; QS-21, Quillaja saponaria Molina, fraction 21

1. Lal H et al., N Eng J Med 2015, 372: 2087-96; 2. Cunnigham A et al, N Eng J Med 2016,75:1019-32

Adjuvanted subunit vaccine pivotal phase III program: ZOE-50 and ZOE-701,2

New England Journal of Medicine, 2015, 2016

1.Lal H, et al. N Engl J Med 2015;372:2087‒96; 2. Cunningham AL, et al. N Engl J Med 2016;75:1019‒32

PHN, postherpetic neuralgia; VE, vaccine efficacy

Adjuvanted subunit vaccine pivotal phase III program: ZOE-50 and ZOE-701,2

New England Journal of Medicine, 2015, 2016

ZOE-50 and ZOE-70 studies conducted at the same sites

Subjects ≥70 years of age were randomly assigned to ZOE-50 or ZOE-70

Study design

and objectivesZOE-501

(Zoster-006)

ZOE-702

(Zoster-022)

Study designRandomized, observer-blind, placebo-controlled, multicentre,

multinational (North America, Europe, Latin America, Asia-Pacific)

Schedule 2 doses administered 2 months apart

Primary objectivesVEHZ in subjects

≥50 years of age

VEHZ in subjects

≥70 years of age

Primary objectives

(pooled analysis)

VEPHN in individuals ≥70 years of age

VEHZ efficacy in individuals ≥70 years of age

Actual enrolment 16160 14816

1.Lal H, et al. N Engl J Med 2015;372:2087‒96; 2. Cunningham AL, et al. N Engl J Med 2016;75:1019‒32

PHN, postherpetic neuralgia; VE, vaccine efficacy

ZOE-50 & ZOE-70: Study design

Randomisation

1:1

Visit 1

Month 0

Visit 2

Month 2

Visit 3

Month 3 Study

conclusion

contact

Placebo group (NaCl solution)

Vaccine group (SHINGRIX)

Vaccination visits Follow-up contacts/visits*

Active surveillance for efficacy and safety

through monthly contacts

Visit 6

Month 38

Visit 5

Month 26

Visit 4

Month 14

Blood sampling

Blood sampling: all subjects at Visit 1 and Visit 3; humoral and cellular-mediated immunity subsets of subjects at the other visits.

*In case of suspected HZ, the subject had additional visits and contacts for follow-up of HZ

SHINGRIX, herpes zoster subunit vaccine; NaCI, sodium chloride

Prepared October 2017

Adjuvanted subunit vaccine

Efficacy

Adjuvanted subunit vaccine demonstrated efficacy in all age

groups ≥50 years of age1,2

Age (years)SHINGRIX Placebo VEHZ

(95% CI)*HZ cases (n) HZ cases (n)

≥501 6 (7344) 210 (7415)97.2%

(93.7, 99.0)

≥602 3 (3852) 123 (3890)97.6%

(92.7, 99.6)

≥701 1 (1711) 48 (1724)97.9%

(87.9, 100)

Included 7344 randomized subjects ≥50 years of age, who received a second dose of the vaccine and did not develop a

confirmed case of HZ within 1 month after the second dose. n=number of subjects within each age group. Mean follow-up 3.8

years

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

CI, confidence interval; VE, vaccine efficacy

1. Lal H, et al. N Engl J Med 2015;372:2087‒96; 2. McElhaney et al, ID WEEK 2016.

Pre-specified analyses from ZOE-50


Adjuvanted subunit vaccine demonstrated

efficacy in all age groups ≥70 years of age

Age (years)

SHINGRIX Placebo VEHZ

(95% CI)*HZ cases (n) HZ 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) of age and ZOE-70 (subjects ≥70 years of age). Included 16,596 randomized subjects

≥50 year of age, 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. Mean follow-up 3.8 years

*p<0.0001 for all comparisons

n, number of subjects within each age group.

1. Cunningham AL, et al. N Engl J Med 2016;75:1019‒32

Pre-specified, pooled analyses from ZOE-50 and ZOE-70


High efficacy for Adjuvanted subunit vaccine sustained with

minimal decline up to 4 years post initial vaccination (ZOE-70)*

Years†

SHINGRIX Placebo

VEHZ

(95% CI)‡HZ cases

(n)

Rate(cases per 1000

person-years)

HZ cases

(n)

Rate(cases per 1000

person-years)

Year 1 2 (8250) 0.2 83 (8346) 10.1 97.6%(90.9, 99.8)

Year 2 7 (8039) 0.9 87 (8024) 11.1 92.0%(82.8, 96.9)

Year 3 9 (7736) 1.2 58 (7661) 7.7 84.7%(69.0, 93.4)

Year 4 7 (7426) 1.0 56 (7267) 8.2 87.9%(73.3, 95.4)

Va

cc

ine

eff

ica

cy b

y

ye

ar

po

st

va

cc

ina

tio

n

*Subjects followed-up for a mean of 3.7 years at the time of this publication†Year 1:30‒395 days after the second vaccination; Year 2: 396‒760 days after the second vaccination; Year 3: 761‒1125 days after

the second vaccination; Year 4: >1125 days after the second vaccination to the last contact date.

n=number of subjects within each age group‡p<0.001 for all comparisons

CI, confidence interval; SHINGRIX, herpes zoster subunit vaccine; VE, vaccine efficacy

1. Cunningham AL, et al. N Engl J Med 2016;75:1019‒32


Adjuvanted subunit vaccine greatly reduced HZ complications,

such as PHN, among all groups ≥50 years of age*1

PHN defined as HZ-associated pain rated as ≥3 on a 0‒10 scale, occurring or persisting for at least 90 days following the onset of

rash using Zoster Brief Pain Inventory questionnaire. Pooled data from ZOE-50 (subjects ≥50 years of age) and ZOE-70 (subjects

≥70 years of age)

*All subjects randomized in the study who received a second dose of the vaccine. Final analysis data cut-off date: July 1, 2014;

mean follow-up 3.8 years; †p<0.001 for both comparisons

CI, confidence interval; SHINGRIX, herpes zoster subunit vaccine ; PHN, postherpetic neuralgia; VE, vaccine efficacy

Pre-specified, pooled analyses from ZOE-50 and ZOE-70

1. Cunningham AL, et al. N Engl J Med 2016;75:1019‒32;

Age,

years

SHINGRIX Placebo

VEHZ

(95% CI)†PHN cases

(n)

Rate(cases per

1000

person-years)

PHN cases

(n)

Rate(cases per

1000

person-years)

≥50 4 (13881) 0.1 46 (14035) 1.2 91.2%(75.9, 97.7)

≥70 4 (8250) 0.1 36 (8346) 0.9 88.8%(68.7, 97.1)


Summary: Adjuvanted subunit vaccine efficacyConsistent efficacy across all ages groups ≥50 years of age

High efficacy regardless of age in all ≥50 years old (>90%)1,2

High efficacy sustained with minimal decline up to 4 years post initial vaccination2*

HZ complications, such as PHN, were greatly reduced in all ≥50 years of age2

– z

– z

*Subjects have been followed for a mean of 3.7 years

YOA, years of age

1. Lal H, et al. N Engl J Med 2015;372:2087‒96; 2.Cunningham AL, et al. N Engl J Med 2016;75:1019‒32


Adjuvanted subunit vaccine

Safety


Overall incidences of SAEs, deaths and pIMDs were similar

between Adjuvanted subunit vaccine and placebo (up to 1 year post

last vaccination)

0

2

4

6

8

10

12

14

16

SHINGRIX Placebo SHINGRIX Placebo SHINGRIX Placebo

SAEs Fatal SAEs pIMDs

Perc

en

tag

e (

%)

SAEs, fatal SAEs and pIMDs

Related by investigator's assessment

SAEs, serious adverse events; pIMD, potential immune-mediated disease

Colindres R. Safety summary of investigational vaccine: SHINGRIX (SHINGRIX). ACIP February 22, 2017 [last accessed 2017 June]. Available from:

www.cdc.gov/vaccines/acip/meetings/downloads/slides-2017-02/zoster-02-gsk.pdf


http://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2017-02/zoster-02-gsk.pdf

Local adverse reactions to Adjuvanted subunit vaccine

were transient1,2

Solicited local symptoms reported during 7 days post vaccination:

any grade overall by subject

0

20

40

60

80

100

Pain Redness Swelling

SHINGRIX ZOE-50(n=4382)

Placebo ZOE-50(n=4377)



ZOE-50: Overall median duration of 3 days for pain, redness and swelling3

ZOE-70: Overall median duration of 2 days for pain; 3 days for redness and swelling2

Perc

en

tag

e (

%)

n= Number of subjects with at least 1 documented dose

%= Percentage of subjects reporting the symptom at least once when the intensity is maximum

1. Lal H, et al. N Engl J Med 2015;372:2087‒96; 2.Cunningham AL, et al. N Engl J Med 2016;75:1019‒32; 3. Colindres R. Safety summary of investigational vaccine: SHINGRIX

(SHINGRIX). ACIP February 22, 2017 [last accessed 2017 June]. Available from: www.cdc.gov/vaccines/acip/meetings/downloads/slides-2017-02/zoster-02-gsk.pdf



Local grade 3 adverse reactions to Adjuvanted

subunit vaccine were also limited and transient1-4

0

5

10

15

20

25

Pain Redness Swelling





Solicited local symptoms reported during 7 days post vaccination:

grade 3 overall by subject

ZOE-50: Median duration of grade 3 pain = 1 day; redness and swelling = 2 days3

ZOE-70: Median duration of grade 3 pain = 1.5 days; redness = 2 days; swelling = 1 day4

Perc

en

tag

e (

%)

Grade 3 = Redness and swelling at the injection site were scored as grade 3 for those more than 100 mm. All other symptoms

were scored as 3 for preventing normal activity; n= Number of subjects with at least 1 documented dose; %= Percentage of

subjects reporting the symptom at least once when the intensity is maximum

1.Study 110390 clinical study summary; 2016 [last accessed 2017 June]. Available from: www.gsk-clinicalstudyregister.com/study/110390#rs; 2. Study 113077 clinical study

summary; 2016 [last accessed 2017, June]. Available from: www.gsk-clinicalstudyregister.com/study/113077#rs; 3. Lal H, et al. N Engl J Med 2015;372:2087‒96;

4.Cunningham AL, et al. N Engl J Med 2016;75:1019‒32


http://www.gsk-clinicalstudyregister.com/study/110390


Systemic adverse reactions to Adjuvanted

subunit vaccine were transient 1,2

0

20

40

60

80

100

Fatigue Fever (≥37.5°C/≥99.5°F)

GI* Headache Myalgia Shivering





Solicited systemic symptoms reported during 7 days post vaccination:

any grade overall by subject

Perc

en

tag

e (

%)

ZOE-50: Median duration of 2 days for fatigue, GI, HA and myalgia; 1 day for fever and shivering3

ZOE-70: Median duration of 2 days for fatigue, GI, HA, myalgia and fever; 1 day for shivering2

*GI symptoms included nausea, vomiting, diarrhoea, and/or abdominal pain

GI, gastrointestinal; HA, headache; n= Number of subjects with at least 1 documented dose; % = Percentage of subjects reporting

the symptom at least once when the intensity is maximum

1. Lal H, et al. N Engl J Med 2015;372:2087‒96; 2.Cunningham AL, et al. N Engl J Med 2016;75:1019‒32; 3. Colindres R. Safety summary of investigational vaccine: SHINGRIX

(SHINGRIX). ACIP February 22, 2017 [last accessed 2017 June]. Available from: www.cdc.gov/vaccines/acip/meetings/downloads/slides-2017-02/zoster-02-gsk.pdf



Systemic grade 3 adverse reactions to Adjuvanted subunit

vaccine were also limited and transient1,2

0

5

10

15

20

25

Fatigue Fever(>39°C/>102.2°F)

GI* Headache Myalgia Shivering





Perc

en

tag

e(%

)

ZOE-50: Median duration of all grade 3 symptoms = 1 day3

ZOE-70: Median duration of grade 3 myalgia = 2 days; shivering, fatigue, GI and HA = 1 day4

Grade 3: temperature >39°C (preferred route: oral); all other symptoms were scored as 3 for preventing normal activity.

*GI symptoms included nausea, vomiting, diarrhoea and/or abdominal pain

GI, gastrointestinal; HA, headache; n= Number of subjects with at least 1 documented dose; %= Percentage of subjects

reporting the symptom at least once when the intensity is maximum

1.Study 110390 clinical study summary; 2016 [last accessed 2017 June]. Available from: www.gsk-clinicalstudyregister.com/study/110390#rs ; 2. Study 113077 clinical study

summary; 2016 [last accessed 2017, June]. Available from: www.gsk-clinicalstudyregister.com/study/113077#rs; 3. Lal H, et al. N Engl J Med 2015;372:2087‒96; 4

. Cunningham AL, et al. N Engl J Med 2016;75:1019‒32

Solicited systemic symptoms reported during 7 days post vaccination

grade 3 overall by subject




Vaccine compliance was high (>94%);

almost all subjects returned for a second dose1,2

N = 7698

ZOE-501

of subjects received the

second dose of SHINGRIX95.6%


second dose of placebo96.4%

Total vaccinated cohort

(n=7698)

(n=7713)

ZOE-702


second dose of SHINGRIX94.4%


second dose of placebo95.6%

Total vaccinated cohort

(n=6950)

(n=6950)

1. Lal H, et al. N Engl J Med 2015;372:2087‒96; 2.Cunningham AL, et al. N Engl J Med 2016;75:1019‒32


Summary: safety and adverse reactionsBased on available data, the benefit: risk profile for

Adjuvanted subunit vaccine is favourable

Safety data from the SHINGRIX clinical program has not detected any safety

signals, and the benefit of SHINGRIX outweighs the risk1

Overall incidences of SAEs, deaths and pIMDS were similar between SHINGRIX and

placebo (no imbalances overall or within any time frame)1

The most frequently reported symptom was pain at the injection site; myalgia,

fatigue and headache were the most frequently reported general symptoms2,3

The majority of reactions, both local and systemic, were mild to moderate in intensity

and of short duration (1‒3 days)2,3

– z

–z

–z

Vaccine compliance with 2 doses was high (>94%)2,3

–z

1. Colindres R. Safety summary of investigational vaccine: SHINGRIX (HZ/su). ACIP February 22, 2017 [last accessed 2017 June]. Available from:

www.cdc.gov/vaccines/acip/meetings/downloads/slides-2017-02/zoster-02-gsk.pdf ; 2. Lal H, et al. N Engl J Med 2015;372:2087‒96; 3.Cunningham AL, et al. N Engl J Med

2016;75:1019‒32



1.Lal H, et al. N Engl J Med 2015;372:2087‒96; 2. Cunningham AL, et al. N Engl J Med 2016;75:1019‒32; 3. Colindres R. Safety summary of investigational vaccine: SHINGRIX (HZ/su). ACIP February 22, 2017 [last accessed 2017 June].

Available from: www.cdc.gov/vaccines/acip/meetings/downloads/slides-2017-02/zoster-02-gsk.pdf ; 4. Study 113077 clinical study summary; 2016 [last accessed 2017, June]. Available from: www.gsk-

clinicalstudyregister.com/study/113077#rs; 5. Study 110390 clinical study summary; 2016 [last accessed 2017 June]. Available from: www.gsk-clinicalstudyregister.com/study/110390#rs

Summary: efficacy and safety in pivotal Phase III programAdjuvanted subunit vaccine provided efficacy across all age groups ≥50 years of age with an

acceptable safety and tolerability profile

>90% efficacy shown in all age groups ‒from 50 to over 80 years of age

(pooled data from 2 pivotal phase 3 trials)1,2

There was no significant decline in efficacy during an ongoing follow-up period

(mean 3.8 years),2 and immunogenicity was maintained for at least 9 years3

SHINGRIX eliminated almost all occurrences of PHN 2,4

Adverse reactions were mostly transient and of mild-to-moderate intensity, with a

median duration of 3 days2,3,4,5

– z

– z

– z

Efficacy

Adverse Reactions

– z





Is HZ a Risk Factor for Stroke?

HZ as a Risk Factor for Stroke

• There are 5 studies demonstrating an increased

risk of stroke following an episode of HZ (see

following slides)

• Greatest risk is in the first 2 weeks

– Risk Ratio 1.31 - 2.27

• Risk increases with cases of HZ ophthalmicus

– Risk Ratio = 4.29

Stroke: Theoretical Mechanisms

“VZV is the only human virus that has been proven

to replicate in cerebral arteries and produce stroke”

Thrombosis,

occlusions,

infarctions,

aneurysms,

hemorrhage

Viral infection

Damages and

weakens cerebral

artery walls

Nagel M, et al. Clin Infect Dis 2014; 58(11):1504-6.Sreenivasan N, et al. PLoS ONE 2013; 8(7):e69156.

Rationale for HZ Vaccination

• Inform your patients

• Should be an incentive for you to offer vaccine

• Should be an incentive for patient to accept

Acute Zoster Pain• Loss of work

• Reduced quality of life

This should be

enough

• PHN• Ocular complications

• Scarring

• Super infections

Stroke

Emerging Risk Factors for HZ:

Chronic Obstructive Pulmonary

Disease (COPD)

COPD as a Risk Factor for HZ

• 4 studies assessing the risk of HZ in

patients with COPD

– 1 study showed little to no risk of HZ:

OR = 1.05 (0.96-1.14)

– 3 studies showed a significant increase in

risk of HZ in patients with COPD: risk

increase ranges from 1.32 to 1.85

Risk-based Approach: COPD

COPD should be a trigger/opportunity for you

to offer vaccination:

– Patient is at higher risk

– Quick discussion for you

– Patient more likely to accept because they

understand their condition and how it makes

them prone to complications


Diabetes

Diabetes as a Risk Factor for HZ

• 6 studies demonstrated that diabetes is a risk factor for HZ

– Risk ranges from 1.17 to 3.30

• 1 study showed risk associated with type 1 (OR = 1.27) but

not type 2 (OR = 1.01) diabetes

– However, “The lack of effect found with type 2 diabetes must be

interpreted cautiously, as negative confounding by ethnic group is

possible”

• The type 2 diabetes population may have included South Asian patients,

known to be at lower risk of HZ and higher risk of diabetes

Risk-based Approach: Diabetes

• Diabetes should be a trigger/opportunity for

you to offer vaccination:

– Patient is at higher risk

– Quick discussion for you because they

understand their condition and how it makes

them prone to complications


Statin Use

Statin Use and HZ Risk

Reference Change Results

Canada

Antoniou.

Clin Infect

Dis 2014.

Patients aged > 66 years

Risk of HZ in patients taking statins:

HR = 1.13 (1.10-1.17)

Patients aged > 66 years

Risk of HZ in patients

with diabetes taking statins:

HR = 1.18 (1.09-1.27)

Take-home Messages

• Every visit is a vaccine opportunity

• HZ vaccination should be offered to all patients older than

50 years

• However, a risk-based approach would be an excellent

start

– You have the skill

– They deserve to know

– They value your recommendation

• Immunization is your best medicine

Thank You

• Any Questions?

Documents

An Update on Herpes Zoster - s3.amazonaws.com · SPS: Study Design • RCT: double-blind, placebo-controlled • Subjects: – 38,546 subjects enrolled, ≥ 60 years of age – History