IF YOU CAN

PREVENT
SHINGLES
SUFFERING,
WHY
WOULDN’T
YOU? 1

Vaccinate now for protection that lasts1*

Ref: 1. SHINGRIX PI Version SNX/PI/IN/2022/03 dated 04-Jul-2022

*Shingrix does not protect 100% individuals vaccinated. Median follow-up period of 3.1-4 years in ZOE-50/70

PM-IN-SGX-PMNO-220001
Date of preparation: February 2023
 Clinical Presentation
Herpes
Zoster:
Clinical
Presentation
Table of contents

Abbreviations...................................................................................................................... 6
Module 1: Herpes zoster: clinical presentation and impact of disease............................. 8

1.1 Natural history of herpes zoster............................................................................... 8

1.1.1 Varicella zoster virus..................................................................................................................8

1.1.2 Clinical presentation of varicella zoster virus infection................................................... .9

1.1.3 Herpes zoster-associated pain............................................................................................. 10

1.1.4 Non-pain-related complications of herpes zoster........................................................... 11

1.1.5 Factors increasing the risk of herpes zoster and its complications ........................... 12

1.2 The burden of herpes zoster....................................................................................13

1.2.1 Medical burden associated with herpes zoster.......................................................... 13

1.2.1.1 VZV seropositivity in the general population.............................................................. .13

1.2.1.2 Lifetime risk of herpes zoster .......................................................................................... 13

1.2.1.3 Burden of herpes zoster in patients with underlying conditions........................... 13

1.2.1.4 Incidence of herpes zoster in older adults.................................................................... 14

1.2.1.5 Incidence and prevalence of herpes zoster complications..................................... .15

1.2.1.6 Hospitalisation associated with herpes zoster............................................................ 15

1.2.1.7 Mortality associated with herpes zoster..................................................................... .16

1.2.1.8 Recurrence of herpes zoster............................................................................................ 16

1.2.1.9 Impact of herpes zoster and its complications on quality of life .............................17

1.2.1.10 Impact of herpes zoster in frail individuals.....................................................................17

1.2.2 Economic burden associated with herpes zoster and its complications............. 18

1.3 Advantages and limitations of current antiviral and analgesic therapies ..............19

1.4 Currently available options for herpes zoster prevention.....................................20

1.4.1 Antivirals as prophylactic therapy for herpes zoster in patients

who are immunocompromised .......................................................................................... 20

References........................................................................................................................ 55

5
 Abbreviations

ACV acyclovir

AE adverse event

AIDS acquired immunodeficiency syndrome

AOR adjusted odds ratio

AUD Australian dollars

BOI burden of illness

CI confidence interval

CMI cell-mediated immunity

COPD chronic obstructive pulmonary disease

DNA deoxyribonucleic acid

DM diabetes mellitus

EMA European Medicines Agency

ESRD end-stage renal disease

FDA Food and Drug Administration

gE glycoprotein E

GP general practitioner

HIV human immunodeficiency virus

HM haematological malignancies

HSCT haematopoietic stem cell transplantation

HR hazard ratio

HSV herpes simplex virus

HZ herpes zoster

HZBOI vaccine efficacy for burden of illness due to HZ

HZO herpes zoster ophthalmicus

HZ/su herpes zoster subunit vaccine (Shingrix)

IBD inflammatory bowel disease

IC immunocompromised

IL-2 interleukin-2

IRR incidence rates ratio

LOC local operating companies

LTPS Long-term persistence substudy

MIAVHS Miami Veterans Administration Healthcare system

6
NHS National Health Service

PHN post-herpetic neuralgia

PPV23 23-valent pneumococcal polysaccharides vaccine

PsA psoriatic arthritis

PsO psoriasis

QoL quality of life

RCT randomised controlled trial

RPHRN rapidly progressive herpetic retinal necrosis

RA rheumatoid arthritis

RR relative risk

RZV recombinant zoster vaccine (Shingrix)

SAE Serious adverse event

SF-12 Short-form 12 health survey

SHI statutory health insurance

SLE systemic lupus erythematosus

SPS Shingles prevention study

STPS Short-term persistence substudy

UK United Kingdom

US United States

VE vaccine efficacy

VEHZ vaccine efficacy against herpes zoster

VZV varicella zoster virus

YoA years of age

ZAP zoster-associated pain

ZEST Zostavax Efficacy and Safety Trial

ZVL zoster vaccine live (Zostavax)

7
 Module 1: Herpes zoster: clinical presentation and impact of disease

1.1 Natural history of herpes zoster

1.1.1 Varicella zoster virus

VZV is a human alpha-herpes virus that causes varicella during primary

infection, establishes latency in sensory neurons, and causes HZ when
reactivated. Viral reactivation is associated with impaired immunity – either
due to underlying immunodeficiency, or immunosenescence, a natural age-
related decline in immune system function.

Varicella zoster virus (VZV) is a human alpha-herpes virus and its genome is a linear, double-
stranded deoxyribonucleic acid (DNA) molecule.1 Varicella zoster virus consist of a lipid
envelope enclosing an icosahedral nucleocapsid.1 VZV-specific glycoproteins are part of the
virion envelope1 and play a role in virus entry and cell-to-cell spread.2 In particular, the most
abundant VZV glycoprotein, glycoprotein E (gE), plays a central role in VZV infection and
replication.3 It has been shown to contribute to fusion of membranes4 as well as cell-to-cell
spread via binding to the insulin-degrading enzyme, which is a receptor for VZV.2

During primary infection, VZV particles from skin lesions enter sensory nerves and migrate
through primary afferent nerve tissue to become latent in cranial nerve ganglia, dorsal root
ganglia and autonomic ganglia along the entire neuraxis.5-7 Infected T cells have also been
suggested to deliver VZV to ganglia.1 These ganglia contain the genomic DNA of VZV, but do not
contain infectious virus.7 While latent VZV is non-infectious, it can reactivate in sensory neurons
to form virions which can spread from a single ganglion to neural tissue and the associated
dermatome and cause herpes zoster (HZ) [Figure 1.1].5,7,8 The infection is usually limited to a
single dermatome and the characteristic rash is the result of neurological damage due to viral
replication in sensory ganglia causing destruction of the neurons and satellite cells.1,7,8

Figure 1.1 Establishing latency of VZV in sensory nerve ganglia8

It has not yet been established what triggers VZV reactivation and HZ development, but
the increased susceptibility among people with impaired cell-mediated immunity (CMI)
demonstrates the important role CMI plays in preventing reactivation of latent VZV within
the neuron or, if reactivation occurs, preventing the development of HZ.5,7 In contrast, people
with impaired B cell and humoral responses do not have a higher risk of development of HZ.9,10
Furthermore, patients with impaired B and T cell responses who have pre-existing anti-VZV

8
antibodies remain at a high risk of VZV reactivation;9 evidence suggests that a low level of pre-
existing anti-VZV antibodies does not impact the development of VZV but may impact the
severity of disease.10
CMI comprises VZV-specific memory T cells which include cytotoxic T-cell populations that
recognise VZV proteins.10,11 When the virus is latent in sensory neurons, CMI is thought to be
maintained by both “endogenous boosting” in response to subclinical reactivation of VZV
and “exogenous boosting” in response to exposure to VZV [Figure 1.2].5,10,12 Endogenous and
exogenous boosting can occur at any point in a person’s life, but may not be the only immune
response factors responsible for preventing HZ.10 An alternative/additional theory is that
the persistence of CMI could result from the initial clonal expansion of VZV-specific T cells
with helper and effector functions, without any requirement for subsequent restimulation.10
Irrespectively, a decline in VZV-specific CMI is thought to be the most common reason
for reactivation of VZV and can be a result of ageing or immunosuppressive diseases
or therapies.13,14

Figure 1.2 The pathogenesis of HZ. Adapted from Kimberlin DW, et al. N Engl J Med. 2007.8

Age-related changes to the immune system, also called immunosenescence, affect both the
innate (monocytes, natural killer cells and dendritic cells) and adaptive (B and T cells) immune
system, with the adaptive immune system being most affected.15 The number of naïve T cells
declines with age and the available naïve T cells exhibit many functional defects. These include
restricted diversity of the T cell populations, reduced interleukin-2 (IL-2) production and
impaired differentiation in effector cells, which leads to a decreased immune response to new
antigens. Repeated exposure to antigens also contributes to immunosenescence by limiting
the variety of T cell populations. Similarly, the number of naïve B cells, as well as the diversity
of the B cell pool, decreases with age. Additionally, B cell function declines with age due to
impaired communication among immune cells.15 Immunosenescence is in part responsible for
the increased prevalence and severity of infectious diseases and the low efficacy of vaccination
in older adults.15 The natural decline in VZV-specific memory T cells with age is associated with
an increased risk of HZ.10

1.1.2 Clinical presentation of varicella zoster virus infection

The initial presentation of HZ includes the onset of acute neuropathic pain and a
unilateral rash of itchy, contagious blisters, most frequently on the chest and
face, which typically heals in 2–4 weeks.

VZV causes two distinct diseases with different clinical presentations: varicella (chickenpox) and HZ
(shingles).6

Varicella
Primary VZV infection results in varicella, seen usually in children 1–9 YoA. Less frequently,
adults or individuals who are immunocompromised (IC) develop varicella, which in these
cases tends to be associated with more severe disease.6 VZV causes cell-associated viraemia,

9
 after which a diffuse skin rash occurs.16 This diffuse, vesicular, pruritic skin rash is the main
characteristic of varicella, combined with fever.6 Other potential symptoms include headache,
malaise and loss of appetite. The characteristic rash begins as macules and progresses to
papules and then fluid-filled vesicles, followed by crusting. VZV is highly infectious and virus
transmission can occur through direct contact with the skin lesions or via respiratory aerosols.6
Herpes zoster

HZ often starts with a prodromal phase, which is characterised by pain, itching, numbness
or tingling (paraesthesias), unpleasant sensations (dysaesthesias) or sensitivity to touch
(allodynia) in one to three dermatomes6 before rash appears. Additional symptoms include
malaise, headache and fever.13 After a few days, a unilateral maculopapular rash develops on
the affected area6,14 [Figure 1.3]. The rash is usually accompanied by acute pain, which could
be similar in intensity to prodromal pain, worse, less or might appear for the first time after the
rash has occurred.13 Following the onset of the rash, vesicles form, which scab over in ~10 days,
after which they are no longer contagious.6 The rash typically heals in 2‒4 weeks, but may leave
scarring and pigmentation changes. 5,13 As skin lesions disappear, pain decreases and usually
resolves completely within 4–6 weeks.6

The most frequent sites of HZ are the chest and face, especially the eye, due to VZV reactivation
in the thoracic nerves and the ophthalmic region of the trigeminal nerve, respectively.6,13 The
occurrence of the characteristic rash usually makes the diagnosis of HZ straightforward.13
However, VZV reactivation can lead to dermatomal pain without rash, called zoster sine herpete,
and in these instances diagnosis cannot be made based on the clinical presentation. 5

In IC patients, HZ may initially present in a typical way; however, the rash may be more severe
and its duration prolonged. 5 Individuals who are IC also have an increased risk of disseminated
disease. 5 Individuals who are IC are also more likely to develop recurrent HZ compared with
individuals who are immunocompetent.17

Figure 1.3 Clinical illustration of HZ rash

1.1.3 Herpes zoster-associated pain

Pain is the most common symptom of HZ. Post-herpetic neuralgia (PHN), is

conventionally defined as pain persisting for ≥90 days after the appearance of
acute HZ rash

Pain is the most common symptom of HZ.18 Prodromal pain typically precedes the appearance
of HZ rash.13 Once the characteristic HZ rash appears, there is great variability in the duration of
pain. It is generally accepted that HZ-associated pain can be divided into three phases:19
– Acute pain that occurs within 30 days of rash onset.19
– Subacute herpetic neuralgia: pain that persists beyond the acute phase but resolves before the
diagnosis criteria of PHN are met.19
– PHN, which is conventionally defined as pain persisting for ≥90 days after the appearance of
acute HZ rash20.

Prodromal pain
Prodromal pain precedes the appearance of HZ rash in 70–80% of patients.13 Pain typically

10
begins several days before the onset of rash.13 The prodromal phase is typically 2‒3 days in
duration, but longer durations of ≥1 week are not uncommon.13

Acute pain
Acute pain is experienced by the majority of patients, with 96% of patients reporting acute
pain in one study.18 HZ pain has been associated with interference in patients’ activities of daily
living.21 In comparison to other pain-provoking conditions (using the total pain rating index
scores of the short-form McGill Pain Questionnaire for acute and chronic pain conditions),
acute HZ pain has been ranked as being greater than labour pain and post-surgical pain, but
less than pain from abdominal hysterectomy and acute headache.22

Post-herpetic neuralgia
PHN is the most common complication of HZ.13,23 PHN is conventionally defined as pain
persisting for ≥90 days after the appearance of acute HZ rash.20

PHN is characterised by several pathological findings, such as degeneration of affected

neuronal cell bodies and axons, atrophy of the dorsal horn, scarring of the dorsal root ganglion
and loss of epidermal innervation.13 A variety of types of pain are often described by patients
suffering from PHN, including continuous burning or throbbing pain, intermittent sharp
pain and allodynia (pain due to a stimulus that does not normally provoke pain).13 PHN has
been ranked as being less than pain from fibromyalgia, but greater than arthritis or chronic
cancer pain in a comparison of total pain rating index scores using the short-form McGill Pain
Questionnaire.22 The pain can have a substantial impact on a patient’s quality of life (QoL),
affecting sleep, mood, work and activities of daily living, and has been associated with social
withdrawal, depression and suicidal ideation.5

1.1.4 Non-pain-related complications of herpes zoster

Non-pain-related complications of HZ include, among others, herpes zoster

ophthalmicus (HZO) with potential cranial nerve complications that can lead to
impaired vision or hearing, and stroke.

The non-pain-related complications of HZ are provided in Table 1.1.

Table 1.1. Overview of HZ-associated complications

Complication Description

HZO5,13 – HZ with eye involvement

– Wide range of complications, such as keratitis, uveitis/iritis, corneal
ulceration, conjunctivitis, choroiditis, oculomotor palsy, optic atrophy,
retinitis, acute and chronic glaucoma, etc.
Acute VZV – Usually occurs few days after rash onset
encephalitis6 – Characterised by acute or subacute delirium and few focal neurological
signs
– Other symptoms include headache, meningismus, fever, ataxia and seizures
Myelitis 5,6,13
– Due to direct VZV invasion of spinal cord
– Most commonly follows thoracic HZ
– Neurological symptoms develop ~12 days after rash onset
– Symptoms include bladder dysfunction, weakness of lower extremities,
asymmetric reflexes and sensory disturbances
VZV retinitis6,13 – Acute retinal necrosis in immunocompetent and immunocompromised
patients
– Progressive outer retinal necrosis or rapidly progressive herpetic retinal
necrosis (RPHRN) in patients with AIDS
– RPHRN can occur after HZO or after HZ involving a remote dermatome
Post-herpetic pruritus – Can occur with PHN or independently from PHN
(itch)13 – Can persist after HZ rash resolves
– Chronic pruritus can lead to substantial disability due to disruptive need to
scratch

11
 Ramsay Hunt – Peripheral facial nerve palsy (unilateral facial weakness) combined with
syndrome5,6,24 zoster vesicles on ear, hard palate or tongue
– Additional symptoms include malaise, fever, pain, vertigo, hearing loss,
sensitivity to sound, tinnitus and loss of taste
Stroke5,13,25 – VZV reactivation in the cerebral arteries, with or without zoster rash,
directly causes pathological vascular remodelling and stroke (VZV
vasculopathy)
– Can cause ischaemic or haemorrhagic stroke
Cutaneous – Generally, only occurs in patient who are immunocompromised
disseminated – Is not life-threatening; however, it is a marker for VZV viraemia
disease5
Visceral disseminated – Can occur in patients who are profoundly immunocompromised
disease (without skin – With antiviral treatment, the fatality rate is 5–15%; pneumonia as the most
involvement)5 common cause of death

AIDS, acquired immunodeficiency syndrome; HZ, herpes zoster; HZO, herpes zoster ophthalmicus;
PHN, post-herpetic neuralgia; RPHRN, rapidly progressive herpetic retinal necrosis; VZV, varicella
zoster virus

1.1.5 Factors increasing the risk of herpes zoster and its complications

Individuals who are older or IC due to underlying disease or immunosuppressive

therapy are at high risk of developing HZ. The majority of individuals who
develop HZ are ≥50 YoA. Also, the risk of developing PHN increases with
increasing age.

Risk factors for herpes zoster

Populations at increased risk for developing HZ are those having a decline in immune function,
including older adults or individuals who are at increased risk of HZ due to underlying conditions
[Figure 1.4].6

Figure 1.4 Meta-analysis - Risk factors for HZ.26

*Studies reported HZ risk within the following age groups: ≥60 years (36 studies), ≥50 years (2 studies), ≥40 years
(1 study). AIDS, acquired immune deficiency syndrome; COPD, chronic obstructive pulmonary disease; CRD, chronic renal
disease; CV, cardiovascular; HIV, human immunodeficiency virus; HZ, herpes zoster; IBD, inflammatory bowel disorder; RA,
rheumatoid arthritis; SLE, systemic lupus erythematosus.
Disclaimer: Data cannot be stratified by age for 18-49 years vs ≥50 YoA. Shingrix is indicated for prevention of herpes zoster
(HZ) and postherpetic neuralgia (PHN), in adults 50 years of age or older; Shingrix vaccination schedule consists of two
doses of 0.5 ml each: an initial dose followed by a second dose which can be administered between 2 and 6 months after the
first dose.

12
The majority (68%) of individuals who develop HZ are ≥50 YoA, with a mean age of onset of
59.4 years.27 Although HZ can affect individuals at a younger age, it occurs less frequently and
is usually associated with less severe disease.28

1.2 The burden of herpes zoster

1.2.1 Medical burden associated with herpes zoster

1.2.1.1 VZV seropositivity in the general population

Worldwide, most adults are at risk of HZ through reactivation of VZV infection.8 In the US,
Europe and Australia, >90% of the population is infected with VZV during the first three decades
of life.63-65 Indeed, ≥95.5% of the US population ≥20 YoA had been infected with VZV.64 In parts
of Asia, primary VZV infection occurs by the fourth decade of life at similar prevalence levels.66
In addition, more than 90% of individuals by the age of 40 YoA were seropositive for VZV in
16 European countries.67 In India, >90% by the age of 40 years have latent VZV in their nervous
system.31

1.2.1.2 Lifetime risk of herpes zoster

The individual lifetime risk of developing HZ is ~30%.60 Incidence rates of HZ are generally similar
across North America, Japan and Europe.68-77 Studies using various designs and conducted in
different populations in the US, Canada, South America, Europe, Asia and Australia showed
that the incidence of HZ ranged between 3 and 5 per 1,000 person-years across all age groups
[Figure 1.5].78

Figure 1.5 Incidence of HZ per 1,000 person-years.

Figure reproduced from Kawai K et al. BMJ Open 2014 under a Creative Commons Attribution License
(http://creativecommons.org/licenses/by-nc/3.0/)78

1.2.1.3 Burden of herpes zoster in patients with underlying conditions

Studies have shown higher risk of HZ in patients with autoimmune conditions including systemic
lupus erythematosus, rheumatoid arthritis, psoriasis, psoriatic arthritis and patients with
underlying conditions including COPD, diabetes mellitus (DM) and asthma [Table 1.3].26,47,79-86

13
 Table 1.3. Risk of HZ inpatients with underlying conditions26,47,79-86

Underlying condition Country Risk for HZ* (95% CI)

Autoimmune conditions
SLE Global†,26 RR = 2.08 (1.56–2.76)
RA Global †,26
RR = 1.51 (1.31–1.75)
Other underlying conditions
Spain30 • RR = 1.05 (1.00–1.11)
DM US85 • IRR = 1.68 (1.67–1.70)
Global †,26
• RR = 1.24 (1.14–1.35)
South Korea86 • AOR = 1.32 (1.28–1.35)
Asthma
Global †,26
• RR = 1.24 (1.16–1.31)
• COPD: RR = 1.24 (1.14–1.35)
Spain30,82
• COPD-ICS: RR = 1.61 (1.52–1.71)82
• All COPD: HR = 1.68 (1.45–1.95)

Taiwan83 • COPD-ICS: HR = 2.09 (1.38–3.16)

COPD
• COPD-OS: HR = 3.00 (2.40–3.75)
US84 • COPD: IRR = 4.16 (4.02–4.31)
Japan47 • COPD: HR = 1.24 (1.04–1.47)
Global†,26 • COPD: RR = 1.41 (1.28–1.55)

AOR, adjusted odds ratio; DM, diabetes mellitus; IRR, incidence rates ratio; RR, relative risk;
HR, hazard ratio; COPD-ICS, COPD patients with inhaled corticosteroids prescriptions; COPD-OS,
COPD patients with oral steroids; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus
*Compared to non-COPD/DM/Asthma. †Pooled data from a systematic literature review of
88 publications across 16 countries.

1.2.1.4 Incidence of herpes zoster in older adults

Two-thirds of HZ cases occur in adults ≥50 YoA.

A systematic literature review identified 69 publications across 19 countries reporting HZ

incidence rates, and in which a steady increase in cumulative HZ incidence over time was
observed across all regions.87 A meta-regression analysis of 59 studies included in the systematic
literature review estimated that 14.9 million cases of HZ occurred worldwide in adults ≥50 YoA
in 2020, which was projected to increase to 19.1 million by 2030 in the absence of vaccination.88

The risk of HZ increases sharply in individuals ≥50 YoA and continues to increase into late life.5,27
Over the coming years, the incidence of HZ is expected to rise in most countries due to ageing
populations and a predicted rise in the incidence of immunocompromising conditions in older
individuals.89 The described meta-regression analysis found that the incidence of HZ increases
with age, and that the incidence rate of HZ was lower in males compared with females.88

Herpes Zoster in India:

A systematically conducted literature search of Herpes Zoster in India yielded 27 studies,
published between January 2011 and May 2020, reporting 3124 HZ clinical cases, with high
proportions in older adults (>50 years of age: 15.0–81.3%). Thoracic dermatome was consistently
reported as the most frequent site affected by HZ (38.9–71.0%). Postherpetic neuralgia and
secondary bacterial infections were the two most frequent complications (10.2–54.7% and
3.5–21.0%, respectively).159

14
Besides advanced age, human immunodeficiency virus (HIV) seropositivity, diabetes mellitus,
prolonged steroid use, and malignancies with therapy were the frequently associated
predisposing/co-morbid conditions in the study.

1.2.1.5 Incidence and prevalence of herpes zoster complications

Over 30% of cases of HZ may be associated with complications.

Post-herpetic neuralgia
PHN is the most frequent complication of HZ. The risk of developing PHN varies from 5% to more
than 30%, depending of the type of study design and age distribution of study populations.78
Three studies reported PHN lasting up to ≥10 years.28,90,91 Both the incidence and duration of
PHN pain increase with age [Figure 1.7].5,50,90,92

Figure 1.7. Percentage of HZ cases with PHN in the US.93

HZ herpes zoster; PHN, post-herpetic neuralgia

1.2.1.6 Hospitalisation associated with herpes zoster

Globally, the overall HZ-related hospitalisation rates range widely from 2 to 25 per 100,000
person-years in studies including individuals with HZ of all ages, due to the variation in
admission criteria in the different settings.78 Hospitalisation rates with a primary diagnosis of
HZ were estimated at 4.1 per 100,000 person-years in France 71 and 4.4 per 100,000 person-
years in England.108 Hospitalisation rates increased steeply with age, with the majority of cases
occurring in adults ≥50 YoA.78 In studies conducted in the US, Australia and Germany, HZ-
associated hospitalisation rates ranged from 10 to 31/100,000 person-years in adults 60–69
YoA up to 65–100/100,000 person-years in adults ≥80 YoA.109-111 In Italy, hospitalisation rates in
adults ≥50 YoA were 10.3 per 100,000 person-years for HZ and 1.9 per 100,000 person-years for
PHN as primary diagnoses and 17.5 and 2.9 per 100,000 person-years, respectively, for primary
and secondary diagnoses combined.59 A primary diagnosis of HZ or PHN was responsible for
2,829 hospitalisations annually in Italy in immunocompetent adults ≥15 YoA, with 92.3% of those
admissions in adults ≥50 YoA. PHN was responsible for 16.9% of all HZ-related admissions. In
older adults, hospitalisation rates due to HZ and PHN increased progressively with age.59

15
 1.2.1.7 Mortality associated with herpes zoster

Analysis of data from North America, Europe and Asia-Pacific found mortality rates associated
with HZ were 0.02–0.47 per 100,000 person-years, with the majority of deaths occurring in adults
≥60 YoA.78 Across Europe, among people >50 YoA, HZ mortality rates vary widely by country
from 0.002/100,000 person-years in Poland to 0.070/100,000 person-years in Denmark.112 In
all seven European countries investigated, there was a trend towards higher mortality rates in
older age groups, with the increase occurring from 70–74 YoA.112 When considering HZ coded
as a primary and secondary diagnosis, the mortality rate was estimated at 0.29 per 100,000
person-years in France 71 and 0.6 per 100,000 person-years in Spain.113

1.2.1.8 Recurrence of herpes zoster

The risk of recurrent HZ ranged from 1% to 6% across several studies [Table 1.4]; those
with longer follow-up tended to report a higher risk (5–6%).78 For example, a large study of
~35,000 individuals with HZ in Japan, with 6.5 years’ follow-up, estimated a recurrence rate
of 6.4%.114 A US study estimated a recurrence rate of 6.2% after 8 years’ follow-up, which was
similar to the rate of initial HZ episodes in the same population.17 The risk of HZ recurrence
was greater among IC individuals, in individuals with HZ-associated pain lasting for ≥30
days after the initial episodes, in women, and in individuals ≥50 YoA at the initial HZ episode17

Table 1.4. HZ recurrence rate after vaccination in individuals with prior HZ occurrence

Recurrence
Age Follow up Population Recurrence Publication
Country and/or City rate among IC
(years) (years) (n)* rate “total” year
individuals

Minnesota, USA17 >22 7.3 1,669 6.2% 12% 2011

Shozu, Japan 115
≥50 3 NA 1.01% NA 2016
Mizazaki, Japan 114
1–90 6 34,877 6.41% NA 2017
Israel116 NA 2 NA 2.9% NA 2013

South NA 10 NA 5.3% 6.9% 2019

Korea117
California, USA118 ≥50 10 11,716 10.26% NA 2020
Australia 119
≥45 8 17,413 0.4% Recent 2020
immunosup-
pression: 16.96
cases per 1,000
person years

The table has been independently created by GSK from the original data from Shiraki K, et al. Open
Forum Infect Dis 2017;4:ofx007, Yawn P, et al. Mayo Clin Proc 2011;86:88-93, Nakamura Y, et al. J Am
Acad Dermatol 2016;75:950-95, Weitzman D, et al. J Infect 2013;67:463-9, Kim Y. G., et al. J Korean Med
Sci 2019;34:e1, Tseng HF, et al. J Infect Dis. 2020;222(5):798-806, and Qian J, et al. J Am Acad Dermatol.
2020:S0190-9622(20)32114-9.
HZ, herpes zoster; IC, immunocompromised; NA, not available

In patients with HZO in the MIAVHS study the overall 1-, 3-, and 5-year recurrence rates for
eye disease or rash were 8%, 17% and 25%, respectively.96 Uveitis and ocular hypertension were
identified as risk factors for recurrent or chronic disease, whereas age was not a significant risk
factor.

16
Figure 1.8. Recurrence of HZ by age group, from Batram Dermatol Ther 2021.29

10

Percentage of incident HZ cases (%)

8.9
9
50-59 YoA
8
6.7 ≥60 YoA
7
6
5
4
3
1.8
2 1.0 0.9 0.6
1
0

1 recurrence 2 recurrences 3 or more

recurrences

Number of HZ recurrences per patient

HZ, herpes zoster; YoA, years of age

1.2.1.9 Impact of herpes zoster and its complications on quality of life

Two disease-specific questionnaires are used to assess how pain and discomfort associated
with HZ and PHN affect patients’ daily lives: the ‘Zoster Brief Pain Inventory’ questionnaire and
the ‘Zoster Impact’ questionnaire.120,121 In addition, QoL may be measured using generic health-
related QoL instruments including the EQ-5D,121 a widely used utility instrument, and the Short
form-12 health survey (SF-12).122

Pain associated with HZ and its complications has a substantial impact on many aspects
of everyday life, including physical, psychological, social and functional health domains
[Table 1.5].18,91,121,123-128 There is also a clear correlation between increasing severity of pain and
greater interference with these daily activities.126

Table 1.5. Impact of pain associated with HZ and PHN on different health domains126

Physical Psychological
– Fatigue – Reduced mobility – Depression – Difficulty
– Anorexia – Physical inactivity – Anxiety concentrating
– Weight loss – Insomnia – Emotional distress – Fear

Social Functional
– Withdrawal – Loss of independence – Dressing – Travelling
– Isolation – Change in social role – Bathing – Cooking
– Attendance at – Eating – Housework
fewer social – Mobility – Shopping
gatherings

HZ, herpes zoster; PHN, post-herpetic neuralgia

Overall, QoL has been shown to decrease as HZ-associated pain increases, as assessed using
the EQ-5D survey.129 Non-pain-related HZ complications, such as ophthalmic or neurological
complications, can also have negative effects on patient QoL; however, further research is
required to assess the extent of the impact that these non-pain-related complications have
on patients’ QoL.126

1.2.1.10 Impact of herpes zoster in frail individuals

Older adults are at an increased risk of having severe pain during the acute phase, and of
developing complications such as PHN, which can have a devastating impact on QoL.125,130,131
Particularly in frail individuals, HZ can lead to an inability to recover the lifestyle, interests,
and level of functional activity that existed before HZ, and may also be associated with

17
 depression.130,132 Antiviral therapy can reduce both rash extent and duration and acute pain
severity, if administered within 72 hours of rash onset, but has not been shown to decrease the
incidence of PHN.133,134 Nonsteroidal anti-inflammatory drugs or acetaminophen or opioids are
commonly used for the treatment of acute pain and PHN associated with HZ.135 However, the
application of drugs to manage HZ in frail, co-morbid, and often poly- medicated patients must
be carefully considered, as frail individuals could be affected more by treatment- related side
effects than non- frail individuals.136

1.2.2 Economic burden associated with herpes zoster and its complications

HZ is associated with significant economic burden. While PHN is associated

with significant additional costs, the overall cost of acute HZ is driving
majority of costs associated with the overall burden of disease.

Direct economic burden

HZ is associated with a significant direct economic burden, although healthcare costs differ
from country to country. As healthcare costs are generally collected retrospectively, some
associated care may be missed if it was not correctly documented. Thus, it is likely that HZ-
related costs are underestimated.137 The annual healthcare costs associated with acute pain
in HZ in the US range from US$ 757 to US$ 1313 per patient.138 The overall annual direct medical
burden associated with HZ is estimated to exceed US $1 billion.139 Direct costs, including
outpatient costs (including medical visits, diagnostic tests and medication), hospitalisation and
inpatient costs are the key contributors to the overall cost burden of HZ and PHN.140 PHN, the
most common complication of HZ, is associated with significant additional costs.138 However,
when considering the overall burden of disease, the overall cost of acute HZ is higher than that
for PHN.140
Several public health impact studies have been conducted [Table 1.6] that demonstrate that
vaccination with RZV leads to a reduction in HZ cases, PHN cases, HZ-related complications
and deaths, as well as lower resource utilisation (i.e. physicians’ visits and hospitalisations),
when compared with vaccination with zoster vaccine live (ZVL, Zostavax) or no vaccination.
See Module 3 for an in-depth discussion of the economic models used.
Table 1.6. Summary of modelling outcomes for vaccination With RZV versus no vaccination.

Compli-
Hospitaliz GP
HZ cases PHN cases cation
Country Population Time frame -ations visits pre- NNV
prevented prevented cases
prevented vented
prevented
UK146 70 YoA Over 1 year 30,262 5,409 4,455 1,993 HZ=12
(n=722,616)
PHN=65
Italy147 65 YoA At Year 3 30,848 7,064 - -
(n=778,000)
Canada148 ≥60 YoA Remaining 554,504 166,196 73,711 - HZ=11
lifetime
PHN=34
US149 ≥50 YoA Over 15 years 4,600,000 368,000 - 14,400 1,300,000
(cumulative) (cumulative) (cumulative) (cumulative)
The table has been independently created by GSK from the original data from Van Oorschot DAM, et al.
BMJ Open. 2019;9:e025553; McGirr A, et al. Appl Health Econ Health Policy. 2019;17:723-732; Volpi A, et al.
Hum Vaccin Immunother. 2020;16:327-334; and Patterson BJ, et al. Mayo Clin Proc Innov Qual Outcomes.
2021;5:596-604
GP, general practitioner; HZ, herpes zoster; NNV, number needed to vaccinate; PHN, post-herpetic
neuralgia; YoA, years of age
In the UK, the total mean cost of healthcare has been calculated at £103 per acute HZ episode.70
In Sweden, the cost per HZ patient in 2020 was estimated to be €548 (unpublished data). The
annual healthcare cost per HZ case in Australia was estimated to range between AUD$537 and
AUD$561, which translates to an overall healthcare cost of AUD$32.8 million per year.111 The
direct economic burden of HZ in Italy was estimated at €28.2 million, €21.5 million of which was
associated with the treatment of acute HZ.59

18
In an analysis of a statutory health insurance (SHI) database in Germany, payer-related costs
associated with HZ were similar for the total population and for those ≥50 YoA (e.g. annual
inpatient costs of €2,984 and €3,081 per user, respectively); and the same was true for PHN (e.g.
annual inpatient costs of €3,738 and €3,891 per user, respectively).75 For the overall population,
the annual cost per HZ case from a payer perspective was estimated as €210, totalling €85
million, and for PHN was €1,123, totalling €20 million (due to the lower incidence of PHN vs HZ).75
The cost of HZ and PHN rose with increasing age, and for the ≥50 YoA group costs were €229/
case and €62 million in total for HZ, and €1,039 and €17 million, respectively, for PHN.75 Notably,
from a societal perspective, the sick-leave costs were €6,530 and €6,901 per user, respectively,
for PHN, compared with €1,367 and €1,660 per user, respectively, for HZ.75
In Manitoba, Canada, a 50% increase in HZ diagnoses between 1997/98 and 2012/14 led to an
increase in the cost of prescriptions to treat HZ-related pain of 174% to CAN$332,981 in 2011/12.141
PHN accounted for 82.8% of drug costs, primarily driven by the 212% increase in the use of
anticonvulsants, i.e. gabapentin, to treat PHN during this time.141
In Belgium, the mean direct medical cost due to ambulatory-treated HZ was €247; for those who
were hospitalised, cost increased to €5,438.142 In a Dutch study, the presence of significant PHN
was shown to significantly increase costs, with median costs (direct and indirect healthcare
costs and loss of productivity) of €100‒€175 per 3 months for those with significant pain compared
with €25‒€60 per 3 months in those without pain.62
In the US, PHN was responsible for an overall healthcare cost of US$2,159‒US$5,387 per patient.138
However, healthcare costs depend on type of insurance, and PHN-associated healthcare costs
could be as high as US$9,310 for Medicaid patients.143
The cost of HZ management increases with pain severity and the duration of pain
experienced.70,75,140 In the UK, outpatient costs for HZ ranged from £60.15 per case for those with
no pain to £124.89 in those with severe pain, and for PHN costs ranged from £38.61 per month in
those with mild pain to £52.15 per month in those with severe pain.70 The total mean cost per PHN
episode in the UK is estimated at £341 if pain persists for ≥1 month and £397 if pain is endured for
≥3 months (compared with £103 for acute HZ pain, i.e. if pain resolves in <1 month).70
A study in the US found that HZ increased the total healthcare costs among patients with COPD.
Patients with both HZ and COPD had an increased rate of all-cause outpatient visits (IRR 1.18;
95% CI 1.15–1.22; P<0.001) compared to those with COPD but without HZ. Higher all-cause total
costs were observed in the first year of the observation period, with an adjusted cost difference
between US$110 and US$536 (95% CI) per patient per month (P<0.004).144
For patients with systemic lupus erythematosus and HZ associated with corticosteroid use,
disease-specific costs for HZ were calculated as US$2,079.145
Indirect economic burden
HZ is associated with an additional, indirect economic burden, in part because patients lose
working time due to illness and pain. Individuals ≥60 YoA with HZ in the US lose an average of
129 hours of work per HZ episode (including those progressing to PHN), amounting to estimated
costs of US$2,437 per episode for the working population.93 In a UK study of 70 patients, a total of
307 workdays were lost over a follow-up period of 6 months, with caregivers losing an additional
52 workdays.150 The total average cost per HZ case to the patient, National Health Service (NHS)
and the wider society over 6 months was calculated at £524 [Table 1.7].150
Table 1.7. Mean cost per case of HZ over a 6-month follow-up period in the UK [adapted from150]

Age Number of patients Mean cost, £ (range)

<65 years 45 526.3 (20-3,578)
≥65 years 25 519.9 (48-4,218)
Overall 70 524.0 (20-4,218)

HZ, herpes zoster

In an analysis of an SHI database in Germany, costs associated with HZ from a societal perspective
were €376 per case in the overall population, totalling €152 million, and €353 per case for those
≥50 YoA, totalling €96 million; for PHN, these costs were €1,645, €30 million, €1,298 and €21 million,
respectively.75
Of 428 individuals ≥50 YoA with HZ engaged in full- or part-time employment enrolled in a study spanning
eight countries (Argentina [n=37], Brazil [n=36], Costa Rica [n=6], Mexico [n=49], Canada [n=160], Korea
[n=45], Taiwan [n=49] and Thailand [n=46]), 57.7% reported work time loss due to their concurrent
episode of HZ.151 Overall mean work time loss was 9.1 (SD 15.6) days. Baseline work effectiveness
(at initial physician assessment; patient rated on a scale of 0–100%) was significantly lower in individuals

19
 reporting work time loss (mean 50.3% vs 71.4%; P<0.001) and a significantly greater proportion of
individuals with work time loss reported a decrease in work effectiveness than those without work time
loss (89.1% vs 66.0%; P<0.001). Furthermore, work time loss was a significant negative predictor of QoL
using the EQ-5D, as was moderate/severe worst pain compared with mild pain.151
1.3 Advantages and limitations of current antiviral and analgesic therapies

Despite the advantages of antiviral therapy for the management of HZ and acute
pain, there are also several limitations in clinical practice (in particular, if treatment
initiation is delayed). Supplementary treatment with analgesics is often required
for pain management.

There are advantages to treating HZ with antiviral therapies, which support their use as a first-line treatment
in adults with HZ [Table 1.8].13 Antivirals have been shown to be effective in decreasing the incidence of new
lesion formation, accelerating healing and reducing acute pain in clinical trials.152 Antivirals are well tolerated,
with the most commonly reported adverse events (AEs) being nausea and headache. These occur in <20% of
patients and at a similar rate to placebo.152 In addition, antiviral therapy is a relatively low-cost treatment for
HZ, as the three standard antiviral treatments are all off-patent, with generic forms widely available.
Despite these benefits, antiviral therapies have considerable limitations, especially in ‘real-life’ settings
[Table 1.8]. For example, the delay in treatment initiation is a considerable problem in clinical practice. The
efficacy reported in randomised controlled trials (RCTs) was in subjects who initiated treatment within
72 hours of rash onset, yet no studies have been performed in which antiviral therapy is initiated later, i.e. >72
hours after rash onset (see the appendix for further information).134 Delays in diagnoses and obtaining the
necessary treatment means that patients often do not start antiviral therapy within the recommended 72-
hour timeframe.13,89,126,153 Furthermore, there is high-quality evidence demonstrating that acyclovir does not
reduce the incidence of PHN, and insufficient evidence to determine the effect of other antiviral treatments.152
Table 1.8. Summary of the advantages and limitations of antiviral therapy13

Advantages Limitations
– Delays in treatment initiation, no studies when initiation is >72 h post
– Proven efficacy in acute HZ
rash onset134
– Limited evidence for efficacy against PHN,152 current treatments are
– Well tolerated
suboptimal; only palliative therapies are available154
– Low cost (generic) – ACV-resistant isolates

– May require inconvenient dosing regimens, 1–5 times per day

ACV, acyclovir; HZ, herpes zoster; PHN, post-herpetic neuralgia

1.4 Currently available options for herpes zoster prevention

1.4.1 Antivirals as prophylactic therapy for herpes zoster in patients who are
immunocompromised

In patients who are IC, antiviral therapy is often used as prophylactic treatment
of HZ, due to lack of better preventive treatment.

Antiviral therapy is commonly used as prophylactic therapy for HZ (as well as other viruses such as herpes
simplex virus [HSV] and cytomegalovirus) in IC populations, which show a higher risk of infection or reactivation
compared with individuals who are immunocompetent.155 Extensive literature on the use of antivirals as
prophylactic therapy for VZV reactivation in paediatric patients and young adults is available, but there are
relatively fewer studies focusing on HZ in older adults.
Due to the risk of varicella in IC patients, antiviral therapy remains the primary option in these patients.155-157
The benefits of antiviral therapy include limited AEs and protection from other viruses; however, there are
concerns regarding increased rates of renal toxicity and neurotoxicity,156 as well as rebound virus activation
after treatment cessation.155 Furthermore, long-term administration of antiviral in IC patients can lead to the
development of drug resistance. The emergence of isolates resistant to acyclovir is increasingly recognised
in immunocompetent individuals with herpetic keratitis. Antiviral drug resistance monitoring for HSV and VZV
may therefore be required to encourage rational use of antiviral therapy in high-risk populations.158

20
SHINGRIX:
Product
Information

Product
Table of contents

Abbreviations .............................................................................................................24
Module 2: Preclinical development, recommendations, formulation and
manufacturing.............................................................................................................25

2.1 Preclinical development of RZV........................................................................25

2.1.1 Rationale for the development of RZV for the prevention of herpes zoster..... 25

2.1.2 Formulation of RZV .......................................................................................................... 25

2.1.3 Selection of glycoprotein E as the antigen for RZV................................................. 26

2.1.4 Selection of AS01B as the adjuvant for RZV in preclinical studies.........................27

2.2 RZV composition................................................................................................ 27

2.3 Practical features of RZV...................................................................................28

2.4 Reconstitution and packaging...........................................................................28

2.5 Worldwide RZV indications and recommendations..........................................29

References .................................................................................................................. 61

23
 Abbreviations
AIDS acquired immune deficiency syndrome
CDC Centers for Disease and Prevention
CHO Chinese hamster ovary
CMI cell-mediated immunity
DOPC dioleoylphosphatidylcholine
gE glycoprotein E
HIV human immunodeficiency virus
HZ herpes zoster
HZ/su herpes zoster subunit vaccine
HZO herpes zoster ophthalmicus
IC immunocompromised
IFN interferon
IL interleukin
IM intramuscular
JCVI Joint Committee on Vaccination and Immunisation
LOC local operating companies
LPS lipopolysaccharide
MoH Ministry of Health
MPL 3-O-desacyl-4’-monophosphoryl lipid A
NACI National Advisory Committee on Immunization
PHN post-herpetic neuralgia
PI Prescribing Information
QS-21 Quillaja saponaria Molina, fraction 21
RZV recombinant zoster vaccine (Shingrix)
SmPC summary of product characteristics
STIKO Standing Committee on Vaccination
TLR toll-like receptor
UMV universal mass vaccination
VZV varicella zoster virus
YoA years of age
ZVL zoster vaccine live (Zostavax)

24
Module 2: Preclinical development, recommendations, formulation and
manufacturing

2.1 Preclinical development of RZV

2.1.1 Rationale for the development of RZV for the prevention of herpes zoster

There is a substantial unmet medical need associated with herpes zoster and its
potentially debilitating complications, particularly in older adults and those who are
immunocompromised, mainly due to the limitations of the current standard of care using
antivirals, and moderate efficacy and contraindications associated with vaccination with
live-attenuated vaccine in these populations.

Worldwide, most adults are at risk of herpes zoster (HZ) through reactivation of
varicella zoster virus (VZV) infection.1 In the US, Europe (apart from Italy) and Australia,
>90% of the population is infected with VZV during the first three decades of life.2-4
Older individuals are particularly susceptible to HZ and its complications, with two-
thirds of cases of HZ occurring in individuals ≥50 years of age (YoA) and the incidence
of both increasing with age.5-7 Immunocompromised (IC) individuals are also at
increased risk of HZ, including recurrent HZ.7 Up to 33% of cases of HZ are associated
with complications.8 Post-herpetic neuralgia (PHN), often defined as chronic pain
persisting for at least 3 months after rash onset, is the most common HZ-associated
complication and substantially decreases the patient’s quality of life.9,10 Other HZ-
associated complications include herpes zoster ophthalmicus (HZO), which can lead
to loss of vision. Other less common complications include facial nerve palsy, myelitis
and encephalitis.7
Treatment of HZ with antiviral therapy initiated within 72 hours of rash onset effectively
reduces the duration of the rash and the severity of acute HZ-associated pain;11
however, initiation of antiviral therapy within 72 hours of rash onset often cannot be
achieved.10,12 Furthermore, the effectiveness of antiviral therapy in preventing PHN is
unclear.13
In addition to the medical burden imposed by HZ and its complications, they also
impose a substantial direct and indirect economic burden, with estimated direct
annual costs exceeding US$1 billion in the US, and costs increasing with the level and
duration of pain.14,15
The substantial unmet medical need associated with HZ, a serious medical condition
that can lead to many debilitating complications, particularly in older adults and
those who are IC, provided the rationale for the development of a new vaccine for the
prevention of HZ. To address this need, GSK developed RZV, a non-live subunit vaccine
against HZ, which was licensed in the US in October 2017,20,21 and Europe in 2018.22-24
2.1.2 Formulation of RZV

RZV is a non-live HZ vaccine composed of a subunit antigen, a recombinant

truncated form of VZV envelope gE and the AS01B Adjuvant System, designed
to enhance immune responses and provide high and durable protection against
HZ and its complications. RZV has been demonstrated as immunogenic with a
tolerable safety profile in preclinical studies (see Module 3 for clinical data).

The GSK HZ vaccine, RZV, is an adjuvanted recombinant subunit vaccine

(gE/AS01B).20,25 The antigen component of the vaccine is a truncated form of the VZV
envelope glycoprotein E (gE) which is the most abundant gE expressed on the surface
of virus-infected cells.26 The dose of gE antigen used in RZV is 50 µg.23,27 The adjuvant
component of RZV is AS01B, which consists of liposomes and two immunoenhancers,
50 µg of Quillaja saponaria Molina, fraction 21 (QS-21) and 50 µg of 3-O-desacyl-4’-
monophosphoryl lipid A (MPL).27

25
 – Liposomes are artificial vesicles with a phospholipid bilayer (composed of
dioleoylphosphatidylcholine [DOPC] and cholesterol) surrounding an aqueous
core.28 As liposomes alone are usually inert carriers, they have been developed
as a drug delivery system.28,29 Within adjuvants, liposomes act as vessels for the
immunostimulatory components.29 The use of liposomes in AS01B was developed to
improve the tolerability of QS-21.28
– QS-21 is a natural saponin molecule purified from the bark of the South American
Quillaja saponaria Molina tree.28,30 It was first studied as an adjuvant for veterinary
vaccines.28 It enhances both antibody- and cell-mediated immune responses, with
induction of cytotoxic T-lymphocyte responses. Due to the surfactant nature of QS-
21, it can also increase cell permeability to proteins, inducing intracellular immune
responses.28
– MPL is a purified, non-toxic endotoxin derivative prepared from the lipopolysaccharide
(LPS) of Salmonella minnesota R595 strain.28,30 MPL has been shown to activate
toll-like receptor 4 (TLR4), an innate receptor on antigen-presenting cells, which
therefore plays a role in humoral and cellular immunity.30,31 It has immunostimulatory
properties similar to LPS but lacks the reactogenicity of native LPS.31 Nearly 30 years
of development and clinical research have shown that MPL can be administered in
humans with an acceptable risk/benefit profile.30

Figure 2.1 Vaccine composition of RZV.28

Images adapted from Shutterstock, ID 209784145 and Franz Eugen Köhler, Köhler’s Medizinal-Pflanzen
[Public domain].

Note: HZ/su should now be referred to as RZV

HZ/su, herpes zoster subunit; MPL, monophosphoryl lipid A; QS-21, Quillaja saponaria
Molina, fraction 21; RZV, recombinant zoster vaccine
2.1.3 Selection of glycoprotein E as the antigen for RZV

Glycoprotein E is the most abundant VZV glycoprotein expressed on the surface of

virus-infected cells.36 It plays a central role in the initiation and progression of VZV
infections, by contributing to the fusion of membranes during infection.32 In addition,
the interaction between gE and the insulin-degrading enzyme cellular receptor is
critical for infection by both cell-free and cell-associated VZV.33
Glycoprotein E has been shown to stimulate both cellular and humoral immune
responses, and it is a major target of cell-mediated immune responses following VZV
infection.34 VZV seropositive adults have a high frequency of circulating gE-specific
CD4+ T cells (via the central and effector memory pattern).35,36 As gE is only expressed

26
during viral replication, this supports a consistent role for gE-specific CD4+ T cells in
the control of VZV infection.36 Additionally, primary VZV infections induce antibodies
against many VZV proteins including gE.34,35
2.1.4 Selection of AS01B as the adjuvant for RZV in preclinical studies

As VZV gE is a good immunisation target but a relatively weak immunogen when

administered as a single antigen, it was necessary to combine it with an Adjuvant
System to ensure an optimal immune response. GSK investigated several adjuvants
and, based on series of preclinical and clinical studies, chose AS01B for this vaccine.39
AS01B is composed of two immunostimulants, the plant extract QS-21 (50 μg) and the
bacterial cell wall extract MPL (50 μg), and liposomes (5 μL).28 The Adjuvant System
was designed to enhance the immune responses, and especially VZV-specific CMI,
which is considered essential to prevent VZV reactivation.

2.2 RZV composition

RZV is supplied as two vials, one containing a single-dose

of gE (active ingredient) in a lyophilised form which needs
to be reconstituted using the other vial containing a single
dose of the Adjuvant System AS01B in suspension.20
While it is recommended to administer the reconstituted
vaccine immediately, the reconstituted vaccine is stable for a maximum of 6 hours at 2
to 8ºC.20,21,23,27 The composition of the vials, which are preservative-free, is shown below
[Table 2.1 and Table 2.2].
Table 2.1 Composition of the gE vaccine component (lyophilised)

Ingredient Function

gE Active ingredient

Sucrose Cake stability

Polysorbate 80 Protein solubilisation and recovery

Dipotassium phosphate (K2HPO4) Buffering agent

Sodium dihydrogen phosphate dihydrate

Buffering agent
(NaH2PO4 •2H2O)

gE, glycoprotein E

Table 2.2 Composition of the AS01B Adjuvant System (liquid)

Ingredient Function

3-O-desacyl-4’-MPL Immunoenhancer
Purified QS-21 Immunoenhancer
DOPC Liposomes membrane build-up
Liposomes membrane build-up and quenching of
Cholesterol
QS-21 lytic activity

Disodium phosphate anhydrous (Na2HPO4) Buffering agent

Potassium dihydrogen phosphate (KH2PO4) Buffering agent

NaCl Tonicity adjuster

Water for injection Solvent
Note: Components of the AS01B Adjuvant System are the same as those in the AS01E Adjuvant System used in the
Mosquirix vaccine
DOPC, dioleoylphosphatidylcholine; MPL, 3-O-desacyl-4’-monophosphoryl lipid A; QS-21, Quillaja saponaria Molina,
fraction 21

27
 2.3 Practical features of RZV

The key storage and administration features of RZV, are shown below [Table 2.3].27,37
Information may vary in country Prescribing Information, therefore kindly also refer
to country Prescribing Information.

Table 2.3 Practical features of RZV

Feature Prescribing Information (India)37

Two doses (0.5 mL each)
an initial dose followed by a second dose 2 months later.
Dose and schedule If flexibility in the vaccination schedule is necessary, the second
dose can be administered between 2 and 6 months after the first
dose
Intramuscular injection, preferably in the deltoid muscle of the
Administration
upper arm
Can be given concomitantly with unadjuvanted seasonal influenza
Administration with vaccine, PPV23 or reduced antigen Tdap.
other vaccines When given concomitantly with other injectable vaccines, the
vaccines should always be administered at different injection sites
3-year shelf life at 2-8ºC in original package protected from light
Storage
Maximum of 6 hours at 2 to 8ºC once reconstituted

2.4 Reconstitution and packaging

RZV is supplied as two vials, one containing a single-dose of gE (active ingredient) in

a lyophilised form which needs to be reconstituted using the other vial containing a
single dose of the Adjuvant System in suspension.37

Prior to reconstitution, the powder and suspension should be inspected visually for
any foreign particulate matter or changes to its appearance. If either is observed, the
vaccine should not be reconstituted.37

RZV must be reconstituted prior to administration.27, 37

1. Withdraw the entire contents of the vial containing the suspension into the syringe.

2. Add the entire contents of the syringe into the vial containing the powder.

3. Shake gently until the powder is completely dissolved.

The reconstituted vaccine should be an opalescent, colourless to pale-brownish

liquid. The reconstituted vaccine should also be inspected visually for any foreign
particulate matter or variation in its appearance. If either is observed, RZV should not
be administered.27, 37

After reconstitution, the vaccine should be used promptly; however, if this is not
possible, the vaccine may be stored in a refrigerator (2 to 8°C) for up to a maximum of
6 hours. If it is not used within this time, the vaccine should be discarded.27, 37

28
2.5 Worldwide RZV indications and recommendations

Table 2.4 RZV recommendations in the US, Canada, Germany, UK, Spain, and Australia

Recommending Immunocompetent
Country IC specifics^
body (year) populations
General
• Patients who are, or will
population: • ≥50 years be, immunodeficient or
US CDC (2018)43
immunosuppressed due to disease
IC population:
or therapy
CDC (2021)*,44
• ≥50 years

• Previously
• Discretionary recommendation;
received ZVL
based on expert opinion
Canada NACI (2018) 45

• Previous episode
• Will reassess as evidence evolves
of HZ

Germany STIKO (2018)46 • ≥60 years • Provided a list of examples for IC

UK JCVI (2021)48 • ≥60 years • PHE to consider the definition of IC

• ≥65 years At risk includes: HSCT, SOT, JAK

inhibitor therapy, HIV, hematologic
Spain MoH (2021)50 • Beginning in 2022
malignancies, and solid tumors
after confirmation
undergoing chemotherapy
of dose availability
• Specialist advice needed for mild
• ≥60 years (≥1 to moderate IC conditions
Australia ATAGI (2021)51 year since last HZ
episode) • Contraindicated for severe IC
conditions

*Approved unanimously at the CDC Advisory Committee on Immunization Practices (ACIP) meeting on
October 20, 2021
ATAGI, Australian Technical Advisory Group on Immunisation; CDC, US Centers for Disease Control
and Prevention; HIV, human immunodeficiency virus; HSTCT, hematopoietic stem cell transplant; HZ,
herpes zoster; IC, immunocompromised; JAK; janus kinase; JCVI, Joint Committee on Vaccination and
Immunisation; MoH; Ministry of Health; NACI, Canadian National Advisory Committee on Immunization;
PHE, Public Health England; RZV, recombinant zoster vaccine; SOT, solid organ transplant; STIKO,
Standing Committee on Vaccination; ZVL, zoster vaccine live
^Disclaimer Shingrix is indicated for prevention of herpes zoster (HZ) and postherpetic neuralgia
(PHN), in adults 50 years of age or older.

As of October 2022, RZV has been licensed in 48 countries including the US, Canada,
Japan, China, Europe (under centralised procedure), Brazil, Switzerland, South Korea,
Singapore, Australia, New Zealand, the UK and India.

29
SHINGRIX:
Clinical
Evidence

Clinical Evidence
Table of contents

Abbreviations..................................................................................................34

3A.1 RZV efficacy data in older adults............................................................ 36

3A.1.1 Introduction to the Phase III ZOE studies.............................................. 36
3A.1.2 RZV efficacy against HZ in older adults ≥50 YoA.................................. 36
3A.1.3 RZV duration of efficacy against HZ (in ZOE studies)......................... 37
3A.1.4 Long-term efficacy studies: extensions of ZOE-50 and ZOE-70.....38
3A.1.5 RZV efficacy against HZ complications in older adults.......................38
3A.1.6 Efficacy in individuals with pre-existing medical conditions............. 39
3A.1.7 Efficacy in subgroup analysis by gender, geographic region, and
ancestry/ethnicity........................................................................................ 39
3A.1.8 Efficacy in adults with pre-existing potential immune-mediated
diseases...........................................................................................................40

3A.2 RZV reactogenicity in older adults........................................................ 40

3A.3 RZV immunogenicity data in older adults..............................................43

3A.3.1 RZV immunogenicity in ZOE studies.......................................................44
3A.3.2 RZV duration of immunogenicity.............................................................44
3A.3.3 RZV immunogenicity in subjects with history of HZ...........................44

3A.4 Post-licensure effectiveness and dose schedule compliance.............. 46

3A.4.1 Completion of the two-dose schedule....................................................46
3A.4.2 Effectiveness of RZV ..................................................................... 47

3A.5 Co-administration of RZV with other vaccines..................................... 48

3A.5.1 Seasonal influenza vaccine.........................................................................48
3A.5.2 Pneumococcal polysaccharide vaccine.................................................48
3A.5.3 Tdap vaccine...................................................................................................48

3A.6 Clinical evidence involving ZVL .......................................................... 49

3A.6.1 Efficacy of RZV versus ZVL.........................................................................49
3A.6.2 Immunogenicity, safety and reactogenicity of RZV versus ZVL......49
3A.6.3 Revaccination of ZVL recipients with RZV.............................................50

Module 3B: Clinical evidence in individuals at increased risk of HZ............... 51

References.......................................................................................................63

33
 Abbreviations
ACIP Advisory Committee on Immunization Practices
AE adverse event
AID autoimmune disease
ART antiretroviral therapy
auHSCT autologous hematopoietic stem cell transplant
CI confidence interval
CLL chronic lymphocytic leukaemia
CMI cell-mediated immunity
ELISA enzyme-linked immunosorbent assay
EMA European Medicines Agency
EQ-5D EuroQoL 5-dimension questionnaire
FHA filamentous haemagglutinin
FI frailty index
gE glycoprotein E
GBS Guillain-Barré syndrome
GMC geometric mean concentration
GMR geometric mean ratio
GMT geometric mean titre
HIV human immunodeficiency virus
HZ herpes zoster
HZO herpes zoster ophthalmicus
HZ/su herpes zoster subunit vaccine
IC immunocompromised
ICT immunosuppressive cancer therapy
IM intramuscular
IQR interquartile range
LOC local operating company
LTFU long-term follow-up
MedDRA Medical Dictionary for Regulatory Activities
mIU milli-international unit

34
MM multiple myeloma
MPL monophosphoryl lipid A
mTVC modified total vaccinated cohort
NHBCL Non-Hodgkin B-cell lymphoma
PCV13 13-valent pneumococcal conjugate vaccine (Prevenar 13)
PHN post-herpetic neuralgia
pIMD potential immune-mediated disease
PPV23 23-valent pneumococcal polysaccharide vaccine (Pneumovax 23)
PMR peak memory response
PRN pertactin
PT pertussis toxin
QoL quality of life
QS-21 Quillaja saponaria Molina, fraction 21
RA rheumatoid arthritis
RZV recombinant zoster vaccine (Shingrix)
SAE serious adverse event
SC subcutaneous
SF-12 short form-12 health survey
SF-36 short form-36 health survey
SFC spot-forming cell
Tdap tetanus, diphtheria and acellular pertussis
TVC total vaccinated cohort
US United States
VE vaccine efficacy
VEHZ vaccine efficacy against herpes zoster
VEPHN vaccine efficacy against post-herpetic neuralgia
VRR vaccine response rate
VZV varicella zoster virus
YoA years of age
ZBPI zoster brief pain inventory
ZVL zoster vaccine live (Zostavax)

35
 3A.1 RZV efficacy data in older adults
3A.1.1 Introduction to the Phase III ZOE studies

Two pivotal Phase III studies of RZV run in parallel in adults above 50 YoA and
above 70 YoA, respectively, demonstrated efficacy of the vaccine against HZ,
PHN and other complications, with an acceptable safety profile.

Two randomised, placebo-controlled, observer-blind, multinational (18 countries

across Asia, Europe, Latin America, North America and Australia), Phase III trials
were undertaken to determine the efficacy of RZV:
• The ZOster Efficacy research in adults 50 YoA or older study, also called
ZOE-50 or Zoster-006, NCT01165177.7,8
• The ZOster Efficacy research in adults 70 YoA or older study, also called
ZOE-70 or Zoster-022, NCT01165229.8,12
Both studies were conducted concurrently at the same study sites and
participants were randomised to receive two doses of either RZV or placebo.12
Of note, subjects >70 YoA from all study sites were randomly assigned to either
the ZOE-50 or ZOE-70 study, and only then were randomised to receive two
doses of either RZV or placebo.

Study Design ZOE-50253 ZOE-70254

and Objectives (Zoster-006) (Zoster-022)

Randomised, placebo-controlled, multicentre,

Experimental design multinational (North America, Europe, Latin
America, Asia-Pacific)
• Shingrix Vaccine Group (0.5 mL suspension
intramuscular (IM) injection at months 0 and 2
Study arms
• Placebo Group (0.5 mL suspension [0.9% saline
solution]), IM injection at months 0 and 2
HZ efficacy in persons ≥50 HZ efficacy in
Primary objectives
YoA persons ≥70 YoA

Primary objectives in PHN efficacy in 70+

pooled analysis HZ efficacy in 70+

Actual enrollment 16,160 14,816

A pre-specified analysis of data pooled from the ZOE-50 and ZOE-70 studies
was also undertaken with the primary objectives of evaluating VEHZ and vaccine
efficacy against PHN (VEPHN) in participants ≥70 YoA.12 Secondary objectives of
this pooled analysis included the evaluation of VEPHN in participants ≥50 YoA.12

3A.1.2 RZV efficacy against HZ in older adults ≥50 YoA

In ZOE-50, RZV significantly reduced the risk of HZ compared with placebo
in the overall population ≥50 YoA, with HZ confirmed in six RZV recipients
compared with 210 cases in placebo recipients (incidence rate 0.3 vs 9.1 per 1000
person-years), leading to a VEHZ of 97.2% (95% CI: 93.7-99.0; P<0.001). This VE

36
was maintained within each age group (50–59, 60–69 and ≥70 YoA) for a mean
follow-up of 3.2 years [Table 3A.4].7
RZV also significantly reduced the risk of HZ compared with placebo in
participants ≥70 YoA in ZOE-70 (VEHZ 89.8% [95% CI: 84.2-93.7]; P<0.001), with
similar efficacy in participants 70-79 and ≥80 YoA [Table 3A.4] over a mean
follow-up period of 3.7 years.12
In the pre-specified analysis of data pooled from ZOE-50 and ZOE-70, VEHZ
was 91.3% (95% CI: 86.8-94.5; P<0.0001) in participants ≥70 YoA, and was
similar in participants 70-79 and ≥80 YoA over a mean follow-up of 3.8 years
[Table 3A.4].12

Table 3A.4 Efficacy of RZV against HZ in two Phase III trials (ZOE-50,
Zoster-006, NCT01165177; ZOE-70, Zoster-022, NCT01165229)7,12

RZV Placebo VEHZ

Age, years HZ HZ VEHZ, %
n/N n/N P-value
incidence* incidence* (95% CI)
ZOE-50
Overall (≥50) 6/7344 0.3 210/7415 9.1 97.2 (93.7-99.0) <0.001
50-59 3/3492 0.3 87/3525 7.8 96.6 (89.6-99.3) <0.001
60-69 2/2141 0.3 75/2166 10.8 97.4 (90.1-99.7) <0.001
≥70 1/1711 0.2 48/1724 9.4 97.9 (87.9-100.00) <0.001
ZOE-70
Overall (≥70) 23/6541 0.9 223/6622 9.2 89.8 (84.2-93.7) <0.001
70-79 17/5114 0.9 169/5189 8.8 90.0 (83.5-94.4) <0.001
≥80 6/1427 1.2 54/1433 11.0 89.1 (74.6-96.2) <0.001
Pooled ZOE-70 and ZOE-50
Overall (≥70) 25/8250 0.8 284/8346 9.3 91.3 (86.8-94.5) <0.001
70-79 19/6468 0.8 216/6554 8.9 91.3 (86.0-94.9) <0.001
≥80 6/1782 1.0 68/1792 11.1 91.4 (80.2-97.0) <0.001
*Incidence rate per 1000 person-year of participants reporting at least one event of confirmed HZ per year. CI,
confidence interval; HZ herpes zoster; n/N, number of participants with event/Number of participants in analysis
group; RZV, recombinant zoster vaccine; VEHZ, vaccine efficacy against HZ

3A.1.3 RZV duration of efficacy against HZ (in ZOE studies)

In the Phase III ZOE-50 and ZOE-70 studies, VEHZ persisted at high levels for
4 years of available follow-up (mean follow-up ZOE-50: 3.2 years; ZOE-70:
3.7 years), which was confirmed in the analysis of data pooled from both studies
[Figure below].7,12,39

≥50 YoA ≥70 YoA

98.4% 94.2% 100.0% 97.6% 92.0% 84.7%
93.1% (90.9-99.7) 87.9%
(90.6-100) (84.3
- 98.5) (82.8-96.9)
100%
Vaccine Efficacy % (95% CI)

(94.5 -100) (81.2-98.2) (69.0-93.4) (73.3-95.3)

100%
80% 80%
60% 60%
40% 40%
20%
20%
0%
Y1 Y2 Y3 Y4 0%
Y1 Y2 Y3 Y4
n=7340 n=7190 n=7048 n=6859
n=8250 n=8039 n=7736 n=7426
Year of Follow-up After Vaccination Year of Follow-up After Vaccination

37
 3A.1.4 Long-term efficacy studies: extensions of ZOE-50 and ZOE-70
● In recent interim analysis of Long-Term Protection Study (ZOSTER-049),
Shingrix efficacy against shingles was assessed in adults ≥50 years13,14.
● Shingrix demonstrated clinical benefit for up to year 1013,14:
o Over the ≥4 years follow-up, efficacy of 8 1%*,^,13,14
(81.6% (95% I:7 5.2–86.6); follow-up period: ≥4 years, until DLP-Mean
56 (± 0.3) to 9.6 (± 0.3) years post-vaccination; n/N: RZV (52/7,277) vs.
HC (2 8 3/7,277))
o Post-vaccination up to year 10, 89% efficacy against shingles**,^,13,14
(95% CI: 85.6-9 1.3; from 1-month post-dose 2 up to mean of 9.6 (±0.3)
years post-vaccination; n/N: RZV (84/13,881) vs. HC (765/13,881))
o Safety profile remained clinically acceptable for up to year 10 post-
vaccination and no SAEs were considered causally related to vaccination
in ZOSTER-04913,14
CI, Confidence interval; HC, historical controls; HZ, Herpes Zoster; LTFU, long-term follow-up; mTVC, modified
total vaccinated cohort; n, number of individuals having at least one confirmed herpes zoster episode; N, number of
individuals included in each group; PHN, post herpetic neuralgia; RZV, recombinant zoster vaccine; SAE, serious adverse
event; VE, vaccine efficacy; DLP, data lock point, DLP set when the last participant had reached 4-year of follow-up.13,14
*Primary objective (descriptive analysis): VE against HZ over the ZOSTER-0 4 9 study. Follow-up period during interim
analysis: ≥4 years in ZOSTER-049, until DLP - Mean 5. 6 (± 0.3) to 9 .6 (± 0.3) years post-vaccination in ZOE-50/70.
HZ cases (n/N) in RZV group (5 2/7,277) and control group (2 8 3/7,277).13,14
**Secondary objective (descriptive analysis): VE against HZ from 1-month post-dose 2 in the ZOE-50/70
studies up to mean of 9.6 (±0.3) years pos t-vaccination. H Z cases (n/N) in R Z V group (8 4/1 3,881) and control
group (765/13,881).13,14
^Long-Term Follow-Up ZOSTER-049 Study Design: The primary objective was to assess the efficacy of Shingrix in the
prevention of HZ over the total duration of the current LTFU study.13,14
The results of an interim analysis are based on data collected after at least 4 of the 6 additional years of follow-up from
this LTFU. This data is subject to change upon final analysis.13,14
Of the 1 4,648 ZOE-50/70 participants who received at least 1 dose of Shingrix, 7,413 (50.6%) were enrolled for the long-
term efficacy assessment of which 7,277 had previously received both doses of Shingrix and were included in the mTVC
for vaccine efficacy assessment.13,14
For the pooled overall vaccine efficacy analysis (ZOE-50/70) + current LTFU study), the annual efficacy results from
ZOE-50/70 studies were combined with annual estimates from the current LTFU study. The study was initiated on
April 2016, and the DLP for this second interim analysis was on August 2021, when participants had completed at least 4
additional years of follow-up. At this DLP, data accrual was complete through ye ar 9. Results for year 1 0 are also included
although still incomplete, precision of estimates for this time point will increase at the final analysis. All analyses are
descriptive.13,14
Efficacy was evaluated in the mTVC, restricted to participants who received both doses of Shingrix in the ZOE-50/70
studies and did not develop a confirmed HZ episode before 1 month after dose 2.13,14 Analysis included RZV vaccinated vs.
matched HC. As placebo recipient in ZOE-50/70 were vaccinated with RZV there was an absence of an unvaccinated
placebo group. The efficacy analyses (overall and annual) for the period of this LTFU study used HC estimates from
the ZOE-50/70 placebo groups recorded during the trials, adjusted for age and region at randomization during the
ZOE-50/70 studies.13,14 No data are available for year 5 because that period corresponds to the gap between the parent
studies (ZOE-50/70) and the ZOS TER-049 extension study.13,14
ZOSTER-049 Study Limitations:
-Almost half of the former ZOE-50/70 participants did not enroll in this LTFU study;
-At the DLP for the present interim analysis, not all participants had reached a full 1 0 years of follow-up.13,14
3A.1.5 RZV efficacy against HZ complications in older adults
Vaccine efficacy against PHN
The first co-primary objective of the pre-specified analysis of data pooled
from the ZOE-50 and ZOE-70 was to evaluate VEPHN in participants ≥70 YoA.
Secondary objectives included the evaluation of VEPHN in participants ≥50 YoA.12
VEPHN in participants ≥70 YoA was 88.8% (95% CI: 68.7-97.1; P<0.001) [Table 3A.6].
VEPHN was 91.2% (95% CI: 75.9-97.7; P<0.001) in participants ≥50 YoA (secondary
endpoint)
[Table 3A.6]. None of the participants <70 YoA who received RZV developed
PHN.12

38
Table 3A.6. Efficacy of RZV against PHN across age groups in a pre-specified analysis
of pooled data from two Phase III studies (ZOE-50, Zoster-006, NCT01165177; ZOE-70,
Zoster-022, NCT01165229)12
Age group (years) VEPHN % (95% CI)
≥50 91.2 (75.9, 97.7)

≥70 88.8 (68.7, 97.1)

Age group

50-59 100.0 (40.8-100)

60-69 100.0 (-442.9-100)

70-79 93.0 (72.4-99.2)

≥80 71.2 (-51.6-97.1)

Vaccine efficacy against other HZ complications excluding PHN

VE against non-PHN complications of HZ (HZ vasculitis, disseminated disease,
ophthalmic disease, neurological disease, visceral disease, stroke) was assessed in a
post-hoc analysis of pooled data from ZOE-50 and ZOE-70.
Only one subject in the RZV group developed HZ complications compared with
16 subjects in the placebo group. Ophthalmic disease was the most commonly
reported HZ complication in the placebo group (6 out of 10 subjects with HZ
complications).43
VE against non-PHN complications of HZ was 91.6% (95% CI: 43.3-99.8; P=0.004) in
participants ≥70 YoA and 93.7% (95% CI: 59.5-99.9; P<0.001) in those ≥50 YoA [Table
3A.7].8

Table 3A.7. VE against HZ-related complications (excluding PHN) in a post-hoc

analysis8,39

VE (HZ complications, excluding

RZV Placebo
Age strata, PHN)
years
n/N Incidence n/N Incidence VE% (95% CI) P-value

≥70 1/8250 0.0 12/8346 0.4 91.62 (43.38-99.80) 0.004

≥50 1/13881 0.0 5,032 0.3 93.71 (59.53-99.85) <0.001

Age groups
100.00
50-59 0/3491 0.0 1/3523 0.1 1.000
(-3890.43-100.00)
100.00
60-69 0/2140 0.0 3/2166 0.3 0.251
(-142.85-100.00)
70-79 1/6468 0.0 8/6554 0.3 87.39 (5.95-99.72) 0.040
100.00
≥80 0/1782 0.0 4/1792 0.6 0.125
(-51.16-100.00)
Note: Data pooled from two Phase III studies (ZOE-50, Zoster-006, NCT01165177; ZOE-70, Zoster-022, NCT01165229);
Other complications recorded include vasculitis, disseminated disease, herpes zoster ophthalmicus, neurological
disease, visceral disease and stroke CI, confidence interval; HZ, herpes zoster; n/N, number of participants with event/
number of participants in analysis group; PHN, post-herpetic neuralgia; RZV, recombinant zoster vaccine; VE, vaccine
efficacy

39
 3A.1.6 Efficacy in individuals with pre-existing medical conditions
A post-hoc pooled analysis of ZOE trials was undertaken to evaluate the
efficacy and safety profile of RZV patients with selected medical conditions at
enrolment.58 The analysis suggests that RZV efficacy remains high in all selected
medical conditions [Table 3A.1.2].
Table 3A.1.2. RZV efficacy in patients based on underlying medical condition.
Table reproduced from Oostvogels et al. 2019 under a Creative Commons
Attribution License (https://creativecommons.org/licenses/by/4.0/)58
RZV Placebo
Medical Rate of VE %
Rate of
condition N N HZ/1000 (95% CI)
HZ/1000 PY
PY
Hypertension 7,206 0.8 7,226 9.5 91.9 (87.3–95.1)

Osteoarthritis and/or
4,951 0.9 5,032 9.6 91.1 (85.1–95.0)
vertebral disorders

Dyslipidaemia 4,628 0.9 4,707 9.7 91.2 (85.1–95.2)

Diabetes 2,350 0.8 2,372 9.2 91.2 (81.1–96.6)

Osteoporosis/
1,481 0.9 1,528 13.0 92.9 (82.7–97.8)
Osteopenia
Gastroesophageal
1,334 1.2 1,313 9.1 86.9 (69.0–95.4)
reflux disease
Sleep disorder 1,304 0.8 1,309 11.7 93.1 (81.4–98.2)

Prostatic diseases 1,244 0.4 1,285 10.7 96.1 (85.1–99.5)

Hypothyroidism 1,167 0.9 1,147 6.6 86.2 (60.4–96.5)

Depression 1,017 0.5 987 8.1 93.4 (74.1–99.2)

Coronary heart
1,003 0.3 1,055 8.9 97.0 (82.3–99.9)
disease

Cataract 782 1.3 800 14.0 90.4 (73.4–97.5)

Asthma 646 1.2 689 10.9 88.8 (63.6–97.8)

Respiratory
614 1.4 560 8.7 84.5 (46.4–97.1)
disorders*

Renal disorders 308 0.9 300 7.0 86.6 (-4.5–99.7)

*Other than asthma

CI, confidence interval; HZ, herpes zoster; N, total number of patients; PY, person-year; RZV, group that
received with recombinant zoster vaccine (Shingrix); VE, vaccine efficacy

3A.1.7 Efficacy in subgroup analysis by gender, geographic region, and

ancestry/ethnicity
A post hoc analysis of the ZOE efficacy studies suggested high efficacy against
HZ and PHN irrespective of region, or geographic ancestry/ethnicity.60 Across
geographic regions, efficacy against HZ ranged between 95.7 and 97.2% in
≥50-year-olds, and between 87.3% and 95.1% in ≥70-year-olds; efficacy against
PHN ranged between 86.8 and 100% in ≥70-year-olds. Across ancestral/ethnic
groups, efficacy ranged between 88.1 and 100% against HZ and between 65.9
and 100% against PHN in ≥70-year-olds.

40
 Subgroups Vaccine Efficacy Results
Similar efficacy in both the genders ≥50-year-old

• Male: 95.4% (n=2860)
Gender
• Female: 97.0% (n=4480)
≥70-year old:
• Male: 92.0% (n=3736)
• Female: 90.7% (n=4514)

≥50-year-old: 95.7% (n=1291)

Against HZ to 97.2% (n=3785) ≥70-year old:
Geographic 87.3% (n=597) to 95.1% (n=1526)
regionsa
Against PHN in
86.8% (n=4501) to 100% (n=1626)
≥70-year-olds
Against HZ in
88.1% (n=648) to 100% (n=85)
Ancestral/ ≥70-year-olds
ethnic groups Against PHN in
65.9% (n=648) to 100% (n=332)
≥70-year-olds
n = number of participants in the Shingrix group
a
North America (Canada and the U.S.), Latin America (Brazil and Mexico), Europe (Czech Republic, Estonia,
Finland, France, Germany, Italy, Spain, Sweden, and the United Kingdom), and Australia/ Asia (Australia, Hong
Kong, Japan, Republic of Korea [South Korea], and Taiwan).

3A.1.8 Efficacy in adults with pre-existing potential immune-mediated

diseases
Of the 14,645 RZV and 14,660 placebo recipients from the ZOE-50/70 studies,
983 and 960, respectively, reported at least one pre-existing pIMD at enrolment and
were included in the pooled post-hoc analysis of these trials.62 The most frequent
pre-existing conditions were psoriasis, spondyloarthropathy and rheumatoid
arthritis (RA). Vaccine efficacy against HZ in pooled ZOE-50/70 participants with
at least one pIMD at enrolment was 90.5% (95% CI: 73.5, 97.5%).

3A.2 RZV reactogenicity in older adults

The reactogenicity profile was consistent between the ZOE studies:

the most frequent solicited symptoms were pain, myalgia and
fatigue.

The safety and reactogenicity data gathered from the ZOE studies are considered
representative of the overall safety and reactogenicity profile of RZV.7,12
Incidence of AEs After RZV Vs Placebo: Local Reactions
Any grade, overall per patient63
Solicited local symptoms reported within 7 days post-vaccination of any
grade, overall by subject with at least 1 documented dose

41
 100
85.6 SHINGRIX Placebo

Patients with symptoms (%)

80 N=4884 N=4880
69.2
50-69 YoA N=2626 50-69 YoA N=2617
≥70 YoA N=2258 ≥70 YoA N=2263
60
38.5 37.7
40
28.5
23.0
20 12.8 8.8
1.4 1.2 0.9 1.1
0
50-69 ≥70 50-69 ≥70 50-69 ≥70
Pain Redness Swelling

Local reactions were transient, with a median duration of 3 days or less for
any grade.
Grade 3, overall per patient63

Local grade 3 reactions were transient, with a median duration of 1 to 2 days

100
SHINGRIX Placebo
Patients with symptoms (%)

80 N=4884 N=4880
50-69 YoA n=2626 50-69 YoA n=2617
≥70 YoA n=2258 ≥70 YoA n=2263
60

40

20
8.6
4.0 2.7 3.1 0.8 1.3
0.5 0.2 0.0 0.0 0.0 0.0
0
50-69 ≥70 50-69 ≥70 50-69 ≥70
Pain Redness Swelling

*Grade 3 pain=significant pain at rest or pain that prevents normal activity. Grade 3 redness and
swelling=redness/swelling with a diameter >100 mm.

Incidence of AEs After RZV Vs Placebo: Systemic reactions

Any grade, overall per patient63
100
Patients with symptoms (%)

80

60 53.0 51.4
45.1
35.1 36.6 33.1
40
29.0 25.9
18.3 19.5 20.5
20 13.2 14.4 18.6 14.3
9.9 11.8 9.7 13.5
6.6 4.9 3.2 2.7 7.6
0
50-69 ≥70 50-69 ≥70 50-69 ≥70 50-69 ≥70 50-69 ≥70 50-69 ≥70

Myalgia Fatigue Headache Shivering Fev er GI

42
Grade 3, overall per patient255
Grade 3 general adverse events were transient, with a median duration of 2 days or less

Incidence of AEs After RZV Vs

Placebo Grade 3, overall per patient
100
SHINGRIX Placebo
N=4876 N=4881
Patients with symptoms (%)

80
50-69 YoA n=2624 50-69 YoA n=2617
≥70 YoA n=2252 ≥70 YoA n=2264
60

40

20 7.1
0.9 2.8 0.4 6.8 1.3 3.5 0.8 4.9 1.0 1.5 0.4 5.7 0.3 2.2 0.3 0.5 0.2 0.1 0.1 1.5 0.7 1.2 0.4
0
50-69 ≥70 50-69 ≥70 50-69 ≥70 50-69 ≥70 50-69 ≥70 50-69 ≥70

Myalgia Fatigue Headache Shivering Fever GI

*Grade 3 myalgia, fatigue, headache, shivering, and GI=preventing normal acrtivity. Grade 3
fever=>39.00C/102.20F.
GI symptoms included nausea, vomiting, diarrhea, and/or abdominal pain.

Serious Adverse Events (SAEs) and Fatal SAEs at 1 Year Post-Vaccination

Pooled ZOE-50/ZOE-70

100 Incidence of SAEs and Fatal SAEs Shingrix (N=14,645)

Placebo (N=14,660)
80
Percentage (%)

60

40

20 10.1 10.4
1.1 1.1
0
SHINGRIX Placebo SHINGRIX Placebo
SAEs Fatal SAEs

Shingrix was comparable with placebo in overall incidence of SAEs and fatal
SAEs at 1 year post-vaccination.
Reactogenicity trends between dose 1 and dose 2 of RZV
Reactogenicity may contribute to a person’s willingness to be vaccinated,
knowing about expected reactogenicity might help keep high compliance with
the second dose. A post hoc analysis assessed the intensity of solicited AEs
post-dose 2 reported to the same event’s intensity post dose 1.63 Intensity was
graded from 0 to 3, grade 3 indicating the highest severity. Of the vaccinees
who did not experience a specific AE post-dose 1, 72.6–91.7% did not experience
the same event after dose 2. Although the frequency of grade 3 AEs post-dose
2 was the highest in participants reporting the same AEs at grade 3 post-dose
1, 65.8–89.3% of vaccinees with grade 3 specific AEs post-dose 1 reported the
same AEs at lower intensity post-dose 2.

43
 Post-marketing surveillance
Between October 13, 2017 and February 10, 2019
• 9.3 million doses were distributed globally
• The most commonly reported symptoms were consistent with the known
Shingrix reactogenicity profile
• Most common serious AEs: HZ, pyrexia, pain in extremity and pain
Nine deaths after receipt of RZV were reported.65 Five lacked sufficient
information for adequate medical assessment. Of the remaining four reports,
(i) one individual with pre-existing primary membranous nephropathy was
undergoing treatment with rituximab, and died at an unspecified time after
RZV vaccination possibly due to sepsis (ii) two individuals who had cardiac risk
factors died on the same day and three days after RZV vaccination respectively;
their cause of death was reportedly associated to cardiovascular disease,
(iii) one individual was diagnosed with Guillain-Barré syndrome (GBS) who died
possibly of GBS related complications at an unspecified interval after vaccination
with RZV and quadrivalent influenza vaccine. An Observed/Expected analysis
was performed for all-cause mortality considering a risk period of seven days
following vaccination and was found to be below the expected range, possibly
indicating a very high underreporting of this outcome.
A total of 105 reports (from 104 individuals) were received; encompassing
114 pIMDs with a reporting rate of 1.1 per 100,000 doses distributed.65 Events
were distributed over a range of body systems and disease categories with
no evidence of disproportional reporting of any event. An Observed/Expected
analysis was performed for GBS and Bell’s palsy considering a risk period of
42 days, and 7 and 30 days following vaccination, respectively, and was found to
be below the expected range.
The Shingrix EU label states that, in a post-marketing observational study in
individuals aged 65 years or older, an increased risk of GBS (estimated 3 excess
cases per million doses administered) was observed during the 42 days following
vaccination with Shingrix.66 Available information is insufficient to determine a
causal relationship with Shingrix.66

3A.3 RZV immunogenicity data in older adults

RZV induced robust cellular and humoral immune responses in

older adults ≥50 YoA, which translate to a high level of protection
against HZ and its complications. Moreover, RZV immunogenicity
did not vary dramatically with age and cellular responses persisted
up to 10 years.

3A.3.1 RZV immunogenicity in ZOE studies

RZV elicited robust humoral and CMI responses that remained

above baseline at 36 months post-dose 2 in the ZOE trials.

44
In ZOE-50 and ZOE-70 in subjects ≥50 or ≥70 YoA, respectively, humoral immune
response was measured as the serum anti-gE antibody concentration by gE
enzyme-linked immunosorbent assay (ELISA). CMI response was measured
as CD4+ T cells frequency expressing ≥2 activation markers (CD42+) following
stimulation with gE peptides (ZOE-50 only).
RZV induced robust cellular and humoral immune responses in older adults.
After vaccination, 97.8% of RZV and 2.0% of placebo recipients showed a
humoral response.67
At 1 month and 36 months post-dose 2, respectively,
• GMCs of anti-gE antibodies in subjects ≥50 YoA were 41.9-fold above baseline
and 9.3-fold above baseline in the RZV group.
• Overall median frequencies of gE-specific CD42+ T cells in subjects
≥50 YoA were 24.6-fold and 7.9 -fold above baseline in the RZV group at
1 month and 36 months post-dose 2 respectively.67
In an interim analysis of ongoing extension study Zoster-049, anti-gE antibody
concentrations persisted ~6 times above pre-vaccination levels up to Y8 after
vaccination and the frequency of gE-specific CD42+ T-cells remained above
baseline from Y6 to Y8 after vaccination (i.e. until the end of observation for Y2
of Zoster-049).67

3A.3.2 RZV duration of immunogenicity

In a Phase III, open-label study (Zoster-060, NCT02735915), the safety and
persistence of immune response 10 years after primary vaccination was
evaluated in 70 participants who received two doses of RZV in an earlier Phase
II study (Zoster-003, NCT00434577).4,5,22,23
Ten years post-vaccination, the cellular and humoral immune responses
remained ~3.5 fold and ~6 fold above respective baseline in healthy older adults.
In patients who received two additional doses of RZV at month 120 and 122,
strong anamnestic humoral and cell-mediated immune responses were seen
after 1 additional dose.23
Mathematical modelling has been used to predict the persistence of the immune
responses beyond the 10 years observed. All models predicted that the cell-
mediated and humoral immune responses will persist above the baseline levels
for at least 20 years post-dose 1.23

3A.3.3 RZV immunogenicity in subjects with history of HZ

A Phase III, non-randomised, open-label, single arm, multicentre study, in
adults ≥50 YoA with prior physician-documented history of HZ was conducted
(Zoster-033, NCT01827839).15
As a prior episode of HZ does not confer complete protection against subsequent
HZ episodes, vaccination of adults ≥50 YoA with a prior or unknown history of HZ
may be beneficial. Previous studies of RZV excluded adults with a prior history
of HZ, and no information was available on the immunogenicity and safety of
RZV in this population.15 Therefore, the Zoster-033 study (NCT01827839) was
designed to evaluate the immunogenicity and safety of RZV in adults ≥50 YoA
with a prior history of HZ.

45
 The co-primary objectives of the study were:
• To evaluate the anti-gE humoral response rate at month 3 (1 month following
the second dose of RZV) in all study participants ≥50 YoA with a prior physician-
documented history of HZ.
• To evaluate the safety and reactogenicity following administration of RZV
vaccine from the first dose up to 30 days after the second dose.15
The co-primary immunogenicity objective was met, with a VRR for anti-gE
antibodies of 90.2% (95% CI: 81.7–95.7). The humoral immune response to RZV
elicited in adults with history of HZ was robust and of a similar magnitude to
that seen in adults without a documented history of HZ in previous studies.15
Thus, the Zoster-033 study demonstrated that two doses of RZV administered
2 months apart elicited a strong humoral immune response in adults ≥50 YoA
with a prior history of HZ.
No safety concerns were identified in this study regarding the administration of
RZV to adults ≥50 YoA with prior history of HZ.15 Participants reported local and
general AEs with comparable observed incidences to those reported following
vaccination with RZV in other studies.15
Overall, 77.9% (95% CI: 68.2–85.8) of participants reported at least one local
solicited AE and 71.6% (95% CI: 61.4–80.4) of participants reported at least one
general solicited AE. Any solicited AE was reported for 87.5% (95% CI: 76.8–94.4)
of participants with an HZ episode ≤4 years before study start, 66.7% (95% CI:
41.0–86.7) of participants with an HZ episode 5–9 years before study start,
and 69.2% (95% CI: 38.6–90.9) of participants with an episode ≥10 years before
study start. All solicited local symptoms had a median duration of 3 days and
the median duration of solicited general symptoms ranged between 1 day
(gastrointestinal symptoms, shivering and fever) and 3 days (myalgia).15
A total of five SAEs were reported by 3.1% of participants up to the study end;
however, all were considered unrelated to the vaccine by the investigators. No
pIMDs were reported up to the study end. For six (6.3%) participants, a total
of nine suspected HZ episodes were recorded based either on patient self-
reporting or clinical presentation; however, no laboratory confirmation was
obtained.15 Given the lack of a control group and the limitations of the case
definition, the clinical significance of this observation is uncertain.15
Further background on the suspected HZ cases
During the study, nine suspected HZ episodes were recorded for six (6.3%)
participants. Three of the suspected HZ episodes were moderate while the
rest were of mild intensity, and none were considered related to vaccination.15
Based on the protocol, these cases, defined as a new rash characteristic of HZ
(i.e. unilateral, dermatomal and accompanied by pain broadly defined to include
allodynia, pruritus or other sensations), were not laboratory confirmed and were
based either on clinical presentation or patient self-reporting of characteristic
symptoms.15
Considering that RZV has been shown to have >90% efficacy against HZ in
adults aged ≥50 years, the number of subjects with previous history of HZ
reporting suspected episodes of HZ in the Zoster-033 study (NCT01827839) was
unexpected.15 Therefore, these HZ cases were carefully evaluated by GSK and
several observations led to the conclusion that in the absence of confirmatory
information, it was not likely these were true HZ episodes:15

46
• First, 25–40% of self-reported suspected cases reported across other Phase
III clinical studies proved to be false positives after testing.
• Second, there was a significant unexplained geographic bias in the cases (all
nine reported at the same Canadian site; none in Russia).
• Third, several reports were not typical Zoster cases, for example, one subject
reported three recurrent episodes of HZ, of which two episodes presented
with an atypical duration.
Other studies on use of RZV in subjects with previous history of HZ
A Phase IIIb open-label study (Zoster-056, NCT02690207) investigated the
safety of RZV among participants of ZOE-50 and ZOE-70 who were randomised
to receive the placebo.68 As part of this study, the frequency of HZ recurrence
was found to be very low. Of the 292 participants who had a confirmed HZ
episode during the parent study, only one participant experienced an HZ
episode.68 The episode occurred between dose 1 and dose 2 of RZV.68
A second Phase III study (Zoster-062, NCT04091451) is also underway, and is
assessing the safety and immunogenicity of RZV among adults ≥50 YoA with
a history of HZ. RZV will be provided under a two-dose schedule at 0 and
2 months.30 Patients will be followed up for 2 years post completion of the
vaccination schedule, with the study primary endpoint comparing the incidence
of HZ recurrence in the RZV group with the placebo group.
3A.4 Post-licensure effectiveness and dose schedule compliance

Post-licensure data has demonstrated that RZV is effective

against HZ and HZ-associated complications. Compliance with
the two-dose schedule remains similar to that seen in the pivotal
Phase III trials ZOE-50 and ZOE-70.
3A.4.1 Completion of the two-dose schedule
RZV was approved in the US in October 2017, and 2-dose compliance has been
monitored through to September 2019. During this time, ~7.1 million first-doses
and ~4.2 million second-doses of RZV were administered.69 Of those who
received a confirmed first dose, the two-dose series was completed within 6
months by 70% of patients and within 12 months by 80% of patients.69 Similarly,
a cohort study of 978,000 adults ≥65 YoA in the US reported a 90% uptake of the
second dose within 12 months.70
Vaccine uptake data has also been collected in Canada since approval of RZV in
October 2017 for vaccination of adults ≥50 YoA. Two cohorts receiving different
two-dose schedules were identified among patients who received a confirmed
first-dose between January 1, 2018 and November 30, 2018: a 0, 2 month
schedule (N=155,747) and a 0, 6 month schedule (N=55,524). The 2-dose series
completion rates for each cohort were 65% and 75%, respectively.71

3A.4.2 Effectiveness of RZV

The effectiveness of RZV against HZ and HZ-associated

complications has been assessed in a number of real-world
evidence studies, which were conducted independently from GSK.

47
 Effectiveness against HZ:

A retrospective cohort study (administrative claims database, OptumLabs

Data Warehouse) of 174,000 adults ≥50 YoA in the US determined a vaccine
effectiveness against HZ of 85.5% (95% CI 83.5–87.3%), which remained ≥80% for
all age groups (50–59, 60–69, 70–79 and ≥80 YoA).72 Vaccine effectiveness was
similar regardless of prior vaccination with ZVL: 84.8% vs 87.1% for those with
prior ZVL (within the previous 5 years) compared to no prior ZVL vaccination,
respectively.72
A retrospective cohort study of 78,356 patients in an electronic health records
database from Kaiser Permanente Hawaii between January 1, 2018 and
December 31, 2019, was conducted to determine the
effectiveness of RZV against HZ among healthy adults
≥50 YoA in Hawaii.73 The two-dose schedule of RZV was
completed by 11,864 (15.1%) patients, among whom the
incidence rate of HZ was 325.6 (95% CI 217.7–464.4)
cases per 100,000 person-years.73 In comparison, the
incidence rate of HZ in the unvaccinated group was
1063.3 (95% CI 1006.0–1122.8) cases per 100,000 person-
years, which resulted in a vaccine effectiveness of 83.5%
(95% CI 74.9–89.2) against HZ.73
A prospective (Medicare Part D beneficiaries) study
of 978,000 adults ≥65 YoA in the US found an overall vaccine effectiveness of
70.1% (95% CI 68.6–71.5%), and a vaccine effectiveness against PHN of 76.0%
(95% CI 68.4–81.8%).70 RZV is administered according to a two-dose schedule,
with the second dose to be received 2–6 months after the first dose.74 Receipt
of the second dose more than 6 months (180 days) post-first dose did not
affect vaccine effectiveness against HZ compared with those who received
the second dose within the recommended 6 months (71.7% vs 70.0%).70 Vaccine
effectiveness against HZ among those who received ZVL within the past 5 years
was 63.0% (95% CI 58.3–67.2%).70
The study also included patients at increased risk of HZ due to underlying
immunocompromising conditions or autoimmune disease (AID).70 Vaccine
effectiveness was analysed separately and found to be 64.1% (95% CI 57.2–
69.8%) among immunocompromised patients and 68.0% (95% CI 62.3–72.8%)
among those with AID, compared to the overall population (70.1%, 95% CI 68.6–
71.5%).70

Effectiveness against HZ ophthalmicus:

The same study of 978,000 adults ≥65 YoA in the US, as discussed above,
determined a vaccine effectiveness against herpes zoster ophthalmicus (HZO)
of 66.8% (95% CI 60.7–72.0).70
The study of 78,356 adults ≥50 YoA in Hawaii, discussed above, also reported a
vaccine effectiveness against HZO of 93.3% (95% CI 48.7–99.1%).73
A study of ~4.8 million patients in the US between 2018 and 2019 found that
RZV had an adjusted vaccine effectiveness of 89.1% against HZO. The incidence
rate of HZO in the vaccinated cohort was 25.5 cases per 100,000 person-
years, compared with 76.7 cases per 100,000 person-years in the unvaccinated
cohort.75

48
3A.5 Co-administration of RZV with other vaccines
3A.5.1 Seasonal influenza vaccine
Co-administration of Shingrix and IIV4 showed no safety concerns and no
evidence for interference in the immune response to any of the antigens in
either vaccine
3A.5.2 Pneumococcal polysaccharide vaccine
Co-administration of Shingrix and PPSV23 showed no safety
concerns and no evidence for interference in the immune response
to any of the antigens in either vaccine.
3A.5.3 Tdap vaccine
Co-administration of RZV and reduced-antigen-content diphtheria-tetanus-
acellular pertussis vaccine (Tdap) showed no safety concerns and met non-
inferiority for the immune responses to the antigens in either vaccine, except
pertactin (PRN) antigen in Tdap. Based on a comparison of immune responses
of pertussis antigens from this study and the diphtheria-tetanus-acellular
pertussis (DTaP) vaccine efficacy study, these data do not suggest a clinically
relevant interference between RZV and Tdap.

3A.6 Clinical evidence involving ZVL

3A.6.1 Efficacy of RZV versus ZVL

While there are no head-to-head clinical trials comparing the

efficacy of RZV versus ZVL, a network meta-analysis has been
performed to compare the two vaccines.

A systematic literature review identified 25 publications relating to 21 clinical

trials of three HZ vaccines; RZV (n=6), ZVL (n=14) and Biken’s live-attenuated
OKAVAX (n=1, see Module 2, Section 2.4.2 for more details).78 Of these
publications, 18 were included in a network meta-analysis to compare the
efficacy, safety and reactogenicity of RZV with ZVL.78 For efficacy outcomes,
evidence was available only to compare RZV with ZVL delivered subcutaneously.
RZV was found to be 41% (95% CI 34–47%) more efficacious against HZ in adults
≥60 YoA than ZVL, and 54% (95% CI 43–65%) more efficacious against HZ
in adults ≥70 YoA than ZVL.78 In terms of efficacy against PHN, RZV was 23%
(95% CI 9–37%) and 22% (95% CI 7–37%) more efficacious than ZVL in adults ≥60
YoA and ≥70 YoA, respectively.78
3A.6.2 Immunogenicity, safety and reactogenicity of RZV versus ZVL

The immunogenicity of RZV has been compared with ZVL in a

head-to-head trial among HZ vaccine-naïve adults 50-59 YoA and
70-85 YoA. Reactogenicity of RZV was greater than ZVL, but there
was no difference in safety profiles of the two vaccines.

The University of Colorado, Denver, undertook a randomised, double-blind,

Phase I, investigator-sponsored study (Zoster-046, NCT02114333) to compare
the immunogenicity, reactogenicity and safety of RZV and the live-attenuated
HZ vaccine ZVL in subjects 50-59 and 70-85 YoA.18,19 The study recruited around
160 participants in order to determine the immunogenicity, reactogenicity and

49
 safety of both vaccines in participants without prior HZ vaccination (50–59 YoA
and 70–85 YoA) compared with participants 70-85 YoA who received HZ vaccine
≥5 years previously.
Vaccination with both ZVL and RZV increased gE-specific responses, but at
peak memory response (PMR) after vaccination (30 days after ZVL or after the
second dose of RZV), gE-specific CD4+ and CD8+ T-cell responses were ≥10-
fold higher in RZV compared with ZVL recipients.19 T cell memory responses,
including gE–IL2+ and VZV-IL2+ spot-forming cells (SFCs), were higher in RZV
recipients than ZVL recipients, and cytotoxic and effector responses were
lower.
At 1 year after vaccination, all gE-Th1 and VZV-IL2+ SFCs remained higher in RZV
compared to ZVL recipients.19 The adjuvant system of RZV (AS01B) was identified
as the key factor in the marked increase in immunological response after RZV
vaccination compared with ZVL. AS01B was suggested to compensate for age-
related weakening of the immune system, potentially explaining the observed
difference in long-term immunogenicity between RZV and ZVL.79
The network meta-analysis discussed in Section 4A.9.1 above found that RZV
resulted in greater reactogenicity after vaccination than ZVL, as expected for an
adjuvanted vaccine.78 However, there was no statistically significant difference
in the occurrence of SAEs between RZV, ZVL and placebo across all 14 clinical
trials.78
3A.6.3 Revaccination of ZVL recipients with RZV

In the Phase I University of Colorado study, Zoster-046, immunogenicity

outcomes were compared between HZ vaccine-naïve participants (N=90) and
those who had received ZVL ≥5 years prior (N=70).18,19 There was no difference
in immunogenicity outcomes for RZV between vaccine-naïve participants and
prior ZVL recipients at all time points measured (pre-vaccination, 1 month post-
dose 1, 1 month post-dose 2, 11 months post-dose 2).18,19
In a Phase III, open-label, group-matched, multicentre study (Zoster-048,
NCT02581410), the immunogenicity, reactogenicity and safety of RZV (two
doses, 2 months apart) were assessed in adults ≥65 YoA (N=430) who received
ZVL ≥5 years earlier compared (HZ-PreVac) with adults not previously
vaccinated with ZVL (HZ-NonVac).20 In the HZ-PreVac group, the adjusted
GMC for anti-gE antibodies was 48589.4 mIU/mL (95% CI: 42649.4-55356.6 mIU/
mL), with responses non-inferior to those in the HZ-NonVac group (adjusted
GMC 50522.9 mIU/mL [95% CI: 44347.4-57558.4 mIU/mL]), a month after the
last vaccination (adjusted GMC ratio for HZ-NonVac vs HZ-PreVac: 1.04 [95%
CI: 0.92-1.17]; pre-defined criterion: upper limit of 95% CI <1.5). There were no
apparent differences in CD42+ T cell frequencies between the groups.20
There were no safety concerns.20 There were no clinically meaningful differences
in the frequencies of solicited local and general AEs (all and grade 3) between the
study groups. The incidence of unsolicited events within 30 days of vaccination
was slightly higher in the HZ-PreVac group (36.3% [95% CI: 29.8-43.1]) compared
with the HZ-NonVac group (24.2% [95% CI: 18.6-30.5]). However, there were no
clinically relevant differences in reported unsolicited AEs between study groups,
as AEs were distributed across various Medical Dictionary for Regulatory
Activities (MedDRA) classes and no clustering or patterns could be identified.

50
The incidence of SAEs was similar between the groups with no SAEs considered
vaccine-related by the investigators.20 Fatal SAEs were reported in 2 subjects
in the HZ-PreVac group and 3 subjects in the HZ-NonVac group.80 At least
1 pIMD was reported in 2 subjects in the HZ-PreVac group and 4 subjects in the
HZ-NonVac group. None of the reported SAEs or pIMDs were assessed by the
investigator to be causally related to vaccination.80
Module 3B: Clinical evidence in individuals at increased risk of HZ

Two phase I/II clinical studies, Zoster-001 and Zoster-015, were conducted in
subjects with autologous hematopoietic stem cell transplant or HIV infection.
A total of 135 adults, of whom 73 were ≥50 years of age, received at least one
dose of SHINGRIX, which was shown to be immunogenic and well-tolerated.
References

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53
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75. Lu A, Sun Y, Porco TC et al. Effectiveness of the recombinant zoster vaccine for
herpes zoster ophthalmicus in the United States. Ophthalmology 2021;128:1699-
1707.
76. Tomczyk S, Bennett NM, Stoecker C et al. Use of 13-valent pneumococcal conjugate
vaccine and 23-valent pneumococcal polysaccharide vaccine among adults
aged ≥65 years: recommendations of the Advisory Committee on Immunization
Practices (ACIP). MMWR Morb Mortal Wkly Rep 2014;63:822–825.
77. Min JY, Mwakingwe-Omari A, Riley M et al. The adjuvanted recombinant zoster
vaccine co-administered with the 13-valent pneumococcal conjugate vaccine
in adults aged >/=50 years: A randomized trial. J Infect 2021. doi: 10.1016/j.
jinf.2021.12.033. Online ahead of print.
78. McGirr A, Widenmaier R, Curran D et al. The comparative efficacy and safety of
herpes zoster vaccines: A network meta-analysis. Vaccine 2019;37:2896-2909.
79. Levin MJ, Weinberg A. Immune responses to zoster vaccines. Hum Vaccin
Immunother 2019;15:772-777.
80. Dagnew AF, Klein NP, Herve C et al. The Adjuvanted Recombinant Zoster Vaccine
in Adults Aged >/=65 Years Previously Vaccinated With a Live-Attenuated Herpes
Zoster Vaccine. J Infect Dis 2020:jiaa083

GSK is not responsible for 3rd party data

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Indication*

Shingrix is indicated for prevention of herpes zoster (HZ) and postherpetic

neuralgia (PHN), in adults 50 years of age or older.

Important Safety Information*

Contraindications: Hypersensitivity to the active substances or to any of the
excipients.
Undesirable effects:
very common: headache, gastrointestinal symptoms (including nausea,
vomiting, diarrhoea and/or abdominal pain), myalgia, injection site reactions
(such as pain, redness, swelling), fatigue, chills, fever.
common: injection site pruritus, malaise.

Please refer full prescribing information here

https://india-pharma.gsk.com/media/7399/shingrix.pdf

or can scan given QR code

*SHINGRIX PI Version SNX/PI/IN/2022/03 dated 04-Jul-2022

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 For the use only of a Registered Medical Practitioner or a Hospital or a Laboratory

Abbreviated Prescribing Information of SHINGRIX

Herpes zoster vaccine (recombinant, adjuvanted)

ACTIVE INGREDIENT: Each 0.5 ml dose of reconstituted vaccine contains

Varicella Zoster Virus glycoprotein E antigen 50 mcg adjuvanted with AS01B
suspension containing plant extract Quillaja saponaria Molina fraction 21
(QS-21) 50 mcg, 3-O-desacyl-4’-monophosphoryl lipid A Ph. Eur. from
Salmonella Minnesota 50 mcg. INDICATION: prevention of herpes zoster
(HZ) and post-herpetic neuralgia (PHN), in adults 50 years of age or
older. DOSAGE AND ADMINISTRATION: Posology: Primary vaccination
schedule consists of two doses of 0.5 ml each: an initial dose followed by
second dose 2 months later. If flexibility is necessary, second dose can be
given between 2 and 6 months after first dose. Need for booster dose has
not been established. Can be given with same schedule in those previously
vaccinated with live attenuated HZ vaccine. Not indicated for prevention
of primary varicella infection (chickenpox). Paediatric Population: Safety
and efficacy in children and adolescents not established. Method of
Administration: For intramuscular injection only, preferably in deltoid
muscle CONTRA-INDICATIONS: Hypersensitivity to active substances or
to any of excipients. SPECIAL WARNINGS and SPECIAL PRECAUTIONS:
Prior to immunization: Appropriate medical treatment and supervision be
available in case of anaphylactic event. Postpone vaccination in subjects
suffering from acute severe febrile illness. However, minor infection should
not result in deferral. Protective immune response may not be elicited in all
vaccinees. Vaccine is for prophylactic use only; not intended for treatment
of established clinical disease. DO NOT ADMINISTER INTRAVASCULARLY
OR INTRADERMALLY. Subcutaneous Route Not Recommended as may
lead to an increase in transient local reactions. Give with caution to individuals
with thrombocytopenia or any coagulation disorder as bleeding may occur
following intramuscular injection. Syncope can occur as psychogenic
response to needle injection. This can be accompanied by neurological
signs such as transient visual disturbance, paraesthesia and tonic-clonic
limb movements during recovery. Ensure procedure to avoid injury from
fainting. No safety, immunogenicity or efficacy data for replacing a dose of
SHINGRIX with a dose of another HZ vaccine. Limited data to support use
in individuals with history of HZ and in frail individuals including those with
multiple comorbidities. Evaluate risk-benefit on individual basis. Systemic
immunosuppressive medications and immunodeficiency: Limited data
available of safety and immunogenicity in immunocompromised subjects
with human immunodeficiency virus (HIV) or haematopoietic stem cell
transplant (HCT). Use in other immunosuppressive or immunodeficient
conditions isunder investigation. Adequate immune response may not
be elicited in these individuals. Carefully consider potential benefits
and risks for use in immunocompromised persons. Interaction with
other medicinal products and other forms of interaction: Can be given

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concomitantly with unadjuvanted inactivated seasonal influenza vaccine,
23- valent pneumococcal polysaccharide vaccine (PPV23) or reduced
antigen diphtheria-tetanus-acellular pertussis vaccine (dTpa). Administer
concomitant vaccines at different injection sites. Adverse reactions of
fever and shivering were more frequent when co-administered with PPV23.
Pregnancy and Lactation: No data from use of SHINGRIX in pregnant
women. Animal studies do not indicate direct or indirect harmful effects
with respect to pregnancy, embryonal/foetal development, parturition or
post-natal development. Preferable to avoid SHINGRIX during pregnancy.
Effect on breast-fed infants of administration to mothers has not been
studied. Unknown whether SHINGRIX is excreted in human milk. Animal
studies do not indicate direct or indirect effects with respect to fertility in
males or females. ADVERSE EFFECTS: Safety profile presented based
on pooled analysis of data generated in placebocontrolled clinical studies
on 5,887 adults 50-69 years of age and 8,758 adults ≥ 70 years of age and
from post-marketing surveillance data. Very common (≥1/10): injection site
reactions (such as pain, redness, swelling), fatigue, chills, fever, headache,
gastrointestinal symptoms (including nausea, vomiting, diarrhoea and/or
abdominal pain), myalgia, Common (≥1/100 to <1/10): injection site pruritus,
malaise, Uncommon (≥1/1,000 to <1/100): lymphadenopathy, arthralgia.
Rare (≥1/10,000 to <1/1,000): hypersensitivity reactions including rash,
urticaria, angioedema.

Version: SHI/API/IN/2022/02 dated 01-Nov-2022

Registered medical practitioners can refer company website

www.gsk-india.com/product-prescribing-information.aspx for full
Product Information.

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Report any adverse events with any GSK products to india.pharmacovigilance@gsk.com.
Trademarks are owned by or licensed to the GSK group of companies.
© 2023 GlaxoSmithKline group of companies or its licensor. All rights reserved.
GlaxoSmithKline Pharmaceuticals Ltd.
Registered Office: Dr. Annie Besant Road, Mumbai - 400 030.