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04-Sep-17
1
Herpes Zoster: The disease and the vaccines
Tony Cunningham
Centre for Virus Research
The Westmead Institute for Medical Research
Sydney, Australia
Declarations
• Chair, Publications committee, GSK Shingrix ZoE50 and ZoE70 trials
• Member, Global Adult Vaccine Advisory Board, Merck
• Chair, Zostavax Advisory Board, BioCSL/Sequirus
Take home message
• From November 2016
• Management of herpes zoster demands immunization of all people between 70 and 79 with Zostavax
• To prevent: Herpes zostero Post-herpetic neuralgia
• Contraindications: Severely immune- compromised patients
• Vaccine efficacy 50-65% so breakthroughs may occur and require antiviral treatment, less severe though
• Duration ~ 10 years so a booster may be necessary
• A new competing vaccine with different characteristics may be available in 2018
Zoster: Latency and Reactivation
Herpes Zoster (shingles)
• Usually unilateral, vesicular cutaneous eruption with a dermatomal distribution
• Acute pain accompanies the rash in >90% of individuals aged over 50 years
• The most common complication is post herpetic neuralgia (PHN), defined as pain persisting for 90 or more days after rash onset
• >50% of population >85 years will get zoster
Gnann, Jr. & Whitley 2002 Dworkin et al. 2007
Risk factors for Herpes Zoster
• Increasing age
Less opportunity for boosting?– Less frequent exposure to varicella cases
– Less frequent contact with multiple ill children
• Decline in cell-mediated immunity– Immunosenescence
- Cell-mediated immunosuppressive disorders
Haematological malignancies
Immunosuppressive drugs
HIV: 12-17 fold increased risk
Thomas & Hall Lancet Infect Dis 2004;4(1):26-33; Liesegand Curr Opin Ophthalmol 2004;15:531-6: Donohue et al Arch Int Med 1995;155(15):1605-9
04-Sep-17
2
Herpes zoster and PHN increase with age in
Australia
Stein A et al Vaccine 2009
0
1
2
3
4
5
6
30 40 50 60 70 80 >85Age (years)
RC
F (p
er
10
0,0
00
PB
MC
)
Rate of HZ Complications
Neurologic (incl PHN)
Cutaneous
Ocular Involvement
Sacral Dermatome Involvement
Visceral Complications
ZOSTAVAX™N=19,270
298
41
14
6
9
nIncidence
Rate*
5.0
0.7
0.2
0.1
0.2
PlaceboN=19,276
634
118
40
25
29
nIncidence
Rate*
10.7
2.0
0.7
0.4
0.5
*Birch C et al, Sex Transm Infect 2003;79:298-300
Zoster Diagnosis
• Clinical diagnosis alone
– ‘shingles’
• Laboratory diagnosis needed in
– immunosuppressed patients
– less common & atypical presentations
– (eg. genital*,HZ oticus)
– complicated presentations (eg. dissemination, CNS disease)
– Vesicle NAT or IF
*Birch C et al, Sex Transm Infect 2003;79:298-300
Five ‘ages’ of vaccines
• Infancy: multiple
• Adolescence: papillomavirus, HSV, EBV
• Pregnancy
• Older adults: influenza, pneumococcus, shingles
• Any, Epidemic: influenza, Ebola, Dengue, ?Zika
11
Adult immunization is not prioritized
PCV (3+ doses)
PCV (4 doses)
DTaP (4 doses)
DTaP (3+ doses)
Varicella (1 dose)
Hep B (3 doses)
Polio (3 doses)
Full ped schedule3
US Pediatric Coverage Rates %
Adult pneumo (65+, ever)
Flu (18+, per season)
Hepatitis B (19+, >3 doses)
Zoster (60+, ever)
US Adult Coverage Rates %
Tetanus/Tdap (50+, past 10 years)
1. CDC. MMWR. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6433a1.htm2. CDC. MMWR. https://www.cdc.gov/mmwr/volumes/65/ss/ss6501a1.htm.
Types of vaccines
● Whole virus
● Live attenuated
● Inactivated
● Split
● Sub-unit
04-Sep-17
3
Shingles Prevention Study (SPS)
• A double-blind, placebo-controlled trial
– 22 Sites
• Live, attenuated VZV vaccine
– Oka/Merck strain (Median = 24,600 pfu)
– 14-fold greater titer than childhood vaccine
• Subjects = 38,500
– Median age = 69 years
– 60-69 years = 20,750
– ≥ 70 years = 17,800 (46%)
– ≥ 80 years = ~2500 (>6.5%)
Oxman al. NEJM 352; 2271: 2005
SPS: Endpoints
• Herpes Zoster (incidence/1000/year)– Mean follow-up = 3.13 years
• Burden of Illness (BOI)– Sum of all severity of illness scores for each of two treatment
groups - vaccinees and placebo recipients
• Post-herpetic neuralgia (PHN)– Significant pain (≥ 3 on ZBPI)
– ≥90 days after rash onset
– 95% of subjects completed the study
Efficacy(95% CI)
51.3%(44.2 - 57.6)
63.9% 37.6%
0
2
4
6
8
10
12
All 60-69 yr ≥70 yr
Incid
en
ce o
f H
Z
Vaccine
Placebo
Vaccine Efficacy for Incidence of Herpes Zoster
Vaccine Efficacy for Incidence of PHN
Efficacy(95% CI)
66.5%(47.5 - 79.2)
65.7%(20.4 - 86.7)
66.8%(43.3 - 81.3)
0.0
0.5
1.0
1.5
2.0
2.5
All Subjects 60-69 yr ≥70 yr
Incid
en
ce o
f P
HN
Vaccine
Placebo
SPS: Conclusions
• In the full SPS population Zostavax significantly altered the natural history of zoster
– Prevented zoster in the younger group of vaccinees (60-69)
– Prevented OR attenuated zoster in the older group of vaccinees (>70)
– Efficacy and safety essentially replicated in several large postmarketing studies (Kaiser Permanente, CA etc)
– Low rates of severe injection site reactions (~1%)
SPS ZEST Study in 50-59 year olds:
HZ incidence decreased by 70%, HZ pain by 73% (ie greater VE)
Duration of effectiveness of herpes zoster vaccine Kaiser Permanente Southern California, 2007–2015.
Hung Fu Tseng et al. J Infect Dis. 2016;213:1872-1875
04-Sep-17
4
Zoster vaccines for Immunecompromised patients
• Zostavax, ACIP Recommendations:
Live attenuated vaccines, such as Zostavax, contraindicated for severely immune-compromised - >20mg prednisone daily for >2 weeks, - Hemopoietic Stem Cell Tx - hematologic malignancies not in remission for >3 months, esp advanced Hodgkins disease, (ie cytotoxic therapy within past 3 months), including CLL
- T cell immunodeficiency, including HIV+ pts with CD4<15%
• Cf HZ/su GSK (Recombinant VZV gE + adjuvant ASO1B) – not contraindicated and safe in immunecompromised (HSCT, HIV <15% CD4)
Zostavax: issues
• Moderate efficacy, lower in >80
• Duration of effectiveness ?8-10 years
-Need a booster, probably at 10 years
• Unsafe in severely immunecompromised
• Safety in moderately immunecompromised pts needs better definition
Zostavax in Australia
• Nov 2016: Approved for National Immunization program
• 70-79 yo with catchup (private 50 years)
• Now >50% vaccine dose distribution within a year
• Implications for new vaccine
Recombinant VZV glycoprotein E + T cell adjuvant
Pathogen
Glycoprotein Antigen
Adjuvants act as substitutes for natural T cell stimulants
• Viral proteins alone may be insufficiently immunogenic• Adjuvants act as substitutes for viral immune stimulants
enhancing and directing the immune response
T cell stimulating adjuvant Systems
• Combinations of:
- Classical adjuvants: aluminum salts, emulsion, liposomes
- Immunostimulants: MPL, QS21, (CpG),
(d)MPL QS21
0
20
40
60
80
100
1 2 3
50-59 YOA
60-69 YOA
70+ YOA
Vac
cin
e re
spo
nse
rat
e (%
)
gE/AS01B (HZ) gE/AS01E Post-dose 2 (M3) gE/Saline
Phase I/II: T cell responses to HZ/su (gE/AS01B) but not gE alone diminish little with advancing age
Chlibek et al 2015
04-Sep-17
5
Phase III Trials of GSK HZ/su (Shingrix)
• Placebo - RCT in Europe, USA, Asia, Australia
• Two doses IMI two months apart, 96% compliance
• ZoE-50: 15,411 evaluable adults > 50 years, stratified in 10 year blocks, -
• ZoE-70: 13,900 adults >70 years focusing on PHN
- two papers published in NEJM,
- abstract on immunology presented to IHW
96.57 97.36 97.93 97.58 97.16
0
10
20
30
40
50
60
70
80
90
100
50-59 60-69 >=70 >=60 OVERALL/>=50
%
LL>25%
Secondary Objectives Primary Objective
ZOE-50: GSK Herpes Zoster (HZ/su) Vaccine Efficacy
Lal H, Cunningham AL et al, N Engl J Med, 2015
ZOE-70 trial: efficacy against HZ and PHN
13,900 Adults >70, average age 75.2 years • vaccine efficacy = 90% (95% CI 84-94)
- similar in 70-79 and >80
- efficacy against PHN: 89% (69-97)
- ie no additional efficacy against PHN cf HZ
• Efficacy against PHN in (Pooled) Adults>50 : 91% (76-98) - No cases <70 years
(Cunningham, Lal, Levin ..Heineman et al NEJM 2016)
Cunningham AL et al N Engl J Med 2016
ZOE-70: Risk of development of Herpes zoster after vaccination
Cunningham AL et al.N Engl J Med 2016
ZOE-70: Risk of development of post-herpetic neuralgia after vaccination
04-Sep-17
6
Chlibek R. Heineman TC et al Vaccine,
2016,
gE-specific CD4 T cell responses after two
doses of HZ/su
>70 years ----
Baseline -----
ZoE-50 & 70: reactogenicity and safety
• Systemic: - Severe (grade III); 11.5% vs 2.5%
• Local/injection site
– Severe: 9.5/8.5% vs 0.4/0.2%: lasted on average 2 days
– 96% of all subjects received second dose
– 91% with severe reactions returned for second injection
– No increased reactogenicity after second dose
– IMI less reactogenic than s/c injection
Serious adverse events were similar in placebo and recipient
No increased autoimmune diseases or exacerbations
HZ/su in immunecompromised patients
• Phase I-II trials of HZ/su in autologous HSCT for HD, AML, Myeloma:
- comparable immunogenicity (antibody and CD4 T cells) and reactogenicityto immunocompetents; maintained for 1 year
- Phase III trial data soon to be submitted
• HIV: HZ markedly diminished by ART: still 3-5X risk if CD4<200
- Phase I-II trials HZ/su in 3 cohorts: good immunogenicity maintained for duration, 18 mo. No worsening of CD4 counts, safe
• Need to compare Zostavax vs HZ/su in mildly immuncompromisedpatients respectively (ie autoimmune diseases and Rx with biologics)
Shingrix, HZ/su: issues• Two doses: likely compliance in real world setting,
Efficacy after a single dose?
• Will high reactogenicity (severe local: 9%) reduce uptake?
• Duration of efficacy to be determined (T cell immunogenicity plateaus for 3-9 years- promising)
• - long term followup trials commenced
• Can it be used as a booster after Zostavax?
• Risk of auto-immunity with new adjuvants: needs long term post marketing surveillance
• Efficacy in severely immunecompromised: phase III trial results available soon
HZ/su:Implications
• HZ/su development and trialling confirms several scientific hypotheses:
- vaccines consisting of a single pathogen protein and adjuvant(s) can be efficacious -and more than a live attenuated vaccine
- such a combination may cut through immunosenescence= hope for other vaccines in older subjects
- Pathogen/vaccine/adjuvant immunology is of increasing relevance for (rational) vaccine development
Take home Message
• From November 2016
• Management of herpes zoster demands immunization of all people between 70 and 79 with Zostavax
• To prevent: Herpes zoster
– Post-herpetic neuralgia
• Contraindications: Severely immune- compromised patients
• Vaccine efficacy 50-65% so breakthroughs may occur and require antiviral treatment, less severe though
• Duration ~ 10 years so a booster may be necessary
• A new competing vaccine with different characteristics may be available in 2018
04-Sep-17
7
HZ/su: Remaining Immunologic questions• Duration of humoral and CD4 T cell responses (>9 years)?
• Mechanisms:
- Relative importance of T cells in boosting antibodies vs other mechanisms
- Role and importance of polyfunctional CD4 T cells
- Is there a CD8 T cell response?
- Role of innate immune responses (NK, mono, DCs)
• Immune correlates of protection difficult to define because few breakthrough HZ cases
• However difference in protection against HZ in Zostavax and HZ/sucorrelates with CD4 T cell response: (2x vs 39x baseline)
• ? with CD8 T cell responses: available soon
• Will these responses be improved after HZ/su boosting of Zostavax?
Antiviral treatment of herpes zoster
• Oral famciclovir, valaciclovir or, if complications, IV aciclovir
• Treat up to 72 hpi or if new vesicles appearing, disseminated lesions, HZ opthalmicus/oticus
• Check renal function and modify dosage if necessary
• Treat pain with systemic analgesics, no topical LA, capsaicin
• If pain moderate/severe: add amitryptaline, pregabelin
• If pain prolonged > 4 weeks refer to pain specialist
• If ophthalmic zoster, refer to ophthalmologist
• Consider immunosuppression, pregnancy
• No evidence antivirals prevent PHN defined as pain >90 days
The Pivotal Phase 3 Program: ZOE-50 and ZOE-70
40
ZOE 50/70 efficacy studies conducted at the same sites.Subjects ≥70 years of age were randomly assigned to ZOE-50 or ZOE-70.
Study Design and Objectives
ZOE-50(Zoster-006)
ZOE-70(Zoster-022)
Experimental designRandomized, observer-blind, placebo-controlled, multicenter,
multinational (North America, Europe, Latin America, Asia, Australia)
Primary objectives HZ efficacy in persons ≥50 YOA HZ efficacy in persons ≥70 YOA
Primary objectives in
pooled analysis
PHN efficacy in 70+
HZ efficacy in 70+
Actual enrollment 16,160 enrolled 14,816 enrolled
HZ, herpes zoster; PHN, postherpetic neuralgia; YOA,
years of age.
Laboratory diagnosis
• Antigen detection (IF etc)
• Nucleic acid testing (NAT)
– VZV
– Multiplex (eg HSV 1/2, VZV etc)
• Serology
– VZV-specific IgM
– ‘immune status’ (FAMA, gpELISA)
– (avidity)
95% of young Australian adults (~25 YO) immune
Heininger U et al Lancet 2006;9544:1365, Arvin AM, Clin Micro Rev 1996; 9,:361-81
Complications of Zoster
• Neurologic
– PHN
– Limb weakness
& Peripheral palsies
– Sensory loss
– Meningitis
– Myelitis
– Encephalitis
– Hearing loss
• Ophthalmic
– Visual impairment
– Ptosis
• Cutaneous
– Scarring
– Bacterial superinfection
• Disseminated disease
– Pneumonia
– Hepatitis
04-Sep-17
8
VZV Pathogenesis
Courtesy C. Hood
Trials in Progress
• Co-administration with other ‘adult’ vaccines
- Tdap, influenza, pneumococcal conjugate vaccine
• Immunization of previous Zostavax recipients
• Safety and immunogenicity in other severe immunecompromising conditions
• - renal transplant
• - solid organ tumours
• - Hematologic malignancies
Duration of protection of Zostavax
• Short term Persistence Sub study:– 7320 Zostavax /6950 placebo recipients, 89% of which accepted the offer of
Zostavax; all participants followed for 4-7 years
– VE = 39.6% for zoster, 60% for pHN and 50% for BOI
• Long term Persistence Sub study:– Open label Multicentre study, followed up 6867 vaccine recipients for 7-12 years.
No unvaccinated concurrent control group so original SPS placebo recipients used as controls.
– VE = 21% for zoster, 35% for PHN and 37% for BOI
– ie provides evidence for waning of efficacy but probably significant to 8 years when analysed annually
• Booster dose at 10 years: in >70 year old CMI responses were stimulated to levels similar to those of a first response in 60-69 YO
(Levin M et al JID 2016)
Age dependent incidence of herpes zoster and PHN in Australia
Stein A et al Vaccine 2009
Immunosenescence
• Progressive decline in systemic immunity• Increased prevalence of cancer, autoimmune and chronic
diseases• Poor response to immunization• Increased vulnerability to common infectious diseases
(influenza etc)• Mechanism:
– decline in innate immunity: NK cells, DCs, PMNs– naïve T cells less diverse, more memory T cells, signalling
defects
• Role of late reactivation of CMV still controversial• Role of adjuvants (cf MF59 for influenza)
04-Sep-17
9
Incidence of Herpes zoster is increasing globally.Trend in zoster ED visits - NSW
02
04
06
08
01
00
NS
W N
on A
dm
itte
d E
D V
isits p
er
100
,000
pop
ula
tio
n
1998 2000 2002 2004 2006 2008 2010 2012
Year
<25 <25 predicted 25-49 25-49 predicted
50-59 50-59 predicted 60-69 60-69 predicted
70-79 70-79 predicted 80+ 80+ predicted
02
04
06
08
01
00
NS
W A
dm
itte
d E
D V
isits p
er
10
0,0
00
pop
ula
tio
n
1998 2000 2002 2004 2006 2008 2010 2012
Year
<25 <25 predicted 25-49 25-49 predicted
50-59 50-59 predicted 60-69 60-69 predicted
70-79 70-79 predicted 80+ 80+ predicted
• Rates of ED visits increased with age.
• Most ED visits are not admitted
• Increasing trend in non-admitted ED visits over time, most prominent in older population)
MacIntyre R et al Plos One 2015
Clinical Manifestation of Zoster
Acute pain
Characteristic dermatomal rash
May or may not occur; most
common is PHN
Prodromal Phase
Acute Phase
Complications
Resolves
1. Oxman MN. In: Varicella-Zoster Virus: Virology and Clinical Management. Cambridge: Cambridge University Press, 2000:246–275.
Nature of Pain in PHN
1. Bowsher D. In: Herpes Zoster and Postherpetic Neuralgia, 2nd Revised and Enlarged Edition. Vol. 11. Amsterdam: Elsevier Science B.V., 2001:143–147.
CMI to VZV Decreases With Age
CMI=cell-mediated immunity
PBMC=peripheral blood mononuclear cell
RCF=responder cell frequency
Age group (years)
Shingrix group Placebo group Vaccine efficacy (95% CI)†
Shingles cases (N)* Shingles cases (N)*
≥50 6 (7344) 210 (7415)97.2%
(93.7-99.0)
≥60 3 (3852) 123 (3890)97.6%
(92.7-99.6)
≥70 1 (1711) 48 (1724)97.9%
(87.9-100)
53
Efficacy in all age groups >50 years old (ZOE-50)1-3
*Included 7344 randomized subjects ≥50 years old without immunocompromise, who received a second dose of the vaccine and did not develop a confirmed case of shingles within 1 month after the second dose. N=number of subjects within each age group.
†P-value for all comparisons <0.001. Two-sided exact P-value conditional to number of cases.
CI, confidence interval.
1. Lal H, et al. N Engl J Med. 2015.2. Shingrix (prescribing information). Research Triangle Park, NC: GlaxoSmithKline; 2017.3. Data on file. 54
Efficacy in all age groups >70 years old
Age range (years)
Shingrix group Placebo group Vaccine efficacy(95% CI)†
Shingles cases (N)* Shingles cases (N)*
70-79* 19 (6468) 216 (6554)91.3%
(86.0-94.9)
≥80* 6 (1782) 68 (1792)91.4%
(80.2-97.0)
*Pooled data from ZOE-50 (subjects ≥ 50 years) and ZOE-70 (subjects ≥70 years). Included 16,596 randomized subjects ≥50 years old, without immunocompromise, who received a second dose of the vaccine and did not develop a confirmed case of shingles within one month after the second dose. N=number of subjects within each age group.
†P-value for all comparisons <0.0001.2
CI, confidence interval.
1. Shingrix (prescribing information). Research Triangle Park, NC: GlaxoSmithKline; 2017.
2. Data on file.
Pre-specified, Pooled Analyses from ZOE-50 and ZOE-70*
04-Sep-17
10
Pathogenesis of Herpes zoster
• VZV
– latent within neurones mainly (2-5 copies/cell) reactivation
– Usually only once (5% second)
– Different to HSV but mechanism unknown
Necrosis and inflammation in nerve root, DRG and nerve
• VZV No apoptosis of infected neurones in vitro
Neurone/support cell lysis in DRG is probably immunopathologic
SPS: Efficacy
• HZ Incidence
–51.3% (44.2 – 57.6%)
• Burden Of Illness
–61.1% (51.1 – 69.1%)
• Post Herpetic Neuralgia
–66.5% (47.5 – 79%)
Licensure, availability and uptake worldwide
• USA: ACIP recommendation: immunize all immunocompetent persons>60 with one dose of Zostavax– over 25 million doses distributed since 2006
– overall uptake: 10.0% in 2009, 14.4% in 2010, 2014:24%
• UK: Sept 2013: Funded immunization program: all people > 70 and catchup cohort >79
• Australia: National Immunization Program funded for all i/c people >70 from Nov 2016; Catchup 71-79; Private market >50 since 2008
58
Minimal decline in efficacy up to 4 years post initial vaccination1
Years*
Shingrix VACCINE GROUP PLACEBO GROUP
Vaccineefficacy
(95% CI)†
Shingles cases (N)
Rate of shingles
(cases per 1000 person-years)
Shingles cases (N)
Rate of shingles(cases per 1000 person-years)
Year 1 2 (8250) 0.2 83 (8346) 10.197.6%
(90.9-99.8)
Year 2 7 (8039) 0.9 87 (8024) 11.192.0%
(82.8-96.9)
Year 3 9 (7736) 1.2 58 (7661) 7.784.7%
(69.0-93.4)
Year 4 7 (7426) 1.0 56 (7267) 8.287.9%
(73.3-95.4)
Vac
cin
e e
ffic
acy
by
year
po
st v
acci
nat
ion
CI, confidence interval.
*Year 1: from 30 days to 395 days after the second vaccination. Year 2: from >396 days to 760 days after the second vaccination. Year 3: from >761 days to 1125 days after the second vaccination. Year 4: from >1125 days after the second vaccination to the last contact date. N=number of subjects within each age group.
†P-value for all efficacy comparisons with placebo <0.001.
1. Cunningham AL, NEJM. 2016.
To prevent 1 HZ case in the 60+ population, you would need to vaccinate 10 individuals with Shingrix or 32
individuals with Zostavax®
Assuming a 2nd dose compliance of 69% for Shingrix.
Shingrix
Zostavax®
Vaccinate 10 individuals
withVaccinate 32 individuals with
to prevent 1 HZ
Case
Assuming a 2nd dose compliance of 69% for Shingrix.
HZ/su as a booster following Zostavax?
• Important where high ZV coverage: data soon to be published
• HZ/su after natural herpes zoster (physician documented):
- no safety concerns but high reactogenicity as for ZOE 50/70
- good response rate antibody to vaccine for patients >50: - 90.2%
- similar across all age groups
Godeaux O et al Hum Vacc Immuno 2017
04-Sep-17
11
• One month post-dose 2, 93.3% of HZ/su recipients ≥50 YOA met the
criteria for vaccine response.
VRR, vaccine response rate ≥2-fold increase in gE-specific CD42+ frequencies as compared to pre-vaccination levels; or
≥2-fold above the cut-off (320/106 gE-specific CD42+).
Anti-gE cell-mediated immune responses (in ZOE-50 CMI cohort)
Q3 (75th
percentile
Median (50th
percentile)
Q1 (25th
percentile)
Sustained CD4 T cell Response at 9 years
• Both cellular and humoral immune responses persisted through 9 years
• Immune responses were stable since year 4
• Immune response persistence above baseline was independent of age (60-69 and ≥70 YOA)