Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Recombinant Zoster Vaccine (RZV) and Herpes Zoster Live-Attenuated Vaccine (ZVL)

About

CDC vaccine recommendations are developed using an explicit evidence-based method based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Introduction

Since 2008, ZOSTAVAX®, a one-dose of herpes zoster live-attenuated vaccine (ZVL), has been recommended by the Advisory Committee on Immunization Practices (ACIP) for the prevention of herpes zoster in immunocompetent adults aged 60 years and older.12

On October 20th, 2017, SHINGRIX, a two-dose, adjuvanted, recombinant zoster vaccine (RZV) was approved by the FDA for the prevention of herpes zoster in immunocompetent adults aged 50 years and older. From 2015–2017, the ACIP reviewed evidence and considerations regarding the use of RZV (formerly referred to as herpes zoster subunit vaccine or HZ/su) in the United States to prevent herpes zoster and its complications. As part of ACIP’s process, a systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) of the evidence for both herpes zoster vaccines was conducted and presented to ACIP. There were no conflicts of interest reported by CDC and ACIP Herpes Zoster Work Group members involved in the GRADE analysis.

The GRADE approach was adopted by ACIP in 2010 as the framework for evaluating the scientific evidence that informs recommendations for vaccine use. GRADE was used to evaluate both RZV and ZVL. Evidence of benefits and harms were reviewed based on the GRADE approach3.

Separate GRADE analyses were conducted for each vaccine.

  • RZV: GRADE was used to evaluate routine vaccination of healthy older adults with the recombinant zoster vaccine. The primary policy question was “Should a two-dose series of the recombinant zoster vaccine be given routinely to immunocompetent adults aged 50 years and older for the prevention of herpes zoster?”
  • ZVL: GRADE was used to evaluate routine vaccination of healthy older adults with the live-attenuated herpes zoster vaccine (ZVL). The primary policy question was “Is one dose of ZVL safe and effective at preventing herpes zoster and postherpetic neuralgia PHN in the United States among immunocompetent adults aged 50 years and older?”

Methods and GRADE

GRADE of RZV studies

We conducted a systematic review of evidence on the efficacy and safety of a two dose regimen of recombinant zoster vaccine (RZV or SHINGRIX) to immunocompetent adults aged 50 years and older. We assessed outcomes and evaluated the quality of evidence using the GRADE approach.

We identified studies in Medline, Embase, CINAHL, Cochrane, Scopus and clinicaltrials.gov, without any language or date restrictions. Search terms are described in Table 1.

Articles were included if they provided data on vaccination with RZV and 1) involved human subjects; 2) reported primary data; 3) included immunocompetent adults aged 50 years or older; 4) included data relevant to the outcomes being measured; and 5) included data for the dosage and timing being recommended (50 µg gE/AS01B, 2 doses at 0 and 2 months). Efforts were also made to obtain unpublished and other relevant data by hand-searching reference lists, and consulting with vaccine manufacturers and subject matter experts. Title and abstracts were screened independently by two separate reviewers. After title and abstract screening, 22 studies were identified for in-depth review. Of these, 6 were still ongoing or had not yet reported results; 3 studies were done among immunocompromised participants; and 3 included co-administration of RZV with another vaccine as the intervention. This left 10 studies for the GRADE analysis45678910111213. Characteristics of these studies are presented in Table 2.

Beneficial and harmful outcomes for assessment were selected by the Work Group during work group calls and via online surveys where members were asked to rank the importance of relevant outcomes. The outcomes deemed critical by the work group were prevention of herpes zoster, prevention of PHN, and serious adverse events related to vaccination. Outcomes deemed important by the work group were duration of protection against herpes zoster and reactogenicity, specifically Grade 3 reactions (reactions that prevent normal activities) following vaccination.

The results of the GRADE analysis were presented to ACIP in February 2017.

Table 1. Evidence retrieval strategy, RZV

Database Search terms
Medline (OVID) 1946- (herpes zoster and subunit) OR (HZ ADJ5 subunit) OR HZ su OR GSK 1437173A
Embase (OVID) 1947- (herpes zoster and subunit) OR (HZ ADJ5 subunit) OR HZ su OR GSK 1437173A
CINAHL (Ebsco) 1982- (herpes zoster and subunit) OR (HZ ADJ5 subunit) OR HZ su OR GSK 1437173A
Cochrane Library ("herpes zoster" and subunit) OR (HZ NEAR/5 subunit) OR "HZ su" OR "GSK 1437173A"
Clinicaltrails.gov herpes zoster subunit OR HZ subunit OR RZV OR GSK 1437173A
Scopus TITLE-ABS-KEY(("herpes zoster" and subunit) OR (HZ NEAR/5 subunit) OR "HZ su" OR "GSK 1437173A") AND NOT INDEX(medline)

Abbreviations: RZV: Recombinant zoster vaccine

Table 2. Characteristics of Included Studies, RZV

Author, year Study design (N=total enrolled) Population VE [95% CI] Safety
Cunningham, 2016 RCT, 18 countries
(N=14,816)
Immunocompetent adults ≥70 yrs VE (HZ): 89.8%

[84.2-93.7]

VE (PHN): 88.8%

[68.7-97.1]

VE (HZ), by year post vaccination:

1y: 97.6%

[90.9-99.8]

2y: 92.0%

[82.8-96.9]

3y: 84.7%

[69.0-93.4]

4y: 87.9%

[73.3-95.4]

Serious adverse events (SAE)Intervention: 0.2%

[0.1-0.3]

Placebo: 0.1%

[0.0-0.2]

Reactogenicity

Intervention: 11.9%

[9.2-15.0]

Placebo: 2.0%

[1.0-3.6]

Lal, 2015 RCT, 18 countries
(N=16,160)
Immunocompetent
adults ≥50 yrs
VE (HZ): 97.2%

[93.7-99.0]

Serious adverse eventsIntervention: 0.0%

[0.0-0.1]

Placebo: 0.0%

[0.0-0.1]

Reactogenicity

Intervention: 15.6%

[14.5-16.7]

Placebo: 1.9%

[1.5-2.3]

Chlibek, 2013 RCT, 3 countries
(N=410)
Immunocompetent
adults ≥50 yrs
N/A Serious adverse events
No vaccine-related SAEs reported through month 14Reactogenicity
Intervention: 9.3%
Placebo: 5.3%
Chlibek, 2014 and Chilbek, 2016+ RCT, 4 countries
(N=715)
Immunocompetent
adults ≥60 yrs
N/A Serious adverse events
No vaccine related SAEs through month 72Reactogenicity:
Specific Grade 3 symptoms: 1.2%-4.8% (myalgia most commonly reported symptom)
Lal, 2018+ RCT, 2 countries
(N=119)
Immunocompetent
adults ≥50 yrs
N/A Serious adverse events
No vaccine related SAEs through month 12Reactogenicity
Any solicited Grade 3 symptoms:
Intervention: 15.1%
Leroux-Roels, 2012+ RCT, Belgium
(N=135)
Immunocompetent
adults 50-70 yrs
N/A Serious adverse events
No vaccine related SAEs through month 42Reactogenicity
Specific Grade 3 symptoms: 0%-20% (redness most commonly reported symptom)
Vink, 2017+ RCT, Japan
(N=60)
Immunocompetent
adults ≥50 yrs
N/A Serious adverse events
No vaccine related SAEs through month 12Reactogenicity
Specific Grade 3 symptoms: 0%-5% (redness most commonly reported symptom)
Godeaux, 2017+ Non-RCT, 2 countries
(N=96)
Immunocompetent
adults ≥50 yrs
N/A Serious adverse events
No vaccine related SAEs through month 12Reactogenicity
Any Grade 3 symptoms: Not reported
Specific Grade 3 symptoms: 0%-10% (fatigue most commonly reported symptom)
Lal, 2013+ Non-RCT, Australia
(N=10)
Immunocompetent
adults 50-69 yrs
N/A Serious adverse events
No serious adverse events reportedReactogenicity
Any Grade 3 symptoms: Intervention: 40%

Abbreviations: RZV: Recombinant zoster vaccine; VE: vaccine efficacy/effectiveness; 95% CI: 95% Confidence Interval; HZ: herpes zoster; PHN: post-herpetic neuralgia; SAE: Serious adverse events; RCT: randomized controlled trial; Non-RCT: non-randomized clinical trial;

+ No comparison group: no participants received no vaccine or placebo.

GRADE of ZVL studies

We conducted a systematic review of evidence on the effectiveness and safety of a live attenuated herpes zoster vaccine (ZVL or ZOXTAVAX®) for immunocompetent adults aged 50 years and older. We assessed outcomes and evaluated the quality of evidence using the GRADE approach.

We identified studies in Medline, Embase, CINAHL, Cochrane, Scopus and clinicaltrials.gov, without any language or date restrictions. Search terms are described in Table 3.

Articles were included if they provided data on vaccination with one dose of ZVL and 1) involved human subjects; 2) reported primary data; 3) included immunocompetent adults aged 50 years or older; and 4) included data relevant to the outcomes being measured. Efforts were also made to obtain unpublished and other relevant data. Title and abstracts were screened independently by two separate reviewers. After title and abstract screening, 159 studies were identified for further review. Of these, 52 did not report outcomes of interest, 27 did not report data for ZVL, 23 had results reported in another study, 11 were still ongoing or had not yet reported results; and 7 were individual case reports. This left 40 studies for the GRADE analysis14151617181920212223242526272829303132333435363738394041424344454647484950515253. Characteristics of these studies are presented in Table 4.

The outcomes deemed critical by the work group were prevention of herpes zoster, prevention of PHN, and serious adverse events related to vaccination. Outcomes deemed important by the work group were duration of protection against herpes zoster (defined as 4 or more years post vaccination) and reactogenicity following vaccination.

The results of the GRADE analysis were presented to ACIP in June 2017.

Table 3. Evidence retrieval strategy, ZVL

Database Strategy
Medline (OVID) 1946- (zostavax OR (zoster AND (vaccine ADJ2 live*)) OR (zoster AND (attenuated ADJ2 live)) OR (zoster AND (vaccine ADJ2 attenuated)) OR ((zoster ADJ3 vaccin*) AND shingles))
Embase (OVID) 1947- (zostavax OR (zoster AND (vaccine ADJ2 live)) OR (zoster AND (attenuated ADJ2 live)) OR (zoster AND (vaccine ADJ2 attenuated)) OR ((zoster ADJ3 vaccin*) AND shingles))
CINAHL (Ebsco) 1982- (zostavax OR (zoster AND (vaccine N2 live*)) OR (zoster AND (attenuated N2 live)) OR (zoster AND (vaccine N2 attenuated)) OR ((zoster N3 vaccin*) AND shingles))
Cochrane Library (zostavax OR (zoster AND (vaccine NEAR/2 live*)) OR (zoster AND (attenuated NEAR/2 live)) OR (zoster AND (vaccine NEAR/2 attenuated)) OR ((zoster NEAR/3 vaccin*) AND shingles))
Clinicaltrails.gov Zostavax OR "zoster live vaccine" OR "zoster live attenuated" OR "zoster vaccine attenuated"
Scopus TITLE-ABS-KEY(zostavax OR (zoster AND (vaccine W/2 live*)) OR (zoster AND (attenuated W/2 live)) OR (zoster AND (vaccine W/2 attenuated)) OR ((zoster NEAR/3 vaccin*) AND shingles)) AND NOT INDEX(medline)

Table 4. Characteristics of Included Studies, ZVL

Author, year Study design (N=total enrolled) Population VE [95% CI] Safety
Oxman, 2005
(SPS)
RCT, USA(N=38,546) Immunocompetent
adults ≥60y
VE (HZ): 51.3%

[44.2-57.6]

VE (PHN): 66.5%

[47.5-79.2]

Serious adverse events (SAE)
Intervention: 1.9%
Placebo: 1.3%, p<0.05*Reactogenicity
Intervention: 48%
Placebo: 17%, p<0.05
Schmader, 2012 (STPS) RCT w/limitations, USA(N=14,270) Immunocompetent
adults ≥60y
VE (HZ), by year post vaccination:

4y*: 44.6%

[20.5-61.8]

5y*: 43.1%

[5.1-66.5]

6y: 30.6%

[-6.0-54.6]

*HZ events and person-years follow-up pooled for SPS and STPS

VE (PHN), 3 to 7 years post vaccination: 60%

[-10-87%]

Serious adverse events
No serious adverse events related to the vaccination reported.
Morrison, 2015 (LTPS) RCT w/limitations, USA(N=6,867) Immunocompetent
adults ≥60y
VE (HZ), by year post vaccination:

7y*: 46.0%

[28.4–60.2]

8y*: 31.1%

[11.2–47.6]

9y: 6.8%

[−16.5-26.4]

10y: 14.1%

[−11.3-34.9]

11y: −1.7%

[−57.1-37.9]

*HZ events and person-years follow-up pooled for STPS and LTPS

VE (PHN), 7 to 11 years post vaccination: 35% [9-56]

Serious adverse events
No serious adverse events related to the vaccination reported.
Schmader, 2012 (ZEST) RCT, North America and Europe
(N=22,439)
Immunocompetent
adults 50-59y
VE (HZ): 69.8%

[54.1-80.6]

Serious adverse events
Intervention: 0.6%
Placebo: 0.5%, p>0.05Reactogenicity
Intervention: 64%
Placebo: 14%, p<0.05
Langan, 2013 Cohort, USA
(N=766,330)
Medicare enrollees,
adults ≥65y
VE (HZ): 48%

[39-56]

VE (PHN): 59%

[21-79]

Did not report safety results.
Tseng, 2014 Cohort, USA
(N=21,476)
KPSC members, adults ≥60y who later undergo chemotherapy Hazard ratio (HZ, vaccinated vs unvaccinated): 0.58

[0.46-0.73]

Did not report safety results.
Tseng, 2016b Cohort, USA
(N=3,492)
KPSC members, adults ≥60y with end-state renal disease Hazard ratio (HZ, vaccinated vs unvaccinated):
0.49 [0.29-0.85]
Did not report safety results.
Tseng, 2015 Cohort, USA
(N=2,310)
KPSC members, adults ≥60y Risk ratio (PHN, vaccinated vs unvaccinated): 0.59

[0.41-0.85]

Did not report safety results.
Baxter, 2017 Cohort, USA
(N=1.3 million)
KPNC members, adults ≥50y VE (HZ): 49.1%

[47.5-50.6]

Did not report safety results.
Marin, 2015 Case control, USA
(N=628)
Adults aged ≥60y VE (HZ): 54.2%

[32.0-69.2]

VE (PHN): 55.2%

[0.0-91.6]

Did not report safety results.
Baxter, 2016a Cohort, USA
(N=1.3 million)
KPNC members, adults ≥50y VE (PHN) = 68.7%

[64.6-72.3]

Did not report safety results.
Tseng, 2016a Cohort, USA
(N=706,312)
KPSC members, adults ≥60y VE (HZ), by year post vaccination:

1y: 68.7%

[66.3-70.9]

2y: 49.5%

[45.7-53.1]

3y: 39.1%

[33.8-43.9]

4y: 35.2%

[28.3-41.4]

5y: 37.1%

[29.1-44.2]

6y: 32.9%

[23.1-41.5]

7y: 16.5%

[1.4-29.3]

8y: 4.2%

[-24.0-25.9]

Did not report safety results.
Izurieta, 2017 Cohort, USA
(N=1,891,984)
Medicare enrollees,
adults ≥65y
VE (HZ), by year post vaccination

≤3y: 33%

[32-35]

≥4y: 19%

[17-22]

Did not report safety results.
Murray, 2011 RCT, Canada, Germany, Spain, UK, US
(N=11,999)
Immunocompetent
adults ≥60y
Did not report VE. Estimated risk of SAEs within 42 days was 1.41% for vaccine recipients versus 1.12% for placebo, with a relative-risk of 1.26

[0.91-1.73]

MacIntyre, 2010 RCT, Australia, Canada, Germany, Italy, Spain, UK
(N=475)
Immunocompetent
adults ≥60y
Did not report VE. Serious adverse events
No SAE related to vaccine reported within 28 daysReactogenicity
Intervention: 36%
Placebo: 11%
Mills, 2010 RCT, USA
(N=101)
Immunocompetent
adults ≥50y
Did not report VE. Serious adverse events
No SAE related to vaccine reported within 28 daysReactogenicity
Intervention: 46%
Placebo: 4%
Beals, 2016 RCT, USA
(N=224)
Immunocompetent
adults ≥50y
Did not report VE. Serious adverse events
No SAE related to vaccine reported within 42 daysReactogenicity
Intervention: 52%
Placebo: 13%
Hata, 2016 RCT, Japan
(N=62)
KPNC members, adults ≥60y Did not report VE. Serious adverse events
No SAE related to vaccine reported within 42 daysReactogenicity
Intervention: 8%
Placebo: 11%
Macaladad, 2007 RCT, Brazil, Costa Rica, Colombia, Mexico, Peru, Venezuela, Phillipines
(N=21)
Immunocompetent
adults ≥30y
Did not report VE. Serious adverse events
No SAE related to vaccine reported within 42 daysReactogenicity
Intervention: 11%
Placebo: 0%
Zoran, 2016 RCT, USA
(N=28,785)
Immunocompetent
adults ≥60y
Did not report VE. Reactogenicity
Specific Grade 3 symptoms: 0.4%-0.9% (erythema most commonly reported symptom)
Baxter, 2012 Cohort, USA
(N≈29,000)
KPNC members, adults ≥60y Did not report VE. Compared rates of adverse events in a 42-day risk time period immediately following vaccination with rates in the same cohort in a subsequent comparison time period. Found increased relative risks for coronary atherosclerosis and other heart disease, percutaneous transluminal coronary angioplasty, systemic lupus erythematosus and connective tissue disorders. But after medical chart review found no safety concerns within 42 days of vaccination.
Tseng, 2012 Cohort, USA
(N= 193,083)
Adults ≥50y Did not report VE. Compared rates of adverse events using a case-centered and self-controlled case series design and found no increased risk for cerebrovascular events; cardiovascular events; meningitis; encephalitis; and encephalopathy; and Ramsay-Hunt syndrome and Bell's palsy. The risk of allergic reaction was significantly increased within 1-7 days of vaccination [relative risk = 2.13, 95% confidence interval (CI): 1.87-2.40 by case-centred method and relative rate = 2.32, 95% CI: 1.85-2.91 by SCCS]
Berger, 1998+ RCT§ Immunocompetent
adults ≥55y
Did not report VE. Any injection-site symptoms:
Intervention: 26.5%
Kerzner, 2007+ RCT, USA and Europe
(N=762)
Immunocompetent

adults ≥50y

Did not report VE. Serious adverse events
No SAEs related to vaccine reported within 28 days.Reactogenicity
Any injection-site symptoms:
Intervention: 35%
Tyring, 2007+ RCT, USA, Canada, UK, Germany, Belgium
(N=698)
Immunocompetent
adults ≥55y
Did not report VE. Serious adverse events
No SAEs related to vaccine reported within 42 days.Reactogenicity
Any injection-site symptoms:
Intervention: 62%
Gilderman, 2008+ RCT, USA
(N=367)
Immunocompetent
adults ≥50y
Did not report VE. Serious adverse events
No SAEs related to vaccine reported within 28 days.Reactogenicity
Any injection-site symptoms:
Intervention: 46%
Leroux-Roels, 2012+ RCT, Belgium
(n=155)
Immunocompetent
adults 50-70y
Did not report VE. Serious adverse events
No SAEs related to vaccine reported within 12 months.Reactogenicity
Redness at injection-site:
Intervention: 62% (4% were considered grade 3).
Vesikari, 2013+ RCT, Finland, Germany, Italy, Spain, Netherlands
(N=759)
Immunocompetent
adults ≥70y
Did not report VE. Serious adverse events
No SAEs related to vaccine reported within 28 days.Reactogenicity
Any injection-site symptoms:
Intervention: 46%
Diez-Domingo, 2015+ RCT, Germany and Spain
(N=354)
Immunocompetent
adults ≥50y
Did not report VE. Serious adverse events
No SAEs related to vaccine reported within 28 days.ReactogenicityIntramuscular administration resulted in significantly fewer injection-site reactions compared to subcutaneous administration[47.2% vs 69.5%, respectively]
Arnou, 2011+ Non-RCT, France
(n=96)
Immunocompetent
adults ≥50y
Did not report VE. Serious adverse events
No SAEs related to vaccine reported within 28 days.Reactogenicity
Any injection-site symptoms:
Intervention: 52%
(2 individuals reported severe injection-site reactions)
Hata, 2013+ Non-RCT, Japan
(N=20)
Immunocompetent
adults 60-70y with diabetes mellitus
Did not report VE. Serious adverse events
No SAEs related to vaccine reported within 1 year.Reactogenicity
Intervention: 10%
Morrison, 2013+ Non-RCT, USA
(N=13,681)
Immunocompetent
adults ≥64y with documented herpes zoster
Did not report VE. Serious adverse events
Rates of SAEs not significantly different among those with or without prior zoster (0.95% and 0.66%, respectively; p= .37)
Stanford, 2014+ Non-RCT, USA
(N=54)
Immunocompetent
adults ≥50y
Did not report VE. Serious adverse events
No SAEs related to vaccine reported within 35 days.Reactogenicity
Any injection-site symptoms:
Intervention: 64%
Yao, 2015+ Non-RCT, Taiwan
(N=150)
Adults ≥50y with any underlying chronic illness in stable condition Did not report VE. Serious adverse events
No SAEs related to vaccine reported within 28 days.Reactogenicity
Any injection-site symptoms:
Intervention: 36%
Choi, 2016+ Non-RCT, Korea
(N=180)
Adults ≥50y with any underlying chronic illness in stable condition Did not report VE. Serious adverse events
No SAEs related to vaccine reported within 42 days.Reactogenicity
Any injection-site symptoms:
Intervention: 53%
Levin, 2003+ Non-RCT, USA
(N=196)
Immunocompetent
adults ≥60y previously received VZV vaccine
Did not report VE. Serious adverse events
No SAEs related to vaccine reported within 42 days.Reactogenicity
Pain at injection-site:
Intervention: 48%
Lelic, 2016+ Non-RCT, Canada
(N=240)
Nursing home residents, adults ≥80y Did not report VE. No adverse events related to vaccine reported within 42 days.
Levin, 2016+ Non-RCT, USA
(N=600)
Adults ≥60y with any underlying chronic illness in stable condition, including adults ≥70y who previously received ZVL Did not report VE. Serious adverse events
No SAEs related to vaccine reported within 1 year.Reactogenicity
Any injection-site symptoms:
Intervention: 44%
Baxter, 2016b+ Non-RCT, USA
(N=376,531)
KPNC members who received ZVL Did not report VE. No association found between sudden sensorineural hearing loss and ZVL, OR=0.424 (95% CI: 0.08-1.53)
Willis, 2016+ Non-RCT, global Merck Adverse Event Reporting System worldwide postmarketing adverse event database Did not report VE. Merck’s 10 year post-marketing analysis reviewed 23,556 reports with a total of 45,898 adverse events. The majority of reported adverse events were non-serious (93%). Most commonly reported adverse events were injection-site reactions and herpes zoster. There were some reports of PCR-confirmed VZV rash caused by Oka/Merck vaccine strain.

Abbreviations: ZVL: Live-attenuated zoster vaccine; VE: vaccine efficacy/effectiveness; 95% CI: 95% Confidence Interval; HZ: herpes zoster; PHN: post-herpetic neuralgia; SAE: Serious adverse events; RCT: randomized controlled trial; Non-RCT: non-randomized clinical trial; SPS: Shingles Prevention Study; STPS: Short-term Persistence Study; LTPS: Long-term Persistence Study; VZV: varicella zoster virus; KPNC: Kaiser Permanente Northern California; KPSC: Kaiser Permanente Southern California; OR: Odds ratio

*In the Shingles Prevention Study, adverse event substudy, significantly more subjects in the vaccine group had serious adverse events than in the placebo group (1.9% vs. 1.3%, respectively; P=0.03); A post hoc, subject-by-subject review found no clinically meaningful differences between the groups in the pathophysiology, nature, timing, intensity, or outcome of these events. (Oxman, NEJM, 2005)

** Ad-hoc analysis of reactogenicity among participants of the Shingles Prevention Study (Oxman, NEJM, 2005)

+ No comparison group: no participants received no vaccine or placebo.

§ Did not report number of subjects who received ZVL

Results

GRADE of RZV studies

Table 5. Included data, by outcome, RZV

Outcome Number of subjects (number of studies) Comparison groups Findings
Prevention of herpes zoster 50-59y: 7,017 (1)
60-69y: 4,307 (1)
≥70y: 16,596 (1)
2 dose RZV vs placebo VE [95% CI]
  • 50-59y: 96.6% [89.6-99.3]
  • 60-69y: 97.4% [90.1-99.7]
  • ≥70y: 91.3% [86.8-94.5]
Prevention of post-herpetic neuralgia ≥50y: 27,916 (1)
≥70y: 16,596 (1)
2 dose RZV vs placebo VE [95% CI]
  • ≥50y: 91.2% [75.9-97.7]
  • ≥70y: 88.8% [68.7-97.1]
Duration of protection against herpes zoster (up to 4 years post vaccination) 14,693 (1) 2 dose RZV vs placebo VE remained about 85% in the first 4 years following vaccination
Serious adverse events 29,965 (8) 2 dose RZV vs placebo No differences in serious adverse events between vaccinated and placebo groups. No serious adverse events related to vaccination found.
Reactogenicity (Grade 3 reaction) 10,590+ (8) 2 dose RZV vs placebo Grade 3 reactions more commonly reported in vaccinated populations compared to placebo.

In phase III clinical trials (n=9,936):

  • 16.5% of vaccine recipients reported any Grade 3 reaction compared to 3.1% of placebo recipients.
  • 9.4% of vaccine recipients reported Grade 3 injection-site reactions, compared to 0.3% of placebo recipients.
  • 10.8% of vaccine recipients reported Grade 3 systemic reactions, compared to 2.4% of placebo recipients.

Safety and immunogenicity studies reported similar reactogenicity rates among participants receiving RZV

Abbreviations: y: years-old; RZV: recombinant zoster vaccine; VE: vaccine efficacy/effectiveness; 95% CI: 95% Confidence Interval

+In the ZOE 50/70 Phase III clinical trials, reactogenicity data was only collected from a randomly selected sub-set of participants (n=9,936)

Table 6. Summary of the evidence for select outcomes with use of RZV in immunocompetent adults aged 50 years and older

Outcomes Design (# studies) Initial Evidence Risk of Bias Inconsistency Indirectness Imprecision Others Evidence type Outcome evidence type Overall Evidence Type
Benefits
Prevent herpes zoster 1 RCT 1 Not Serious Not Serious Not Serious Not Serious None 1 1 1
Prevent post-herpetic neuralgia 1 RCT 1 Not Serious Not Serious Not Serious Not Serious None 1 1
Duration of protection against herpes zoster (up to 4 years post vaccination) 1 RCT 1 Not Serious Not Serious Not Serious Not Serious None 1 1
Harms
Serious adverse events (after any dose) 2 RCT 1 Not serious Not serious Not Serious Not Serious None 1 1 1
4 RCT with no placebo 1 Serious*(-1) Not Serious Serious(-1) Not Serious None 3
2 Non-RCT 2 Serious*(-1) Not Serious Serious(-1) Not Serious None 4
Reactogenicity (Grade 3 reaction) 2 RCT 1 Not serious Not serious Not Serious Not Serious None 1 1
4 RCT with no placebo 1 Serious*(-1) Not Serious Serious(-1) Not Serious None 3
2 Non-RCT 2 Serious*(-1) Not Serious Serious(-1) Not Serious None 4

Abbreviations: RZV: recombinant zoster vaccine; RCT: randomized controlled trial; Non-RCT: non-randomized clinical trial

*Studies were non-blinded, open-label trials

‡No placebo comparison group. Did not directly meet our policy question of comparing outcomes between vaccine and placebo recipients

GRADE of ZVL studies

Table 7. Included data, by outcome, ZVL

References in this table:54

Outcome Number of subjects (number of studies) Comparison groups Findings
Prevention of herpes zoster 50-59y: 22,439 (1)
≥60y: ~4.7 million (8)
One dose ZVL vs placebo or no vaccine Vaccine efficacy against herpes zoster, clinical trial data:

VE [95% CI]

  • 50-59y: 70% [54-81]
  • 60-69y: 64% [56-71]
  • 70-79y: 41% [28-52]
  • ≥80y: 18% [-29-48]

VE from observational studies in adults ≥60y ranged from 33% to 51% (within 4 years post vaccination)

Prevention of post-herpetic neuralgia ≥60y: ~4 million (8) One dose ZVL vs placebo or no vaccine Vaccine efficacy against herpes zoster, clinical trial data:

VE [95% CI]

  • 60-69y: 65.7% [20.4-86.7]
  • ≥70y: 66.8% [43.3-81.3]

VE from observational studies in adults ≥60y ranged from 41% to 69% (within 4 years post vaccination)

Duration of protection against herpes zoster (up to 4 years post vaccination) ≥60y: ~3.9 million (5) One dose ZVL vs placebo or no vaccine RCT (SPS, STPS, LTPS)

VE, ≥60y, by year post vaccination:

  • 1y: 62.0 [49.6–71.6]
  • 2y: 48.9 [34.7–60.1]
  • 3y: 46.8 [31.1–59.2]
  • 4y: 44.6 [20.5–61.8]
  • 5y: 43.1 [5.1–66.5]
  • 6y: 30.6 [−6.0 to 54.6]
  • 7y: 46.0 [28.4–60.2]
  • 8y: 31.1 [11.2–47.6]
  • 9y: 6.8 [−16.5 to 26.4]
  • 10y: 14.1 [−11.3 to 34.9]
  • 11y: −1.7 [−57.1 to 37.9]

Observational studies: ZVL wanes year by year. Beyond 4 years, all studies estimates VE ≤40% after 4 years post vaccination

Serious adverse events ≥50y: ~712,000 (28) One dose ZVL vs placebo or no vaccine No differences in serious adverse events between vaccinated and placebo groups in RCTs.

Overall found no serious adverse events associated with ZVL

In clinical trials 2 subjects with varicella-like rashes and zoster like rashes had PCR confirmed Oka/Merck strain varicella [54].

Reactogenicity ≥50y: ~310,000 (25) One dose ZVL vs placebo Injection-site reactions were the most common adverse reaction related to vaccination

4 studies reported moderate/severe (grade 3) injection-site reactions that ranged between 0%-4% of vaccine recipients

Abbreviations: y: years-old; ZVL: Live-attenuated zoster vaccine; VE: vaccine efficacy/effectiveness; 95% CI: 95% Confidence Interval; RCT: randomized controlled trial; SPS: Shingles Prevention Study; STPS: Short-term Persistence Study; LTPS: Long-term Persistence Study

Table 8. Summary of the evidence for select outcomes with use of ZVL in immunocompetent adults aged 50 years and older

Outcomes Design
(# studies)
Initial Evidence Risk of Bias Inconsistency Indirectness Imprecision Others Evidence type Outcome evidence type Overall Evidence Type
Benefits
Prevent herpes zoster 2 RCT 1 Not Serious Not Serious Not Serious Not Serious None 1 1 1
7 Obs 3 Serious*(-1) Not Serious Not Serious Not Serious None 4
Prevent post-herpetic neuralgia 1 RCT 1 Not Serious N/A Not Serious Not Serious None 1 1
2 RCT with limitations 2 Not Serious Not Serious Not Serious Serious(-1) None 3
5 Obs 3 Serious**(-1) Not Serious Not Serious Not Serious None 4
Duration of protection against herpes zoster (4 or more years post vaccination) 2 RCT with limitations 2 Not Serious Not Serious Not Serious Not Serious None 2 2
3 Obs 3 Serious*(-1) Not Serious Not Serious Not Serious None 4
Harms
Serious adverse events (after any dose) 8 RCT 1 Not serious Not serious Not Serious Not Serious None 1 1 1
13 RCT with limitations 2 Serious(-1) Not Serious Not Serious Not Serious None 3
7 Obs 3 Serious*(-1) Not Serious Not Serious Not Serious None 4
Reactogenicity 15 RCT 1 Not serious Not serious Not Serious Not Serious None 1 1
5 Non-RCT 2 Serious(-1) Not Serious Not Serious Not Serious None 3
5 Obs 3 Serious*(-1) Not Serious Not Serious Not Serious None 4

Abbreviations: ZVL: Live-attenuated zoster vaccine; RCT: randomized controlled trial; Non-RCT: non-randomized clinical trial; Obs: observational study

*Outcome assessors were likely aware of intervention received by participants.

**Outcome assessors were likely aware of intervention received by participants. PHN may have been underreported – PHN diagnosis based on healthcare encounters not self-report.

†Limitations due to comparison groups. During the STPS, placebo participants could receive ZVL and censoring due to vaccination may have introduced bias that increased incidence of HZ among remaining placebo recipients. During the LTPS, there were no unvaccinated controls so comparison group was modeled.

‡Studies were non-blinded, open-label trials with no comparison group.

Summary

The evidence type for use of recombinant zoster vaccine in immunocompetent adults aged 50 years and older was determined to be type 1 (high level of evidence). The evidence type for use of the live attenuated herpes zoster vaccine in immunocompetent adults aged 50 years and older was determined to be type 1 (high level of evidence). The Advisory Committee on Immunization Practices reviewed the results of both GRADE analysis as well as other data demonstrating high burden of herpes zoster and PHN among the target population, cost effectiveness and implementation analysis.

In October 2017, ACIP recommended:

  • Recombinant zoster vaccine (RZV) is recommended for the prevention of herpes zoster and related complications for immunocompetent adults aged 50 years and older.
  • RZV is recommended for the prevention of herpes zoster and related complications for immunocompetent adults who previously received ZVL.
  • RZV is preferred over ZVL for the prevention of herpes zoster and related complications.

These recommendations serve as a supplement to the 2008 Prevention of Herpes Zoster Recommendations of ACIP, for the use of ZVL in adults age 60 years and older15556. The Policy Note detailing the 2017 ACIP recommendations for use of herpes zoster vaccine in adults aged 50 years and older are available on the ACIP website.

View the complete list of GRADE evidence tables‎

  1. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report: Recommendations and Reports. 2008 Jun 6;57(5):1-30.
  2. Hales CM, Harpaz R, Ortega-Sanchez I, Bialek SR, Centers for Disease Control and Prevention (CDC). Update on recommendations for use of herpes zoster vaccine. MMWR Morb Mortal Wkly Rep. 2014 Aug 22;63(33):729-31.
  3. Evidence-Based Recommendations-GRADE. 2015 [July 2015].
  4. Cunningham AL, Lal H, Kovac M, Chlibek R, Hwang SJ, Díez-Domingo J, Godeaux O, Levin MJ, McElhaney JE, Puig-Barberà J, Vanden Abeele C. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. New England Journal of Medicine. 2016 Sep 15;375(11):1019-32.
  5. Lal H, Cunningham AL, Godeaux O, Chlibek R, Diez-Domingo J, Hwang SJ, Levin MJ, McElhaney JE, Poder A, Puig-Barberà J, Vesikari T. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. New England Journal of Medicine. 2015 May 28;372(22):2087-96.
  6. Chlibek R, Bayas JM, Collins H, de la Pinta ML, Ledent E, Mols JF, Heineman TC. Safety and immunogenicity of an AS01-adjuvanted varicella-zoster virus subunit candidate vaccine against herpes zoster in adults≥ 50 years of age. The Journal of infectious diseases. 2013 Jul 31;208(12):1953-61.
  7. Chlibek R, Smetana J, Pauksens K, Rombo L, Van den Hoek JA, Richardus JH, Plassmann G, Schwarz TF, Ledent E, Heineman TC. Safety and immunogenicity of three different formulations of an adjuvanted varicella-zoster virus subunit candidate vaccine in older adults: a phase II, randomized, controlled study. Vaccine. 2014 Mar 26;32(15):1745-53.
  8. Chlibek R, Pauksens K, Rombo L, van Rijckevorsel G, Richardus JH, Plassmann G, Schwarz TF, Catteau G, Lal H, Heineman TC. Long-term immunogenicity and safety of an investigational herpes zoster subunit vaccine in older adults. Vaccine. 2016 Feb 3;34(6):863-8.
  9. Lal H, Poder A, Campora L, Geeraerts B, Oostvogels L, Abeele CV, Heineman TC. Immunogenicity, reactogenicity and safety of 2 doses of an adjuvanted herpes zoster subunit vaccine administered 2, 6 or 12 months apart in older adults: Results of a phase III, randomized, open-label, multicenter study. Vaccine. 2018 Jan 2;36(1):148-54.
  10. Leroux-Roels I, Leroux-Roels G, Clement F, Vandepapelière P, Vassilev V, Ledent E, Heineman TC. A phase 1/2 clinical trial evaluating safety and immunogenicity of a varicella zoster glycoprotein e subunit vaccine candidate in young and older adults. The Journal of infectious diseases. 2012 Aug 7;206(8):1280-90.
  11. Vink P, Shiramoto M, Ogawa M, Eda M, Douha M, Heineman T, Lal H. Safety and immunogenicity of a Herpes Zoster subunit vaccine in Japanese population aged≥ 50 years when administered subcutaneously vs. intramuscularly. Human vaccines & immunotherapeutics. 2017 Mar 4;13(3):574-8.
  12. Godeaux O, Kovac M, Shu D, Grupping K, Campora L, Douha M, Heineman TC, Lal H. Immunogenicity and safety of an adjuvanted herpes zoster subunit candidate vaccine in adults≥ 50 years of age with a prior history of herpes zoster: A phase III, non-randomized, open-label clinical trial. Human vaccines & immunotherapeutics. 2017 May 4;13(5):1051-8.
  13. Lal H, Zahaf T, Heineman T. Safety and immunogenicity of an AS01-adjuvanted varicella zoster virus subunit candidate vaccine (RZV) A phase-I, open-label study in Japanese adults. Human vaccines & immunotherapeutics. 2013 Jul 13;9(7):1425-9.
  14. Arnou R, Fiquet A, Thomas S, Sadorge C. Immunogenicity and safety of ZOSTAVAX() approaching expiry potency in individuals aged >50 years. Human Vaccines. 2011;7(10):1060-5.
  15. Baxter R, Bartlett J, Fireman B, Marks M, Hansen J, Lewis E, et al. Effectiveness of Live Zoster Vaccine in Preventing Postherpetic Neuralgia (PHN). Open Forum Infectious Diseases. 2016a;3(suppl_1):128-.
  16. Baxter R, Bartlett J, Fireman B, Marks M, Hansen J, Lewis E, Aukes L, Chen Y, Klein NP, Saddier P. Long-Term Effectiveness of the Live Zoster Vaccine in Preventing Shingles: A Cohort Study. American Journal of Epidemiology. 2017 Jun 21:1-9.
  17. Baxter R, Lewis N, Bohrer P, Harrington T, Aukes L, Klein NP. Sudden-Onset Sensorineural Hearing Loss after Immunization: A Case- Centered Analysis. Otolaryngology – Head and Neck Surgery (United States). 2016b;155(1):81-6.
  18. Baxter R, Tran TN, Hansen J, Emery M, Fireman B, Bartlett J, et al. Safety of ZostavaxTM–a cohort study in a managed care organization. Vaccine. 2012;30(47):6636-41.
  19. Beals CR, Railkar RA, Schaeffer AK, Levin Y, Kochba E, Meyer BK, et al. Immune response and reactogenicity of intradermal administration versus subcutaneous administration of varicella-zoster virus vaccine: an exploratory, randomized, partly blinded trial. The Lancet Infectious Diseases. 2016;16(8):915-22.
  20. Berger R, Trannoy E, Hollander G, Bailleux F, Rudin C, Creusvaux H. A dose-response study of a live attenuated varicella-zoster virus (Oka strain) vaccine administered to adults 55 years of age and older. Journal of Infectious Diseases. 1998;178 Suppl 1:S99-103.
  21. Choi WS, Choi JH, Choi JY, Eom JS, Kim SI, Pai H, et al. Immunogenicity and Safety of a Live Attenuated Zoster Vaccine (ZOSTAVAXTM) in Korean Adults. Journal of Korean Medical Science. 2016;31(1):13-7.
  22. Diez-Domingo J, Weinke T, Garcia de Lomas J, Meyer CU, Bertrand I, Eymin C, et al. Comparison of intramuscular and subcutaneous administration of a herpes zoster live-attenuated vaccine in adults aged >50 years: a randomized non-inferiority clinical trial. Vaccine. 2015;33(6):789-95.
  23. Gilderman LI, Lawless JF, Nolen TM, Sterling T, Rutledge RZ, Fernsler DA, et al. A double-blind, randomized, controlled, multicenter safety and immunogenicity study of a refrigerator-stable formulation of Zostavax. Clinical & Vaccine Immunology: CVI. 2008;15(2):314-9.
  24. Hata A, Inoue F, Hamamoto Y, Yamasaki M, Fujikawa J, Kawahara H, et al. Efficacy and safety of live varicella zoster vaccine in diabetes: a randomized, double-blind, placebo-controlled trial. Diabetic Medicine. 2016;33(8):1094-101.
  25. Hata A, Inoue F, Yamasaki M, Fujikawa J, Kawasaki Y, Hamamoto Y, et al. Safety, humoral and cell-mediated immune responses to herpes zoster vaccine in subjects with diabetes mellitus. Journal of Infection. 2013;67(3):215-9.
  26. Izurieta HS, Wernecke M, Kelman J, Wong S, Forshee R, Pratt D, et al. Effectiveness and Duration of Protection Provided by the Live-attenuated Herpes Zoster Vaccine in the Medicare Population Ages 65 Years and Older. Clin Infect Dis. 2017;64(6):785-93.
  27. Kerzner B, Murray AV, Cheng E, Ifle R, Harvey PR, Tomlinson M, et al. Safety and immunogenicity profile of the concomitant administration of ZOSTAVAX and inactivated influenza vaccine in adults aged 50 and older. Journal of the American Geriatrics Society. 2007;55(10):1499-507.
  28. Langan SM, Smeeth L, Margolis DJ, Thomas SL. Herpes Zoster Vaccine Effectiveness against Incident Herpes Zoster and Post-herpetic Neuralgia in an Older US Population: A Cohort Study. PLOS Medicine. 2013;10(4):e1001420.
  29. Lelic A, Verschoor CP, Lau VW, Parsons R, Evelegh C, Bowdish DM, et al. Immunogenicity of Varicella Zoster Vaccine and Immunologic Predictors of Response in a Cohort of Elderly Nursing Home Residents. Journal of Infectious Diseases. 2016;5:5.
  30. Leroux-Roels I, Leroux-Roels G, Clement F, Vandepapeliere P, Vassilev V, Ledent E, et al. A phase 1/2 clinical trial evaluating safety and immunogenicity of a varicella zoster glycoprotein e subunit vaccine candidate in young and older adults. Journal of Infectious Diseases. 2012;206(8):1280-90.
  31. Levin MJ, Schmader KE, Pang L, Williams-Diaz A, Zerbe G, Canniff J, et al. Cellular and Humoral Responses to a Second Dose of Herpes Zoster Vaccine Administered 10 Years After the First Dose Among Older Adults. J Infect Dis. 2016;213(1):14-22.
  32. Levin MJ, Smith JG, Kaufhold RM, Barber D, Hayward AR, Chan CY, et al. Decline in varicella-zoster virus (VZV)-specific cell-mediated immunity with increasing age and boosting with a high-dose VZV vaccine. Journal of Infectious Diseases. 2003;188(9):1336-44.
  33. Macaladad N, Marcano T, Guzman M, Moya J, Jurado F, Thompson M, et al. Safety and immunogenicity of a zoster vaccine in varicella-zoster virus seronegative and low-seropositive healthy adults. Vaccine. 2007;25(11):2139-44.
  34. MacIntyre CR, Egerton T, McCaughey M, Parrino J, Campbell BV, Su SC, et al. Concomitant administration of zoster and pneumococcal vaccines in adults >60 years old. Human Vaccines. 2010;6(11):894-902.
  35. Marin M, Yawn BP, Hales CM, Wollan PC, Bialek SR, Zhang J, et al. Herpes zoster vaccine effectiveness and manifestations of herpes zoster and associated pain by vaccination status. Human vaccines & Immunotherapeutics. 2015;11(5):1157-64.
  36. Mills R, Tyring SK, Levin MJ, Parrino J, Li X, Coll KE, et al. Safety, tolerability, and immunogenicity of zoster vaccine in subjects with a history of herpes zoster. Vaccine. 2010;28(25):4204-9.
  37. Morrison VA, Johnson GR, Schmader KE, Levin MJ, Zhang JH, Looney DJ, et al. Long-term persistence of zoster vaccine efficacy. Clinical Infectious Diseases. 2015 (LTPS);60(6):900-9.
  38. Morrison VA, Oxman MN, Levin MJ, Schmader KE, Guatelli JC, Betts RF, et al. Safety of zoster vaccine in elderly adults following documented herpes zoster. Journal of Infectious Diseases. 2013;208(4):559-63.
  39. Murray A, Lawless J, Reisinger K, Stek J, Sausser T, Xu J, et al. Safety & tolerability of zoster vaccine in adults >60 years old. Journal of the American Geriatrics Society [Internet]. 2010; 58: [S21-s2 pp.].
  40. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. New England Journal of Medicine. 2005 (SPS);352(22):2271-84.
  41. Schmader KE, Levin MJ, Gnann JW, Jr., McNeil SA, Vesikari T, Betts RF, et al. Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years. Clinical Infectious Diseases. 2012 (ZEST);54(7):922-8.
  42. Schmader KE, Oxman MN, Levin MJ, Johnson G, Zhang JH, Betts R, et al. Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy. Clinical Infectious Diseases. 2012(STPS);55(10):1320-8.
  43. Stanford U, National Institute of A, Infectious D. T Cell Responses to Varicella Zoster Virus (VZV). 2014.
  44. Tseng HF, Harpaz R, Luo Y, Hales CM, Sy LS, Tartof SY, et al. Declining Effectiveness of Herpes Zoster Vaccine in Adults Aged >60 Years. Journal of Infectious Diseases. 2016a;213(12):1872-5.
  45. Tseng HF, Lewin B, Hales CM, Sy LS, Harpaz R, Bialek S, et al. Zoster Vaccine and the Risk of Postherpetic Neuralgia in Patients Who Developed Herpes Zoster Despite Having Received the Zoster Vaccine. Journal of Infectious Diseases. 2015;212(8):1222-31.
  46. Tseng HF, Liu A, Sy L, Marcy SM, Fireman B, Weintraub E, et al. Safety of zoster vaccine in adults from a large managed-care cohort: a Vaccine Safety Datalink study. J Intern Med. 2012;271(5):510-20.
  47. Tseng HF, Luo Y, Shi J, Sy LS, Tartof SY, Sim JJ, et al. Effectiveness of Herpes Zoster Vaccine in Patients 60 Years and Older With End-stage Renal Disease. Clin Infect Dis. 2016b;62(4):462-7.
  48. Tseng HF, Tartof S, Harpaz R, Luo Y, Sy LS, Hetcher RC, et al. Vaccination against zoster remains effective in older adults who later undergo chemotherapy. Clin Infect Dis. 2014;59(7):913-9.
  49. Tyring SK, Diaz-Mitoma F, Padget LG, Nunez M, Poland G, Cassidy WM, et al. Safety and tolerability of a high-potency zoster vaccine in adults >/= 50 or years of age. Vaccine. 2007;25(10):1877-83.
  50. Vesikari T, Hardt R, Rumke HC, Icardi G, Montero J, Thomas S, et al. Immunogenicity and safety of a live attenuated shingles (herpes zoster) vaccine (Zostavax) in individuals aged > 70 years: a randomized study of a single dose vs. two different two-dose schedules. Human vaccines & Immunotherapeutics. 2013;9(4):858-64.
  51. vWillis E, Woodward M, Popmihajlov Z, Brown E, Saddier P, Halsey N, et al. Zoster Vaccine Live: A Review of Nearly 10 Years of Postmarketing Experience. Open Forum Infectious Diseases. 2016;3(suppl_1):714-.
  52. Yao CA, Chen LK, Huang KC. The immunogenicity and safety of zoster vaccine in Taiwanese adults. Vaccine. 2015;33(13):1515-7.
  53. Zoran P. Low rates of severe injection-site and systemic adverse events within 7 days postvaccination with ZOSTAVAXTM, a post hoc analysis of two pivotal Phase 3 trials. European Geriatric Medicine. 2016;7:S177.
  54. Zostavax (Frozen) Package Insert [11 pages]. 2006 [May 2006].
  55. Centers for Disease Control and Prevention (CDC. Update on herpes zoster vaccine: licensure for persons aged 50 through 59 years. MMWR. Morbidity and mortality weekly report. 2011 Nov 11;60(44):1528.
  56. Hales CM, Harpaz R, Ortega-Sanchez I, Bialek SR, Centers for Disease Control and Prevention (CDC). Update on recommendations for use of herpes zoster vaccine. MMWR Morb Mortal Wkly Rep. 2014 Aug 22;63(33):729-31.