Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Recombinant Zoster Vaccine (RZV) and Herpes Zoster Live-Attenuated Vaccine (ZVL)
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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 [1-2].
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 approach [3].
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 analysis [4-13]. 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 analysis [14-53]. 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]
|
| Prevention of post-herpetic neuralgia | ≥50y: 27,916 (1) ≥70y: 16,596 (1) |
2 dose RZV vs placebo | VE [95% CI]
|
| 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):
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
| 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]
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]
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:
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 older [1, 55, 56].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.
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