National Center for Immunization & Respiratory Diseases

WG Interpretation of the EtR Regarding Use of RZV in 

Immunocompromised Adults, Considerations for Use, 

and Proposed Policy Options

ACIP Meeting

October 20, 2021

LCDR Tara Anderson, DVM, MPH, PhD

CDC Lead, Herpes Zoster Work Group

Division of Viral Diseases
Policy Question

▪ Should adults aged ≥19 years who are or will be immunodeficient or 

immunosuppressed due to disease or therapy be recommended to 

receive two doses of recombinant zoster vaccine for the prevention of 

herpes zoster and its complications?

▪ Including but not limited to:

1. Hematopoietic stem cell transplant (HSCT) recipients

2. Patients with hematologic malignancies (HM)

3. Renal or other solid organ transplant (SOT) recipients

4. Patients with solid tumor malignancies (STM)

5. People living with HIV

6. Patients with primary immunodeficiencies, autoimmune and inflammatory conditions, 

and taking immunosuppressive medications/therapies

2
Evidence to Recommendations (EtR) Framework:

PICO Question

Population Immunocompromised (IC) adults aged ≥19 years

Intervention Recombinant zoster vaccine (RZV), 2 doses at least 4 weeks apart*

Comparison No vaccine

Critical 

Outcomes

• Herpes Zoster (HZ)

• Serious Adverse Events (SAEs)

Important 

Outcomes

• Postherpetic Neuralgia (PHN)

• HZ-Related Hospitalization

• Immune-Mediated Disease (IMD)

• Graft versus Host Disease (HSCT)

• Graft Rejection (SOT)

• Reactogenicity (Grade 3)

3

*First dose at Month 0 followed by a second dose 2 to 6 months later; For individuals who are or will be immunodeficient or immunosuppressed and who 

would benefit from a shorter vaccination schedule: First dose at Month 0 followed by a second dose 1 to 2 months later.
EtR Framework

EtR Domain Question

Public Health Problem Is the problem of public health importance?

Benefits and Harms How substantial are the desirable anticipated effects?

How substantial are the undesirable anticipated effects?

Do the desirable effects outweigh the undesirable effects?

Values Does the target population feel the desirable effects are 

large relative to the undesirable effects?

Is there important variability in how patients value the 

outcomes?

Acceptability Is the intervention acceptable to key stakeholders?

Resource Use Is the intervention a reasonable and efficient allocation of 

resources?

Equity What would be the impact of the intervention on health 

equity?

Feasibility Is the intervention feasible to implement? 4
EtR Domain: Public Health Problem
How many IC persons in the United States?

▪ ~7 million adults 

with self-reported 

immunosuppressed 

status

Age Group, y Prevalence per 100 US 

Population, % (95% CI)

18-39 1.6 (1.3-1.9)

40-49 2.3 (1.8-2.8)

50-59 4.4 (3.7-5.1)

60-69 3.9 (3.2-4.5)

70-79 3.1 (2.4-3.8)

80+ 2.5 (1.4-3.5)

Total 2.7 (2.4-2.9)

6

Harpaz R, Dahl RM, Dooling KL. Prevalence of Immunosuppression Among US Adults, 2013, JAMA, 2016, 316(23):2547-8. 

Excerpt of Table. Self-reported Immunosuppressed Status.
How many IC persons in the United States?*

*References on slide 75 7

▪ ~22 million with autoimmune 

and/or inflammatory (AI/INF) 

conditions6

• >80 diverse conditions (e.g., 

systemic lupus erythematosus, 

rheumatoid arthritis, 

inflammatory bowel disease)

• Often have underlying immune 

dysfunction, but generally not 

considered frankly IC unless 

iatrogenic (i.e., on IC treatments)

▪ ~3 million among:

• Hematopoietic stem cell transplant 

recipients1

• Patients with hematologic 

malignancies2

• Renal or other solid organ 

transplant recipients3

• Patients with solid tumor 

malignancies2,4

• People living with HIV5

Age-specific prevalence highly variable by condition
HZ Incidence Common in Adults and Increases with Age

~1 million HZ 

cases per year 

in U.S. during 

pre- HZ vaccine 

era1

1. Harpaz et al. Prevention of Herpes Zoster, MMWR, June 6, 2008, Vol 57, #5

2. Figure: CDC, unpublished data; Updated from Harpaz et al. Clinical Infectious Diseases, Volume 69, Issue 2, 15 July 2019, Pages 341–

344, https://doi.org/10.1093/cid/ciy953 8
Public Health Importance

Risk of HZ in IC Groups 1–5

▪ Median HZ incidence 

estimates for these IC groups 

exceeded those reported for 

immunocompetent adults 

>50 years

McKay et al. Herpes zoster risk in immunocompromised adults in the

United States: A systematic review. CID 2020;71(7):e125–34. 

Figure 3. Herpes zoster incidence rates among patients with selected 

immunocompromising conditions. *Studies with low or medium risk of bias. 9
▪ Postherpetic neuralgia (PHN)

– ~6–10% vs ~4% overall in administrative claims databases1

– Between 6% and 45% across IC conditions and studies2

▪ Disseminated HZ

– ~3%2 of IC, but exceedingly uncommon in healthy persons

– 10–17% mortality associated with disseminated HZ among renal 

transplant recipients3,4

▪ Hospitalization: 8% of HCT recipients with HZ5 vs ~<1% of overall Medicare 

beneficiaries with HZ6

Public Health Importance

Severity of HZ in IC Groups 1–5

1Chen et al. Incidence of herpes zoster in patients with altered immune function. Infection 2014; 42(2): 325–34; 2McKay et al. Herpes zoster risk in immunocompromised adults in the United States: A 

systematic review. CID 2020;71(7):e125–34; 3Rommelaere et al. Disseminated varicella zoster virus infection in adult renal transplant recipients: Outcome and risk factors. Transplantation Proceedings. 

2012; 44(9): 2814-2817; 4Kirnap et al. Prevalence and outcome of herpes zoster infection in renal transplant recipients. Exp Clin Transplant. 2015; Apr;13 Suppl 1:280-3; 5Winston et al. Inactivated varicella 

zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, doubleblind, placebo-controlled trial. Lancet (London, England) 2018; 391(10135): 

2116–27; 6Izurieta et al. Effectiveness and duration of protection provided by the live-attenuated herpes zoster vaccine in the Medicare population ages 65 years and older. CID 2017;64(6):785–93. 10
Public Health Importance

Risk of HZ in IC Group 6

▪ ~2 to 4-fold higher risk in 

patients with autoimmune 

conditions than in healthy 

individuals1

▪ ~1.5-fold higher risk for 

unvaccinated Medicare 

beneficiaries with autoimmune 

conditions vs not IC2

Figure adapted from Yun et al. Bars show the IRs of HZ with 95% confidence intervals. Cohorts of healthy 

adults without autoimmune diseases or diabetic conditions and adult patients with diabetes were used as 

controls. SLE=systemic lupus erythematosus; IBD=inflammatory bowel disease; RA=rheumatoid arthritis; 

PsA=psoriatic arthritis; PsO=psoriasis; AS=ankylosing spondylitis.

1Yun et al. Risk of Herpes Zoster in Autoimmune and Inflammatory 

Diseases. Arthritis & Rheumatology 2016;68(9):2328-2337.

2

Izurieta et al. Recombinant Zoster Vaccine (Shingrix) real-world 

effectiveness in the first two years post-licensure. Clinical Infectious 

Diseases, 2021;, ciab125, https://doi.org/10.1093/cid/ciab125

Age and sex-standardized HZ incidence rates, among 

adults ≥20 years with selected autoimmune diseases 

11
Incidence Rate (per 1000 person years) of HZ 

reported in different disease cohorts8

Age Gp Healthy SLE IBD RA PsA PsO

21–30 2.7 24.6 11.6 6.6 N/A 5.9

31–40 3.3 15.2 5.6 8.2 9.8 3.7

41–50 3.9 17.5 10.4 10.0 8.5 6.4

51–60 5.8 20 11.7 14.6 13.2 9.7

61–70 8.5 22.7 19.0 17.1 15.9 13.3

71–85+ 10.6 20.9 23.8 21.3 19.4 21.2

* Yun et al. Risk of Herpes Zoster in Autoimmune and Inflammatory Diseases. Arthritis & Rheumatology 2016;68(9):2328-2337. Excerpt of Table 2. 

Incidence rate of herpes zoster per 1000 person years by 10 year age group and auto-immune disease or comparator cohort. 12

Healthy = individuals without AI/IC conditions or 

diabetes; SLE = systemic lupus erythematosus; IBD = 

inflammatory bowel disease; RA = Rheumatoid 

arthritis; PsO = Psoriasis; PsA = Psoriatic Arthritis

Public Health Importance

Risk of HZ in IC Group 6, cont.

▪ Age-specific incidence rates among some 

21–50-year-olds comparable to or 

substantially higher than corresponding 

rates in healthy adults >60 years*

▪ Immunosuppressive therapies

• ≥1 IC medications = standard of care

• Not possible to define high risk subgroups 

based on anticipated therapies

• Disease modifying antirheumatic drugs, or 

DMARDs (e.g., methotrexate)

• Glucocorticoids

• Biologics (e.g., Janus Kinase inhibitors)

Reference

Higher Risk

Comparable 

Risk
Summary

▪ IC populations are very heterogeneous, both across and 

within groups and among individuals over time

▪ Risk of HZ and HZ complications generally higher in IC 

populations, although there is variability across and within 

IC groups

▪ Not feasible to define every possible IC condition, 

medication/therapy combination

▪ Important to consider broad recommendations and provider 

guidance for IC populations

13
Public Health Problem:

Work Group Interpretation

Is herpes zoster in immunocompromised adults 

of public health importance?

○ No ○ Probably no ○ Probably yes ○ Yes ○ Varies ○ Don't know
EtR Domain: Benefits and Harms
Systematic Review

Additional criteria for GRADE review

• Restricted to PICO-defined population, intervention, comparison, and outcomes

• Comparison group available for outcomes of interest (and not modeled or historical)

• For benefits: at least 2 doses of RZV; for harms: at least 1 dose of RZV

• Vaccine components included in current RZV vaccine (i.e., AS01B adjuvant)

16

Information Sources Inclusion and Exclusion Criteria

• Medline 

• Embase 

• CINAHL 

• Cochrane 

• Scopus 

• clinicaltrials.gov 

• Potentially obtain unpublished and other 

relevant data by hand-searching reference 

lists, and consulting with vaccine 

manufacturers and subject matter experts. 

Inclusion criteria

• Provide data on vaccination with RZV 

• Involve human subjects 

• Include immunocompromised adults 

• Any language 

• Date based on earliest RZV article (estimated ~2012 

with RZV phase I/II trial article by Leroux-Roels et al.) 

Exclusion criteria 

• Animal studies 
COVIDENCE Review PRISMA Diagram

Studies imported for screening

(n = 2406)

Records published after initial data cutoff (4/2021)

(n = 2)

Duplicates removed 

(n=12)

Records assessed for eligibility

(n = 133) Full-text articles excluded (n = 114)

53 duplicate or results published in another manuscript

22 wrong patient population 

14 wrong intervention

13 abstract only

12 study ongoing

Records included in evidence synthesis (n = 19)

7 randomized trial records

4 cohort studies

3 non-randomized experimental studies

5 single-arm studies (4 retrospective, 1 prospective)

Records screened

(n = 2396)

Abstracts & titles removed 

(n = 2263)

17
Appendix 1. Studies Included in the Review of Evidence

Study Study design Country Study Population, Age N Intervention N comparison Outcomes Funding 

Bastidas, 

2019 Phase III RCT Multiple countries, including US

Autologous HSCT recipients 

≥18 years

• 1 dose: 922

• 2 doses: 870

• 1 dose: 924

• 2 doses: 851 

• Confirmed HZ, PHN & HZ-Related Hospitalizations

• Immunogenicity

• Reactogenicity

• SAEs, pIMDs

GSK

Berkowitz, 

2015 Phase I/II RCT Multiple countries, including US Patients with HIV ≥18 years 

• 1 dose: 74

• 2 doses: 72

• 3 doses: 71 

• 1 dose: 49

• 2 doses: 47

• 3 doses: 47 

• Confirmed HZ 

• Immunogenicity

• Reactogenicity

• SAEs

GSK

Dagnew, 

2019 Phase III RCT Multiple countries, including US

Patients with hematological 

malignancy ≥18 years 

• 1 dose: 283 

• 2 doses: 259

• 1 dose: 279

• 2 doses: 257

• Confirmed HZ

• Immunogenicity

• Reactogenicity

• SAEs (including Graft vs. Host Disease, pIMDs) 

GSK

Dagnew, 

2021

Pooled post hoc 

analysis of two Phase III 

RCTs 

Multiple countries, 

including US

Participants with pIMDs not on 

immune-suppressive therapies 

≥50 years; ≥70 years

• 1 dose: 983

2 doses: 936 

• 1 dose: 960 

• 2 doses: 923 

• Post hoc efficacy of RZV in preventing HZ 

• SAEs, pIMDs GSK

Stadtmauer, 

2014 Phase I/II RCT United States Autologous HSCT recipients ≥18 years 

• 3 doses: 30

2 doses: 31 • 3 doses: 30

• Confirmed HZ

• Immunogenicity

• Reactogenicity

• SAEs, pIMDs

GSK

Vink, 2019 Phase II/III RCT

Canada, Czech Republic, 

France, Korea, Spain, 

United Kingdom

Solid tumor patients ≥18 years • 1 dose: 117

• 2 doses: 102

• 1 dose: 115

• 2 doses: 107

• Immunogenicity

• Reactogenicity

• SAE, pIMDs

GSK

Vink, 2020 Phase III RCT

Belgium, Canada, 

Finland, Taiwan, Spain, 

Panama, Korea, Italy

Renal transplant patients ≥18 

years receiving daily 

immunosuppressive therapy 

• 1 dose: 132

• 2 doses: 131

• 1 dose: 132

• 2 doses: 132

• Immunogenicity

• Reactogenicity

• SAEs (including graft rejection, pIMDs)

GSK

Izurieta, 2021 Cohort Study United States Medicare beneficiaries ≥65 

years with IC or AI conditions

• AI 1 dose: 92,069

• IC 1 dose: 60,600

• AI 2 doses: 61,999

• IC 2 doses: 40,442

• AI: 886,123

• IC: 746,654 • Vaccine efficacy of RZV in preventing HZ (stratified 

by IC and AI conditions)

US FDA, 

CMS

Khan, 2021 Cohort Study United States

Patients with IBD ≥50 years in 

the Veterans Affairs Healthcare 

System

• 50–60: 655

• ≥60: 4,220

• 50–60: 5,995

• ≥60: 20,554

• Vaccine efficacy of RZV in preventing HZ (stratified 

by age and steroid use) Pfizer

Abbreviations: AI = Autoimmune; CMS = Center for Medicare and Medicaid Services; FDA = Food and Drug Administration; GSK = GlaxoSmithKline, HSCT = Hematopoietic Stem Cell Transplant; HZ = Herpes Zoster; IBD = Inflammatory Bowel Disease; IC = 

Immunocompromised; pIMDs = Potential Immune-Mediated Disease; RCT = Randomized Control Trial; RZV = Recombinant Zoster Vaccine; SAEs = Serious Adverse Events 18
Outcomes for GRADE

Evidence type: 1=high; 2=moderate; 3=low; 4=very low; ND, no data 19

OutcomeImportance Design (# of 

studies)

Findings Evidence 

Type

Benefits

Herpes Zoster (HZ) Critical RCT(5)

OBS(2)

Postherpetic Neuralgia 

(PHN) Important RCT(1)

HZ-Related 

Hospitalization Important RCT(1)

Harms

Serious adverse events 

(SAE) Critical RCT(7) - Immune-Mediated

Disease Important RCT(6)

- Graft vs. Host Disease

(HCT) Important RCT(1)

- Graft Rejection (SOT) Important RCT(1)

Reactogenicity (Grade 3) Important RCT(6)
Outcome 1: Herpes Zoster (HZ)

Randomized Studies with Unvaccinated Comparator (n=5)

Study Population Events/Vaccine

(n/N)

Events/Placebo

(n/N)

VE 95% CI Study 

Limitations

Bastidas ’19 Autologous HSCT recipients ≥18 49/870 (5.6%) 135/851 (15.9%) 68.2% 55.6 % -77.5% Not serious

• 18-49 subset 9/213 (4.2%) 29/212 (13.7%) 72% 39% - 88%*

• ≥50 subset 40/657 (6.1%) 106/639 (16.6%) 67% 53% - 78%*

Berkowitz ’15 Patients with HIV ≥18 0/72 (0.0%) 0/47 (0.0%) NE NE Not serious

Dagnew ’19 Hematological malignancy ≥18 2/259 (0.77%) 14/256 (5.47%) 87.2% 44.3% - 98.6% Not serious

Dagnew ’21 pIMDs ≥50; ≥70 4/936 (0.43%) 38/923 (4.12%) 90.5% 73.5% - 97.5% Serious**

• 50-59 subset 1/222 (0.45%) 11/201 (5.47%) 92.8% 50.5% - 99.8%

• 60-69 subset 0/159 (0.0%) 8/151 (5.30%) 100% 54.9% - 100%

• 70-79 subset 2/427 (0.47%) 13/450 (2.89%) 84.4% 30.8% - 98.3%

• ≥80 subset 1/128 (0.78%) 6/121 (4.96%) 86.2% -13.5% - 99.7%

Stadtmauer ‘14 Autologous HCT recipients ≥18 0/61 (0%) 2/30 (6.67%) RR: 0.0 0-NA*** Not serious

* Incidence Rate Ratios (IRRs) were presented rather than VE, and VE was calculated using the formula VE = (100 * (1-IRR)).

** While the RCTs met low risk of bias criteria, given this analysis for this subgroup was post hoc and the analysis was not powered for this outcome nor able to 

address type 1 error, this analysis has moderate/high risk of bias. 

*** RR and Wald confidence intervals calculated in R and in SAS. 20
Outcome 1: Herpes Zoster (HZ)

Observational Studies with Unvaccinated Comparator (n=2)

* This study presents with concerns with confounding, with no demographics or risk-factors presented for the immune-compromised and autoimmune populations. Additionally, it is a Medicare 

claims study, reliant on algorithmic determination of immunocompromised and autoimmune status, thus there is significant risk of confounding and information bias in interpreting the VE.

**Khan 2021 reported results of a Cox regression model (HR) without any interaction and found that full dose of RZV was associated with lower risk of HZ compared with the unvaccinated group, 

after adjusting for other baseline and time-varying covariates. Specifically, in the 50 to 60-year-old group, the HR was 0 (95% CI, 0-0;P<.001). The HR was 0.39 (95% CI,0.19-0.80;P1⁄4.01) in the >60-

year-old group. The HRs for steroid and non-steroid users are presented in the table above.

***This was a large cohort analysis, yet the VA patient population may not be generalizable to the general population (e.g., study population was heavily skewed male). Coupled with the authors' 

retrospective case ascertainment, we would consider this analysis moderate/high risk of bias.

Study Design Population n/N (Vaccinated) n/n (Unvaccinated) VE (%) (95% CI) Study 

Limitations

Izurieta, 

2021

Prospective 

cohort

Medicare patients 

≥65 Serious*

• Autoimmune 

condition 167/61,999 (0.27%) 20,640/886,123 (2.33%) 68.0% (62.3% - 72.8%)

• Immunocompromised 143/40,442 (0.35%) 18,504/746,654 (2.48%) 64.1% (57.2% - 69.8%)

Khan, 

2021

Retrospective 

cohort

VAHS patients with 

IBD ≥50 8/4,875 (0.16%) 337/26,549 (1.27%) Hazard Ratios reported below** Serious ***

• 50-60 subset • 0/655 (0.0%)• 69/5,995 (1.15%) • No steroid use: NE

• Steroid use: NE

• >60 subset • 8/4,220 (0.19%)• 268/20,554 (1.30%) • No steroid use: 0.41 (0.19-0.87)

• Steroid use: 0.34 (0.05-2.44)

21
Humoral Immunity Cell-mediated Immunity

Study Population Timing after 

last dose

% Response Rate 

RZV (95% CI)

% Response Rate 

Placebo (95% CI)

% Response Rate 

RZV (95% CI)

% Response Rate 

Placebo (95% CI)

Adjusted Humoral GMR 

(95% CI)

Bastidas, 

2019 

Autologous HSCT 

patients ≥18

1 Month 67% 0% 93% 0% -

12 Months - - - -

Berkowitz, 

2015 

Patients with HIV 

≥18*

1 Month 96.2% 

(87-99.5%)

2.8% 

(0.1-14.5%)

90% 

(68.3-98.8%)

16.7% 

(3.6-41.4%)

-

12 Months 91.7% 

(80-97.7%)

0%

(0-9.5%)

64.5% 

(45.4-80.8%)

0% 

(0-13.2%)

-

Dagnew, 

2019 

Patients with 

hematological 

malignancy ≥18

1 Month 65.4% 

(58.7-71.7%)

0.5% 

(0.0-2.8%)

83.7% 

(69.3-93.2%)

6.8% 

(1.4-18.7%)

29.75 (21.09–41.96)

12 Months 52.1% 

(44.2-59.9%)

3.6% 

(1.2-8.1%)

66.7% 

(48.2-82.0%)

6.5% 

(0.8-21.4%)

-

Stadtmauer, 

2014 

Autologous HCT 

recipients ≥18

1 Month - - - - 42.20 (16.07-110.82)

12 Months - - - - 8.81 (3.41-22.80)

Vink, 2019 Solid Tumor 

Patients ≥18

1 Month 86.2% 0.0% 50.0% 0.0% 14.4 (10.7-19.5)**

12 Months 51.5% 0.0% 17.6% 0.0% -

Vink, 2020 Renal transplant 

patients ≥18

1 Month 80.2% 4.2% 71.4% 0.0% 14.00 (10.90–17.99)***

12 Months 66.7% 6.4% 56.7% 0.0% -

Outcome 1: HZ – Immunogenicity as Surrogate

Randomized Studies with Unvaccinated Comparator (n=6)

*Berkowitz et al. evaluated a 3-dose regimen of RZV, thus immunogenicity results are presented 1 and 12 months after the 3rd dose was received. Stadtmauer evaluated both a 2-

and 3-dose regimen. Results are presented for the 2-dose regimen in the table. 3-dose results can be found in the Appendix.

**CMI GMR: 9.94 (95% CI, 3.63-27.19)

***CMI GMR: 17.26 (5.92–50.36) 

All studies had low risk of bias/no major study limitations. 22
Outcome 1 Evidence Table: Herpes Zoster

23

Certainty Assessment Number of Patients (%) Effect

# Study Design Risk of Bias Inconsistency Indirectness Imprecision Other RZV 2 doses No vaccine Relative (95%) Certainty Importance

Prevent Herpes Zoster (HZ)

5 RCT not 

serious

not 

serious serious** not serious none

• ≥18 years: 0% to 5.6% of 

participants experienced HZ. 

• ≥50 years: 0.43% to 6.1% of 

participants experienced HZ. 

• ≥18 years, 0% to 15.9% of 

participants experienced HZ.

• ≥50 years, 4.12% to 16.6% of 

participants experienced HZ.

• ≥18 years, VE ranged from 68.2% 

(95% CI: 55.6-77.5%) to 87.2% 

(44.3-98.6%), Stadtmauer 

reported an RR of 0.

• ≥50 years, VE ranged from 67% 

(53-78%) to 90.5% (73.5-97.5%).

Type 2 

Moderate

CRITICAL

6

RCT*–

Immunogenicity

not 

serious 

not 

serious

very 

serious*** 

not 

serious none

• Humoral VRR ranged from 

65.4% to 96.2% 

• Cell-mediated VRR ranged from 

50% to 93%.

• Humoral VRR ranged from 

0% to 4.2% and cellmediated VRR ranged from 

0% to 16.7%

• Humoral adjusted GMR ranged 

from 14.00 (95% CI: 10.90-17.99) 

to 42.20 (16.07-110.82)

• Cell-mediated adjusted GMR 

ranged from 9.94 (3.63-27.19) to 

17.26 (5.92-50.36).

Type 3 

Low

2 Cohort not 

serious

not 

serious 

serious 

****

not 

serious

strong 

assoc.

• ≥65 years, AI condition: 

167/61,999 (0.27%) experienced 

HZ

• ≥65 years, IC condition: 

143/40442 (0.35%) experienced 

HZ. 

• 50-60 years: 0/655 (0.0%) 

experienced HZ

• >60 years: 8/4220 (0.19%) 

experienced HZ

• ≥65 years, AI condition: 

20,640/ 886,123 (2.33%) 

experienced HZ

• ≥65 years, IC condition: 

18,504/746,654 (2.48%) 

experienced HZ. 

• 50-60 years: 69/5,995 

(1.15%) experienced HZ

• >60 years: 268/20,554 

(1.30%) experienced HZ

• ≥65 years, AI condition: VE was 

68.0% (62.3 - 72.8%) 

• ≥65 years, IC condition: VE was 

64.1% (57.2 - 69.8%)

• 50-60 years, HR was 0, >60 

years, HR was 0.39 (0.19-0.80) 

Type 3 

Low

*All immunogenicity metrics presented at 1 month after last dose.

**The RCTs cover a wide range of populations that cover some, but not all the populations being considered for the recommendation. Assessing them together results in a downgrade (-1) for indirectness.

***Interpreting immunogenicity results for prevention of HZ faces a very serious (-2) downgrade for indirectness due to indirectness in two domains of the PICO question: population, and outcome. For population, the included studies evaluate the 

immunogenicity of RZV in some, but not all the populations considered for the recommendation. Additionally, there is inconsistency in using the proxy measure of immunogenicity to evaluate vaccine efficacy, or prevention of HZ, given that there 

are no established correlates of protection. 

****The cohort studies assessed incidence of HZ in autoimmune/immunocompromised patients enrolled in Medicare, and IBD patients in the VA, which do not represent all populations under consideration for the recommendation. 
Outcome 4: SAEs

Randomized Studies with Unvaccinated Comparator (n=7)

*These SAEs reflect 6 in the 3-dose gE/AS01B gp: (6/30, 20.0%), and 10 in the 2-dose gp: 10/31 (32.3%). Of those, only 1 was related to vaccination in the 2-dose gp: 1/31 (3.23%).

**RRs were calculated using Wald confidence intervals in R and SAS.

***While the RCTs (ZOE 50/70) met low risk of bias criteria, given this analysis for this subgroup was post hoc and the analysis was not powered for this outcome nor able to address type 1 error, this 

analysis has moderate/high risk of bias. 24

Study Population SAE/Vaccine 

(n/N)

SAE/Placebo 

(n/N)

SAE/Vaccine 

(n/N) related 

to vaccination

SAE/Placebo 

(n/N) related 

to vaccination

RR

(95% CI)** Study Limitations

Bastidas, 

2019

Autologous HSCT patients 

≥18

263/922 

(28.5%)

241/924 

(26.1%)

3/922 

(0.33%)

4/924

(0.43%) 1.09 (0.94, 1.27) Not serious

Berkowitz, 

2015 Patients with HIV ≥18 6/74 (8.1%) 2/49 (4.1%) 0/74 (0.0%)

0/49 

(0.0%) 1.99 (0.42, 9.44) Not serious

Dagnew, 

2019

Patients with hematologic 

malignancy ≥18

66/283 

(23.3%)

82/279 

(29.4%)

1/283

(0.35%)

1/279

(0.36%) 0.79 (0.60, 1.05) Not serious

Dagnew, 

2021

Patients with pIMDs ≥50; 

≥70

144/983 

(14.6%)

112/960 

(11.7%) not disclosed not disclosed 1.26 (1.00, 1.58) Serious***

Stadtmauer, 

2014

Autologous HSCT 

recipients ≥18

16/61 

(26.2%)* 8/30 (26.7%) 1/61(1.6%)

0/30

(0.0%) 0.98 (0.48, 2.04) Not serious

Vink, 

2019 Solid tumor patients ≥18 46/117 (39.3%)

45/115 

(39.1%)

0/117

(0.0%)

0/115 

(0.0%) 1.00 (0.73, 1.38) Not serious

Vink, 

2020

Renal transplant patients 

≥18

26/132 

(19.7%)

33/132 

(25.0%)

0/132 

(0.0%)

1/132 

(0.76%) 0.79 (0.50, 1.24) Not serious
Outcome 4 Evidence Table: SAEs

*Across the 7 included RCTs (one of which was a pooled post-hoc analysis of two RCTs (ZOE-50 and ZOE-70), among a subset of participants who reported at least one pIMD at 

enrollment), there are a wide range of populations included: Autologous HSCT patients (Bastidas, Stadtmauer), patients with HIV (Berkowitz), patients with hematologic malignancies 

(Dagnew 2019), patients with pIMDs (Dagnew 2021), patients with solid tumors receiving cytotoxic or immunosuppressive therapy (Vink 2019), and renal transplant patients on daily 

immunosuppression (Vink 2020). The wide variety of patient sub-populations being pooled together for this analysis results in a downgrade for indirectness (-1). 

25

Certainty assessment No of patients (%) Effect

Certainty Importance No of 

studies

Study 

design

Risk of 

bias Inconsistency Indirectness Imprecision Other RZV Comparison Relative(95% CI)

Serious adverse events

7 RCT

not 

serious not serious serious* not serious none

SAEs ranged from 

8.1% to 39.3%

SAEs ranged from 

4.1% to 39.1%

RR ranged from 0.79 

(0.60, 1.05) to 1.99 

(0.42, 9.44), with 3 

studies reporting RR 

<1, 3 studies 

reporting RR>1, and 

one reporting RR = 1

Type 2

Moderate

CRITICAL
Summary of GRADE

Evidence type: 1=high; 2=moderate; 3=low; 4=very low; ND, no data 26

OutcomeImportance Design (# of 

studies)

Findings Evidence 

Type

Benefits

Herpes Zoster (HZ) Critical RCT(5)

OBS(2)

VE ranged from 68.2% to 87.2% for those 18+, and VE was 90.5% for those over 50 with pIMDs 

not on immunosuppressants. Observational studies showed VE of 64.1% among IC populations, 

68.0% among AI populations.

Type 2

Postherpetic Neuralgia 

(PHN) Important RCT(1) VE of 89% (12%-100%) Type 3

HZ-Related 

Hospitalization Important RCT(1) VE of 85% (32%-97%) Type 3

Harms

Serious adverse events 

(SAE) Critical RCT(7)

Not increased in RZV group: SAEs were common in both vaccine and placebo groups, with RR 

ranging from 0.79 to 1.99 and all confidence intervals including null effect. SAEs attributed to 

vaccination were rare.

Type 2

- Immune-Mediated

Disease Important RCT(6) Not increased in RZV group: RRs ranged from 0.68 to 2.0 but confidence intervals included null effect. Type 4

- Graft vs. Host Disease

(HSCT) Important RCT(1) Not increased in RZV group: RR of 0.83 (0.21, 3.24) Type 4

- Graft Rejection (SOT) Important RCT(1) Not increased in RZV group: RR of 0.57 (0.17, 1.91) Type 3

Reactogenicity (Grade 3) Important RCT(6) Increased in RZV group: The vaccine is reactogenic, with RRs ranging from 1.19 to 2.49 for 

systemic symptoms, and RR=42 for local symptoms. Type 2
Benefits and Harms:

Work Group Interpretation

How substantial are the desirable anticipated 

effects of RZV in IC adults?

○ Minimal ○ Small ○ Moderate ○ Large ○ Varies ○ Don't know
Benefits and Harms:

Work Group Interpretation

How substantial are the undesirable anticipated 

effects of RZV in IC adults?

○ Minimal ○ Small ○ Moderate ○ Large ○ Varies ○ Don't know
Benefits and Harms:

Work Group Interpretation

Do the desirable effects outweigh the 

undesirable effects?

○ Favors intervention (RZV, 2 doses at least 4 weeks apart)

○ Favors comparison (no vaccine)

○ Favors both

○ Favors neither

○ Unclear
EtR Domain: Values
Values

▪ Limited data on knowledge, attitudes, and practices (KAP) 

among IC patients regarding potential use of RZV for 

prevention of HZ and its complications

▪ In general

– Zoster vaccination (including zoster vaccine live, or ZVL, and RZV) is 

increasing (from 6.7% in 2008 to 34.5% in 2018,1 to 41.2% in 20192)

– RZV series completion rates are high 

• Among Medicare enrollees from 2016–2019, 67% received 2 RZV doses3

• 70% completion after 6 months, 80% completion after 12 months 

(IQVIA data)4

1Terlizzi EP and Black LI. Shingles Vaccination Among Adults Aged 60 and Over: United States, 2018. NCHS Data Brief, No. 370, July 2020; 2Kawai K and Kawai AT. Racial/Ethnic 

and Socioeconomic Disparities in Adult Vaccination Coverage. Am. J. Prev. Med. 2021;000(000):1–9; 3Izurieta et al. Recombinant Zoster Vaccine (Shingrix): Real-World 

Effectiveness in the First 2 Years Post-Licensure. Clin. Infect. Dis. 2021 Sep 15;73(6):941-948; 4Patterson et al. Early examination of real-world uptake and second-dose 

completion of recombinant zoster vaccine in the United States from October 2017 to September 2019. Hum. Vaccin. Immunother. 2021 Aug 3;17(8):2482-2487. 31
Values, cont.

▪ Although there is no ACIP recommendation, IC patients 

recognize the increased risk of HZ and many have already 

received RZV*

▪ Concerns related to Grade 3 reactions may discourage some 

IC patients from getting RZV

* Izurieta et al. Recombinant Zoster Vaccine (Shingrix): Real-World Effectiveness in the First 2 Years Post-Licensure. Clin. Infect. 

Dis. 2021 Sep 15;73(6):941-948

32
Summary

▪ IC patients desire the ability to receive RZV to prevent HZ 

and its complications

▪ Many IC patients already pursuing vaccination with RZV

▪ The ACIP HZWG placed high value on prevention of HZ and 

its complications in IC adults

▪ Given the burden of HZ and its complications in these 

patients, it is anticipated that more IC patients would 

pursue vaccination with RZV if recommended by ACIP and 

their provider

33
Values:

Work Group Interpretation

Does the target population feel that the desirable 

effects of RZV are large relative to undesirable effects?

○ No ○ Probably no ○ Probably yes ○ Yes ○ Varies ○ Don't know
Values:

Work Group Interpretation

Is there important uncertainty about, or variability in, 

how much people value the main outcomes?

○ Important uncertainty or variability

○ Probably important uncertainty or variability

○ Probably not important uncertainty or variability

○ No important uncertainty or variability

○ No known undesirable outcomes
EtR Domain: Acceptability
Primary Care Physicians’ Perspective Related to 

Recombinant Zoster Vaccine, 2020*

▪ Objectives: To assess among primary care physicians serving adults 

regarding RZV

– Current practices, attitudes, knowledge, barriers to recommending

– Likelihood of recommending to IC among physicians who had not 

recommended to IC patients

▪ Methods

– Surveyed physicians in existing Vaccine Policy Collaborative Initiative 

(VPCI) sentinel networks

– Family Physician (FP) and General Internist (GIM) results combined 

with any differences highlighted

37 *Hurley et al., unpublished data
Physician Strength of Recommendation for RZV in 

Different Types of Patients, United States, 2020 

Recommendations Consistent with ACIP Recommendations

38 *Hurley et al., unpublished data
Physician Strength of Recommendation for RZV in Different 

Types of Patients, United States, 2020 (n=632) 

Recommendations Among Populations without an ACIP recommendation 

*Hurley et al., unpublished data 39
Likelihood of Recommending RZV to Different Types of IC Patients Among 

Physicians Who Had Not Recommended RZV to IC Patients*

*Hurley et al., unpublished data 40
Summary

▪ Given highly specialized care and increased HZ risk among IC patients, 

work group noted vaccination is favored if there are no safety concerns

– Although currently available evidence considered acceptable, additional safety 

data is a research need

▪ Despite lack of a recommendation from ACIP, many physicians are 

recommending RZV to patients with IC conditions

– Physicians need more direction on which patients are eligible for RZV

– Substantial minority would be unlikely to recommend RZV to various IC 

patients even if it were licensed, recommended and covered by insurance for 

them (without input from a subspecialist)

▪ Many specialty organizations recommending RZV for IC adults

▪ Anticipate would increase with FDA approval and ACIP recommendation

41
Acceptability: 

Work Group Interpretation

Is RZV in IC adults acceptable to key stakeholders?

○ No ○ Probably no ○ Probably yes ○ Yes ○ Varies ○ Don't know
EtR Domain: Resource Use
Cost-Effectiveness Assessments

*Cost-savingsfrom societal perspective, $140 from healthcare perspective. n/r = not reported.

**Implicit AI/INF scenario: Assuming starting age 25 years, HZ incidence 10/1000PY and duration of IC status 5 years. 

44

Ortega-Sanchez. Economics of vaccinating immunocompromised 19–49-year-old adults against herpes zoster in the US. September 2021 ACIP Meeting. 

Available at: https://www.cdc.gov/vaccines/acip/meetings/slides-2021-09-29.html.
Summary

▪ Base-case: HSCT patients

– Economic value of RZV appears to be favorable (i.e., cost-saving)

– Higher HZ incidence and HZ-related health care costs, and reasonable VE

– Smaller patient population

▪ Scenarios: Other patient groups (e.g., HIV, AI/INF)

– With lower risk of HZ, severe outcomes, and lower health care costs, the 

economic value of RZV vaccination was less favorable relative to HSCT 

patients

– Some AI/INF conditions may have the least favorable estimates of RZV 

use, depending on the underlying risk of HZ

– Larger patient population for AI/INF

45
Summary

▪ Considering results across the base case and scenarios 

from both models, the ACIP HZWG determined the 

estimated economic values to be generally favorable

▪ Given highly specialized care and resources invested for 

base-case and other IC populations, the work group did not 

consider cost-effectiveness assessments to be a main 

driver for decision-making

46
Resource Use:

Work Group Interpretation

Is RZV in IC adults a reasonable and efficient 

allocation of resources?

○ No ○ Probably no ○ Probably yes ○ Yes ○ Varies ○ Don't know
EtR Domain: Equity
What Would be the Impact of the Intervention on 

Health Equity?

▪ 2018 NHIS data1

– Overall, HZ vaccination coverage among adults aged ≥50 and ≥60 years was 

24.1% and 34.5%, respectively

– White adults aged ≥50 and ≥60 years had higher coverage (28.0% and 38.6%, 

respectively) compared with Blacks (12.4% and 18.8%, respectively), Hispanics 

(12.2% and 19.5%, respectively), and Asians (19.6% and 29.1%, respectively)

▪ 2010–2019 NHIS data2

– In general, race/ethnicity, household income, education level, and health 

insurance type significantly associated with receipt of zoster vaccinations 

among adults aged ≥65 years

1Lu P, Hung M, Srivastav A, et al. Surveillance of Vaccination Coverage Among Adult Populations — United States, 2018. MMWR Surveill Summ 2021;70(No. 

SS-3):1–26; 2Kawai K and Kawai AT. Racial/Ethnic and Socioeconomic Disparities in Adult Vaccination Coverage. Am. J. Prev. Med. 2021;000(000):1–9.

49
Summary

▪ Anticipate ACIP recommendation would increase access overall since 

– Increases scope of population eligible to be vaccinated

– Ensures coverage under ACA

▪ However, will likely still be challenges with uptake given

– Previously noted race/ethnicity, household income, education level, and 

insurance disparities

– Variability in health insurance coverage and lack of insurance, which may 

result in out-of-pocket costs for some patients

▪ Important to continue monitoring RZV vaccination through the NHIS, 

including stratifying by health status and race/ethnicity

▪ Work group also noted that equity could potentially be monitored at 

the local level during implementation

50
Equity:

Work Group Interpretation

What would be the impact of RZV in IC adults 

on health equity?

○ Reduced ○ Probably reduced ○ Probably no impact

○ Probably increased ○ Increased ○ Varies ○ Don't know
EtR Domain: Feasibility
Is the Intervention Feasible to Implement?

▪ RZV is a refrigerator-stable, two-dose vaccine 

▪ Can be co-administered with other adult vaccinations

▪ U.S. health care system has experience delivering RZV to 

immunocompetent adults aged ≥50 years

▪ Various systemic factors challenge the adult vaccination 

program in the U.S. 

53
Physicians from smaller (median: 5 providers) and private practices were less likely to stock RZV than 

larger practices or HMO or hospital-based clinics (p=<0.001).

Stocking and Referring Patterns (n=632)

Primary Care Physicians’ Perspective Related to 

Recombinant Zoster Vaccine, 2020

*Hurley et al., unpublished data 54
Do you refer patients to receive SHINGRIX at a location outside 

of your practice? (n=616)

If yes, how often do you refer to the following 

locations? (n= 538)

*Hurley et al., unpublished data 55
Role of Pharmacies

▪ Already a major provider of RZV, with ~60–65% of RZV 

distributed to/administered in pharmacies

▪ Anticipated concerns in the pharmacy setting

– Identification of IC patients (e.g., based on immunosuppressive 

medications, self-reported immunosuppression)

– Standing orders

– Some pharmacies may be out of network, which could result in 

out-of-pocket costs for patients

56
Identification of IC Patients may be Challenging

▪ Highlights need for

– Provider and patient education materials

– Clinical decision support 

▪ Majority of Jurisdictions have lifelong Immunization Information 

Systems (IISs)

– Can receive adult immunization information

– Many do not receive health status information, therefore anticipate will 

increase reliance on other systems (e.g., EHRs) for decision support

▪ Work group noted that clinical decision support guidance would be 

helpful and that it will be important to

– Promote best practices*

– Encourage providers to upload and update RZV vaccination information in 

Jurisdiction IISs

57 *Resources available at Immunization Information Systems (IIS) | CDC
Feasibility:

Work Group Interpretation

Is RZV in IC adults feasible to implement?

○ No ○ Probably no ○ Probably yes ○ Yes ○ Varies ○ Don't know
EtR Summary
EtR Framework

EtR Domain Question Work Group Judgments

Public Health 

Problem

Is the problem of public health importance? Yes

Benefits and 

Harms

How substantial are the desirable anticipated effects? Large

How substantial are the undesirable anticipated effects? Small

Do the desirable effects outweigh the undesirable 

effects?

Favors intervention

Values Does the target population feel the desirable effects are 

large relative to the undesirable effects?

Probably yes

Is there important variability in how patients value the 

outcomes?

Probably not important 

uncertainty or variability

Acceptability Is the intervention acceptable to key stakeholders? Yes

Resource Use Is the intervention a reasonable and efficient allocation 

of resources?

Yes

Equity What would be the impact of the intervention on health 

equity?

Probably increased

Feasibility Is the intervention feasible to implement? Yes

60
EtR Framework

Summary: Work Group Interpretations

Balance of

consequences

Undesirable

consequences

clearly

outweigh

desirable

consequences

in 

most settings

Undesirable

consequences

probably

outweigh

desirable

consequences

in 

most settings

The balance

between

desirable and

undesirable

consequences

is closely

balanced or

uncertain

Desirable

consequences

probably

outweigh

undesirable

consequences

in 

most settings

Desirable

consequences

clearly

outweigh

undesirable

consequences

in 

most settings

There is

insufficient

evidence to

determine 

the balance 

of

consequences

61
EtR Framework

Summary: Work Group Interpretations

Type of

recommendation

We do not 

recommend

the intervention

We recommend 

the intervention for 

individuals based on 

shared clinical

decision-making

We recommend 

the intervention

62
Considerations for Use
Clinical Guidance

▪ Use in IC adults

– RZV may be used irrespective of prior receipt of varicella vaccine or 

zoster vaccine live

▪ Dosing schedule

– First dose at Month 0 followed by a second dose 2 to 6 months later

– For individuals who are or will be immunodeficient or 

immunosuppressed and who would benefit from a shorter 

vaccination schedule: First dose at Month 0 followed by a second 

dose 1 to 2 months later

64
Clinical Guidance, cont.

▪ Coadministration with other vaccines

– CDC’s general best practice guidelines for immunization advise that 

recombinant and adjuvanted vaccines, such as RZV, can be 

administered concomitantly, at different anatomic sites, with other 

adult vaccines

▪ Counseling for reactogenicity

– Providers should counsel patients about expected systemic and local 

reactogenicity before vaccination

65
Clinical Guidance, cont.

▪ Timing of vaccination

– If appropriate, vaccinate prior to immunosuppression

– Otherwise, if possible, consider timing zoster vaccination when 

immune response is likely to be most robust

– RZV may be administered while patients are taking antivirals

– Don’t want to miss the opportunity to vaccinate

66
Special Populations

▪ Persons with a history of herpes zoster

– Should receive RZV

– If experiencing an acute episode, delay vaccination until symptoms abate

▪ Pregnancy 

– Currently no ACIP recommendation for RZV use in pregnancy

– Consider delaying RZV until after pregnancy

– Do not recommend pregnancy testing prior to vaccination

67
Special Populations, cont.

▪ Breastfeeding

– CDC’s general best practices for immunization advise that inactivated, 

recombinant, subunit, polysaccharide, and conjugate vaccines, as well 

as toxoids, pose no risk for mothers who are breastfeeding or for their 

infants

– Therefore, clinicians may consider vaccination without regard to 

breastfeeding status if otherwise indicated

68
Special Populations, cont.

▪ Persons with no documented history of varicella or varicella vaccination

– Laboratory testing

• Commercial IgG ELISAs can be used to assess varicella-zoster virus (VZV) 

seroconversion after wild type infection; however, sensitivity and specificity can vary

• No commercially available assays are sensitive and specific enough to reliably detect 

vaccine seroconversion

– RZV is not indicated for prevention of primary varicella infection, and varicella 

vaccine is contraindicated for many IC patients

• Persons born in the U.S. prior to 1980 are considered immune to varicella; however, 

this criterion does not apply to IC persons

• Persons born in the U.S. after 1980 and IC persons: Refer to ACIP varicella vaccine 

recommendations 

– Safety data regarding use of RZV in VZV naïve persons is limited

69
Policy Options and Discussion
Proposed Draft Recommendation

Two doses of recombinant zoster vaccine are recommended for 

adults aged ≥19 years who are or will be immunodeficient or 

immunosuppressed due to disease or therapy for the 

prevention of herpes zoster and its complications.

71
Acknowledgments

▪ CDC

– Kathleen Dooling

– Angela Guo

– Kai Hong

– Andrew Leidner

– Jessica Leung

– Megan Lindley

– Jessica MacNeil

– Nina Masters

– Ismael Ortega-Sanchez

– Jamison Pike

– Leah Shepersky

– Joanna Taliano

▪ Herpes Zoster Work Group

▪ GRADE Consultants

– Doug Campos-Outcalt

– Rebecca Morgan

▪ University of Colorado Denver, Vaccine Policy 

Collaborative Initiative

– Allison Kempe

– Laura P. Hurley

– Lori A. Crane

– Sean T. O’Leary

– Michaela Brtnikova

– Jessica Cataldi

– Brenda L. Beaty

– Carol Gorman

72
For more information, contact CDC

1-800-CDC-INFO (232-4636)

TTY: 1-888-232-6348 www.cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent the 

official position of the Centers for Disease Control and Prevention.

Thank You
Backup Slides
Slide 8 References

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2. American Cancer Society, https://cancerstatisticscenter.cancer.org; 2019 incidence estimates. 

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4. Halpern MT, Yabroff KR, Cancer Invest, 2008, 26(6):647-51; Derived from Halpern and Yabroff 2000-2004 

data on chemo/radiotherapy among all patients with cancers, adjusted based on proportion of all cancers in 

2007 due to solid organ cancers, further adjusted by projections that solid cancers increased by 20% 

between 2007 and 2018 (data from American Cancer Society website). 

5. CDC, https://www.cdc.gov/hiv/statistics/overview/ataglance.html; 2017 incidence, 2016 prevalence of 

diagnosed HIV infections.

6. Derived from Hayter SM. Autoimmun Rev. 2012 Aug;11(10):754-65 (prevalence 4.5% for all conditions 

excluding psoriasis) and Rachakonda TD. J Am Acad Dermatol. 2014 Mar;70(3):512-6 (prevalence of 3.2% for 

psoriasis alone), applied to projected adult US population in 2020 (US Census: 289.6 million).

75