Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Use of Recombinant Zoster Vaccine in Immunocompromised Adults Aged ≥19 Years

Policy question:	Should adults aged ≥19 years who are or will be immunodeficient or immunosuppressed because of disease or therapy be recommended to receive two doses of recombinant zoster vaccine for the prevention of herpes zoster and related complications?
Population	Immunocompromised adults aged ≥19 years
Intervention	Recombinant zoster vaccine (RZV), 2 doses at least 4 weeks aparta
Comparison	No vaccine
Outcomes	Herpes zoster Serious adverse events Postherpetic neuralgia Herpes zoster-related hospitalization Immune-mediated disease Graft-versus-host-disease (HCT)b Graft rejection (SOT)c Reactogenicity (grade 3)

1. The second RZV dose should typically be given 2–6 months after the first; for persons who are or will be immunodeficient or immunosuppressed and who would benefit from a shorter vaccination schedule, the second dose can be administered 1–2 months after the first.
2. HCT = Hematopoietic cell transplant
3. SOT = Solid organ transplant

Outcome	Importancea	Included in evidence profile
Herpes zoster	Critical	Yes
Serious adverse events	Critical	Yes
Postherpetic neuralgia	Important	Yes
Herpes zoster-related hospitalization	Important	Yes
Immune-mediated disease	Important	Yes
Graft-versus-host-disease (HCT)a	Important	Yes
Graft rejection (SOT)b	Important	Yes
Reactogenicity (grade 3)	Important	Yes

^aThree options: 1. Critical; 2. Important but not critical; 3. Not important for decision making
^bSOT = Solid organ transplant

First author last name, Publication year	Study design	Country	Study Population, Age	Total population	N Intervention	N comparison	Outcomes	Funding source
Bastidas, 2019	Phase III RCT (NCT01610414)	28 countries, including the United States	Autologous HCT recipients ≥18 years old	1 dose: 1,846 2 doses: 1,721	1 dose: 922 2 doses: 870	1 dose: 924 2 doses: 851	Confirmed HZ PHN HZ-related hospitalizations Immunogenicity Reactogenicity pIMD SAEs	GSK
Berkowitz, 2015	Phase I/II RCT (NCT01165203)	Germany, United Kingdom, United States	Patients with HIV ≥18 years old	1 dose: 123 2 doses: 119 3 doses: 118	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 (NCT01767467)	21 countries, including the United States	Patients with hematological malignancies ≥18 years old	1 dose: 562 2 doses: 516	1 dose: 283 2 doses: 259	1 dose: 279 2 doses: 257	Confirmed HZ Post hoc efficacy of RZV in preventing HZ Immunogenicity pIMD Reactogenicity SAEs Graft-versus-host-disease	GSK
Dagnew, 2021a	Pooled post hoc analysis of two Phase III RCTs (NCT01165177, NCT01165229)	Multiple countries, including the United States	Participants with pIMDs not on immune-suppressive therapies ≥50 years old; ≥70 years old	1 dose: 1,943 2 doses: 1,859	1 dose: 983 2 doses: 936	1 dose: 960 2 doses: 923	Post hoc efficacy of RZV in preventing HZ pIMD SAEs	GSK
Stadtmauer, 2014	Phase I/II RCT (NCT00920218)	United States	Autologous HCT recipients ≥18 years old	2 or 3 doses: 91	3 doses: 30 2 doses: 31	3 doses: 30	Confirmed HZ Immunogenicity Reactogenicity pIMD SAEs	GSK
Vink, 2019	Phase II/III RCT (NCT01798056)	Canada, Czech Republic, France, Korea, Spain, United Kingdom	Solid tumor patients ≥18 years old	1 dose: 232 2 doses: 209	1 dose: 117 2 doses: 102	1 dose: 115 2 doses: 107	Immunogenicity Reactogenicity pIMD SAEs	GSK
Vink, 2020	Phase III RCT (NCT02058589)	Belgium, Canada, Finland, Taiwan, Spain, Panama, Korea, Italy	Renal transplant patients ≥18 years old receiving daily immunosuppressive therapy	1 dose: 264 2 doses: 263	1 dose: 132 2 doses: 131	1 dose: 132 2 doses: 132	Immunogenicity Reactogenicity pIMD SAEs Graft rejection	GSK
Izurieta, 2021	Cohort Study	United States	Medicare beneficiaries ≥65 years old with IC or AI conditions	AI: 978,192 IC: 807,254	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 old, in the Veterans Affairs Healthcare System	50–60: 6,650 >60: 24,774	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; HCT = Hematopoietic Cell Transplant; HZ = Herpes Zoster; IBD = Inflammatory Bowel Disease; IC = Immunocompromised; pIMD = Potential Immune-Mediated Diseases; RCT = Randomized Control Trial; RZV = Recombinant Zoster Vaccine; SAEs = Serious Adverse Events

^a. This study included participants from the ZOE-50/70 trials with diagnosed autoimmune and inflammatory conditions not on immunosuppressive therapies. These participants may represent a less severe spectrum of autoimmune and inflammatory disease.

First author last name, Publication year	Age or other characteristic of importance	n/N RZV (%)	n/N comparison (%)	Incidence RZV (per 1000 person-years)	Incidence Comparison (per 1000 person-years)	Comparator	VE (95% CI) [100 x (1-IRR)]	Study Limitations (Risk of Bias)
Bastidas, 2019a	Phase III RCT; Autologous HCT recipients ≥18 years old	49/870 (5.6%)b	135/851 (15.9%)	30.0/1000 p-y	94.3/1000 p-y	Placebo	68.2% (55.6%, 77.5%)	Not serious
	18–49 subset	9/213 (4.2%)	29/212 (13.7%)	21.5/1000 p-y	76.0/1000 p-y		72% (39%, 88%)
	≥50 subset	40/657 (6.1%)	106/639 (16.6%)	33.0/1000 p-y	100.9/1000 p-y		67% (53%, 78%)
Berkowitz, 2015c	Phase I/II RCT; patients with HIV ≥18 years old	0/72 (0.0%)d	0/47 (0.0%)	NE	NE	Placebo	NE	Not serious
Dagnew, 2019e	Phase III RCT; patients with hematological malignancies ≥18 years old	2/259 (0.77%)f	14/256 (5.47%)	8.5/1000 p-y	66.2/1000 p-y	Placebo	87.2% (44.3%, 98.6%)	Not serious
Dagnew, 2021g	Pooled post hoc analysis of 2 Phase III RCTs; persons with pIMD ≥50 years and ≥70 years old	4/936 (0.43%)	38/923 (4.12%)	1.1/1000 p-y	11.1/1000 p-y	Placebo	90.5% (73.5%, 97.5%)	Serioush
	50–59 subset	1/222 (0.45%)	11/201 (5.47%)	1.1/1000 p-y	14.2/1000 p-y		92.8% (50.5%, 99.8%)
	60–69 subset	0/159 (0.0%)	8/151 (5.30%)	0.0/1000 p-y	13.6/1000 p-y		100% (54.9%, 100%)
	70–79 subset	2/427 (0.47%)	13/450 (2.89%)	1.2/1000 p-y	7.9/1000 p-y		84.4% (30.8%, 98.3%)
	≥80 subset	1/128 (0.78%)	6/121 (4.96%)	2.2/1000 p-y	15.1/1000 p-y		86.2% (13.5%, 99.7%)
Stadtmauer, 2014i	Phase I/II RCT; autologous HCT recipients ≥18 years old	0/61 (0.0%)j	2/30 (6.67%)	-	-	Placebo	RR: 0.0 (0.0, NA)k	Not serious
Izurieta, 2021l,m	Prospective cohort; Medicare beneficiaries ≥65 years old with AI/IC conditions					Not vaccinated		Serious n
	AI	167/61,999 (0.27%)	20,640/886,123 (2.33%)	4.44/1000 p-y	14.89/1000 p-y		68.0% (62.3%, 72.8%)
	IC	143/40,442 (0.35%)	18,504/746,654 (2.48%)	5.85/1000 p-y	17.15/1000 p-y		64.1% (57.2%, 69.8%)
Khan, 2021o	Retrospective cohort; IBD patients ≥50 years old in VAHS	8/4875 (0.16%)	337/26549 (1.27%)	1.55/1000 p-y	4.42/1000 p-y	Placebo	HR 2 dose vs. no vaccination: p	Serious q
	50–60 subset	0/655 (0.0%)	69/5,995 (1.15%)	0.00/1000 p-y	3.93/1000 p-y		No steroid use: NE Steroid use: NE
	>60 subset	8/4,220 (0.19%)	268/20,554 (1.30%)	1.80/1000 p-y	4.57/1000 p-y		No steroid use: 0.41 (0.19, 0.87) Steroid use: 0.34 (0.05, 2.44)

Abbreviations: AI = Autoimmune; CI = Confidence Interval; HCT = Hematopoietic Cell Transplant; IC = Immunocompromised; NE = Not Evaluable; pIMD = Potential Immune-Mediated Disease; HR = Hazard Ratio; RCT = Randomized Controlled Trial; RR = Risk Ratio; RZV = Recombinant Zoster Vaccine; VAHS = Veteran’s Affairs Health System; VE = Vaccine Efficacy

^a. A suspected case of HZ was defined as (1) a new rash characteristic of HZ (e.g., unilateral, dermatomal, and accompanied by pain broadly defined to include allodynia, pruritus, or other sensations) or a vesicular rash suggestive of varicella-zoster virus (VZV) infection regardless of distribution, with no alternative diagnosis or (2) clinical symptoms and/or signs suggestive of  VZV infection and specific laboratory findings, such as VZV–positive culture or immunohistological staining or RT-PCR assay in the absence of characteristic HZ rash. Participants with any suspicion of HZ were examined by investigators within 96 hours. Participants were followed up for at least 90 days after rash onset or until the rash resolved and the participant had been pain-free for 4 weeks. HZ episodes were confirmed using RT-PCR assay or, if not possible, by a blinded ascertainment committee.

^b. Data presented in the table above is from the modified total vaccination cohort (mTVC), which included all participants who received 2 doses RZV/Placebo and excludes participants who developed an episode of HZ <1 month after receiving the second dose. Sensitivity analyses in the total vaccinated cohort (TVC), containing all who received at least one dose of RZV/placebo, found 242 confirmed cases of HZ (70/922 in the vaccine group (incidence 34.7/1000 p-y) and 172/924 in the placebo group (incidence 95.6/1000 p-y)), resulting in an IRR of 0.36 (95% CI: 0.27-0.48). Among those aged 18-49 years (TVC), there were 13 cases/230 vaccinated participants (incidence: 25.2/1000 p-y), and 39 cases/229 participants in the placebo group (incidence: 84.9/1000 p-y). Among those aged ≥50 years (TVC), there were 57 cases/692 vaccinated participants (37.9/1000 p-y), and 133 cases/695 placebo recipients (incidence 99.3/1000 p-y). These results corresponded to an IRR of 0.30 (95% CI: 0.15-0.57) for the TVC aged 18-49 years, and an IRR of 0.38 (95% CI 0.28-0.52) for the TVC aged ≥50 years.

^c. Berkowitz, 2015 used a 3-dose regimen of HZ/su at months 0, 2, and 6. 74 participants received 1 dose, 72 received 2 doses, and 71 received 3 doses of HZ/su, and 49 received 1 dose placebo, 47 received 3 doses placebo. In the table above, the denominator was subset to those patients who received at least 2 doses HZ/su/Placebo.

^d. One case of HZ was reported during the study. This case occurred in the HZ/su group 83 days after the subject’s first and only vaccine dose, and thus is not reported in the table because the individual did not complete 2 doses of HZ/su (the pre-determined intervention criteria)

^e. A suspected case of HZ was defined as a new unilateral, dermatomal rash accompanied by pain (broadly defined to include allodynia, pruritus, or other sensations), or a vesicular rash suggestive of VZV infection regardless of the distribution, and no alternative diagnosis; or a clinical presentation and specific laboratory findings (VZV positive PCR, culture, or immunohistochemical staining) specific to VZV infection in the absence of characteristic HZ rash. HZ cases were confirmed by PCR on samples collected from lesions or by a HZ ascertainment committee (HZAC) if the case could not be confirmed or excluded by PCR. The HZAC comprised three physicians with expertise in infectious diseases and hematology or oncology who were masked to treatment assignments and PCR results. Each member classified the reviewed cases as HZ or non-HZ based on the available clinical information from the study site. A suspected case was only considered HZ if the HZAC members concurred unanimously.

^f. The authors assessed post hoc efficacy in the mTVC, which included all participants from the total vaccinated cohort, except those who did not receive the second dose or who developed a confirmed case of HZ before 30 days after dose two (n = 259 in the vaccine group and n = 256 in the placebo group, with results presented above).

^g. The analysis of vaccine efficacy in the subset of pooled ZOE-50/70 participants with pre-existing pIMDs at enrollment was performed in the modified total vaccinated cohort (mTVC), which included all participants who received both doses of study vaccine and did not develop a confirmed HZ episode before 30 days post-dose 2. For the efficacy assessment, only the first confirmed HZ episode in a participant was considered, and the follow-up period ceased at the time of the first occurrence.

^h. 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.

^i. At the start of study, subjects were educated to recognize the signs and symptoms of HZ. They were to contact the study physician immediately for clinical evaluation and sample collection for VZV-specific PCR if they suspected HZ.

^j. At study months 0, 1, and 3, subjects received 3 doses of 50mg VZV gE combined with the liposome-based adjuvant AS01B; 3 doses of 50mg gE combined with the liposome-based adjuvant AS01E; 1 dose of saline followed by 2 doses of gE/AS01B; or 3 doses of saline. The now-licensed SHINGRIX vaccine is administered according to the third protocol: 2 doses of gE/AS01B. In the 3 doses gE/AS01E group, there were 2 cases of HZ among 29 participants (6.9%), however these results are not presented because this was not the adjuvant ultimately used in the SHINGRIX vaccine.

^k. Risk ratio was calculated, along with Wald confidence intervals, in R and SAS.

^l. Beneficiaries were classified into an autoimmune population if they consulted for any of the selected autoimmune conditions included at least twice in the 1 year prior to the index date. Autoimmune definitions were adapted from Cooper et al. 2009. These included patients diagnosed with any of the following conditions 365 days prior to index date: Graves' disease, Hashimoto's thyroiditis, MS, Myasthenia gravis, Polymyalgia rheumatica, Primary biliary cirrhosis, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Scleroderma, Sjogren's syndrome, Systemic lupus erythematosus, Ulcerative colitis (UC), Vitiligo. The authors used a previously published, independently validated algorithm presented by Greenberg and colleagues to determine categories of immunosuppression.

^m. HZ was defined in a claim in an outpatient or professional setting with ICD-10 diagnosis code for HZ (B020, B021, B022.x, B027-B029) in any position with a claim for HZ specific antiviral identified using national drug codes within Medicare part D claims within 7 days of diagnosis. As a sensitivity analysis, the authors defined cases using the same clinical definition without the antiviral prescription.

^n. Overall, this study presents with concerns of confounding, with no demographics or risk-factors presented for the immune-compromised and autoimmune populations. Additionally, given that it is a Medicare claims-based study, reliant on algorithmic determination of immunocompromised and autoimmune status, there remains significant risk of both confounding and information bias in interpreting the VE.

^o. HZ was determined by relevant ICD-9-CM (053.xx) and ICD-10-CM (B02.xx) codes for HZ and their complications. To ensure that the codes accurately reflected incident HZ cases, the clinical notes and laboratory data of each patient who had the code was individually reviewed by 2 members of the team.

^p. In the Cox regression model without any interaction, 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 group, the HR was 0 (95% CI, 0-0). The HR was 0.39 (95% CI,0.19-0.80) in the >60 group.

^q. This was a large cohort analysis, yet the VA patient population may not be generalizable to the general population. Coupled with the authors' retrospective case ascertainment, this analysis has moderate/high risk of bias

Humoral Immunity							Cell-mediated Immunity
First author last name, Publication year	Age or other important characteristic	Timing after last dose	% Response Rate RZV (95% CI)	% Response Rate Placebo (95% CI)	anti-gE antibody concentration (geometric mean (mIU/mL): RZV	anti-gE antibody concentration (geometric mean (mIU/mL): Placebo	% Response Rate RZV (95% CI)	% Response Rate Placebo (95% CI)	# of gE-specific CD4[2+] T cells (per 10^6) median (IQR) or mean +/- SD: RZV	# of gE-specific CD4[2+] T cells (per 10^6) median (IQR) or mean +/- SD: Placebo	Comparator	Adjusted Humoral GMR (95% CI)	Study Limitations (Risk of Bias)
Bastidas, 2019a	Phase III RCT; autologous HCT recipients ≥18 years old	1 Month	67%	0%	12753 (7973.0,20399.4)	443.8 (330.8,595.4)	93%	0%	-	-	Placebo	-	Not serious Indirect, proxy outcome
		12 Months	-	-	3183.8 (1869.8,5421.2)	503.6 (307.8, 824.1)	-	-	-	-		-
Berkowitz, 2015b	Phase I/II RCT; patients with HIV ≥18 years old	1 Month	96.2% (87.0,99.5%)	2.8% (0.1,14.5%)	63812.6 (51183.6,79557.7)	1028.4 (658.9,1605)	90% (68.3,98.8%)	16.7% (3.6, 41.4%)	2578.4 (2056.6, 5298.6)	122.6 (10.7, 270.4)	Placebo	-	Not serious Indirect, proxy outcome
		12 Months	91.7% (80.0,97.7%)	0% (0,9.5%)	25242.2 (19618.9,32477.3)	918 (588,1433.1)	64.5% (45.4,80.8%)	0% (0.0, 13.2%)	1533 (770, 2643.1)	71.8 (1.0, 156.9)		-
Dagnew, 2019c	Phase III RCT; patients with hematological malignancies ≥18 years old	1 Month	65.4% (58.7,71.7%)	0.5% (0.0,2.8%)	13455.6 (10158.9,17795.6)	832.0 (701.1,987.3)	83.7% (69.3, 93.2%)	6.8% (1.4, 18.7%)	3081.9 (1766.2, 7413.6)	99.1 (1.0, 268.3)	Placebo	29.75 (21.09, 41.96)	Not serious Indirect, proxy outcome
		12 Months	52.1% (44.2,59.9%)	3.6% (1.2,8.1%)	5202.7 (4074.8,6642.8)	895.4 (734.5,10901.5)	66.7% (48.2,82.0%)	6.5% (0.8, 21.4%)	1006.7 (416.0, 3284.5)	-		-
Stadtmauer, 2014d,e	Phase I/II RCT; autologous HCT recipients ≥18 years old	1 Month	-	-	11064.6 (4361.2,28071.8)	-	-	-	1990.8 (755.4, 7223.2)	-	Placebo	42.20 (16.07, 110.82)	Not serious Indirect, proxy outcome
		12 Months	-	-	2968.0 (1184.7,7436.1)	-	-	-	2297.6 (946.1, 5442.5)	-		8.81 (3.41, 22.80)
Vink, 2019f	Phase II/III RCT; solid tumor patients ≥18 years old	1 Month	86.2%	0.0%	18291.7 (14432.1,23183.5)	1060.5 (873.9,1287.1)	50.0%	0.0%	778.8 (393.1, 1098.2)	61.8 (17.4, 139.5)	Placebo	14.4 (10.7, 19.5)	Not serious Indirect, proxy outcome
		12 Months	51.5%	0.0%	4477.3 (3482.4,5756.3)	1064.7 (845.9,1340.1)	17.6%	0.0%	332.9 (114.9, 604.6)	51.2 (1.0, 288.6)		-
Vink, 2020g	Phase III RCT; renal transplant patients ≥18 years old	1 Month	80.2%	4.2%	19163.8 (15041.5,24416.0)	1489.4 (1215.8,1824.7)	71.4%	0.0%	2433.07 (SD 2102.29)	156.98 (SD 274.81)	Placebo	14.00 (10.90, 17.99)	Not serious Indirect, proxy outcome

Abbreviations: CI = Confidence Interval; gE = glycoprotein E; GMR = Geometric Mean Ratio; HCT = Hematopoietic Cell Transplant; IQR = Inter-Quartile Range; RCT = Randomized Controlled Trial; RR = Risk Ratio; RZV = Recombinant Zoster Vaccine; SD = Standard Deviation;

^a. Humoral VRR was 45% 24 months after dose 2. The highest anti-gE geometric mean concentrations were recorded 1 month after dose 2 and remained above baseline 24 months after dose 2. Vaccine CMI response was 71% 24 months after dose 2. Frequency of gE-specific CD4[2+] T cells was highest 1 month after dose 2 and declined but remained above pre-vaccination levels through 24 months after dose 2. In the placebo group, humoral response was highest 24 months after dose 2 with no increase observed for anti-gE antibody concentrations at any postvaccination time. CMI was highest 24 months after dose 2 with no increase observed for CD4[2+] T-cell frequencies.

^b. Anti-gE GMCs increased significantly after 3rd dose and reached maximum 1 month after 3rd dose. One year after 3rd dose, levels remained above pre-vaccination concentrations, but decreased 60% between month 7 and 18. The proportions of subjects with anti-gE humoral vaccine responses were between 92.3% and 98.1% at the different timepoints. At month 7, frequency of gE-specific CD4 cells was higher following vaccinated group than saline (P < 0.0001). Frequency peaked 1 month after 2nd dose of RZV but did not increase further after the 3rd dose. GMR of gE-specific CD4 frequencies at 1 month after dose 1 vs.1 month after dose 2 was 1.04; comparable response profile for VZV-specific T cells. The proportion of respondents with vaccine associated CMI response was 40% 1 month after dose 1, 85.7% after dose 2, 90% after dose 3; 64.5% of subjects had CMI levels above response threshold 1 year after last dose. In the placebo group, the proportion of subjects with anti-gE humoral vaccine response was <2.8%, and the proportion of subjects with a vaccine associated CMI response was between 8.3% and 16.7%. No placebo recipients had CMI levels above the response threshold 1 year after the last dose.

^c. The pre-vaccination anti-gE antibody GMC was 964.0 mIU/mL (95% CI 814.5–1140.8) in the vaccine group and 13445.6 mIU/mL (10158.9–17795.6) at month 2, with 142 (65.4%) of 217 participants having a humoral vaccine response. In all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukemia at month 2, 119 (80.4%) of 148 participants had a humoral vaccine response. The adjusted geometric mean anti-gE antibody concen­tration was 23132.9 mIU/mL(16642.8–32153.9). At month 13, the anti-gE antibody GMC was 5202.7 mIU/mL (95% CI 4074.8–6642.8) and 86 (52.1%) of 165 participants had a humoral vaccine response. The proportion of participants with a humoral vaccine response was higher in participants who were vaccinated after immunosuppressive cancer treatments compared with those who were vaccinated during immunosuppressive treatments. Median CD4[2+] T-cell frequencies before vaccination were 77.5 (IQR 1.0–191.4). At month 2, median CD4[2+] T-cell frequencies were 3081.9 (1766.2–7413.6), and 36 (83.7%) of 43 participants had a vaccine response.  At month 13, the median CD4[2+] T-cell frequency was 1006.7 (IQR 416.0–3284.5) and 22 (66.7%) of 33 participants had a CMI vaccine response. For the placebo group: pre-vaccination anti-gE antibody GMC was 883.7 mIU/mL (749.9–1041.4). At month 2, the anti-gE GMC was 832.0 mIU/mL (701.1–987.3), and 1 (0.5%) of 198 participants had a humoral vaccine response. Excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukemia at month 2, 1 (0.8%) of 130 placebo recipients had a humoral vaccine response. The adjusted anti-gE GMC was 7776 mIU/mL (7028–8603). At month 13, 5 (3.6%) of 140 participants had a humoral vaccine response. Median CD4[2+] T-cell frequencies before vaccination were 101.2 (1.0–193.1) in the placebo group, and 99.1 (1.0–268.3) at month 2, and 3 (6.8%) of 44 participants had a vaccine response.

^d. Stadtmauer et al. reported immunogenicity of three dosing regimens: 2 and 3 doses of HZ/su adjuvanted with AS01B (the adjuvant used in RZV), and 1 regimen adjuvanted with AS01E, 3 doses. AS01E was not ultimately used in the RZV vaccine, and the table above only includes results from the 2-dose regimen, as that is the formulation currently used for SHINGRIX.

^e. 1 month after the final dose, anti-gE GMCs were higher in all gE/AS01 groups than in the saline group (P<0.0001). GMCs peaked at month 4 in the 3 gE/AS01 groups and were 25- to 55-fold higher than before vaccination. These GMCs remained high for at least 1 year after the last vaccination, although they decreased 29% to 46% from month 4 to month 15. Approximately one-third of subjects had an anti-gE response after the first dose of gE/AS01B or gE/AS01E. At month 4, response rates were similar for the 3 vaccine groups (72.4%-76.9%). Anti-gE GMCs after vaccination did not increase in subjects with non-Hodgkin B-cell lymphoma, although the GMCs increased for all other diagnoses. At month 4, gE-specific CMI, as measured by the CD4[2+] T-cell frequency after induction with gE, was significantly higher for all gE/AS01 groups than for saline (P<0.0001). The CD4[2+] T-cell frequencies in the gE/AS01B 3-dose and 2-dose groups were superior to that of the saline group. One month after the second dose of gE/AS01B, the CD4[2+] T-cell frequency was 2.3-fold higher after early vaccination (2 and 3 months post-HCT) than after delayed vaccination (3 and 5 months post-HCT). There were no differences in CMI responses according to underlying disease. At month 4, gE-specific CMI was significantly higher for all gE/AS01 groups than for saline (P<0.0001). Additionally, reported CMI GMRs for the 3-dose regimen are not reported in the table above, but are 74.41 (25.74-215.09) for 1 month after last vaccination, and 28.70 (10.92-75.46) for 12 months after last vaccination.

^f. Before vaccination, >99% of participants were seropositive for anti-gE antibody. At month 1, in pooled RZV recipients, the GMC was 24793.1 mIU/mL; both GMCs and humoral vaccine response rates (VRRs) were higher in RZV-PreChemo than in the RZV-OnChemo group.  In pooled RZV recipients, the month 2 GMC was 18291.7 mIU/mL and remained higher in the RZV-PreChemo group than in the RZV-OnChemo group. The humoral VRR to RZV was 93.8% (95% CI, 85.0%-98.3%) at month 2 in the RZV-PreChemo group. At month 13, the GMC was 4477.3 mIU/mL in pooled RZV recipients; both GMCs and humoral VRRs were similar in the RZV-PreChemo group and RZV-OnChemo group. In RZV recipients ≥50 years of age, GMCs tended to be higher at month 2, 6, and 13than in those 18-49 years of age, while humoral VRR tended to be higher only at month 6 and 13. Before vaccination, median CD4[2+] T-cell frequencies were 127.3 in RZV recipients. At month 2, the CMI VRR was 50.0% (95% CI, 28.2%-71.8%). In RZV recipients, the highest median CD4[2+] T-cell frequency was observed at month 2 (778.8), which persisted above baseline up to month 13 (332.9), a level similar to that observed at month 1 (391.9). CMI VRRs followed a similar pattern, with the highest VRR at month2. CD4[2+] T cell frequencies were in similar ranges in RZV recipients 18-49 and ≥50 years of age, whereas CMI VRRs tended to be higher in those 18-49 years of age at all postvaccination time points. For the placebo group, postvaccination anti-gE antibody GMCs and humoral VRRs remained near the pre-vaccination level. Additionally, the CMI GMR, not listed in the table above, was reported as 9.94 (3.63-27.19).

^g. The humoral VRR in the RZV group was 80.2% (95% CI: 71.9%–86.9%) at month 2. Anti-gE antibody GMCs increased from 1354.4 mIU/mL at pre-vaccination to 19163.8 mIU/mL at month 2 and persisted through month 13 at 8545.1 mIU/mL. No apparent differences in anti-gE antibody GMCs were seen linked to the types of maintenance immunosuppressive therapy. Humoral immune responses appeared higher in the 18–49 years of age cohort than in the ≥50 years of age cohort, but within the 18–49 years of age cohort, humoral immune responses similar for ages 18–29 and 30–49 years. The VRR for CMI responses was 71.4% (51.3%–86.8%) in the RZV group at month 2. At pre-vaccination, median CD4[2+] T-cell frequencies were 21.2 in the RZV group. Median frequencies increased to 2149.0 at month 2 and remained significantly elevated over baseline at month 13. At each time point, CMI responses appeared to be higher in the 18–49 years of age cohort. Within the 18–49 years of age cohort, CMI responses were similar for the age 18–29 and 30–49 years of age groups. For the placebo group: postvaccination anti-gE antibody GMCs, humoral VRRs, CD4[2+] T-cell frequencies, and CMI VRRs remained near the pre-vaccination level. At pre-vaccination, median CD4[2+] T-cell frequencies were 59.7 in the placebo group. The CMI GMR, not listed in the table above, was reported as17.26 (5.92-50.36).

First author last name, Publication year	Age or other characteristic of importance	n/N RZV (%)	n/N comparison (%)	n/N related to vaccination (%)	n/N related to vaccination in comparator group (%)	Comparator	RR (95% CI)*	Study limitations (Risk of Bias)
Bastidas, 2019b	Phase III RCT; autologous HCT recipients ≥18 years old	263/922 (28.5%)	241/924 (26.1%)	3/922 (0.33%)	4/924 (0.43%)	Placebo	1.09 (0.94, 1.27)	Not serious
Berkowitz, 2015c	Phase I/II RCT; patients with HIV ≥18 years old	6/74 (8.1%)	2/49 (4.1%)	0/74 (0.0%)	0/49 (0.0%)	Placebo	1.99 (0.42, 9.44)	Not serious
Dagnew, 2019d	Phase III RCT; patients with hematological malignancies ≥18 years old	66/283 (23.3%)	82/279 (29.4%)	1/283 (0.35%)	1/279 (0.36%)	Placebo	0.79 (0.60, 1.05)	Not serious
Dagnew, 2021e	Pooled post hoc analysis of 2 Phase III RCTs; participants with pIMD ≥50; ≥70 years old	144/983 (14.6%)	112/960 (11.7%)	Not disclosed	Not disclosed	Placebo	1.26 (1.00, 1.58)	Seriousf
Stadtmauer, 2014g	Phase I/II RCT; autologous HCT recipients ≥18 years old	16/61 (26.2%)	8/30 (26.7%)	1/61 (1.6%)	0/30 (0.0%)	Placebo	0.98 (0.48, 2.04)	Not serious
Vink, 2019h	Phase II/III RCT; solid tumor patients ≥18 years old	46/117 (39.3%)	45/115 (39.1%)	0/117 (0.0%)	0/115 (0.0%)	Placebo	1.00 (0.73, 1.38)	Not serious
Vink, 2020i	Phase III RCT; renal transplant patients ≥18 years old	26/132 (19.7%)	33/132 (25.0%)	0/132 (0.0%)	1/132 (0.76%)	Placebo	0.79 (0.50, 1.24)	Not serious

Abbreviations: CI = Confidence Interval; HCT = Hematopoietic Cell Transplant; pIMD = Potential Immune-Mediated Disease; RCT = Randomized Controlled Trial; RR = Risk Ratio; RZV = Recombinant Zoster Vaccine; SD = Standard Deviation
*All risk ratios and Wald confidence intervals calculated using R and SAS.

^a. Death, life-threatening event, hospitalization, incapacity to perform normal life functions, medically important event, or congenital anomaly/birth defect. The figures reported in the above table represent individuals who reported at least one SAE during the entire study period or longest period of follow-up, with footnoted details for shorter periods (i.e. 30 days after last vaccination) of follow up and individuals who experienced >1 SAE.

^b. SAEs within 30 days after last vaccination occurred in 7% of both vaccine (n = 68/922) and placebo (n=66/924) recipients. The most frequent SAEs were neoplasms. Three participants in the vaccine group reported 5 serious adverse events (neutropenia, immune thrombocytopenic purpura, cutaneous vasculitis, arthralgia, and atrial fibrillation) that were considered related to vaccination; 4 participants in the placebo group reported 4 such events (constipation, HZ, disseminated cutaneous HZ, and skin eruption). Fatal SAEs occurred in 242 participants (vaccine group, n=118; placebo group, n=124) during the entire study and were mainly due to recurring malignancy and non–HZ–related infections.

^c. Within 30 days after last vaccination, 4 SAEs were reported (2 each in the HZ/su and saline groups), but none were considered related to vaccination. Over the study period, 7 SAEs were reported in 6 of 74 subjects (8.1%) in the HZ/su group, and 2 SAEs were reported in 2 of 49 (4.1%) in the saline group. None were considered related to vaccination. One subject withdrew because of 2 SAEs (portal hypertension and esophageal variceal hemorrhage) 97 days after the second HZ/su dose. No deaths were reported.

^d. Within 30 days of last vaccination, SAEs occurred in 17/283 RZV recipients (6.0%) and 29/279 placebo recipients (10.4%). Of these, none was considered related to vaccination. Within 6 months of the last vaccination, SAEs occurred in 50/283 RZV recipients (17.7%) and 60/279 placebo recipients (21.5%), none of which was considered related by the investigator in the vaccine group, and 1 which was considered related in the placebo group (1/279, 0.4%). For the full study period, the SAE counts are described in the table above, with 1 SAE considered related to vaccination in each of the RZV and placebo groups (1/283, 0.4%, 1/279, 0.4%, respectively). The incidence of SAEs was similar between the study groups during all time periods evaluated. The most frequent SAEs were febrile neutropenia (14 (4.9%) vaccine participants and 11 (3.9% placebo) and pneumonia (11 (3.9%) in each study group).  From first vaccination until study end, fatal SAEs were reported in 29 (10.2%) of 283 participants in the vaccine group and 37 (13.3%) of 279 participants in the placebo group.

^e. The occurrence of fatal SAEs during the entire study period was similar between the RZV (5.1%) and placebo (6.6%) groups and appeared to be similar to the overall pooled ZOE-50/70 population (RZV: 4.3%, placebo: 4.6%).

f. 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.

^g. Through study month 15, 54 SAEs were reported in 33 subjects (6 in the gE/AS01B 3-dose group, 9 in the gE/AS01E 3-dose group, and 8 in the saline group). Only the SAEs reporting using AS01B adjuvant are included, as the AS01E adjuvant was ultimately not included in the RZV vaccine. One SAE was considered possibly related to vaccination by the investigator: pneumonia 105 days after a second dose of vaccine in the gE/AS01B 2-dose group. Nine subjects died during the study: 2 from recurrence of underlying malignancy and 2 from unknown reasons. No deaths were considered vaccination-related.

^h. SAEs reported from the first vaccination through 30 days after last vaccination occurred in 16/117 (13.7%) RZV recipients and 14/115 (12.2%) placebo recipients. SAEs reported from 30 days after last vaccination through the study end occurred in 30/117 (25.6%) RZV recipients and 31/115 (27.0%) placebo recipients. The most frequent SAEs reported were infections and infestations, malignant neoplasms, and neutropenia. Fatal SAEs occurred in 12 (10.3%) of RZV and 11 (9.6%) of placebo recipients. None of the SAEs were considered by the investigators to be causally vaccine related. In addition to the fatalities, 2 participants withdrew due to nonfatal SAEs: 1 RZV recipient experienced brain metastases and febrile neutropenia, and 1 placebo recipient had pulmonary metastases of prostatic cancer, anemia, bilateral hydronephrosis, and acute renal failure.

^i. From first vaccination through month 13, SAEs were reported by 26 (19.7%) RZV and 33 (25.0%) placebo recipients. Of these, 3 SAEs (febrile neutropenia, mucosal inflammation, and Burkitt lymphoma) were considered causally related to vaccination and were reported by 1 placebo recipient. From first vaccination to 30 days after last vaccination, there were 6 SAEs reported in 132 RZV recipients (4.5%) and 5 SAEs reported in 132 placebo recipients 93.8%). From 30 days after last vaccination to study end, there were 21 SAEs reported in the RZV group (15.9%), and 29 SAEs reported in the placebo group (22.0%).

First author last name, Publication year	Age or other characteristic of importance	n/N RZV (%)	n/N comparison (%)	Incidence RZV (per 1000 person-years)	Incidence Comparison (per 1000 person-years)	Comparator	VE (95% CI)	Study limitations (Risk of Bias)
Bastidas, 2019 b	Phase III RCT; autologous HCT recipients ≥18 years old	1/49 (2.0%)	9/135 (6.7%)	0.5/1000 p-y	4.9/1000 p-y	Placebo	89% (22%,100%)	Not serious

Abbreviations: CI = Confidence Interval; HCT = Hematopoietic Cell Transplant; P-Y = Person-Years; RCT = Randomized Controlled Trial; RR = Risk Ratio; RZV = Recombinant Zoster Vaccine; VE = Vaccine Efficacy

^a. PHN = presence of HZ-associated ‘worst’ pain persisting or appearing more than 90 days after onset of the HZ rash; ‘Worst’ pain = HZ-associated pain rated as 3 or greater on the “worst pain” Zoster Brief Pain Inventory question.

^b. Results presented above for modified total vaccination cohort (mTVC), which included individuals who received 2 doses of RZV. Sensitivity analyses were conducted using the total vaccinated cohort (TVC; individuals receiving at least 1 vaccine), with the results are as follows: n/N intervention group (TVC) = 4/70, n/N comparison group (TVC) = 12/172. The reported incidence in the RZV group (TVC) = 1.9/1000 p-y, and reported incidence in the comparison group (TVC) was 5.8/1000 p-y. The VE for the TVC was 67%.

First author last name, Publication year	Age or other characteristic of importance	n/N RZV (%)	n/N comparison (%)	Incidence RZV (per 1000 person-years)	Incidence Comparison (per 1000 person-years)	Comparator	VE (95% CI)	Study limitations (Risk of Bias)
Bastidas, 2019 a	Phase III RCT; autologous HCT recipients ≥18 years old	2/49 (4.1%)	13/135 (9.6%)	1.1/1000 p-y	7.1/1000 p-y	Placebo	85% (32%,97%) b	Not serious

Abbreviations: CI = Confidence Interval; HCT = Hematopoietic Cell Transplant; P-Y = Person-Years; RCT = Randomized Controlled Trial; RR = Risk Ratio; RZV = Recombinant Zoster Vaccine; VE = Vaccine Efficacy

^a. Results in table above presented for modified total vaccination cohort (mTVC), individuals who received 2 doses RZV. The authors conducted sensitivity analyses on the total vaccinated cohort (TVC), evaluating all participants who received at least one dose of the vaccine. Results are as follows: n/N RZV group (TVC) = 4/70; n/N comparison group (TVC) = 20/172. Incidence RZV group (TVC) = 1.9/1000 p-y, incidence comparison group (TVC) = 9.7/1000 p-y.

^b. The authors reported a hazard ratio (HR) of 0.15 (95% CI, 0.03-0.68; P = .01), which was converted to VE using the formula (1-HR)*100%.

First author last name, Publication year	Age or other characteristic of importance	Immune-Mediated Disease type	n/N RZV (%)	n/N Comparison (%)	Comparator	RR (95% CI)*	Study limitations (Risk of Bias)
Bastidas 2019b	Phase III RCT; autologous HCT recipients ≥18 years old	Not specified	13/922 (1.4%)	8/924 (0.9%)	Placebo	1.63 (0.68, 3.91)	Not serious
Dagnew, 2019c	Phase III RCT; patients with hematological malignancies ≥18 years old	Not specified	3/283 (1.1%)	2/279 (0.7%)	Placebo	1.48 (0.25, 8.78)	Not serious
Dagnew, 2021d	Pooled post hoc analysis of 2 Phase III RCTs; participants with pIMD ≥50; ≥70 years old	Exacerbations	27/983 (2.8%)	27/960 (2.8%)	Placebo	0.98 (0.58, 1.65)	Seriouse
		New-Onset	16/983 (1.6%)	23/960 (2.4%)		0.68 (0.36, 1.28)
Stadtmauer, 2014f	Phase I/II RCT; autologous HCT recipients ≥18 years old	New-Onset	0/61 (0.0%)	0/30 (0.0%)	Placebo	NE	Not serious
Vink, 2019g	Phase II/III RCT; solid tumor patients ≥18 years old	Not specified	0/117 (0.0%)	1/115 (0.9%)	Placebo	0.0 (0.0, NA)	Not serious
Vink, 2020h	Phase III RCT; renal transplant patients ≥18 years old	New-Onset	4/132 (3.0%)	2/132 (1.5%)	Placebo	2.0 (0.37, 10.73)	Not serious

Abbreviations: CI = Confidence Interval; HCT = Hematopoietic Cell Transplant; NE = Not evaluable; pIMD = Potential Immune Mediated Disease; RCT = Randomized Controlled Trial; RR = Risk Ratio; RZV = Recombinant Zoster Vaccine
*Risk ratios were calculated using Wald confidence intervals in SAS and R.

^a. Bastidas 2019, Dagnew 2019, and Vink 2019 did not specify the type of pIMD recorded. Dagnew 2021 recorded both exacerbations and new-onset immune-mediated disease, and Stadtmauer 2014 and Vink 2020 only reported new-onset immune-mediated disease.

^b. pIMDs were assessed within 365 days post-last vaccination in the total vaccinated cohort (TVC). In the RZV group, 3 pIMDs were deemed related to vaccination (0.3%), and in the placebo group, 0 were deemed related to vaccination. For the RZV group, MedDRA Primary System Organ class and preferred term included skin and subcutaneous tissue disorders (n=4), blood and lymphatic system disorders (n=3), musculoskeletal and connective tissue disorders (n=2), nervous system disorders (n=2), endocrine disorders (n=2), and infections and infestations (n=1). Psoriasis (n=2) was the most reported pIMD in the RZV group. In the placebo group, interstitial lung disease (n=2) was the most reported.

^c. pIMDs were assessed at three time periods: from first vaccination to 30 days after last vaccination, from first vaccination up to 6 months after last vaccination, and from first vaccination until study end. The table reflects pIMDs from first vaccination until study end. For the RZV group, through 30 days after last vaccination, 1/283 (0.4%) RZV recipients experienced a pIMD, and from first vaccination through 6-months after last vaccination, 3/283 (1.1%) recipients experienced a pIMD. For the placebo group, there were 0/279 (0%) pIMDs reported in the first 30 days after last vaccination, and 1/279 (0.4%) through 6 months after last vaccination. These diseases by MedDRA Preferred Term were autoimmune pancytopenia, gout, and erythema nodosum in the vaccine group, and autoimmune hemolytic anemia and Guillain Barré syndrome in the placebo group.

^d. Exacerbations of pre-existing pIMDs and new-onset pIMDs were assessed over the whole study period. Most frequent pre-existing pIMDs reported at enrolment were psoriasis, spondyloarthropathy, rheumatoid arthritis, and celiac disease; their prevalence was balanced between study groups.

^e. 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.
^f. pIMDs were evaluated over the entire study period.

^g. pIMDs were evaluated at two time periods: from first vaccination through 30 days after last vaccination, and from 30 days after last vaccination through study end. For the period, there were 0 pIMDs reported in both the RZV and placebo groups. Through study end, there were 0/117 (0%) pIMDs reported in the RZV group, and 1/115 (0.9%) reported in the placebo group.

^h. Vink 2020 reported new-onset pIMDs from 30 days after last vaccination to the study end, as is reported in the table above. There were 0 pIMDs reported in either the RZV or placebo group within 0-30 days after last vaccination.

First author last name, Publication year	Age or other characteristic of importance	n/N RZV (%)	n/N comparison group (%)	Comparator	RR (95% CI)*	Study limitations (Risk of Bias)
Dagnew, 2019	Phase III RCT; patients with hematological malignancies ≥18 years old	3/19 (15.8%)a	4/21 (19.0%)a	Placebo	0.83 (0.21, 3.24)	Not serious

Abbreviations: CI = Confidence Interval; RCT = Randomized Controlled Trial; RR = Risk Ratio; RZV = Recombinant Zoster Vaccine

*Risk ratios and Wald confidence intervals were calculated in R and SAS.

^a None of the events was considered related to vaccination by the investigator and most of the events were mild or moderate in intensity.

First author last name, Publication year	Age or other characteristic of importance	n/N RZV (%)	n/N comparator group (%)	Comparator	RR (95% CI)*	Study limitations (Risk of Bias)
Vink, 2020	Phase III RCT; renal transplant patients ≥18 years old	4/132 (3.0%)a,b	7/132 (5.3%)a,b	Placebo	0.57 (0.17, 1.91)	Not serious

Abbreviations: CI = Confidence Interval; HCT = Hematopoietic Cell Transplant; P-Y = Person-Years; RCT = Randomized Controlled Trial; RR = Risk Ratio; RZV = Recombinant Zoster Vaccine; VE = Vaccine Efficacy

*Risk ratios and Wald confidence intervals were calculated in R and SAS.

^a. Renal allograft function and rejections were followed for up to 1 year, reported period for graft rejection is from 30 days after last vaccination until study end.

^b. No episodes of graft rejection were reported in the time interval between the first vaccination up to 30 days after last vaccination (0/132 in both RZV and comparator groups).

First author last name, Publication year	Age or other characteristic of importance	Reaction Type	n/N RZV (%)	n/N comparison (%)	Comparator	RR (95% CI)*	Study limitations (Risk of Bias)
Bastidas, 2019b	Phase III RCT; autologous HCT recipients ≥18 years old	Local	128/901 (14.2%)c	3/892 (0.3%)d	Placebo	42.24 (13.50, 132.21)	Not serious
		Systemic	119/901 (13.2%)e	54/892 (6.0%)f		2.18 (1.60, 2.97)
Berkowitz, 2015	Phase I/II RCT; patients with HIV ≥18 years old	Local	--g	0/48 (0.0%)	Placebo	--	Not serious
		Systemic	--h	--i		--
Dagnew, 2019	Phase III RCT; patients with hematological malignancies ≥18 years old	Local	37/278 (13.3%)	0/274 (0.0%)	Placebo	--	Not serious
		Systemic	43/278 (15.5%)	17/274 (6.2%)		2.49 (1.46, 4.26)
Stadtmauer, 2014	Phase I/II RCT; autologous HCT recipients ≥18 years old	Local	--j	0/30 (0.0%) k	Placebo	--	Not serious
		Systemic	--l	--m		--
Vink, 2019	Phase II/III RCT; solid tumor patients ≥18 years old	Local	13/112 (11.6%)n	0/110 (0.0%)	Placebo	--	Not serious
		Systemic	25/112 (22.3%)o	17/110 (15.5%)p		1.44 (0.83, 2.52)
Vink, 2020	Phase III RCT; renal transplant patients ≥18 years old	Local	14/131 (10.7%)	0/132 (0.0%)	Placebo	--	Not serious

Abbreviations: CI = Confidence Interval; HCT = Hematopoietic Cell Transplant; RCT = Randomized Controlled Trial; RR = Risk Ratio; RZV = Recombinant Zoster Vaccine; VE = Vaccine Efficacy

*Risk ratios and Wald confidence intervals were calculated in R and SAS.

^a. All trials solicited events through electronic diaries for 7 days following each dose. For local reactions, grade 3 was defined as: pain at injection site that prevents normal activity; redness > 10 cm; and swelling > 10 cm. For systemic reactions, grade 3 was defined as: fever >39.0°C; gastrointestinal symptoms, headache, fatigue, shivering, or myalgia that prevents normal activity.

^b. Adverse events were analyzed in the total vaccinated cohort (TVC) which included all participants who received at least 1 dose of vaccine or placebo.

^c. Overall local grade 3 reactions were noted in 128/901 RZV recipients (14.2%). Grade 3 pain was reported in 99/901 (11.0%) RZV recipients, redness in 28/901 (3.1%) RZV recipients, and swelling in 13/901 RZV recipients (1.4%).

^d. Overall local grade 3 reactions were noted in 3/892 placebo recipients (0.3%). Grade 3 pain was reported in 3/892 placebo recipients (0.3%), and grade 3 redness and swelling were reported in 0/892 placebo recipients (0%).

^e. Overall systemic grade 3 reactions were noted in 119/901 (13.2%) RZV recipients. Grade 3 fatigue was reported in 66.901 (7.3%), gastrointestinal symptoms in 18/901 (2.0%), headache in 26/901 (2.9%), myalgia in 56/901 (6.2%), shivering in 35/901 (3.9%), and fever in 3/901 (0.3%) RZV recipients.

^f. Overall systemic grade 3 reactions occurred in 54/892 (6.0%) placebo recipients, with grade 3 fatigue, GI symptoms, headache, myalgia, shivering, and fever occurring in 31/892 (3.5%), 17/892 (1.9%), 10/892 (1.1%), 19/892 (2.1%), 7/892 (0.8%), and 1/892 (0.1%) placebo recipients.

^g. Berkowitz, 2015 did not report overall local and systemic reactions, just symptom-specific. In the RZV group, grade 3 pain was reported in 12/73 (16.4%) RZV recipients, redness in 4/73 (5.5%), and swelling in 1/73 (1.4%).

^h. In the RZV group, grade 3 fatigue was reported in 12/73 (16.4%) RZV recipients, gastrointestinal in 2/73 (2.7%), headache in 6/73 (8.2%), myalgia in 10/73 (13.7%), shivering in 11/73 (15.1%), and fever in 0/73 (0%) RZV recipients.

^i. In the placebo group, grade 3 fatigue was reported in 4/48 (8.3%) recipients, gastrointestinal symptoms in 1/48 (2.1%), headache in 2/48 (4.2%), myalgia in 1/48 (2.1%), and shivering and fever in 0/48 (0%) placebo recipients.

^j. Stadtmauer, 2014 did not report overall local and systemic reactions, just symptom-specific. In the RZV group, two dosing regimens were considered: 3 doses of gE/AS01B, and 2 doses of gE/AS01B with one dose placebo. For the 3-dose regimen, grade 3 pain was reported in 3/30 (10%) recipients, and grade 3 wellness and swelling were reported in 0/30 (0%) recipients. For the 2-dose regimen, grade 3 pain was reported in 1/28 (3.6%) recipients, with grade 3 redness and swelling reported in 0/28 (0%) recipients.

^k. In the placebo group with 3 doses saline, no local reactions were reported (0 reports of pain, redness, and swelling among the 30 recipients).

^l. For the 3-dose regimen: grade 3 fatigue was reported in 4/30 (13.3%), gastrointestinal in 0/30 (0%), headache in 3/30 (10%), myalgia in 8/30 (26.7%), and fever in 1/30 (3.3%). For the 2-dose regimen, fatigue was reported in 1/28 (3.6%), gastrointestinal in 1/28 (3.6%), headache in 0/28 (0%), myalgia in 1/28 (3.6%), and fever in 0/28 (0%).

^m. In the placebo group with 3 doses saline, fatigue was reported in 1/30 (3.3%), and myalgia reported in 1/30 (3.3%) recipients. grade 3 gastrointestinal, headache, and fever were reported in 0/30 (0%) recipients.

^n. Local grade 3 reactions were reported in 13/112 (11.6%) RZV recipients. grade 3 pain was reported in 11/112 (9.8%), redness in 2/112 (1.8%), and swelling in 0/112 (0%) RZV recipients.

^o. Systemic grade 3 reactions were reported in 25/112 (22.3%) RZV recipients, with grade 3 fatigue reported in 16/112 (14.3%), gastrointestinal in 6/112 (5.4%), headache in 6/112 (5.4%), myalgia in 12/112 (10.7%), shivering in 6/112 (5.4%), and fever in 0/112 (0%).

^p. Systemic grade 3 reactions were reported in 17/110 (15.5%) placebo recipients, with grade 3 fatigue reported in 8/110 (7.3%), gastrointestinal in 7/110 (6.4%), headache in 3/110 (2.7%), myalgia in 4/110 (3.6%), shivering in 3/110 (2.7%), and fever in 0/110 (0%).

Certainty Assessment							Number of Patients (%)		Effect
#	Study Design	Risk of Bias	Inconsistency	Indirectness	Imprecision	Other	RZV 2 doses	No vaccine	Relative (95% CI)	Certainty	Importance
Herpes Zoster
5	Randomized Studies	Not serious	Not serious	Serious a	Not serious	None	≥18 yrs: 0% to 5.6% of participants experienced HZ ≥50 yrs: 0.43% to 6.1% of participants experienced HZ	≥18 yrs: 0% to 15.9% of participants experienced HZ ≥50 yrs: 4.12% to 16.6% of participants experienced HZ	≥18 yrs, VE ranged from 68.2% (55.6%,77.5%) to 87.2% (44.3%,98.6%), Stadtmauer reported RR of 0* ≥50 yrs, VE ranged from 67% (53%,78%)** to 90.5% (73.5%,97.5%)	Type 2 Moderate	CRITICAL
6	Randomized Studies - Immunogenicity	Not serious	Not serious b	Very serious c	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 cell mediated VRR ranged from 0% to 16.7%	Humoral adjusted GMR ranged from 14.00 (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	Non-Randomized Studies	Not serious d	Not serious e	Serious f	Not serious	Strong association g	≥65 yrs, AI condition: 167/61,999 (0.27%) experienced HZ ≥65 yrs, IC condition: 143/40442 (0.35%) experienced HZ 50-60 yrs: 0/655 (0.0%) experienced HZ >60 yrs: 8/4220 (0.19%) experienced HZ	≥65 yrs, AI condition: 20,640/ 886,123 (2.33%) experienced HZ ≥65 yrs, IC condition: 18,504/746,654 (2.48%) experienced HZ 50-60 yrs: 69/5,995 (1.15%) experienced HZ >60 yrs: 268/20,554 (1.30%) experienced HZ	≥65 yrs, AI condition: VE was 68.0% (62.3%, 72.8%) ≥65 yrs, IC condition: VE was 64.1% (57.2%, 69.8%) 50-60 yrs, HR was 0; >60 yrs, HR was 0.39 (0.19,0.80)	Type 3 Low
Serious Adverse Events
7	Randomized Studies	Not serious b	Not serious	Serious h	Not serious	None	SAEs ranged from 6/74 (8.1%) to 46/117 (39.3%)	SAEs ranged from 2/49 (4.1%) to 45/115 (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
Postherpetic Neuralgia
1	Randomized Studies	Not serious	Not serious i	Serious j	Serious k	None	1/49 (2.0%)	9/135 (6.7%)	VE: 89% (22%,100%)	Type 3 Low	IMPORTANT
Herpes Zoster-Related Hospitalizations
1	Randomized Studies	Not serious	Not serious i	Serious j	Serious k	None	2/49 (4.08%)	13/135 (9.63%)	VE: 85% (32%,97%)	Type 3 Low	IMPORTANT
Immune-Mediated Disease
6	Randomized Studies	Not serious	Serious l	Serious m	Serious n	None	Not specified IMD ranged from 0.0% (0/61 and 0/117) to 13/922 (1.4%) New onset IMD ranged from 16/893 (1.6%) to 4/132 (3.0%) Exacerbations of existing IMD occurred in 27/983 (2.8%) participants	Not specified IMD ranged from 0% (0/30) to 0.9% (1/115, 8/924) New onset IMD ranged from 2/132 (1.5%) to 23/960 (2.4%) Exacerbations of existing IMD occurred in 27/960 (2.8%) participants	Not specified IMD: RR ranged from 0 (0, NA) to 1.63 (0.68, 3.91) * New onset IMD: RR ranged from 0.68 (0.36, 1.28) to 2.0 (0.37, 10.73) * Exacerbations: RR reported as 0.98 (0.58, 1.65) *	Type 4 Very Low	IMPORTANT
Graft-Versus-Host-Disease
1	Randomized Studies	Not serious	Not serious i	Serious o	Very Serious p	None	3/19 (15.8%)	4/21 (19.0%)	0.83 (0.21, 3.24) *	Type 4 Very Low	IMPORTANT
Graft Rejection
1	Randomized Studies	Not serious	Not serious i	Serious q	Serious r	None	4/132 (3.0%)	7/132 (5.3%)	0.57 (0.17, 1.91) *	Type 3 Low	IMPORTANT
Reactogenicity (grade 3)
6	Randomized Studies	Not serious	Not serious s	Serious t	Not serious	None	Local grade 3 reactions ranged from 3/30 (10.0%) to 128/901 (14.2%) Systemic grade 3 reactions ranged from 13/131 (9.9%) to 25/112 (22.3%)	Local grade 3 reactions ranged from 0/274 (0%) to 3/892 (0.3%) Systemic grade 3 reactions ranged from 54/892 (6.0%) to 17/110 (15.5%)	Local grade 3 reactions: RR ranged from unevaluable to 42.24 (13.50, 132.21) * Systemic grade 3 reactions: RR ranged from 1.19 (0.55, 2.56) to 2.49 (1.46, 4.26) *	Type 2 Moderate	IMPORTANT

Abbreviations: AI = Autoimmune; CI = Confidence Interval; IC = Immunocompromised; IMD = Immune-Mediated Disease; HR = Hazard Ratio; HCT = Hematopoietic Cell Transplant; HZ = Herpes Zoster; RCT = Randomized Controlled Trial; RR = Risk Ratio; RZV = Recombinant Zoster Vaccine; VE = Vaccine Efficacy; VRR = Vaccine Response Rate

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

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

^a. These 5 RCTs cover a wide range of populations: autologous HCT recipients, patients with HIV, patients with hematologic malignancies, and patients with pIMDs. Due to these different subgroups with different underlying conditions, this body of evidence covers some, but not all the populations being considered for the recommendation, resulting in a downgrade (-1) for indirectness, as these subpopulations may have different baseline risks, and the intervention may have a different effect in these subpopulations.

^b. Risk of bias related to blinding of participants and personnel may have been present. Although participants and study staff were blinded to intervention assignments, they may have inferred receipt of vaccine or placebo based on reactogenicity. This was deemed unlikely to overestimate efficacy or underestimate risk of serious adverse events, therefore the risk of bias was rated as not serious.

^c. 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 autologous HCT patients, patients with HIV, patients with hematological malignancies, patients with solid tumors, and renal transplant recipients. These different subgroups represent some, but not all the subgroups under consideration for the population for this 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. Thus, this body of evidence is doubly downgraded.

^d. The two included cohort studies were both determined to have serious risk of bias, the first (using Medicare claims data) presents with significant confounding concerns, with no demographics or risk factors presented for the immune-compromised and autoimmune populations. The second was a VA-based study, which utilized retrospective case ascertainment and had a non-generalizable population, considered to be moderate/high risk of bias. However, this bias is already included in the initial downgrade of evidence to type 3 for non-randomized study data, thus there is no further need for a downgrade for risk of bias.

^e. The two cohort studies resulted in different VE estimates: with the first reporting VE in the autoimmune population of 68.0% (95% CI: 62.3% - 72.8%), and 64.1% (95% CI: 57.2% - 69.8%) in the immune-compromised population. The second study found no reported cases in the 50–60-year age group, corresponding to a VE of 100%, and in those aged >60 years, a HR of 0.41 (95% CI: 0.19-0.87) for those not using steroids, corresponding to an approximate VE of 59%, and for those using steroids: an HR of 0.34 (95% CI: 0.05-2.44), corresponding to a VE of 66%. While these results represent different age groups (65+ for the first study, and 50+ for the second study), the effect estimates are not very heterogeneous, and thus not downgraded for inconsistency.

^f. The two included cohort studies assessed incidence of HZ in different patient populations: the first in autoimmune/immunocompromised patients enrolled in Medicare, and the second in IBD patients in the VA Health System. These patient populations represent different subgroups of the overall population being considered for this recommendation and do not represent the entire range of conditions; thus the evidence is downgraded for indirectness (-1).

^g. Both studies reported a strong association, with the VE or 64.1% in IC patients and 68% in AI patients, and VE of 100% in 50–60-year-olds with IBD in the VA study, and VE of 59% in non-steroid users and 66% in steroid users over the age of 60. Thus, this body of evidence was upgraded (+1)  level due to strength of association.

^h. 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 included populations included: autologous HSCT recipients, patients with HIV, patients with hematologic malignancies, patients with pIMDs, patients with solid tumors receiving cytotoxic or immunosuppressive therapy, and renal transplant patients on daily immunosuppression. The wide variety of patient sub-populations results in a downgrade for indirectness (-1).

^i. This outcome has data from only a single study, and thus cannot downgrade for inconsistency.

^j. This outcome only has data in autologous HCT patients, which does not cover the entire recommended patient population for which a recommendation is being considered. Thus, this study is downgraded (-1) for indirectness.

^k. The total population among the RZV and placebo group in the modified total vaccinated cohort is 184, in which only 10 events of PHN were observed and 15 hospitalizations were observed. Given a corresponding relative risk reduction of 11% (VE 89%) with wide confidence intervals for PHN and 15% with wide confidence intervals for HZ-related hospitalization, this does not meet the threshold for the optimal information size and is thus downgraded (-1) for imprecision.

^l. These results were downgraded (-1) for inconsistency because the calculated risk ratio of pIMDs varied substantially by study: ranging from 0 to 2.00 for unspecified immune-mediated diseases, with additionally different values for exacerbations and new-onset pIMDs.

^m. These studies cover a wide range of populations: solid tumor patients, renal transplant recipients, hematologic malignancies, and patients with pIMDs originally enrolled into the ZOE-50 and ZOE-70 trials. Due to these different subgroups with different underlying conditions, this body of evidence covers some, but not all the populations being considered for the recommendation, resulting in a downgrade (-1) for indirectness

^n. These results were downgraded for imprecision (-1) due to wide confidence intervals crossing the threshold of both harm and benefit.

^o. This outcome only has data in patients with hematological malignancy, which does not cover the entire recommended patient population for which graft-versus-host-disease is a potential harm. Thus, this study is downgraded (-1) for indirectness.

^p. These results were doubly downgraded for imprecision (-2) due to not meeting the optimal information size, with only 7 total events occurring out of 40 total patients and wide confidence intervals crossing the harm/benefit threshold.

^q. This outcome only has data in renal transplant patients, which does not cover the entire patient population for which graft rejection is a potential harm (i.e. other solid organ transplants). Thus, this study is downgraded (-1) for indirectness.

^r. These results were downgraded for imprecision (-1) due to not meeting the optimal information size, and wide confidence intervals crossing the harm/benefit threshold.

^s. Solicited injection site reactions occurred in 14.2% of patients in Bastidas 2019, with solicited systemic reactions occurring in 13.2% of patients. The most common injection-site reaction was pain (11%) and the most common systemic reactions were fatigue (7.3%) and myalgia (6.2%). In Dagnew 2019, solicited injection site reactions occurred in 13.3% of patients, and systemic occurred in 15.5% of patients. In Stadtmauer 2014, local reactions occurred in 10% of patients, and systemic in 26.7% of patients (most commonly fatigue and myalgia). In Vink 2019, solicited local symptoms occurred in 11.6% of patients, most commonly pain (9.8%), and systemic symptoms in 22.3% of patients (most commonly fatigue (14.3%) and myalgia (10.7%). In Vink 2020, local grade 3 reactions occurred in 10.7% of patients, with systemic reactions occurring in 9.9% of patients. Overall, these results were quite consistent and thus were not downgraded for inconsistency, despite occurring across a broad set of population subgroups.

^t. These studies cover a wide range of populations: solid tumor patients, renal transplant recipients, hematologic malignancies, and autologous HCT recipients. Due to these different subgroups with different underlying conditions, this body of evidence covers some, but not all the populations being considered for the recommendation, resulting in a downgrade (-1) for indirectness.

Outcome	Importance	Included in profile	Certainty
Benefits
Prevention of herpes zoster	Critical	Yes	Type 2
Prevention of postherpetic neuralgia	Important	Yes	Type 3
Prevention of herpes zoster-related hospitalizations	Important	Yes	Type 3
Harms
Serious adverse events	Critical	Yes	Type 2
Immune-mediated disease	Important	Yes	Type 4
Graft-versus-host-disease (HCT)a	Important	Yes	Type 4
Graft rejection (SOT)b	Important	Yes	Type 3
Reactogenicity (grade 3)	Important	Yes	Type 2

^a. HCT = Hematopoietic cell transplant

^b. SOT = Solid organ transplant

First author last name, Publication year	Study Design	Country	Study Population	N Intervention	N Comparison	Outcomes	Funding Source	Reason for Exclusion from GRADE
Barghash, 2020	Retrospective chart review	United States	Heart transplant recipients	1 dose: 65 2 doses: 46	0 (No comparison group)	Reactogenicity of RZV Efficacy of RZV in preventing HZ Efficacy of RZV in preventing PHN	No funding disclosed	No comparison group
Baumrin, 2021	Cohort study	United States	Allogeneic HCT recipients ≥18 years old	1 dose: 157 2 dose: 144	0 (No comparison group for safety, reactogenicity, or incidence of HZ) Not listed (for GVHD, historical controls)	SAEs Reactogenicity Incidence of HZ Graft-versus-host-disease	No funding disclosed	No comparison group or historical comparison group without counts.
Camargo, 2020	Retrospective single-center study	United States	Adult allogeneic and autologous HCT recipients	30	0 (No comparison group)	Immunogenicity	NIH	No comparison group
Hirzel, 2021	NRES	Canada	Lung transplant recipients ≥50 years old	1 dose: 49 2 doses: 45	0 (No comparison group)	Immunogenicity of RZV	Multi-organ Transplant Program, Swiss National Science Foundation	No comparison group
Kochhar, 2021	Cohort study	United States	Patients with IBD ≥50 years old	1,180	94,540	Efficacy of RZV for preventing HZ in patients with IBD	No funding disclosed	VE reported only as odds ratio (OR) no counts available for HZ.
Lenfant, 2021	Retrospective chart review	United States	Patients with immune-mediated inflammatory diseases ≥18 years old	1 dose: 359 2 doses: 263	0 (No comparison group)	Incidence of disease flare after RZV Adverse events after RZV Efficacy of RZV in preventing HZ	No financial support	No comparison group
L'Huillier, 2021	NRES	Canada	Solid Organ transplant recipients ≥ 18 years old	23	0 (No comparison group)	Humoral immunogenicity of RZV Rate of vaccine-related adverse events	University Health Network Ajmera Transplant Centre	No comparison group
Pleyer, 2021	NRES	United States	CLL patients who are treatment naive or receiving BTK-Inhibitors ≥18 years old	63	0 (No comparison group)	Response to RZV in untreated CLL and CLL patients treated with BTK-inhibitors Safety and tolerability of RZV in all CLL patients	NIH National Heart, Lung, and Blood Institute, NIAID	No comparison group
Satyam, 2020	Prospective observational study	United States	Patients with IBD: Crohn's Disease or Ulcerative Colitis	67	(No comparison group)	Rate of Disease Flare after RZV Rate of local and systemic adverse events after RZV	No financial support	No comparison group
Stevens, 2020	Retrospective chart review	United States	Rheumatoid Arthritis and other systemic rheumatic disease patients	1 dose: 403 2 doses: 222	0 (No comparison group)	Incidence of disease flare after RZV Incidence of side effects after RZV	Amgen, BMS, Eli Lilly, Crescendo Bioscience, Sanofi	No comparison group

Abbreviations: BMS = Bristol Myers Squibb; CLL = Chronic Lymphoblastic Leukemia; HCT = Hematopoietic Cell Transplant; IBD = Inflammatory Bowel Disease; NIAID = National Institutes of Allergy and Infectious Disease; NIH = National Institutes of Health; NRES = Non-Randomized Experimental Study; RZV = Recombinant Zoster Vaccine

Database	Strategy	Records
Medline (OVID) 1946-	((herpes-zoster OR varicella-zoster OR zoster OR shingles OR zona) ADJ5 vaccin*) OR ((herpes-zoster OR HZ OR varicella-zoster OR zoster) ADJ5 subunit) OR HZ su OR Shingrix OR RZV OR GSK 1437173A AND ( Exp immune system diseases/ OR exp Hematologic Diseases/ OR exp Neoplasms/ OR exp Stem Cell Transplantation/ OR Immunocompromised host/ OR immune system diseases/ OR exp Immune System Phenomena/ OR exp Tissue Transplantation/ OR exp HIV infections/ OR Transplant Recipients/ OR exp Organ Transplantation/ OR Comorbidity/ OR exp inflammatory bowel diseases/ OR exp Psoriasis/ OR asthma/ OR exp vitamin D/ OR Disease Susceptibility/ OR exp Rheumatic Diseases/ OR ((immun* ADJ5 (compromise* OR deficien* OR suppress* OR weak* OR competen* OR incompeten* OR respons* OR reduc* OR disorder* OR inhibit* OR therap* OR dysfunction OR function)) OR immune system* OR (immun* ADJ2 disease*) OR (immun* ADJ2 toleran*) OR immunocompromis* OR immuno-compromis* OR immunosuppress* OR immuno-suppress* OR immunodeficien* OR immuno-deficien* OR immunopatholog* OR auto-immun* OR autoimmun* OR Adverse event* OR adverse reaction* OR adverse effect* OR transplant* OR organ recipient* OR solid-organ recipient* OR (hemato* ADJ5 disease*) OR leukemia* OR lymphoma* OR Hodgkin* OR Non-Hodgkin* OR Myeloma* OR neoplasm* OR cancer* OR malignanc* OR tumor* OR HIV* OR AIDs OR inflammatory OR IBD OR crohn* OR colitis OR psoriasis OR autoinflammatory OR rheumat* OR arthriti* OR AIIRDs OR diabet* OR comorbidit* OR lupus OR SLE OR spondyl* OR asthma* OR Disease Susceptibility OR opportunistic infection* OR chemotherap* OR radiation OR radiotherap* OR hypogammaglobulinemia OR immunoglobulin deficiencies OR Macroglobulinemia OR glomerul*) OR (exp immunosuppressive agents/ OR exp antirheumatic agents/ OR exp Antibodies, Monoclonal/ OR (Glucocorticoid* OR Corticosteroid* OR Glucocorticosteroid* OR antirheumatic drug* OR antirheumatic agent* OR anti-inflammator* OR DMARDS OR Methotrexate OR MTX OR Azathioprine OR mercaptopurine OR Sulfasalazine OR leflunomide OR hydroxychloroquine OR azathioprine OR Aminosalicylates OR 5-aminosalicylic acid OR 5-ASA OR Mesalamine OR Sulfasalazine OR Balsalazide OR monoclonal antibod* OR mono-clonal antibod* OR TNF inhibitors OR TNFi OR TNF alpha OR tumor necrosis factor OR anti-TNF infliximab OR etanercept OR adalimumab OR certolizumab OR golimumab OR abatacept OR tocilizumab OR sarilumab OR rituximab OR secukinumab OR ixekizumab OR belimumab OR anakinra OR canakinumab OR apremilast OR phosphodiesterase inhibitor* OR PDE4 OR Ustekinumab OR guselkumab OR Vedolizumab OR Natalizumab OR tofacitinib OR baricitinib OR Mycophenolic acid OR MPA OR Mycophenolate OR Calcineurin inhibitor* OR cyclosporine OR tacrolimus OR Alkylating agent OR cyclophosphamide)) ) NOT Exp Animals/ NOT exp humans/ 2010 -	732
Embase (OVID) 1988-	((herpes-zoster OR varicella-zoster OR zoster OR shingles OR zona) ADJ5 vaccin*) OR ((herpes-zoster OR HZ OR varicella-zoster OR zoster) ADJ5 subunit) OR HZ su OR Shingrix OR RZV OR GSK 1437173A AND ( Exp immunopathology/ OR exp Hematologic Disease/ OR exp Neoplasm/ OR exp Stem Cell Transplantation/ OR Immunocompromised patient/ OR exp Tissue Transplantation/ OR exp human immunodeficiency virus infection/ OR graft Recipient/ OR exp Organ Transplantation/ OR Comorbidity/ OR exp inflammatory bowel disease/ OR exp Psoriasis/ OR asthma/ OR exp vitamin D/ OR Disease predisposition/ OR exp Rheumatic Disease/ OR ((immun* ADJ5 (compromise* OR deficien* OR suppress* OR weak* OR competen* OR incompeten* OR respons* OR reduc* OR disorder* OR inhibit* OR therap* OR dysfunction OR function)) OR immune system* OR (immun* ADJ2 disease*) OR (immun* ADJ2 toleran*) OR immunocompromis* OR immuno-compromis* OR immunosuppress* OR immuno-suppress* OR immunodeficien* OR immuno-deficien* OR immunopatholog* OR auto-immun* OR autoimmun* OR Adverse event* OR adverse reaction* OR adverse effect* OR transplant* OR organ recipient* OR solid-organ recipient* OR (hemato* ADJ5 disease*) OR leukemia* OR lymphoma* OR Hodgkin* OR Non-Hodgkin* OR Myeloma* OR neoplasm* OR cancer* OR malignanc* OR tumor* OR HIV* OR AIDs OR inflammatory OR IBD OR crohn* OR colitis OR psoriasis OR autoinflammatory OR rheumat* OR arthriti* OR AIIRDs OR diabet* OR comorbidit* OR lupus OR SLE OR spondyl* OR asthma* OR Disease Susceptibility OR opportunistic infection* OR chemotherap* OR radiation OR radiotherap* OR hypogammaglobulinemia OR immunoglobulin deficiencies OR Macroglobulinemia OR glomerul*) OR (exp immunosuppressive agent/ OR exp antirheumatic agent/ OR exp Monoclonal antibody/ OR (Glucocorticoid* OR Corticosteroid* OR Glucocorticosteroid* OR antirheumatic drug* OR antirheumatic agent* OR anti-inflammator* OR DMARDS OR Methotrexate OR MTX OR Azathioprine OR mercaptopurine OR Sulfasalazine OR leflunomide OR hydroxychloroquine OR azathioprine OR Aminosalicylates OR 5-aminosalicylic acid OR 5-ASA OR Mesalamine OR Sulfasalazine OR Balsalazide OR monoclonal antibod* OR mono-clonal antibod* OR TNF inhibitors OR TNFi OR TNF alpha OR tumor necrosis factor OR anti-TNF infliximab OR etanercept OR adalimumab OR certolizumab OR golimumab OR abatacept OR tocilizumab OR sarilumab OR rituximab OR secukinumab OR ixekizumab OR belimumab OR anakinra OR canakinumab OR apremilast OR phosphodiesterase inhibitor* OR PDE4 OR Ustekinumab OR guselkumab OR Vedolizumab OR Natalizumab OR tofacitinib OR baricitinib OR Mycophenolic acid OR MPA OR Mycophenolate OR Calcineurin inhibitor* OR cyclosporine OR tacrolimus OR Alkylating agent OR cyclophosphamide)) ) NOT Exp Animal/ NOT exp human/ 2010 - ; not pubmed/medline	1802 -505 duplicates 1297 unique items
Cochrane Library	[mh "herpes zoster vaccine"] OR (((herpes-zoster OR varicella-zoster OR zoster OR shingles OR zona) NEAR/5 vaccin*) OR ((herpes-zoster OR HZ OR varicella-zoster OR zoster) NEAR/5 subunit) OR "HZ su" OR Shingrix OR RZV OR "GSK 1437173A"):ti,ab AND ( [mh "Immunologic Diseases"] OR [mh "Hematologic Diseases"] OR [mh "Neoplasms"] OR [mh "Cell Transplantation"] OR [mh "Immunocompromised Host"] OR [mh "Autoimmune Diseases of the Nervous System"] OR [mh "Tissue Transplantation"] OR [mh "HIV Infections"] OR [mh "Transplant Recipients"] OR [mh "Organ Transplantation"] OR [mh "Comorbidity"] OR [mh "Inflammatory Bowel Diseases"] OR [mh Psoriasis] OR [mh "Asthma"] OR [mh "Vitamin D"] OR [mh "Disease Susceptibility"] OR [mh "Rheumatic Diseases"] OR ((immun* NEAR/5 (compromise* OR deficien* OR suppress* OR weak* OR competen* OR incompeten* OR respons* OR reduc* OR disorder* OR inhibit* OR therap* OR dysfunction OR function)) OR "immune system*" OR (immun* NEAR/2 disease*) OR (immun* NEAR/2 toleran*) OR immunocompromis* OR immuno-compromis* OR immunosuppress* OR immuno-suppress* OR immunodeficien* OR immuno-deficien* OR immunopatholog* OR auto-immun* OR autoimmun* OR "Adverse event*" OR "adverse reaction*" OR "adverse effect*" OR transplant* OR "organ recipient*" OR "solid-organ recipient*" OR (hemato* NEAR/5 disease*) OR leukemia* OR lymphoma* OR Hodgkin* OR Non-Hodgkin* OR Myeloma* OR neoplasm* OR cancer* OR malignanc* OR tumor* OR HIV* OR AIDs OR inflammatory OR IBD OR crohn* OR colitis OR psoriasis OR autoinflammatory OR rheumat* OR arthriti* OR AIIRDs OR diabet* OR comorbidit* OR lupus OR SLE OR spondyl* OR asthma* OR "Disease Susceptibility" OR "opportunistic infection*" OR chemotherap* OR radiation OR radiotherap* OR hypogammaglobulinemia OR "immunoglobulin deficiencies" OR Macroglobulinemia OR glomerul*):ti,ab OR [mh "Immunosuppressive Agents"] OR [mh "Antirheumatic Agents"] OR [mh "Antibodies, Monoclonal"] OR (Glucocorticoid* OR Corticosteroid* OR Glucocorticosteroid* OR "antirheumatic drug*" OR "antirheumatic agent*" OR anti-inflammator* OR DMARDS OR Methotrexate OR MTX OR Azathioprine OR mercaptopurine OR Sulfasalazine OR leflunomide OR hydroxychloroquine OR azathioprine OR Aminosalicylates OR "5-aminosalicylic acid" OR 5-ASA OR Mesalamine OR Sulfasalazine OR Balsalazide OR "monoclonal antibod*" OR "mono-clonal antibod*" OR "TNF inhibitors" OR TNFi OR "TNF alpha" OR "tumor necrosis factor" OR "anti-TNF infliximab" OR etanercept OR adalimumab OR certolizumab OR golimumab OR abatacept OR tocilizumab OR sarilumab OR rituximab OR secukinumab OR ixekizumab OR belimumab OR anakinra OR canakinumab OR apremilast OR "phosphodiesterase inhibitor*" OR PDE4 OR Ustekinumab OR guselkumab OR Vedolizumab OR Natalizumab OR tofacitinib OR baricitinib OR "Mycophenolic acid" OR MPA OR Mycophenolate OR "Calcineurin inhibitor*" OR cyclosporine OR tacrolimus OR "Alkylating agent" OR cyclophosphamide):ti,ab )	167 -103 duplicates 64 unique items
CINAHL (EbscoHost)	(((herpes-zoster OR varicella-zoster OR zoster OR shingles OR zona) N5 vaccin*) OR ((herpes-zoster OR HZ OR varicella-zoster OR zoster) N5 subunit) OR "HZ su" OR Shingrix OR RZV OR "GSK 1437173A") AND ( (MH "Immunologic Diseases+") OR (MH "Hematologic Diseases+") OR (MH "Neoplasms+") OR (MH "Cell Transplantation+") OR (MH "Immunocompromised Host") OR (MH "Autoimmune Diseases of the Nervous System+") OR (MH "Tissue Transplantation+") OR (MH "HIV Infections+") OR (MH "Transplant Recipients") OR (MH "Organ Transplantation+") OR (MH "Comorbidity") OR (MH "Inflammatory Bowel Diseases+") OR (MH "Psoriasis") OR (MH "Asthma+") OR (MH "Vitamin D") OR (MH "Disease Susceptibility") OR (MH "Rheumatic Diseases+") OR ((immun* N5 (compromise* OR deficien* OR suppress* OR weak* OR competen* OR incompeten* OR respons* OR reduc* OR disorder* OR inhibit* OR therap* OR dysfunction OR function)) OR "immune system*" OR (immun* N2 disease*) OR (immun* N2 toleran*) OR immunocompromis* OR immuno-compromis* OR immunosuppress* OR immuno-suppress* OR immunodeficien* OR immuno-deficien* OR immunopatholog* OR auto-immun* OR autoimmun* OR "Adverse event*" OR "adverse reaction*" OR "adverse effect*" OR transplant* OR "organ recipient*" OR "solid-organ recipient*" OR (hemato* N5 disease*) OR leukemia* OR lymphoma* OR Hodgkin* OR Non-Hodgkin* OR Myeloma* OR neoplasm* OR cancer* OR malignanc* OR tumor* OR HIV* OR AIDs OR inflammatory OR IBD OR crohn* OR colitis OR psoriasis OR autoinflammatory OR rheumat* OR arthriti* OR AIIRDs OR diabet* OR comorbidit* OR lupus OR SLE OR spondyl* OR asthma* OR "Disease Susceptibility" OR "opportunistic infection*" OR chemotherap* OR radiation OR radiotherap* OR hypogammaglobulinemia OR "immunoglobulin deficiencies" OR Macroglobulinemia OR glomerul*) OR ((MH "Immunosuppressive Agents+") OR (MH "Antirheumatic Agents+") OR (MH "Antibodies, Monoclonal+") OR (Glucocorticoid* OR Corticosteroid* OR Glucocorticosteroid* OR "antirheumatic drug*" OR "antirheumatic agent*" OR anti-inflammator* OR DMARDS OR Methotrexate OR MTX OR Azathioprine OR mercaptopurine OR Sulfasalazine OR leflunomide OR hydroxychloroquine OR azathioprine OR Aminosalicylates OR "5-aminosalicylic acid" OR 5-ASA OR Mesalamine OR Sulfasalazine OR Balsalazide OR "monoclonal antibod*" OR "mono-clonal antibod*" OR "TNF inhibitors" OR TNFi OR "TNF alpha" OR "tumor necrosis factor" OR "anti-TNF infliximab" OR etanercept OR adalimumab OR certolizumab OR golimumab OR abatacept OR tocilizumab OR sarilumab OR rituximab OR secukinumab OR ixekizumab OR belimumab OR anakinra OR canakinumab OR apremilast OR "phosphodiesterase inhibitor*" OR PDE4 OR Ustekinumab OR guselkumab OR Vedolizumab OR Natalizumab OR tofacitinib OR baricitinib OR "Mycophenolic acid" OR MPA OR Mycophenolate OR "Calcineurin inhibitor*" OR cyclosporine OR tacrolimus OR "Alkylating agent" OR cyclophosphamide)) ) NOT ((MH Animals+) NOT (MH Humans+)) 2010 - ; exclude Medline records	258 -106 duplicates 152 unique items
Scopus	TITLE-ABS-KEY(((herpes-zoster OR varicella-zoster OR zoster OR shingles OR zona) W/5 vaccin*) OR ((herpes-zoster OR HZ OR varicella-zoster OR zoster) W/5 subunit) OR "HZ su" OR Shingrix OR RZV OR "GSK 1437173A") AND TITLE-ABS-KEY((immun* W/5 (compromise* OR deficien* OR suppress* OR weak* OR competen* OR incompeten* OR respons* OR reduc* OR disorder* OR inhibit* OR therap* OR dysfunction OR function)) OR "immune system*" OR (immun* W/2 disease*) OR (immun* W/2 toleran*) OR immunocompromis* OR immuno-compromis* OR immunosuppress* OR immuno-suppress* OR immunodeficien* OR immuno-deficien* OR immunopatholog* OR auto-immun* OR autoimmun* OR "Adverse event*" OR "adverse reaction*" OR "adverse effect*" OR transplant* OR "organ recipient*" OR "solid-organ recipient*" OR (hemato* W/5 disease*) OR leukemia* OR lymphoma* OR Hodgkin* OR Non-Hodgkin* OR Myeloma* OR neoplasm* OR cancer* OR malignanc* OR tumor* OR HIV* OR AIDs OR inflammatory OR IBD OR crohn* OR colitis OR psoriasis OR autoinflammatory OR rheumat* OR arthriti* OR AIIRDs OR diabet* OR comorbidit* OR lupus OR SLE OR spondyl* OR asthma* OR "Disease Susceptibility" OR "opportunistic infection*" OR chemotherap* OR radiation OR radiotherap* OR hypogammaglobulinemia OR "immunoglobulin deficiencies" OR Macroglobulinemia OR glomerul* OR Glucocorticoid* OR Corticosteroid* OR Glucocorticosteroid* OR "antirheumatic drug*" OR "antirheumatic agent*" OR anti-inflammator* OR DMARDS OR Methotrexate OR MTX OR Azathioprine OR mercaptopurine OR Sulfasalazine OR leflunomide OR hydroxychloroquine OR azathioprine OR Aminosalicylates OR "5-aminosalicylic acid" OR 5-ASA OR Mesalamine OR Sulfasalazine OR Balsalazide OR "monoclonal antibod*" OR "mono-clonal antibod*" OR "TNF inhibitors" OR TNFi OR "TNF alpha" OR "tumor necrosis factor" OR "anti-TNF infliximab" OR etanercept OR adalimumab OR certolizumab OR golimumab OR abatacept OR tocilizumab OR sarilumab OR rituximab OR secukinumab OR ixekizumab OR belimumab OR anakinra OR canakinumab OR apremilast OR "phosphodiesterase inhibitor*" OR PDE4 OR Ustekinumab OR guselkumab OR Vedolizumab OR Natalizumab OR tofacitinib OR baricitinib OR "Mycophenolic acid" OR MPA OR Mycophenolate OR "Calcineurin inhibitor*" OR cyclosporine OR tacrolimus OR "Alkylating agent" OR cyclophosphamide) AND NOT INDEX(medline)	331 -264 duplicates 67 unique items
Sclinicaltrials.gov	vaccine OR vaccines OR immunization OR shingrix OR HZ/su OR "GSK 1437173A" OR subunit| herpes-zoster OR shingles OR zona OR zoster | Adult, Older Adult | First posted from 01/01/2010 to 04/28/2021	108 -14 duplicates 94 unique items