Immunogenicity and safety of live attenuated and recombinant/inactivated varicella zoster vaccines in people living with HIV: A systematic review

Figures & data

Figure 1. Adapted PRISMA 2020 Flow Diagram.

Table 1. Characteristics of included studies.

Source	Vaccine	Trial arms	Geographical area	Study design	Patient number	Patient age Median (IQR)	% female	Endpoints of data collection	Ref
Berkowitz et al., 2015	Subunit HZ vaccine (GlaxoSmith Kline)	3 doses or saline	Germany, USA, UK	RCT	74	46 (23–74)	5/74 (6.8)	At different point times after 3 doses	45
Weinberg et al., 2010	Varivax (Oka, Merck)	2 doses or placebo	USA	NRCT	33	46 (IQR NA)	12/33 (36.3)	12 weeks after 2 doses	46
Nalvakele et al., 2017	Live-attenuated VZV (Oka)	1 dose	USA	Case report	1	31	0	1 month after 1 dose	52
Mullane et al., 2013	Heat-treated ZV vaccine (ZVHT)	4 doses or placebo	USA	RCT	60	45 (IQR NA)	NA	28 days after 4 doses	43
Benson et al., 2018	Live-attenuated ZV (Oka, Merck)	2 doses or placebo	USA	RCT	296	49 (44–46)	44/296 (14.8)	6 weeks after 2 doses	44
Maves et al., 2014	Varivax (Oka – Merck)	2 doses	South Asia	Case report	1	23	0	4 days after 2 doses	53
Su et al., 2018	Live-attenuated VZV (not specified)	NA	USA	Retrospective study	29	>19	NA	NA	54
Levin et al., 2006	Live-attenuated VZV (Oka, Merck)	2 doses	USA	Prospective study	97	5.1 (NA)	56/97 (57.7)	At different point times after 2 doses	12
Su et al., 2018	Live-attenuated VZV (not specified	NA	USA	Retrospective study	12	<19	NA	NA	54
Taweesith et al., 2011	Live-attenuated VZV (Okavax,Sanofi)	2 doses	Bangkok, Thailand	NRCT	60	11.2 (8.5–12.8)	34/60 (56.6)	24 weeks after 2 doses	47
Bekker et al., 2006	Live-attenuated VZV (Varilrix; GlaxoSmithKline)	2 doses	Amsterdam, Netherlands	NRCT	15	8.3 (4.3–11.7)	7/15 (47%)	6 weeks after 2 doses	48
Armenian et al., 2006	Live-attenuated VZV (Varivax, Merck)	1 dose	USA	Prospective study	10	4.5 (IQR NA)	NA	At different point times after 1 dose	49
Gershon et al., 2009	Live-attenuated VZV (Oka, Merck)	2 doses	USA	NRCT	10	9.3 (IQR NA)	NA	At different point times after 1 dose	50
Purswani et al., 2016	Live-attenuated VZV (not specified)	≥3 doses	USA	Prospective study	432	8.0 (4.2, 11.9)	231/432 (53.4)	At different point times after ≥ 3 doses	51

RCT, randomized clinical study; NRCT, not randomized clinical study; NA, not available.

Table 2. Demographic and clinical characteristics of all populations, type of vaccines and geographical areas of the included studies.

Type of research studies
Total	13
Adults, n (%)	6 (46.1)
Pediatrics, n (%)	7 (53.8)
Adults and Pediatrics, n (%)	1 (7.7)
USA, n (%)	9 (69.2)
Asia, n (%)	2 (15.4)
Europe, n (%)	2 (15.4)
Number of patients
Total adults	482
Male, n (%)	344 (71.4)
Female, n (%)	61 (12.7)
Not Available, n (%)	77 (16)
Age (min)	≥18
Total children	509
Male, n (%)	83 (16.3)
Female, n (%)	89 (17.5)
Not Available, n (%)	337 (66.2)
Age (range min-max)	1–17 y.o. (<19 y.o. for 1 study)
Vaccine type
Total adults	482
Varivax Oka/Merck, (1 dose)*, n (%)	2 (0.4)
Varivax Oka (1 dose)**, n (%)	1 (0.2)
Varivax Oka/Merck (2 doses)*, n (%)	31 (6.4)
Varivax Oka/Merck, (2 doses)**, n (%)	1 (0.2)
Live attenuated VZV (Not Available), n (%)	8 (1.7)
HZ/su, GSK (3 doses)*, n (%)	74 (15.4)
Zostavax Oka/Merk (2 doses)*, n (%)	296 (61.4)
Live attenuated VZV (Not Available),* n (%)	9 (1.9)
ZVHT* (1–4 doses), n (%)	60 (12.4)
Total children	509
Varivax Merck, (1 dose)** n (%)	10 (2)
Oka/Merck,(2 doses)**, n (%)	97 (19.1)
Okavax Sanofi, (2 doses)**, n (%)	60 (11.8)
Varilix GSK (2 doses)**, n (%)	15 (2.9)
Oka/Merck, (2 doses)*, n (%)	46 (9)
Live attenuated VZV (Not Available)*, n (%)	12 (2.4)
Not Available (1–3+ doses), n (%)	269 (52.8)
On-ART
Number of adults with available data	431
On-treatment, n (%)	421 (97.7)
Naive, n (%)	10 (2.3)
Number of children with available data	344
On-treatment, n (%)	339 (98.5)
Naive, n (%)	5 (1.5)
ART regimen
Number of adults with available data	57
NNRTI-based, n (%)	27 (90)
PI-based, n (%)	30 (10)
Number of children with available data	59
NNRTI-based, n (%)	36 (61.0)
PI-based, n (%)	23 (39.0)
CD4 cell count
Number of adults with available data	421
CD4 > 200 cells/mcL, n (%)	208 (49.4)
CD4 < 200 cells/mcL, n (%)	213 (50.6)
Number of children with available data	NA
CD4 > 200 cells/mcL, n (%)	NA
CD4 < 200 cells/mcL, n (%)	NA
Viraemia
Number of patients with available data	371
HIV-RNA >200 cp/mL, n (%)	10 (2.7)
HIV-RNA <200 cp/mL, n (%)	361 (97.3)
Number of patients with available data	NA
HIV-RNA >200 cp/mL, n (%)	NA
HIV-RNA <200 cp/mL, n (%)	NA
Resoconto tecniche per inserirle e descriverle nei risultati
Technical method performed for immunogenicity’s assessment^+
Number of adults with available data	423
ELISA, n (%)	391 (92.4)
IFN-γ ELISPOT, n (%)	339 (80.1)
ELISPOT, n (%)	31 (7.3)
RCF, n (%)RCF, n (%)	31 (7.3)
Number of children with available data	457
ELISA, n (%)	327 (71.6)
FAMA, n (%)	129 (28.2)
LPA, n (%)	62 (13.6)
RCF, n (%)	56 (12.3)
ELISPOT, n (%)	26 (5.7)

⁺More than one technical method for each patient*Prevention versus Herpes Zoster; **Prevention versus Varicella; NA, Not Available.

Table 3. Humoral and cell mediated immune response rate in adults detected in each study.

Study First author, year of publication		Humoral immunity					Cell-mediated immunity
		Anti-glycoprotein E antibody concentration Geometric mean titer (95% confidence interval)		Percentage response rate		Time	IFN- γ Elispot GMC, geometric mean concentrations (95% confidence interval)		Percentage response rate		Number of glycoprotein E-specific CD4^2+ T cells (per 10^6 total T cells) Median (interquartile range)		Responder cell frequency (RCF) (responder/10^5 PBMC) Mean (SE)		ELISPOT spot-forming cells (SFC)/10^5 PBMC Mean (SE)		Time
	CD4, ART	ZV (n = 42)	Placebo (n = 14)	ZV (n = 42)	Placebo (n = 14)	28 days after 4 doses	ZV (n = 43)	Placebo (n = 14)	ZV (n = 43)	Placebo (n = 14)	ZV (n = 43)	Placebo (n = 14)	ZV (n = 42)	Placebo (n = 14)	ZV (n = 43)	Placebo (n = 14)	28 days after 4 doses
Mullane, 2014	≤200 cells/mm^3 On ART	229.9 (145.4, 363.3)**	203.1 (111.1, 371.1)	NA	NA		5.3 (3.1, 8.9)	1.9 (1.0, 3.4)	NA	NA	NA	NA	NA	NA	NA	NA
	CD4, ART	Zostavax (n = 296)	Placebo (n = 99)	Zostavax (n = 296)	Placebo (n = 99)	6 weeks after 2 doses	Zostavax (n = 296)	Placebo (n = 99)	Zostavax (n = 296)	Placebo (n = 99)	Zostavax (n = 296)	Placebo (n = 99)	Zostavax (n = 296)	Placebo (n = 99)	Zostavax	Placebo (n = 99)	6 weeks after 2 doses
Benson, 2018	≥200 cells/mm^3 On ART	530.3 (477.8–588.6)**	250.3 (191.7–326.8)	NA	NA		3.8 (1.8–8.0)	1.1 (.3–3.4)	NA	NA	NA	NA	NA	NA	NA	NA
	CD4, ART	RZV (n = 53)	Placebo (n = 36)	RZV (n = 53)	Placebo (n = 36)	7 months after 3 doses	RZV (n = 20)	Placebo	RZV (n = 20)	Placebo (n = 18)	RZV (n = 20)	Placebo (n = 18)	RZV (n = 53)	Placebo (n = 36)	RZV (n = 20)	Placebo (n = 18)	7 months after 3 doses
Berkowitz, 2015	Different groups	63 812.6 (51 183.6–79 557.7)**	1 028.4 (658.9–1 605.0)	51/53 96.2% (87.0 − 99.5	1/36 2.8% (0.1–14.5)		NA	NA	18/20 90.0% (68.3–98.8)	3/18 16.7% (3.6–41.4)	2 578.4 (IQR 2 056.6–5 298.6)**	122.6 (IQR 10.7–270.4)	NA	NA	NA	NA
	CD4, ART	ZVL (n = 31)	Placebo (n = 33)	ZVL (n = 31)	Placebo (n = 33)	12 weeks after 2 doses	ZVL (n = 31)	Placebo (n = 33)	ZVL (n = 31)	Placebo (n = 33)	ZVL (n = 31)	Placebo (n = 33)	ZVL (n = 31)	Placebo (n = 33)	ZVL (n = 31)	Placebo (n = 33)	12 weeks after 2 doses
Weiberg, 2010	CD4 > 400, on ART	NA	NA	NA	NA		NA	NA	NA	NA	NA	NA	5.26 (2.4)*	2.46 (0.8)	3.43 (0.7)	2.65 (0.6)

NA, not available; *p < .05 compared to baseline;** p < .001.

Table 4. Immunogenicity recombinant zoster vaccine according to the number of CD4 cells and to the antiretroviral therapy (ART).

Study First author, year of publication	Humoral immunity							Cell-mediated immunity
	Anti-glycoprotein E antibody concentration Geometric mean titer (95% confidence interval)						Time	Number of glycoprotein E-specific CD4^2+ T cells (per 106 total T cells) Median (interquartile range)						Time
Berkowitz, 2015	RZV (n = 44)	Placebo (n = 29)	RZV (n = 5)	Placebo (n = 3)	RZV (n = 5)	Placebo (n = 4)	7 months after 3 doses	RZV (n = 26)	Placebo (n = 19)	RZV (n = 3)	Placebo (n = 1)	RZV (n = 1)	Placebo (n = 0)	7 months after 3 doses
	CD4 ≥ 200 cells/mm^3, on ART	CD4 ≥ 200 cells/mm^3, on ART	CD4 ≤ 200 cells/mm^3, on ART	CD4 ≤ 200 cells/mm3, on ART	CD4 ≥ 500 cells/mm^3, ART-naive	CD4 ≥ 500 cells/mm3, ART-naive		CD4 ≥ 200 cells/mm^3, on ART	CD4 ≥ 200 cells/mm3, on ART	CD4 ≤ 200 cells/mm^3, on ART	CD4 ≤ 200 cells/mm3, on ART	CD4 ≥ 500 cells/mm^3, ART-naive	CD4 ≥ 500 cells/mm3, ART-naive
	71309.6 (57019.3–89181.5)	928.8 (566.8–1522.1)	47382.6 (9151.2–245336.2)	2553 (610.1–10683.1)	32334.6 (17277.6–60513.4)	1087.6 (60.2–19641.4)		2546.4 (IQR 2056.6–4688.3)	126.1 (IQR 20.3–277)	12547.8 (IQR 5375.6–26852.5)	1 (IQR 1–1)	861.2 (IQR 861.2–861.2)	/

Table 5. Humoral and cell-mediated immune in children according to the different studies.

		Humoral immunity				Cell-mediated immunity
First author, year of publication			FAMA			RCF		LPA
	Study	Control	ZVL (n = 88)	Control group	Time	ZVL (n = 34)	Control group	ZVL^a (n = 52)	Control group	Time
Levin, 2006	I^§	Naturally infected children	46/71 (64,8)	NA	8 weeks post 2^nd dose	14/20 (70)	NA	30/40 (75)	NA	8 weeks post 2nd dose
	II^#		12/17 (70,6)	NA		9/14 (64,3)	NA	10/12 (83,3)	NA
			ELISA
	Study	Control	ZVL^b (n = 34)	Control group	Time	NA	NA	NA	NA	Time
Taweesith, 2010	I^§	Naturally infected children^$	18/22 (81,8)	NA	24 weeks post 2^nd dose	NA	NA	NA	NA	NA
	II^#		9/12 (75)	NA		NA	NA	NA	NA
			ELISA			CFSE dye dilution assay
	Study	Control	ZVL^c (n = 15)	Control group (n = 6)	Time	ZVL^c (n = 15)	Control group (n = 6)	NA	NA	Time
Bekker, 2006	I^§	Non HIV siblings	9/15 (60)	6/6 (100)	6 weeks post 2^nd dose	CD4 SI = 4.2 CD8 SI = 1.5	CD4 SI = 3.9 CD8 SI = 1.6	NA	NA	6 weeks post 2^nd dose
	II^#		NA	NA		NA	NA	NA	NA
			ELISA			LPA
	Study	Control	ZVL^d (n = 9)	Control group	Time	ZVL^d (n = 10)	Control group	NA	NA	Time
Armenian, 2005	I^§	NA	6/9 (66.6)	NA	8 weeks post 1^st dose	7/7 (100)	NA	NA	NA	6 weeks post 2^nd dose
	II^#	NA	NA	NA		2/3 (66,6)	NA	NA	NA
			FAMA			RCF		ELISPOT
	Study	Control	ZVL^a (n = 41)	Control group	Time	ZVL^a (n = 22)	Control group	ZVL^a (n = 10)	Control group	Time
Gershon, 2009	I^§	NA	39/41 (95,1)	NA	12 weeks post 2nd dose	8/22 (33,4)	NA	17/26 (65,4)	NA	12 weeks post 2nd dose
			ELISA			NA	NA	NA	NA	NA
	Study	Control	ZVL (n = 269)	Control group		NA	NA	NA	NA	NA
Purswani, 2015	III^ç	NA	145/269 (53,9	NA	3 weeks post 2nd dose	NA	NA	NA	NA	NA

FAMA: Fluorescent Antibody Membrane Assay; ELISA: Enzyme-Linked Immunosorbent Assay; RCF: Responder Cell Frequency; ELISPOT: Enzyme-Linked ImmunoSPOT; CFSE: 5,6-carboxyfluorescein diacetate succinimidyl ester; LPA: Lymphocyte Proliferation Assay; NA: Not Available.

§ CDC category A, B or N.

# CDC category C.

* 13 out of 15 total children were on HAART.

$ In this study the Control population was represented by HIV infected children, whose CDC category is not available, that were naturally VZV-seropositive at baseline, For this population, the vaccination protocol result was expressed as ΔGMT, between Baseline GMT titer and after the second dose titer.

ç The population characteristics were: CD4% median (Q1,Q3) 35 (30–41), Viral load, log10 copies/mL median (Q1,Q3) 2,6 (1,7–3,0), All the children were on HAART.

a ZVL Oka/Meck 2 doses.

b Okavax Sanofi 2 doses.

c Varilix GSK 2 doses.

d Varivax Meck, 1 dose.

Table 6. Adverse reactions in Adults.

Total	464
Overall local reactions n (%)	380
Overall systemic reactions, n (%)	510
Overall rash, n (%)	20 (3.9)
Overall fever, n (%)	36 (7.1)
Overall fatigue, n (%)	107 (21.0)
Overall headache, n (%)	92 (18.0)
Overall GE symptoms, n (%)	45 (8.8)
ADR after I dose, n (%)	245
ADR after II dose, n (%)	251
ADR after III dose, n (%)	206
Number of patients with available data	1
Live attenuated vaccine VZV (1 dose)
Local reactions, n (%)	0 (0)
Systemic reactions, n (%)	1 (100)
Disseminated varicella, n (%)	1 (100)
Retinal necrosis, n (%)	1 (100)
Meningitis, n (%)	1 (100)
Number of patients with available data	34
Live attenuated vaccine VZV (2 doses)
ADR after dose 1
Local reactions, n (%)	8 (23,5)
Injection site tenderness, n (%)	5 (14,7)
Injection site inflammation, n (%)	3 (8,8)
Systemic reactions, n (%)	11 (32,3)
Systemic rash (non-zosterifom), n (%)	1 (2,9)
Pruritis, n (%)	1 (2,9)
Headache, dizziness, irritability, n (%)	2 (5,9)
Influenza-like illness, n (%)	3 (8,9)
Nausea, vomiting, diarrhea, n (%)	4 (11,8)
ADR after dose 2
Local reactions, n (%)	4 (11,8)
Injection site tenderness, n (%)	3 (8,9)
Injection site inflammation, n (%)	1 (2,9)
Systemic reactions, n (%)	7 (20,6)
Systemic rash (non-zosteriform), n (%)	1 (2,9)
Nosebleed, n (%)	1 (2,9)
Liver enzyme elevation, n (%)	2 (5,9)
Varicella with vesicular rash, n (%)	1 (2,9)
Fever, n (%)	1 (2,9)
Macropapular lesions, n (%)	1 (2,9)
Number of patients who received RZV (3 doses)	73
Recombinant zoster vaccine (RZV) (3 doses)
ADR After dose 1
Local reactions, n (%)	98
Pain, n (%)	69 (94,5)
Redness, n (%)	17 (23,3)
Swelling, n (%)	12 (16,4)
Systemic reactions, n (%), n (%)	128
Fatigue, n (%)	30 (41,1)
Gastrointestinal, n (%)	13 (17,8)
Headache, n (%)	25 (34,2)
Myalgia, n (%)	34 (32,9)
Shivering, n (%)	19 (26)
Fever, n (%)	7 (9,6)
After dose 2
Local reactions, n (%)	87
Pain, n (%)	57 (78)
Redness, n (%)	19 (26)
Swelling, n (%)	11 (15,1)
Systemic reactions, n (%)	159
Fatigue, n (%)	41 (56,1)
Gastrointestinal, n (%)	18 (24,6)
Headache, n (%)	32 (43,8)
Myalgia, n (%)	33 (45,2)
Shivering, n (%)	23 (31,5)
Fever, n (%)	12 (16,4)
After dose 3
Local reactions, n (%)	57
Pain, n (%)	43 (58,9)
Redness, n (%)	9 (12,3)
Swelling, n (%)	5 (6,8)
Systemic reactions, n (%)	149
Fatigue, n (%)	36 (49,3)
Gastrointestinal, n (%)	8 (11)
Headache, n (%)	33 (45,2)
Myalgia, n (%)	32 (43,8)
Shivering, n (%)	20 (27,4)
Fever, n (%)	11 (15,1)
Number of patients who received ZV (2 doses)	296
Live attenuated zoster vaccine (ZV) (2 doses)**
Local reactions, n (%)	124
Injection site reactions, n (%)	124 (41,9
Systemic reactions, n (%)	27
Fever (>38.3°C), n (%)	12 (4,1)
Rashes (generalized, varicella-like or HZ-like), n (%)	15 (5,1)
Number of patients who received ZV ht (2 doses)	60
Heat inactivated Zoster vaccine (ZVHT) (1–4 doses)
Local reactions, n (%)	2 (3,3)
Systemic reactions, n (%)	34 (56,7)*

*34 people had ≥ 1 adverse events;**ADR not specified after which dose.

Table 7. Adverse reaction in children*.

Number of patients with available data	224	Cat N A B^a	Cat C^b	NA^c
Number of patients who received ZVL (1 dose)	10
ZVL (1 dose)
Local reactions, n (%)	1 (10)
Systemic reactions, n (%)	5 (50)
Fever, n (%)	3 (30)			3(100)
Nonpruritic papula, n (%)	1 (10)			1(100)
Generalized malaise, n (%)	1 (10)			1(100)
Number of patients who received ZVL (2 doses)	214
ZVL (2 doses)
ADR after dose 1
Local reactions (pain, erythema, induration), n (%)	20 (9,4)	8 (40)	1 (5)	11 (55)
Grade 3 local reaction, n (%)	4 (1,9)	4 (100)
Systemic reactions, n (%)	40 (18,7)	21 (52,5)	2 (5)	17 (42,5)
Fever, n (%)	9 (22,5)	5 (55,5)		4 (44,5)
Grade 3 Fever, n (%)	4 (1,9)	4 (100)
Otitis/sinusitis, n (%)	8 (3,7)	6 (75)	2 (25)
Rash, n (%)	5 (2,3)	2 (40)		3 (60)
Viral syndrome, n (%)	8 (0,5)	7 (87,5)	1 (12,5)
Grade 1 Sore throat, n (%)	2 (0,9)	1 (50)		1 (50)
Grade 2 sore throat, n (%)	1 (0,5)	1 (100)
Headache, n (%)	6 (2,8)	1 (16,7)		5 (83,3)
Nausea, n (%)	1 (0,5)	1 (100)
Vomiting, n (%)	1 (0,5)	1 (100)
Grade 2 neutropenia, n (%)	1 (0,5)	1 (100)
Grade 2 increased serum amylase, n (%)	1 (0,5)	1 (100)
Varicella like vescicles, n (%)	2 (0,9)			2 (100)
Creative phosphate kinase elevation, n (%)	1 (0,5)			1 (100)
Grade 2 neutropenia, n (%)	1 (0,5)			1 (100)
Not Available, n (%)	35 (16,4)
ADR after dose 2
Local reactions (pain, erythema, induration), n (%)	13 (6,1)	5 (38,5)	2 (15,4)	6 (46,2)
Grade 3 local reaction, n (%)	1 (0,5)		1 (100)
Systemic reactions, n (%)	24 (11,2)	17 (70,9)	5 (20,8)	2 (8,3)
Fever, n (%)	7 (3,3)	4 (57,1)	2 (28,6)	1 (14,3)
Grade 3 Fever, n (%)	2 (0,9)	2 (100)
Otitis/sinusitis, n (%)	6 (2,8)	5 (83,3)	1 (16,7)
Rash, n (%)	1 (0,5)	1 (100)
Viral syndrome, n (%)	7 (3,3)	6 (85,7)	1 (14,3)
Grade 2 Allergic reaction, n (%)	1 (0,5)	1 (100)
Pneumonia unrelated to vaccine, n (%)	4 (1,9)	1 (25)	3 (75)
Grade 2 otitis, n (%)	1 (0,5)	1 (100)
Grade 4 seizure, n (%)	1 (0,5)	1 (100)
Grade 2 thrombocytopenia, n (%)	1 (0,5)	1 (100)
Grade 2 neutropenia, n (%)	1 (0,5)	1 (100)
Grade 4 neutropenia, n (%)	1 (0,5)		1 (100)
Diarrhea, n (%)	1 (0,5)		1 (100)
Varicella like vescicles, n (%)	1 (0,5)			1 (100)
Other, n (%)	1 (0,5)	1 (100)

*more than one ADR is available per each child.

^bBased on CDC classification; N = Not symptomatic; A = Mildly symptomatic; B = Moderately symptomatic.

^cBased on CDC classification; C = Severely symptomatic.

^dClassification not available.