Immunogenicity and safety of human diploid cell vaccine (HDCV) vs. purified Vero cell vaccine (PVRV) vs. purified chick embryo cell vaccine (PCECV) used in post-exposure prophylaxis: a systematic review and meta-analysis

Figures & data

Figure 1. Flowchart of literature selection.

Table 1. Study characteristics

Study	Year	Country	Study design^a	Number	Sex ratio (Male/Female)	Age	Categories of exposure	Vaccine name/manufacturer	RIG^b	Immunogenicity^c	Safety^c
PVRV^e
Li^Citation14	2020	China	RCT	150	0.92	10–60	NR^d	NR	-	√	√
Fan^Citation15	2019	China	RCT	200	0.92	40 ± 26.7	NR	Guangzhou NuoCheng	NR	×	√
Chen^Citation16	2018	China	RCT	200	1.17	2–68	I & II	Guangzhou NuoCheng	-	×	√
Peng^Citation17	2016	China	RCT	869	NR	>2	II	NR	NR	×	√
Peng^Citation17	2016	China	RCT	941	NR	>2	II	NR	NR	×	√
Peng^Citation17	2016	China	RCT	881	NR	>2	II	NR	NR	×	√
Bose^Citation18	2016	India	RCT	60	3	5–77	II & III	Rabivax-S	±	√	√
Ramezankhani^Citation19	2016	Iran	RCT	702	3.74	26.8 ± 13.1	II & III	Verorab	NR	×	√
Fang^Citation20	2014	China	RCT	28	NR	19–60	II	Liaoning ChengDa	NR	√	√
Wang^Citation21	2011	China	RCT	200	0.63	6–67	NR	Speeda	NR	√	×
Wang^Citation21	2011	China	RCT	50	1.27	16–78	NR	Verorab	NR	√	×
Liu^Citation22	2011	China	RCT	30	0.88	22–57	NR	SPEEDA	NR	√	√
Ashwathnarayana^Citation23	2009	India	RCT	50	5.25	8–55	II & III	Verorab	±	√	√
Shu^Citation24	2007	China	RCT	300	NR	>2	II & III	Liaoning ShengWu	-	×	√
Shu^Citation24	2007	China	RCT	300	NR	>2	II & III	Changchun ChangSheng	-	×	√
Cao^Citation25	2007	China	RCT	1250	0.69	2–80	I & II	Liaoning ChengDa	-	×	√
Cao^Citation25	2007	China	RCT	1180	0.97	2–80	I & II	Verorab	-	×	√
Sampath^Citation26	2005	Pakistan	RCT	75	NR	NR	II	Abhayrab	-	√	×
Sampath^Citation26	2005	Pakistan	RCT	67	NR	NR	III	Abhayrab	-	√	×
Sampath^Citation26	2005	Pakistan	RCT	88	NR	NR	III	Abhayrab	+	√	×
Huang^Citation27	2018	China	P. O.	58	2.22	NR	NR	NR	NR	×	√
Liu^Citation28	2012	China	P. O.	398	1.17	2–67	NR	Verorab	-	√	√
Lu^Citation29	2010	China	P. O.	300	0.99	3–65	II	Verorab	-	×	√
Niu^Citation30	2019	China	R. O.	5347	NR	NR	NR	Changchun ChangSheng	NR	×	√
PCECV^f
Peng^Citation17	2016	China	RCT	813	NR	>2	II	NR	NR	×	√
Bose^Citation18	2016	India	RCT	60	2.75	5–77	II & III	Rabipur	±	√	√
Ramezankhani^Citation19	2016	Iran	RCT	747	4.7	27.4 ± 13.9	II & III	Rabipur	NR	×	√
Fang^Citation20	2014	China	RCT	28	NR	19–60	II	Rabipur	NR	√	√
Shao^Citation31	2013	China	RCT	400	NR	18–59	II & III	Rabipur	NR	√	√
Ashwathnarayana^Citation23	2009	India	RCT	50	4	7–48	II & III	Rabipur	±	√	√
D.J. Briggs^Citation32	2000	Thailand	RCT	57	0.97	5–66	II & III	NR	±	√	√
Benjavongkulchai^Citation33	1997	Thailand	RCT	17	NR	NR	I & II	Kaketsuken	-	√	√
Benjavongkulchai^Citation33	1997	Thailand	RCT	21	NR	NR	III	Kaketsuken	+	√	√
Benjavongkulchai^Citation33	1997	Thailand	RCT	21	NR	NR	III	Kaketsuken	+	√	√
Sirikun^Citation34	2018	Thailand	P. O.	29	0.45	19–73	III	Rabipur	+	√	√
Narayana^Citation35	2014	India	P. O.	129	3.61	18–55	II & III	Vaxirab-N	±	√	√
Lu^Citation29	2010	China	P. O.	300	0.95	3–65	II	NuoHua	-	×	√
HDCV^g
Li^Citation14	2020	China	RCT	150	0.86	12–60	NR	NR	-	√	√
Fan^Citation15	2019	China	RCT	200	0.56	43 ± 28.9	NR	Chendu KangHua	-	×	√
Chen^Citation16	2018	China	RCT	200	1.3	2–68	I & II	Kanghua	-	×	√
Sudarshan^Citation36	2008	India	RCT	29	4	15–55	II & III	Rabivax	±	√	√
Sudarshan^Citation36	2008	India	RCT	16	4	15–55	II & III	MIRV	±	√	√
Sudarshan^Citation36	2008	India	RCT	148	3.11	5–55	II & III	Rabivax	±	√	√
Benjavongkulchai^Citation33	1997	Thailand	RCT	39	NR	NR	III	NR	+	√	√
Yan^Citation37	2018	China	P. O.	700	NR	7–60	NR	Kanghua	±	×	√
Huang^Citation27	2018	China	P. O.	53	1.79	NR	NR	NR	NR	×	√
Wilde^Citation38	1995	Thailand	P. O.	100	2.13	2–60	III	NR	±	√	√
Anderson^Citation39	1980	America	P. O.	90	1.5	1–83	NR	Wyeth Laboratories	+	√	√
Bahmanyar^Citation40	1976	Iran	P. O.	45	3.1	3–90	NR	Institute Merieux	±	√	×
Niu^Citation30	2019	China	R. O.	464	NR	NR	NR	Kanghua	NR	×	√

a: RCT represents randomized controlled trial; P. O. represents reprospective observational; R. O. represents retrospective observational. b: RIG represents rabies immunoglobulin; ”-” represents no injection of RIG; ”+” represents injection of RIG; ”±” represents injection of RIG for part of the subjects. c: ”√” represents the study provide corresponding data; ”×” represents not. d: NR represent not reported. e: PVRV represents purified Vero cell vaccine. f: PCECV represents purified chick embryo cell vaccine. g: HDCV represents human diploid cell vaccine.

Figure 2. Quality assessment of included studies. “+” represents low risk of bias; “?” represents unclear risk of bias; “-” represents high risk of bias.

Figure 3. The pooled incidence of total ARs of HDCV, PVRV and PCECV.

Table 2. Multiple comparisons of 3 rabies vaccines about safety and immunogenicity (Case/Total)

Study	Vaccine type	Safety											Immunogenicity (D14)^a
		Local AR							Systemic AR				Sero conversion	RVNA titer [GMT(95%CI) /Subjects, IU/ml]
		Local pain	Erythema	Pruritus	Edema	Induration		Headache		Fever	Myalgia	Weakness
Benjavongkulchai (1997)	PCECV	13/72	1/72	0/72	0/72	0/72		1/72		16/72	15/72	0/72	55/55	1.86(NR)/22
Benjavongkulchai (1997)	HDCV	3/40	1/40	0/40	0/40	0/40		1/40		0/40	0/40	0/40	38/39	3.10(NR)/39
Fang (2014)	PVRV	0/28	0/28	0/28	1/28	0/28		0/28		1/28	0/28	0/28	NR^b	NR
Fang (2014)	PCECV	2/33	0/33	0/33	1/33	0/33		0/33		1/33	0/33	0/33	NR	NR
Bose (2016), 1	PVRV	20/30	3/30	2/30	2/30	5/30		7/30		4/30	3/30	11/30	27/27	20.57(17.03  ~ 24.84)/27
Bose (2016), 1	PCECV	21/31	0/31	3/31	3/31	4/31		5/31		2/31	5/31	9/31	29/29	16.01(12.46  ~ 20.57)/29
Bose (2016), 2	PVRV	13/30	0/30	1/30	1/30	1/30		5/30		1/30	2/30	7/30	27/27	16.47(13.39  ~ 20.26)/27
Bose (2016), 2	PCECV	9/31	0/31	0/31	1/31	1/31		2/31		0/31	2/31	4/31	29/29	14.13(11.42  ~ 17.47)/29
Ashwathnarayana (2009)	PCECV	1/50	0/50	1/50	0/50	0/50		0/50		0/50	0/50	0/50	50/50	6.88(6.11  ~ 7.75)/50
Ashwathnarayana (2009)	PVRV	1/50	0/50	1/50	0/50	0/50		0/50		0/50	0/50	0/50	48/48	6.65(5.91  ~ 7.49)/48
Ramezankhani (2016)	PVRV	27/702	9/702	7/702	4/702	0/702		8/702		11/702	6/702	5/702	NR	NR
Ramezankhani (2016)	PCECV	28/747	8/747	1/747	2/747	0/747		16/747		10/747	5/747	11/747	NR	NR
Li (2020)	HDCV	6/150	0/150	2/150	3/150	2/150		4/150		3/150	1/150	0/150	149/150	21.47(18.91  ~ 24.36)/150
Li (2020)	PVRV	7/150	0/150	1/150	3/150	1/150		4/150		3/150	0/150	1/150	148/150	20.78(18.21  ~ 23.71)/150
Chen (2018)	HDCV	7/200	2/200	2/200	2/200	5/200		1/200		3/200	0/200	5/200	NR	NR
Chen (2018)	PVRV	11/200	5/200	6/200	5/200	4/200		6/200		25/200	1/200	26/200	NR	NR
Lu (2010)	PCECV	19/300	1/300	11/300	1/300	4/300		4/300		3/300	0/300	8/300	NR	NR
Lu (2010)	PVRV	15/300	1/300	13/300	1/300	4/300		5/300		4/300	0/300	9/300	NR	NR
Huang (2018)	HDCV	1/53	0/53	0/53	0/53	0/53		1/53		1/53	0/53	1/53	NR	NR
Huang (2018)	PVRV	5/58	0/58	0/58	0/58	0/58		1/58		2/58	0/58	3/58	NR	NR
Pooled PVRV		99/1548	18/1548	31/1548	17/1548	15/1548		36/1548		51/1548	12/1548	62/1548	250/252	-
Pooled PCECV		93/1264	10/1264	16/1264	8/1264	9/1264		28/1264		32/1264	27/1264	32/1264	163/168	-
Pooled HDCV		17/443	3/443	4/443	5/443	7/443		7/443		7/443	1/443	6/443	263/267	-
RR, 95%CI (HDCV vs. PVRV)		0.51 (0.20 ~ 0.98)*	0.79 (0.12 ~ 2.63)	1.15 (0.17 ~ 3.72)	1.04 (0.26 ~ 2.83)	1.82 (0.41 ~ 5.19)		0.74 (0.15 ~ 2.36)		0.20 (0.03 ~ 0.64)*	0.46 (0.02 ~ 2.10)	0.25 (0.06 ~ 0.73)*	1.00 (0.75 ~ 1.34)	0.03 (−0.26 ~ 0.32)
RR, 95%CI (HDCV vs. PCECV)		0.49 (0.20 ~ 0.95)*	1.58 (0.19 ~ 5.79)	2.35 (0.24 ~ 9.99)	1.33 (0.20 ~ 4.73)	2.24 (0.38 ~ 6.86)		1.60 (0.24 ~ 5.73)		0.27 (0.03 ~ 0.92)*	0.32 (0.01 ~ 1.36)	0.48 (0.08 ~ 1.65)	1.00 (0.68 ~ 1.46)	0.16 (−0.17 ~ 0.49)
RR, 95%CI (PVRV vs. PCECV)		1.08 (0.65 ~ 1.87)	0.71 (0.19 ~ 1.67)	0.67 (0.18 ~ 1.66)	1.07 (0.29 ~ 2.62)	0.98 (0.34 ~ 2.25)		0.57 (0.17 ~ 1.35)		1.07 (0.27 ~ 2.91)	1.82 (0.41 ~ 5.85)	0.61 (0.24 ~ 1.21)	1.00 (0.71 ~ 1.39)	0.13 (−0.03 ~ 0.28)

a: Immunogenicity data were obtained 14 days after the first vaccination dose. b: NR represents not reported. *: Difference was statistically significant.

Figure 4. Pooled seroconversion rates on day 7 of HDCV, PVRV and PCECV.

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