Post-exposure prophylaxis (PEP) for rabies with purified chick embryo cell vaccine: a systematic literature review and meta-analysis

Figures & data

Figure 1. Flow chart of search and selection procedure.

n, number of items in each category; PCECV, purified chick embryo cell vaccine; PrEP, pre-exposure prophylaxis; RVNA, rabies virus neutralizing antibodies; GMT, geometric mean titer.

Table 1. RVNA GMTs from studies comparing IM and ID administration of PCECV.

Regimen; vaccination days	Age group, administration route	RIG	Assay		GMT (range or 95% CI)
				n	Day 7	Day 14	Day 28/30	Day 90/91	Ref
Healthy volunteers
1-1-1-1-1-1; 0, 3, 7, 14, 30, 90	Adults, IM	None	MNT	31–35	<0.1	8.2 (0.8–111.1)	12.92 (1.29–177.8)	4.86 (0.6–123.0)	[21]
	Adults, ID	None	MNT	50–61	<0.1	7.13 (0.2 – 110.9)	4.45 (0.63–53.09)	2.27 (0.3–32.9)	[21]
1-1-1-1-1; 0, 3, 7, 14, 28	Adults, IM	None	RFFIT	46	-	6.9 (95% CI: 6.3–7.5)	11.5 (95% CI: 10.8–12.3)	7.0 (95% CI:6.4–7.7)	[36]
2-2-2-2-2; 0, 3, 7, 14, 28	Adults, ID	None	RFFIT	45	-	4.2 (95% CI: 3.7–4.7)	7.6 (95% CI: 6.9–8.3)	4.8 (95% CI: 4.3–5.4)	[36]
1-1-1-1-1; 0, 3, 7, 14, 28	Children and adults, IM	None	RFFIT	18	-	-	-	-	[40]
2-2-2-2; 0, 3, 7, 28	Children and adults, ID	None	RFFIT		Highly elevated	-	-	-	[40]
Bite cases
1-1-1-1-1-1; 0, 3, 7, 14, 30, 90	Children and adults, IM	HRIG	RFFIT	36–37	0.29 (<0.05–19.1)	12.3 (0.4–301.0)	18.5 (0.5–217.0)	4.7 (0.5–60.9)	[9]
2-2-2-1-1; 0, 3, 7, 30, 90	Children and adult, ID	HRIG	RFFIT	53–58	0.34 (0.05–19.1)	28.5 (1.1–1380)	10.9 (1.5–171.0)	3.0 (0.4–59.1)	[9]
Individuals at risk
1-1-1-1-1-1; 0, 3, 7, 14, 28, 91	Children and adults, IM	None	MNT	15	0.02 (<0.1–0.2)	3.1 (0.3–16.7)	10.3 (2.1–35.9)	4.9 (1.4–9.6)	[39]
	Children and adults, IM	HRIG	MNT	15	0.3 (<0.1–0.9)	1.7 (0.3–4.7)	3.3 (1.2–9.1)	3.0 (0.9–7.4)	[39]
	Children and adults, IM	ERIG	MNT	16	0.01 (0.1–0.1)	0.8 (0.3–40)	3.3 (1.1–12.0)	2.5 (0.7–7.7)	[39]
3-1; 0, 14	Children and adults, IM	None	MNT	16	0.05 (<0.1–0.5)	2.0 (0.8–9.6)	7.3 (3.0–25.9)	1.8 (0.8–4.2)	[39]
	Children and adults, IM	HRIG	MNT	15–16	0.3 (<0.1–0.7)	0.6 (0.2–1.3)	3.4 (1.1–13.4)	1.0 (0.1–2.4)	[39]
8-4-1-1; 0, 7, 28, 91	Children and adults, ID	None	MNT	15–16	0.04 (<0.1–0.4)	5.4 (1.8–16.7)	5.8 (2.4–13.4)	2.7 (0.8–10.2)	[39]
	Children and adults, ID	HRIG	MNT	16	0.2 (<0.1–0.6)	2.1 (0.4–8.2)	2.1 (0.4–13.3)	1.5 (0.2–8.1)	[39]
4-4-1-1; 0, 7, 28, 91	Children and adults, ID	None	MNT	15–16	0.02 (<0.1–0.3)	7.2 (1.8–26)	7.2 (1.5–23.2)	2.7 (0.9–5.9)	[39]
	Children and adults, ID	HRIG	MNT	15–16	0.3 (<0.1–0.8)	2.6 (0.7–16.7)	2.8 (1.0–10.7)	1.9 (0.4–9.1)	[39]
	Children and adults, ID	ERIG	MNT	16	0.02 (<0.1–0.2)	2.2 (0.4–13.4)	2.8 (0.4–14.9)	2.5 (0.7–11.3)	[39]

IM: intramuscular; ID: intradermal; RVNA: rabies virus neutralizing antibodies; RIG: rabies immunoglobulin; PCECV: purified chick embryo cell vaccine; CI: 95% confidence interval; n: number of participants with available results; MNT: mouse neutralization test; RFFIT: rapid fluorescent focus inhibition test; HRIG: human RIG; ERIG: equine RIG; GMT: geometric mean titer.

Table 2. Overview of the estimates for the percentage of participants with RVNA titers ≥0.5 IU/mL following vaccination with PCEV by IM and ID administration in interventional studies.

	IM administration				ID administration
Analyses	ES (95% CI)	I^2 (p)	Studies; subgroups (n)		ES (95% CI)	I^2 (p)	Studies; subgroups (n)
Day 7
Overall	44% (24–65%)	96.6% (p ≤ .001)	9; 19 (734)		39% (13–69%)	95.5% (p ≤ .001)	5; 9 (273)
Healthy volunteers	44% (19–70%)	97.5% (p ≤ .001)	6; 12		30% (0–81%)	97.1% (p ≤ .001	3; 3
Bite cases	*				NA
People at risk	*				*
Healthy volunteers and people at risk	47% (27–68%)	96.6% (p ≤ .001)	8; 18		39% (13–69%)	95.5% (p ≤ .001)	5; 9 (273)
Vaccine potency
Low potency	NA				*
Normal potency	15% (6–26%)	80.1% (p ≤ .001)	4; 8		*
High potency	64% (42–83%)	93.4% (p ≤ .001)	4; 10		*
NR	*				*
RIG
No RIG provided, overall	45% (21–70%)	97.4% (p ≤ .001)	9; 13		22% (4–48%)	93.3% (p ≤ .001)	5; 6
No RIG provided, healthy volunteers	53% (23–82%)	98.1% (p ≤ .001)	6; 9		30% (0–81%)	0% (p ≤ .001)	3;3
No RIG provided to people at risk	*				*
No RIG provided, healthy volunteers and people at risk combined	50% (25–75%)	97.5% (p ≤ .001)	9; 12		22% (4–48%)	93.3% (p ≤ .001)	5; 6
No RIG provided, bite cases	*				NA
ERIG	*				*
HRIG	*				*
Assay
MNT	41% (24–65%)	96.6% (p ≤ .001)			*
MNT, no RIG provided	25% (6–49%)	86.0% (p ≤ .001)			*
RFITT	47% (19–75%)	97.5% (p ≤ .001)			*
RFITT, no RIG provided	58% (25–88%)	98.0% (p ≤ .001)			*
Quality
Low quality	53% (29–76%)	93.2% (p ≤ .001))			*
Acceptable	31% (3–69%)	98.3% (p ≤ .001)			*
Day 14
Overall	99% (97–100%)	71.6% (p ≤ .001)	16; 34 (1754)		100% (99–100%)	0% (p = .91)	14; 27 (962)
Healthy volunteers	99% (98–100%)	71.6% (p ≤ .001)	8; 18 (1311)		100% (99–100%)	0% (p = .63)	6; 11 (450)
Bite cases	99% (95–100%)	35.4% (p = .19)	5; 5 (221)		100% (99–100%)	0% (p = 1.00)	4; 4 (202)
People at risk	96% (88–100%)	72.4% (p ≤ .001)	4; 11 (222)		100% (99–100%)	0% (p = .75)	4; 13 (310)
Children	*				*
Pregnant	*				*
HIV	*				*
Vaccine potency
Low potency, all subgroups (overall)	NA				*
Normal potency, all subgroups (overall)	98% (95–100%)	80.1% (p ≤ 00.1)	5; 12		100% (99–100%)	0% (p = 1.00)	5; 5
Normal potency, healthy volunteers and people at risk combined	98% (95–100%)	81.9% (p ≤ 00.1)	4;11		100% (99–100%)	0% (p = 1.00)	4; 4
Normal potency, healthy volunteers and people at risk combined, no RIG provided	100% (99–100%)	3.4% (p = .41)	4;8		100% (99–100%)	0% (p = .98	3;3
High potency, all subgroups (overall)	99% (96–100%)	67.3% (p ≤ 00.1)	10; 19		100% (99–100%)	0% (p = .78)	8; 18
High potency, healthy volunteers and people at risk combined	99% (96–100%)	69.0% (p ≤ 00.1)	8; 17		100% (99–100%)	0% (p = .72)	7; 17
High potency, healthy volunteers and people at risk combined, no RIG provided	100% (100–100%)	0% (p ≤ .82)	8;13		100% (99–100%)	0% (p = .98)	6; 12
NR, all subgroups (overall)	*				*
Dose
All subgroups (overall)	Strata not comparable with ID vaccines				Strata not comparable with IM vaccines
RIG
No RIG provided, all subgroups (overall)	100% (100–100%)	0% (p = .60)	14; 26		100% (100–100%)	0% (p = .99)	9; 15
No RIG provided, healthy volunteers	100% (100–100%)	0% (p = .69)			100% (99–100%)	0% (p = .44)
No RIG provided, bite cases	98% (93–100%)	23.9% (p = .27)			*
No RIG provided, people at risk	100% (98–100%)	0% (p = .91)			100% (99–100%)	0% (p = 1.00)
No RIG provided, volunteers and people at risk combined	100% (100–100%)	0% (p = .89)	12; 23		100% (100–100%)	0% (p = .99)
ERIG, all subgroups(overall)	77% (37–100%)	92.6% (p ≤ .001)	3; 4		100% (96–100%	51.7% (p = .10)	4; 4
HRIG, all subgroups (overall)	90% (69–100%)	77.7% (p ≤ .001)	3; 4		100% (98–100%)	0% (p = .60)	3; 8
Assay
MNT, all subgroups	96% (89–100%)	74.9% (p ≤ .001)			99% (97–100%)	12.1% (p = .34)
MNT, no RIG provided	100% (99–100%)	0% (p = .92)			100% (98–100%)	0% (p = .71)
RFITT, all subgroups	99% (98–100%)	68.9 (p ≤ .001)			100% (100–100%)	0% (p = 1.00)
RFITT, no RIG provided	100% (99–100%)	12.6% (p = .30)			100% (100–100%)	0% (p = 1.00)
ELISA	*				*
Other assays	*				*
Quality assigned according to the SIGN
Low quality, all subgroups	99% (96–100%)	64.9% (p ≤ .001)	10; 18		100% (99–100%)	0% (p = .79)	8; 17
Low quality, no RIG provided	100% (99–100%	0% (p = .71)	9;13		100% (99–100%)	0% (p = .99)	7; 13
Acceptable quality, all subgroups	99% (97–100%)	76.2% (p ≤ .001)	6; 16		100% (99–100%)	0% (p = .85)	6; 10
Acceptable quality, no RIG provided	100% (100–100%	0% (p = .56)	5;13		*
Day 90
All subgroups (overall)	100% (100–100%)	0% (p = 1.00)	5; 7 (326)		97% (92–100%)	83.1% (p ≤ .001)	8; 16 (601)
Healthy volunteers	100% (99–100%)	0% (p = .93)	3;4		91% (79–99%)	90.1% (p ≤ .001)	4; 8
Bite cases	*				*
People at risk	*				*
Healthy volunteers and people at risk	NA				96% (89–100%)	84.6% (p ≤ .001)
All subgroups (overall), without low vaccine potency	100% (100–100)	0% (p = .48)	5; 7		99% (99–100%)	0% (p = .84)	8; 13

RVNA: rabies virus neutralizing antibodies; PCECV: purified chick embryo cell vaccine; ES: estimate for the proportion of individuals with RVNA titers ≥0.5 IU/mL; n: number of participants included in the analyses (when available); NR: not reported; NA: no data available; RIG: rabies immunoglobulin; MNT: standard mouse neutralization test; RFFIT: rapid fluorescent focus inhibition test; ERIG: equine RIG; HRIG: human RIG; IM: intramuscular, ID: intradermal; SIGN: Scottish Intercollegiate Guidelines Network.

Note: * The analyses were not performed due to the insufficient number of comparable studies per subgroup.

Figure 2. Estimates for the proportion of individuals with RVNA titers ≥0.5 IU/ml on day 14 following vaccination with PCECV by intramuscular administration, stratified by population and including (a) or omitting (b) studies providing RIG at first administration, and stratified by number of doses and including (c) or omitting (d) studies providing RIG at first administration.

RVNA, rabies virus neutralizing antibodies; ES, estimate for the proportion of individuals with RVNA titers ≥0.5 IU/ml; PCECV, purified chick embryo cell vaccine; RIG, rabies immunoglobulin; N, number of participants with available results; MNT, standard mouse neutralization test; RFFIT, rapid fluorescent focus inhibition test; ERIG, equine RIG; HRIG, human RIG; NR, not reported.

Figure 2. (Continued)

Figure 3. Estimates for the proportion of individuals with RVNA titers ≥0.5 IU/ml on day 14 following vaccination with PCECV by intramuscular administration, stratified by RIG administration.

RIG, rabies immunoglobulin; RVNA, rabies virus neutralizing antibodies; ES, estimate for the proportion of individuals with RVNA titers ≥0.5 IU/ml; PCECV, purified chick embryo cell vaccine; CI, confidence interval; N, number of participants with available results; MNT, standard mouse neutralization test; NR, not reported; RFFIT, rapid fluorescent focus inhibition test.

Figure 4. Meta-analysis of the proportion of individuals with RVNA titers ≥0.5 IU/ml on day 14 following vaccination with PCECV by intradermal administration, stratified by population (a) and number of doses (b).

RVNA, rabies virus neutralizing antibodies; ES, estimate for the proportion of individuals with RVNA titers ≥0.5 IU/ml; PCECV, purified chick embryo cell vaccine; CI, confidence interval; N, number of participants with available results; MNT, standard mouse neutralization test; RFFIT, rapid fluorescent focus inhibition test; ERIG, equine RIG; HRIG, human RIG; NR, not reported.

Figure 5. Estimates for the proportion of individuals with RVNA titers ≥0.5 IU/ml on day 14 following vaccination with PCECV by intradermal administration, stratified by RIG administration.

RVNA, rabies virus neutralizing antibodies; ES, estimate for the proportion of individuals with RVNA titers ≥0.5 IU/ml; PCECV, purified chick embryo cell vaccine; RIG, rabies immunoglobulin; CI, confidence interval; N, number of participants with available results; RFFIT, rapid fluorescent focus inhibition test; MNT, standard mouse neutralization test; ELISA, enzyme-linked immunosorbent assay; NR, not reported.

Table 3. Adverse reactions after PCECV by IM administration, reported in interventional studies.

Regimen; days	Age group	AE type	AE (% of individuals reporting the AE [n/N])	Country	Ref
Healthy volunteers
1-0-1; 0, 30	Adults (N = 10)	Local	gInjection site pain (0% [0/10])	Germany, Austria, Yugoslavia	[42]
3; 0	Adults (N = 23)	Local	Injection site pain (4% [1/23])
1-1-1-1-1-1; 0, 3, 7, 14, 30, 90	Children and adults (N = 110)	Local	Injection site pain (9% [10/110])
1-1-1-1-1-1; 0, 3, 7, 14, 30, 90	Adults (N = 34)	Systemic	Generalized mild rash (6% [2/35])	Thailand	[21]
2-1-1; 1, 8, 22	Children (N = 119)	Solicited, local	Injection site pain (38% [45/119]); erythema (2% [2/119]); induration (2% [2/119])	China	[25]
		Solicited, systemic	Loss of appetite (12% [14/119]); nausea (6% [7/119]); headache (9% [11/119]); myalgia (9% [11/119]); fatigue (15% [18/119]); arthralgia (3% [3/119]); fever (7% [8/119])
		Unsolicited, NR	At least possibly related to the vaccination AEs (7%); most common AE: URTI (≥2%)
		SAE	No SAE (0% [0/119])
Essen 1-1-1-1-1; 1, 4, 8, 15, 29	Children (N = 118)	Solicited, local	Injection site pain 40% [47/118]); erythema (1% [1/118]); induration (0% [0/118])
		Solicited, systemic	Loss of appetite (8% [10/118]); nausea (8% [10/118]); headache (8% [10/118]); myalgia (11% [13/118]); fatigue (13% [15/118]); arthralgia (1% [1/118]); fever (3% [3/118])
		Unsolicited, NR	At least possibly related to the vaccination AEs (5%); most common AE: URTI (≥2%)
		SAEs	No SAE (0% [0/118])
Zagreb 2-1-1; 1, 8, 22	Adults (N = 197)	Solicited, local	Injection site pain (9% [18/197]); erythema (1% [1/197]); induration (1% [1/197])
		Solicited, systemic	Loss of appetite (0% [0/197]); nausea (1% [2/197]); headache (4% [7/197]); myalgia (0% [0/197]); fatigue (5% [9/197]); arthralgia (2% [3/197]); fever (3% [5/197])
		Unsolicited	At least possibly related to the vaccination AEs (3%); most common AE: URTI (≥2%)
Essen 1-1-1-1-1; 1, 4, 8, 15, 29	Adults (N = 200)	Solicited, local	Injection site pain (11% [22/200]); erythema (2% [3/200]); induration (1% [1/200])
		Solicited, systemic	Loss of appetite (1% [2/200]); nausea (1% [2/200]); headache (4% [8/200]); myalgia (1% [2/200]); fatigue (4% [7/200]); arthralgia (2% [3/200]); fever (3% [5/200])
		Unsolicited	At least possibly related to the vaccination AEs (8%); most common AE: URTI (≥2%)
Zagreb 2-1-1; 0, 7, 21	Adults (N = 549)	Unsolicited SAE	Any (19% [102/549]) SAE (0% [0/549])	China	[27]
Essen 1-1-1-1-1; 0, 3, 7, 14, 28		Unsolicited SAE	Any (19% [51/275]) SAE (0.4% [1/275])
Zagreb 2-1-1; 0, 7, 21	Indian adults (N = 126)	Unsolicited SAE	Any (4% [5/126]) injection site pain and fever were most commonly reported; systemic hypersensitivity (0% [0/126) SAE (0% [0/126])	India	[44]
Essen 1-1-1-1-1; 0, 3, 7, 14, 28		Unsolicited; local and systemic SAE	Any (11% [13/123]); systemic hypersensitivity (0% [0/123) SAE (0% [0/123])
Zagreb 2-1-1; 0, 7, 21	Adults (N = 29)	Local and systemic	Any AE (14% [2/14]) and (13% [2/15])	Philippines	[35]
2-2-2-2-2; 0, 3, 7, 14, 28	Adults (N = 45)	Local	Pain (1% [2/45]) Itching (2% [5/45])	India	[36]
Bite cases
1-1-1-1-1; 0, 3, 7, 14, 28	Children and adults (N = 50)	Local	Any (10% [5/50]); injection site pain (4% [2/50]); itching (6% [3/50]); any reaction to equine RIG (0% [0/35])	India	[20]
Essen 1-1-1-1-1; 0, 3, 7, 14, 30, 90	Children and adults (N = 57)	-	In decreasing order of frequency of occurrence: erythema, pain and/or swelling at the site of injection, fever (33%)	Thailand	[9]
1-1-1-1-1-1; 0, 3, 7, 14, 30, 90	Children and adults (N = 91)^a	Local	Pain (10% [13/139]); erythema (1% [2/139]) Induration (0% [0/139)	India	[23]
		Systemic	Headache (2% [4/139); myalgia (8% [9/139]) Fever (1% [1/139])
1-1-1; 0, 3, 7	Children and adults (N = 33)	Local	Adenopathy (8% [5/60])	India	[31]
1-1-1-1-1-1; 0, 3, 7, 14, 30, 90	Children and adults (N = 10)	Systemic	Any (0% [0/10])
Individuals at risk
1-1-1-1-1-1; 0, 3, 7, 14, 30, 90	Children and adults (N = 37)^a	Local	Pain (10% [13/139]); erythema (1% [2/139]); induration (0% [0/139])	India	[23]
		Systemic	Headache (2% [4/139]); myalgia (8% [9/139]); fever (1% [1/139])
		SAE	No SAE (0% [0/139])
Zagreb 2-1-1; 0, 7, 21	Adults (N = 32) (96 inoculations)	NR; local	Pain(5% [5/96]); pruritus (2% [2/96]); edema (2% [2/96]); induration (1% [1/96]); erythema (1% [3/96])	China	[26]
		NR; systemic	Headache (1% [1/96]); fever (1% [1/96]); myalgia (0% [0/96]); malaise (5% [5/96]); pruritus (0% [0/96]); sleepiness (1% [1/96])
See ET	Adults (N = 77)^b	Local	Any (57%); severe AEs (16%): pain, induration, or redness	Germany	[45]
		Systemic	Any (31%)^c; severe AEs (15%); general reactions such as fatigue, headache, and dizziness
1-1-1-1-1-1; 0, 3, 7, 14, 28, 91 3-1; 0-14 1-1-1-1-1-1; 0, 3, 7, 14, 28, 91 1-1-1-1-1-1; 0, 3, 7, 14, 28, 91 3-1; 0-14	Children and adults (N = 76)	Local	Any (66% [50/76]); pain (49% [37/76]) Itching (10% [8/76]); erythema (1% [1/76]) Induration (1% [1/76]); inguinal lymhadenopathy (18% [14/76]) Axillary lymhadenopathy (4% [3/76]); buttock pain (1% [1/76])	Thailand	[39]
		Systemic	Any (25% [19/76]); feverish feeling (14% [11/76]); headache (12% [9/76]); weakness (7% [5/76]); influenza-like (3% [2/76]); dizziness (4% [3/76]); diarrhea (1% [1/76])

PCECV: purified chick embryo cell vaccine; AE: adverse event; N: number of study participants/inoculations for each administered regimen; n: number of participants reporting the AE; SAE: serious adverse event; URTI: upper respiratory tract infection; NR: not reported; IM: intramuscular; RIG: rabies immunoglobulin.

^aResults reported for the entire population (N = 139).

^bResults reported for the entire population (N = 88).

^cHighest rates reported after first and second vaccinations.

Table 4. Adverse reactions after PCECV by IM administration reported in observational studies.

Regimen; days	Population	AE type	AE (% of individuals reporting the AE [n/N])	Country	Ref
2-1-1; 0, 7, 21	Children with WHO category II animal exposure (N = 57)	Local	Any (33% [19/57]); pain was the most common AE	China	[48]
		Systemic	Any (37% [21/57]); fever was the most common systemic AE, most patients with fever were <5 years
2-1-1; 0, 7, 21	Adults with WHO category II animal exposure (N = 75)	Local	Any (28% [21/75]); pain was the most common AE
		Systemic	Any (8% [6/75]); fever was the most common systemic AE
1-1-1-1-1; 0, 3, 7, 14, 28	Children with WHO category II animal exposure (N = 57)	Local	Any (32% [18/57]); pain was the most common AE
		Systemic	Any (26% [15/57]); fever was the most common systemic AE, most patients with fever were <5 years
1-1-1-1-1; 0, 3, 7, 14, 28	Adults with WHO category II animal exposure (N = 69)	Local	Any (23% [16/69]); pain was the most common AE
		Systemic	Any (7% [5/69]); fever was the most common AE
1-1-1-1-1; 0,3, 7,14,28	Pregnant adult women with dog or cat wounds (N = 71)	Local	Pain (23% [16/71]); erythema (1% [1/71])	China	[49]
		Systemic	Fever (3% [2/71]); headache (1% [1/71]); fatigue (18% [13/71])
		Any	Any AE (46% [33/71])
1-1-1-1-1; 0, 3, 7, 14, 30	Children with moderate to severe PEM who were exposed to potentially rabid animals (N = 39)		No SAE(0% [0/39]) Minor AEs resolved within a few days	India	[54]
1-1-1-1-1-1; 0, 3, 7, 14, 30, 90	Adult volunteers bitten by clinically or laboratory-proven rabid animals (N = 48)	Local	Pain (8% [4/48]); soreness (2% [1/48]); erythema (2% [1/48])	India	[55]
		Systemic	Rash (6% [3/48]); headache (6% [3/48]); discomfort (2% [1/48])
1-1-1-1-1-1; 0, 3, 7, 14, 30, 90	Children and adults bitten by dogs (N = 29)		Any (0% [0/29])	India	[57]
1-1-1-1-1-1, 0, 3, 7, 14, 30, 90	Adult volunteers bitten by proven rabid animals (N = 21)	Local	Mild local reactions were ignored by most vaccines; all patients were alive after 15 months	Thailand	[59]
		Systemic	Pain (5% [1/21]); headache (5% [1/21]); fever (5% [1/21]); rash (10% [2/21])
1-1-1-1-1-1; 0, 3, 7, 14, 28, 90	Children and adults moderately to severely exposed to laboratory-proven rabid animals (N = 27)	Local	AE (pain at infection sites) were mild and self-limiting	Thailand	[61]
2-1-1; 0, 7, 21	Children and adults moderately to severely exposed to laboratory-proven rabid animals (N = 55)	Local	AE (pain at infection sites) were mild and self-limiting

PCECV: purified chick embryo cell vaccine; AE: adverse event; N: number of study participants/inoculations for each administered regimen; n: number of participants reporting the AE; WHO: World Health Organization; SAE: serious adverse event; IM: intramuscular.

Table 5. Adverse reactions after PCECV by ID administration reported in interventional studies.

Regimen; days	Population	AE type	AE (% of individuals reporting the AE [n/N])	Country	Ref
Healthy volunteers
4-0-2-0-1-1; 0, 7, 14, 30, 90	Adults (N = 86)	Local and systemic	At least one mild or moderate AE (47%) No SAE (0%)	Lithuania	[8]
		Local	Erythema (56%); pain (38%)
		Systemic	Headache (49%); fatigue (39%); malaise (43%)
2-2-2-1-1; 0, 3, 7, 30, 90	Adults (N = 157)	Local and systemic	No SAE (0% [0/157])	Czech Republic	[41]
2-2-2-1-1; 0, 3, 7, 30, 90	Adults (N = 55)	Local	Itching, erythema, induration (reported by most vaccines)	Thailand	[21]
2-2-2-2; 0, 3, 7, 30	Children and adults (N = 62)	Local	Pain (2% [1/62])	Philippines	[32]
		Systemic	Dizziness (8% [5/62]); headache (2% [1/62])
1-1-1-1-1; 0, 3, 7, 14, 28	Adults (N = 45)	Local	Pain (4% [10/46]); itching (2% [0/46])	India	[36]
4-4-4; 0, 3, 7	Adults (N = 38)	Solicited, local, and systemic	Itching; induration and pain; fever; erythema, myalgia, and lymphadenopathy (37% [14/35])	India	[37]
Bite cases
2-2-2-1-1; 0, 3, 7, 30, 90	Children and adults (N = 79)	-	In decreasing order of frequency of occurrence: erythema, pain, and/or swelling at the site of injection, fever (48%)	Thailand	[9]
2,2,2,1,1; 0, 3, 7, 28, 90	Children and adults (N = 58)	Local	Pain (3% [2/58]); itching (3% [2/58]); induration (7% [4/58])	India	[29]
		Systemic	Fever (7% [4/58]); myalgia (0% [0/58]); headache (0% [0/58])
4-4-4-0-0; 0, 3, 7	Adults (N = 45)	Local and systemic	Any (15.6% [7/45])	India	[33]
		Local^a	Itching, erythema, pain (2% [12/540])
		Systemic^a	Fever, myalgia (1% [4/540])
2-2-2-0-1-1; 0, 3, 7, 30, 90	Children and adults (N = 113)	Systemic	Headache or fever (3% [3/113])	Philippines	[10]
2-2-2-2; 0, 3, 7, 28	Adults (N = 43)	Local^b	Erythema (1% (11/344]); itching (5% [16/344]); pain (1% [3/344]); induration (1% [4/344]) All AE were self-limiting	India	[7]
Individuals at risk
2-2-2-0-1-1; 0, 3, 7, 14, 28, 90	Adults (N = 53)	Local^c	Swelling (7% [28/424]); erythema (5% [24/424]); pain (1% [7/424]); AEs were minor and self-limiting No SAEs (0% [0/424])	India	[22]
		Systemic	Any (0% [0/53])
2-2-2-2-2; 0, 3, 7, 28, 90	Adults (N = 43)	Local	Pain (9% [4/43]); induration (11% [5/43]) Itching (9% [4/43]); erythema (9% [4/43])	India	[28]
		Systemic	Fever (2% [1/43]); headache (2% [1/43])
8-4-1-1; 0, 7, 28, 90	Adults (N = 39)	Local	Pain (8% [3/39]); induration (10% [4/39]); itching (8% [3/39]); erythema (8% [3/39])
		Systemic	Fever (3% [1/43]); headache (3% [1/43])
2-2-2-0-1-1; 0, 3, 7, 28, 90	Adults (N = 42)	-	Pain (10% [4/42]); itching (7% [3/42]); erythema (5% [2/42]);induration (5% [2/42]); fever (2%1/42]); arthralgia(2% [1/42]); AEs were self-limiting		[30]
8-4-1-1; 0, 7, 28, 91 4-4-1-1; 0, 7, 28, 91 8-4-1-1; 0, 7, 28, 91 4-4-1-1; 0, 7, 28, 91 4-4-1-1; 0, 7, 28, 91	Children and adults (N = 76)	Local	Any (92% [70/76]); pain (10% [8/76]) Itching (64% [49/76]); erythema (32% [24/76]) Induration (35% [27/76]); wheal (1% [1/76]) Ecchymosis (1% [1/76]) Inguinal lymhadenopathy (35% [27/76]); axillary lymhadenopathy (5% [4/76) Buttock pain (1% [1/76)	Thailand	[39]
		Systemic	Any (14% [11/76]); feverish feeling (7% [5/76]); headache (4% [3/76]); weakness (5% [4/76]); influenza-like (1% [1/76]); rash (3% [2/76]); dizziness (3% [2/76]); diarrhea (1% [1/76])
NR	Children and adults (N = 81)	Local	Pain (7% [6/81]); itching (65% [53/81]); erythema (100% [81/81]); induration (63% [51/81]);lymphadenopathy (27% [22/81])	Thailand	[38]
		Systemic	Dizziness (2% [2/81]); myalgia (2% [2/81]); cold (7% [6/81]); feverish (5% [4/81]); weakness (4% [3/81]); headache (5% [4/81]); malaise (2% [2/81]); stiffness (4% [3/81])
NR	Children and adults (N = 52)	Local	Pain (27% [14/52]); itching (67% [32/52]); erythema (100% [52/52]); induration (63% [33/52]); lymphadenopathy (19% [10/52])
		Systemic	Dizziness (0% [0/52]); myalgia (4% [2/52]); cold (6% [3/52]); feverish (4% [2/52]); weakness (6% [3/52]); headache (2% [1/52]); malaise (6% [3/52]); stiffness (4% [2/52])

PCECV: purified chick embryo cell vaccine; AE: adverse event; N: number of study participants/inoculations for each administered regimen; n: number of participants reporting the AE; SAE: serious adverse event; ID: intradermal; NR: not reported.

^aReported for 45 × 3 doses x 4 sites (N = 540 inoculations).

^bReported for 43 × 8 doses (N = 344 inoculations).

^cReported for 53 × 8 doses (N = 424 inoculations).

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