Immunogenicity and safety of an inactivated enterovirus 71 vaccine co-administered with measles-mumps-rubella vaccine and live-attenuated Japanese encephalitis vaccine: a phase 4, single-center, randomized controlled trial

Figures & data

Table 1. Baseline characteristics of the study participants in the full analysis set

Characteristic	Group 1 (n = 123)	Group 2 (n = 124)	Group 3 (n = 122)	P value
Male, no. (%)	59 (47.97)	66 (53.23)	66 (54.10)	.582
Ethnic Han, no. (%)	123 (100.00)	123 (99.19)	121 (99.18)	.775
Age, months	8.30 ± 0.57	8.37 ± 0.72	8.39 ± 0.73	.891
Height, cm	71.19 ± 2.68	70.38 ± 2.42	70.68 ± 2.67	.095
Weight, kg	8.88 ± 0.99	8.82 ± 0.94	9.00 ± 1.06	.408

Data are no. (%) of participants or mean ± SD. Study groups were as follows: simultaneous receipt of enterovirus 71 (EV71) vaccine (dose 1) and measles-mumps-rubella vaccine (MMR) on d 0 and EV71 vaccine (dose 2) and live-attenuated Japanese encephalitis vaccine (LA-JEV) on d 30 (Group 1); receipt of MMR and LA-JEV on d 0 and 30, respectively (Group 2); or receipt of doses 1 and 2 of EV71 vaccine on d 0 and 30, respectively (Group 3).

Figure 1. Trial profile.

Table 2. Seropositive and seroconversion rates of enterovirus 71 (EV71), measles, mumps, rubella, and Japanese encephalitis (JE) antibody pre and post vaccination, per-protocol sets

Variable	Group 1		Group 2 or Group 3		P value
	n (%)	95% CI	n (%)	95% CI
EV71 neutralizing antibody (N)	110		112
Seropositive pre-vaccination	4 (3.64)	(3.52,6.89)	6 (5.36)	(5.18,8.50)	.768
Seropositive post-vaccination	109 (99.09)	(95.04,99.98)	112 (100)	(96.76,100.00)	.495
Seroconversion	107 (97.27)	(92.24,99.43)	109 (97.32)	(92.37,99.44)	1.000^a
Measles IgG antibody (N)	110		116
Seropositive pre-vaccination	0 (0.00)	(0.00,3.37)	0 (0.00)	(0.00,3.21)	-
Seropositive post-vaccination	108 (98.18)	(93.59,99.78)	115 (99.14)	(95.29,99.98)	.963
Seroconversion	108 (98.18)	(93.59,99.78)	115 (99.14)	(95.29,99.98)	.963
Mumps IgG antibody (N)	110		116
Seropositive pre-vaccination	2 (1.82)	(1.76,5.13)	3 (2.59)	(2.51,5.71)	1.000
Seropositive post-vaccination	107 (97.27)	(92.24,99.43)	111 (95.69)	(90.23,98.59)	.777
Seroconversion	106 (96.36)	(90.95,99.00)	109 (93.79)	(87.96,97.54)	.402
Rubella IgG antibody (N)	110		116
Seropositive pre-vaccination	0 (0.00)	(0.00,3.37)	2 (1.72)	(1.66,4.87)	.498
Seropositive post-vaccination	105 (95.45)	(89.71,98.51)	112 (96.55)	(91.41,99.05)	.935
Seroconversion	105 (95.45)	(89.71,98.51)	110 (94.83)	(89.08,98.08)	.827
JE neutralizing antibody (N)	110		116
Seropositive pre-vaccination	6 (5.45)	(2.03,11.49)	3(2.59)	(0.54,7.37)	-
Seropositive post-vaccination	96 (87.27)	(79.57,92.86)	103(88.79)	(81.60,93.90)	.725
Seroconversion	90 (81.82)	(73.33,88.53)	100 (86.21)	(78.57,91.91)	.368

Study groups were as follows: simultaneous receipt of enterovirus 71 (EV71) vaccine (dose 1) and measles-mumps-rubella vaccine (MMR) on d 0 and EV71 vaccine (dose 2) and live-attenuated Japanese encephalitis vaccine (LA-JEV) on d 30 (Group 1); receipt of MMR and LA-JEV on d 0 and 30, respectively (Group 2); or receipt of doses 1 and 2 of EV71 vaccine on d 0 and 30, respectively (Group 3).

^aNon-inferiority was achieved, as the lower bound of the two-sided 95% CI was > − 10%.

Table 3. Geometric mean titer (GMT)/concentration (GMC) of enterovirus 71 (EV71), measles, mumps, rubella, and Japanese encephalitis (JE) antibody pre and post vaccination, per-protocol sets

	Group 1	Group 2 or Group 3
Variable	GMT/GMC (95% CI)	GMT/GMC (95% CI)	P value
EV71 neutralizing antibody (N)	110	112
Pre-vaccination GMT	4.13 (4.00,4.27)	4.18 (4.03,4.33)	.539
Post-vaccination GMT	96.86 (75.67,123.99)	101.25 (78.22,131.06)	.901
Measles IgG antibody (N)	110	116
Pre-vaccination GMC	35.49 (32.24,39.06)	38.39 (35.44,41.57)	.087
Post-vaccination GMC	2982.53 (2545.55,3494.53)	2797.91 (2371.76,3300.64)	.260
Mumps IgG antibody (N)	110	116
Pre-vaccination GMC	30.85 (28.03,33.95)	30.27 (27.40,33.43)	.703
Post-vaccination GMC	532.63 (457.18,620.53)	424.89 (367.10,491.78)	.035
Rubella IgG antibody (N)	110	116
Pre-vaccination GMC	2.62 (2.45,2.80)	2.89 (2.65,3.15)	.146
Post-vaccination GMC	79.56 (68.58,92.30)	75.70 (66.16,86.61)	.415
Japanese encephalitis neutralizing antibody (N)	110	116
Pre-vaccination GMT	2.60 (2.52,2.68)	2.55 (2.49,2.60)	.273
Post-vaccination GMT	7.12 (6.32,8.01)	7.33 (6.55,8.20)	.688

Study groups were as follows: simultaneous receipt of enterovirus 71 (EV71) vaccine (dose 1) and measles-mumps-rubella vaccine (MMR) on d 0 and EV71 vaccine (dose 2) and live-attenuated Japanese encephalitis vaccine (LA-JEV) on d 30 (Group 1); receipt of MMR and LA-JEV on d 0 and 30, respectively (Group 2); or receipt of doses 1 and 2 of EV71 vaccine on d 0 and 30, respectively (Group 3). GMT: geometric mean titer; GMC: geometric mean concentration.

Table 4. Adverse reactions (ARs) reported following any vaccination

Adverse reactions	Group 1 (N = 123)	Group 2 (N = 124)	Group 3 (N = 122)	Total (N = 369)	P value
					Three groups	Group 1 vs 2	Group 1 vs 3
Solicited	77 (62.60)	68 (54.84)	45 (36.89)	190 (51.49)	<.001	.245	<.001
Local	6 (4.88)	6 (4.84)	7 (5.74)	19 (5.15)	.915
Redness	5 (4.07)	4 (3.23)	7 (5.74)	16 (4.34)	.560
Induration	1 (0.81)	2 (1.61)	4 (3.28)	7 (1.90)	.320
Pruritus	3 (2.44)	1 (0.81)	0 (0.00)	4 (1.08)	.230
Swelling	0 (0.00)	0 (0.00)	3 (2.46)	3 (0.81)	.036	1.000	.122
Rash	1 (0.81)	1 (0.81)	0 (0.00)	2 (0.54)	1.000
Systemic	75 (60.98)	66 (53.23)	43 (35.25)	184 (49.86)	<.001	.248	<.001
Fever	68 (55.28)	59 (47.58)	32 (26.23)	159 (43.09)	<.001	.253	<.001
Diarrhea	25 (20.33)	18 (14.52)	17 (13.93)	60 (16.26)	.356
Irritability	10 (8.13)	6 (4.84)	7 (5.74)	23 (6.23)	.570
Decreased appetite	9 (7.32)	3 (2.42)	3 (2.46)	15 (4.07)	.108
Nausea/vomiting	6 (4.88)	3 (2.42)	3 (2.46)	12 (3.25)	.576
Allergy	4 (3.25)	4 (3.23)	1 (0.82)	9 (2.44)	.407
Fatigue	3 (2.44)	1 (0.81)	3 (2.46)	7 (1.90)	.577
Unsolicited	1 (0.81)	1 (0.81)	2 (1.64)	4 (1.08)	.700
Cough	1 (0.81)	0 (0.00)	2 (1.64)	3 (0.81)	.219
Abdominal distention	0 (0.00)	1 (0.81)	0 (0.00)	1 (0.27)	1.000
Overall	77 (62.60)	68 (54.84)	46 (37.70)	191 (51.76)	<.001	.245	<.001

Data are no. (%) of participants. Participants can have more than 1 reported AR. Study groups were as follows: simultaneous receipt of enterovirus 71 (EV71) vaccine (dose 1) and measles-mumps-rubella vaccine (MMR) on d 0 and EV71 vaccine (dose 2) and live-attenuated Japanese encephalitis vaccine (LA-JEV) on d 30 (Group 1); receipt of MMR and LA-JEV on d 0 and 30, respectively (Group 2); or receipt of doses 1 and 2 of EV71 vaccine on d 0 and 30, respectively (Group 3).