Clinical evaluation for batch consistency of an inactivated enterovirus 71 vaccine in a large-scale phase 3 clinical trial

Figures & data

Figure 1. Trial profile.

Table 1. Demographic characteristics of the study subjects, by treatment groups

	Batch 1	Batch 2	Batch 3	Placebo
Immunogenicity analysis cohort	n = 1139	n = 1153	n = 1138	n = 3441
Age (month)	17.4 (8.1)	17.5 (7.9)	17.5 (7.9)	17.6 (8.0)
Boy	671 (58.9)	677 (58.7)	641 (56.3)	1876 (54.5)
Height (cm)	80.6 (8.2)	80.7 (8.1)	80.8 (8.1)	80.8 (8.1)
Weight (kg)	12.2 (2.2)	12.3 (2.2)	12.2 (2.2)	12.2 (2.2)
BMI (kg/m^2)	18.8 (2.4)	18.9 (2.6)	18.8 (2.5)	18.7 (2.3)
Safety analysis cohort	n = 1199	n = 1230	n = 1200	n = 3631
Age (month)	17.4 (8.0)	17.4 (7.9)	17.5 (7.9)	17.4 (8.0)
Boy	704 (58.7)	725 (58.9)	675 (56.3)	1990 (54.8)
Height (cm)	80.5 (8.2)	80.6 (8.0)	80.7 (8.1)	80.7 (8.1)
Weight (kg)	12.2 (2.2)	12.2 (2.2)	12.2 (2.2)	12.2 (2.2)
BMI (kg/m^2)	18.8 (2.4)	18.9 (2.7)	18.8 (2.5)	18.7 (2.3)

Data are mean (SD), and number (%). N, number of subjects; SD, standard deviation; BMI, body mass index.

Table 2. Immune response among different batches of EV71 vaccine or placebo in subjects who were seronegative at baseline on day 56, by treatment and age groups

Assessment variables	Vaccine					Placebo	P value^#
	Pooled batches	Batch 1	Batch 2	Batch 3	P value*
6–11 mo	n = 998	n = 343	n = 330	n = 325		n = 997
GMT (U/mL)	439.1 (402.1–479.5)	420.1 (359.8–490.5)	413.1 (353.7–482.4)	489.6 (422.3–567.6)	0.24	3.6 (3.3–3.9)	<0.001
Proportion with NTAb titer ≥ 8U/mL	983, 98.5 (97.5–99.2)	337, 98.3 (96.0–99.4)	325, 98.5 (96.3–99.6)	321, 98.8 (96.7–99.7)	0.86	189, 19.0 (16.6–21.6)	<0.001
Proportion with NTAb titer ≥ 32U/mL	957, 95.9 (94.4–97.0)	326, 95.0 (92.0–97.1)	315, 95.5 (92.5–97.4)	316, 97.2 (94.6–98.7)	0.32	57, 5.7 (4.4–7.4)	<0.001
12–35 mo	n = 2432	n = 796	n = 823	n = 813		n = 2444
GMT (U/mL)	473.0 (447.3–500.2)	401.5 (362.0–445.4)	492.2 (448.6–540.1)	533.6 (486.0–585.8)	<0.001	4.1 (3.8–4.4)	<0.001
Proportion with NTAb titer ≥ 8U/mL	2404, 98.9 (98.3–99.2)	783, 98.4 (97.2–99.1)	818, 99.4 (98.5–99.8)	803, 98.8 (97.7–99.4)	0.15	504, 20.6 (19.0–22.3)	<0.001
Proportion with NTAb titer ≥ 32U/mL	2342, 96.3 (95.5–97.0)	761, 95.6 (93.9–96.9)	794, 96.5 (94.9–97.6)	787, 96.8 (95.3–97.9)	0.42	209, 8.6 (7.5–9.8)	<0.001
Total	n = 3430	n = 1139	n = 1153	n = 1138		n = 3441
GMT (U/mL)	462.9 (441.6–485.3)	407.0 (373.5–443.6)	468.1 (432.2–507.0)	520.6 (481.2–563.3)	<0.001	4.0 (3.7–4.2)	<0.001
Proportion with NTAb titer ≥ 8U/mL	3387, 98.8 (98.3–99.1)	1120, 98.3 (97.4–99.0)	1143, 99.1 (98.4–99.6)	1124, 98.8 (97.9–99.3)	0.23	693, 20.1 (18.8–21.5)	<0.001
Proportion with NTAb titer ≥ 32U/mL	3299, 96.2 (95.5–96.8)	1087, 95.4 (94.0–96.6)	1109, 96.2 (94.9–97.2)	1103, 96.9 (95.7–97.8)	0.18	266, 7.7 (6.9–8.7)	<0.001

Data are GMT (95% CI) or n, % (95% CI). GMT, geometric mean titer; n, number of subjects. *The P values were calculated for the comparison among the 3 batches of EV71 vaccines. #The P values were calculated for the comparison between the pooled EV71 vaccine group and the placebo group.

Table 3. The GMT ratios among different batches of EV71 vaccine in subjects who were seronegative at baseline on day 56, by treatment and age groups

Batch number	n	GMT (95% CI)	GMT ratio (95% CI)
6–11 mo
Batch 1	343	420.1 (359.8–490.5)	1.02 (0.82–1.27)
Batch 2	330	413.1 (353.7–482.4)
Batch 1	343	420.1 (359.8–490.5)	0.89 (0.69–1.06)
Batch 3	325	489.6 (422.3–567.6)
Batch 2	330	413.1 (353.7–482.4)	0.84 (0.68–1.05)
Batch 3	325	489.6 (422.3–567.6)
12–35 mo
Batch 1	796	401.5 (362.0–445.4)	0.82 (0.71–0.94)
Batch 2	823	492.2 (448.6–540.1)
Batch 1	796	401.5 (362.0–445.4)	0.75 (0.66–0.87)
Batch 3	813	533.6 (486.0–585.8)
Batch 2	823	492.2 (448.6–540.1)	0.92 (0.81–1.05)
Batch 3	813	533.6 (486.0–585.8)
Total
Batch 1	1139	407.0 (373.5–443.6)	0.87 (0.77–0.98)
Batch 2	1153	468.1 (432.2–507.0)
Batch 1	1139	407.0 (373.5–443.6)	0.78 (0.70–0.88)
Batch 3	1138	520.6 (481.2–563.3)
Batch 2	1153	468.1 (432.2–507.0)	0.90 (0.80–0.99)
Batch 3	1138	520.6 (481.2–563.3)

n, number of subjects. The equivalence margin of GMT is 0.67–1.5. The results were calculated on basis of subjects whom completed the two-dose immune schedule and had their serum detection results at day 56.

Table 4. Summary of solicited adverse reactions, unsolicited adverse events and serious adverse event in the safety analysis cohort

Reaction severity	Vaccine (n = 3629)				Placebo (n = 3631)	P value^#
	Batch 1 (n = 1199)	Batch 2 (n = 1230)	Batch 3 (n = 1200)	P value*
Solicited adverse reactions within 0–7 d
Any	595, 49.6 (46.8–52.5)	641, 52.1 (49.3–54.9)	600, 50.0 (47.1–52.9)	0.42	1786, 49.2 (47.6–50.8)	0.23
Grade 3 *	30, 2.5 (1.7–3.6)	17, 1.4 (0.8–2.3)	28, 2.3 (1.6–3.4)	0.11	59, 1.6 (1.3–2.1)	0.16
Injection-site adverse reactions
Any	138, 11.5 (9.8–13.5)	146, 11.9 (10.1–13.8)	139, 11.6 (9.9–13.6)	0.96	397, 10.9 (10.0–12.0)	0.33
Grade 3	3, 0.3 (0.1–0.8)	0, 0.0 (0.0–0.4)	2, 0.2 (0.0–0.7)	0.18	3, 0.1 (0.0–0.3)	0.51
Systemic adverse reactions
Any	534, 44.5 (41.7–47.4)	578, 47.0 (44.2–49.8)	539, 44.9 (42.1–47.8)	0.42	1621, 44.6 (43.0–46.3)	0.47
Grade 3	27, 2.3 (1.5–3.3)	17, 1.4 (0.8–2.3)	26, 2.2 (1.5–3.2)	0.23	56, 1.5 (1.2–2.0)	0.21
Unsolicited adverse events within 0–28 d	591, 49.3 (46.4–52.2)	635, 51.6 (48.8–54.5)	576, 48.0 (45.1–50.9)	0.19	1761, 48.5 (46.9–50.1)	0.32
Serious adverse events	1, 0.1 (0.0–0.5)	3, 0.2 (0.1–0.8)	4, 0.3 (0.1–0.9)	0.46	20, 0.6 (0.4–0.9)	0.02
Infections and infestations	0, 0.0 (0.0–0.4)	2, 0.2 (0.0–0.7)	4, 0.3 (0.1–0.9)	0.13	16, 0.4 (0.3–0.7)	0.03
Injury, poisoning, and procedural complications	0, 0.0 (0.0–0.4)	0, 0.0 (0.0–0.4)	0, 0.0 (0.0–0.4)	-	3, 0.1 (0.0–0.3)	0.25
General disorders and administration site conditions	0, 0.0 (0.0–0.4)	0, 0.0 (0.0–0.4)	0, 0.0 (0.0–0.4)	-	1, 0.0 (0.0–0.2)	1.00
Cardiac disorders	1, 0.1 (0.0–0.5)	0, 0.0 (0.0–0.4)	0, 0.0 (0.0–0.4)	0.33	0, 0.0 (0.0–0.1)	0.50
Gastrointestinal disorders	0, 0.0 (0.0–0.4)	1, 0.1 (0.0–0.5)	0, 0.0 (0.0–0.4)	1.00	0, 0.0 (0.0–0.1)	0.50

Data are n, % (95% CI). n, number of subjects; Any, all the subjects with certain adverse reactions. *Grade 3 events were severe (i.e., prevented activity). *The P values were calculated for the comparison among the 3 batches of EV71 vaccines. #The P values were calculated for the comparison between the pooled EV71 vaccine group and the placebo group.