Enterovirus A71 vaccine effectiveness in preventing enterovirus A71 infection among medically-attended hand, foot, and mouth disease cases, Beijing, China

Figures & data

Figure 1. Flow chart of subject enrollment in the test-negative design case-control study for the estimates of EV-A71 vaccine effectiveness during 2017, in Beijing, China.

Note: HFMD: hand, foot, and mouth disease. EV-A71: enterovirus A71. BMSIIP: Beijing Management System of Information for the Immunization Program. VE: vaccine effectiveness.

Table 1. Comparison of demographic characteristics and virus infection between mild vaccinated and non-vaccinated HFMD cases.

Characteristic	Vaccinated n (%)	Non-vaccinated n (%)	p-value
Sex
Male	102 (65.4)	1205 (60.1)
Female	54 (34.6)	799 (39.9)	0.196
Age group (months)
6–35	67 (42.9)	611 (30.5)	<0.001
36–59	89 (57.1)	1393 (69.5)
Illness onset to sampling (days)
≤3	114 (73.1)	1569 (78.3)	0.130
>3	42 (26.9)	435 (21.7)
Type of specimen
Throat swab	130 (6.9)	1759 (93.1)
Rectal swab	22 (10.5)	187 (89.5)	0.151
Fecal samples	4 (6.5)	58 (93.5)
EV-A71
Positive	7 (4.5)	361 (18.0)	<0.001
Negative	149 (95.5)	1643 (82.0)
CV-A16*
Positive	28 (18.8)	239 (14.5)	0.163
Negative	121 (79.6)	1404 (85.5)
CV-A6*
Positive	40 (26.8)	517 (31.5)	0.243
Negative	109 (73.2)	1126 (68.5)
OEV*
Positive	33 (22.1)	303 (18.4)	0.267
Negative	116 (77.9)	1340 (81.6)

Note: HFMD: hand, foot, and mouth disease. EV: enterovirus. EV-A71: enterovirus A71. CV-A16: coxsackievirus A16. CV-A6: coxsackievirus A6. OEV: otherenterovirus than EV-A71, CV-A16 and CV-A6.

*368 EV-A71 positive cases were excluded.

Figure 2. Monthly number of the cases testing negative and positive for enterovirus by serotype.

Note: EV-A71: enterovirus A71. CV-A16: coxsackievirus A16. CV-A6: coxsackievirus A6. Others: otherenterovirus than EV-A71, CV-A16 and CV-A6. Negative: negative for all enteroviruses.

Figure 3. Timeline of number of subjects receiving two doses of EV-A71 vaccine.

Note: EV-A71: enterovirus A71. The number of subjects who received EV-A71 vaccine were excluded: (1) who only received one dose of EV-A71 vaccine, and (2) who received a second dose of EV-A71 vaccine that was <28 days before the illness onset.

Table 2. Comparison of demographic characteristics and virus infection between mild EV-A71-positive cases and EV-A71-negative controls.

Characteristic	Cases(n = 368) n (%)	Controls^a (n = 1792) n (%)	p-value
Sex
Male	214 (58.2)	1093 (61.0)	0.310
Female	154 (41.8)	699 (39.0)
Age group (months)
6–35	96 (26.1)	582 (32.5)	0.016
36–59	272 (73.9)	1210 (67.5)
Vaccination status
Yes	7 (1.9)	149 (8.3)	<0.001
No	361 (98.1)	1643 (91.7)
Illness onset to sampling (days)
≤3	305 (82.9)	1415 (79.0)	0.103
>3	63 (17.1)	377 (21.0)
Type of specimen
Throat swab	310 (16.4)	1579 (83.6)
Rectal swab	44 (21.1)	165 (78.9)	0.119
Fecal samples	14 (16.4)	48 (83.6)

Note: EV: enterovirus. EV-A71: enterovirus A71. CV-A16: coxsackievirus A16. CV-A6: coxsackievirus A6. OEV: otherenterovirus than EV-A71, CV-A16 and CV-A6.

^aControls tested negative for EV-A71 infection,including children who were positive for an enterovirus other than EV-A71 and children who were negative for all enteroviruses.

Table 3. Crude and adjusted estimates of vaccine effectiveness against mild, medically-attended EV-A71-HFMD for different number of doses and age group.

	Vaccinated No./total (%)		Vaccine effectiveness
Groups	Cases	Controls^a	Crude (95% CI)	Adjusted(95% CI)
Total VE
One dose	3/364 (0.8)	46/1689 (2.7)	70.3 (4.0 to 90.8)	69.8 (1.6 to 90.7)^b
Two doses	4/365 (1.1)	103/1746 (5.9)	82.3 (51.7 to 93.5)	83.7 (54.9 to 94.1)^b
Age groups (months)
One dose
6–35	1/94 (1.1)	17/535 (3.2)	67.2 (−149.2to 95.7)	68.2 (−143.0 to 95.8)^c
36–59	2/270 (0.7)	29/1154 (2.5)	71.0 (−22.1 to 93.1)	69.6 (−29.9 to 92.9)^c
Twodoses
6–35	2/95 (2.1)	47/565 (8.3)	76.3 (0.7 to 94.3)	77.3 (4.6 to 94.6)^c
36–59	2/270 (0.7)	56/1181 (4.7)	85.0 (38.2 to 96.4)	86.8 (44.6 to 96.9)^c

Note:HFMD: hand, foot, and mouth disease. EV: enterovirus. EV-A71: enterovirus A71. CV-A16: coxsackievirus A16. CV-A6: coxsackievirus A6. OEV: otherenterovirus than EV-A71, CV-A16 and CV-A6.

^aControls tested negative for EV-A71 infection,including children who were positive for an enterovirus other than EV-A71 and children who were negative for all enteroviruses.

^bAdjusted for sex, age, and calendar months.

^cAdjusted for sex, and calendar months.

Table 4. Estimates of vaccine effectiveness in sensitivity analysis, using controls who were positive for an enterovirus other than EV-A71.

	Vaccinated No./total (%)		Vaccine effectiveness
Groups	Cases	Controls^a	Crude (95% CI)	Adjusted (95% CI)
Total VE
One dose	3/364 (0.8)	30/1089 (2.8)	70.7 (3.3 to 91.1)	71.7 (5.2 to 91.5)^b
Two doses	4/365 (1.1)	71/1130 (6.3)	83.5 (54.4 to 94.0)	87.1 (63.7 to 95.4)^b
Age groups (months)
One dose
6–35	1/94 (1.1)	11/350 (3.1)	66.9 (−160.0 to 95.8)	67.3 (−158.3 to 95.9)^c
36–59	2/270 (0.7)	19/739 (2.6)	71.7 (−22.2 to 93.5)	74.4 (−14.2 to 94.3)^c
Twodoses
6–35	2/95 (2.1)	30/369 (8.1)	75.7 (−3.6 to 94.3)	77.6 (3.2 to 94.8)^c
36–59	2/270 (0.7)	41/761 (5.4)	86.9 (45.4 to 96.9)	89.2 (53.2 to 97.5)^c

Note: EV:enterovirus. EV-A71: enterovirus A71. CV-A16: coxsackievirus A16. CV-A6: coxsackievirus A6. OEV: other enteroviruses than EV-A71, CV-A16 and CV-A6.

^aControls tested negative for EV-A71 infection but were positive for an enterovirus other than EV-A71.

^bAdjusted for sex, age, and calendar months.

^cAdjusted for sex, and calendar months.

Table 5. Estimates of vaccine effectiveness in sensitivity analysis, using pan-EV negative controls.

	Vaccinated No./total (%)		Vaccine effectiveness
Groups	Cases	Controls^a	Crude (95% CI)	Adjusted (95% CI)
Total VE
One dose	3/364 (0.8)	16/600 (2.7)	69.7 (−4.8 to 91.2)	67.6 (−12.7 to 90.7)^b
Two doses	4/365 (1.1)	32/616 (5.2)	79.8 (42.3 to 92.9)	80.3 (43.1 to 93.1)^b
Age groups (months)
One dose
6–35	1/94 (1.1)	6/185 (3.2)	67.9 (−170.4to 96.2)	68.8 (−163.8to 96.3)^c
36–59	2/270 (0.7)	10/415 (2.4)	69.8 (−39.0 to 93.4)	69.5 (−64.7 to 98.0)^c
Twodoses
6–35	2/95 (2.1)	17/196 (8.7)	77.4 (−0.1 to 94.9)	77.9 (1.8 to 95.0)^c
36–59	2/270 (0.7)	15/420 (3.6)	79.9 (11.2 to 95.4)	80.4 (11.7 to 95.7)^c

Note:EV: enterovirus. EV-A71: enterovirus A71. CV-A16: coxsackievirus A16. CV-A6: coxsackievirus A6. OEV: otherenterovirus than EV-A71, CV-A16 and CV-A6.

^aControls tested negative for all enteroviruses.

^bAdjusted for sex, age, and calendar months.

^cAdjusted forsex, and calendar months.

Figure 4. Phylogentic analysis of VP1 gene of EV-A71 strains from HFMD virological surveillance during the 2016–2017 in Beijing, China^#.

Note: EV-A71: enterovirus A71.HFMD: hand, foot, and mouth disease.^# The EV-A71 strains analyzed in this study were indicated with solid triangles and squares, and the vaccine strains were shown with solid dots. ▲the strains isolated in 2016, ■ the strains isolated in 2017; ● vaccine strains