Safety and immunogenicity of conjugate vaccine for typhoid (Vi-DT): Finding from an observer-blind, active-controlled, randomized, non-inferiority, phase III clinical trial among healthy volunteers

Figures & data

Figure 1. CONSORT flow diagram showing the number of patients who were screened, randomized into the treatment groups, completed the study, and included in the analysis.

Table 1. Demographics information of enrolled participants.

Characteristics		Vi-DT Group	Vi-TT Group	Total	p-value
Overall		N = 345	N = 115	N = 460
Gender	Male (%)	148 (42.90)	49 (42.61)	197 (42.83)	.957
	Female (%)	197 (57.10)	66 (57.39)	263 (57.17)	.831
Age (years)	Mean (SD)	21.68 (10.07)	21.39 (10.00)	21.61 (10.04)	.794
6 months to less than 2 y		N = 9	N = 3	N = 12
Gender	Male (%)	5 (55.56)	2 (66.67)	7 (58.33)	.735
	Female (%)	4 (44.44)	1 (33.33)	5 (41.67)	.089
Age (years)	Mean (SD)	0.72 (0.09)	1.02 (0.38)	0.80 (0.23)	.044
2 to 18 y		N = 114	N = 38	N = 152
Gender	Male (%)	59 (51.75)	14 (36.84)	73 (48.03)	.111
	Female (%)	55 (48.25)	24 (63.16)	79 (51.97)	.231
Age(years)	Mean (SD)	11.99 (3.69)	11.92 (3.79)	11.97 (3.70)	.927
18 to 45 y		N = 222	N = 74	N = 296
Gender	Male (%)	84 (37.84)	33 (44.59)	117 (39.53)	.303
	Female (%)	138 (62.16)	41 (55.41)	179 (60.47)	.604
Age (years)	Mean (SD)	27.50 (7.10)	27.08 (7.24)	27.40 (7.13)	.663

Table 2. Anti-vi-IgG ELISA response for seroconversion - non-inferiority data at week 4 for immunogenicity set.

	Vi-DT Group		Vi-TT Group		Difference	p-value
		Seroconversion rate (97.5% CI)		Seroconversion rate (97.5% CI)
All ages	344/345	99.71 (98.04, 99.96)	114/115	99.13 (94.27, 99.87)	0.73 (−8.23, 9.69)	.8553
Age Strata 1	9/9	100.00 (70.09, 100.00)	3/3	100.00 (43.85, 100.00)	0.00 (0.00, 0.00)	NA
Age Strata 2	114/114	100.00 (96.74, 100.00)	38/38	100.00 (90.82, 100.00)	0.00 (0.00, 0.00)	NA
Age Strata 3	221/222	99.55 (97.49, 99.92)	73/74	98.65 (92.73, 99.76)	0.90 (−3.30, 5.11)	.4381

Table 3. Anti-vi-IgG ELISA GMT at week 24 for immunogenicity set.

	Vi-DT Group		Vi-TT Group		p-value
	N	GMT (95% CI)	N	GMT (95% CI)
All ages	317/345	122.06 (107.77, 138.25)	103/115	118.49 (99.46, 141.15)	.8723
Age Strata 1	7/9	46.96 (28.79, 76.60)	3/3	32.56 (6.42, 165.08)	.3732
Age Strata 2	113/114	101.84 (86.78, 119.52)	38/38	142.82 (110.65, 184.35)	.0332
Age Strata 3	197/222	140.09 (117.63, 166.85)	62/74	112.48 (88.95, 142.24)	.1379

Table 4. Solicited adverse Events.

Solicited AEs	Vi-DT Group		Vi-TT Group		p-value*
	Number of AEs/ Number of participants (%)	Related to vaccine	Number of AEs/ Number of participants (%)	Related to vaccine
Immediate reactions
All ages	1/345 (0.29)	1/345 (0.29)	0/115 (0.00)	0/115 (0.00)	1.0000
Age Strata 1	0/9 (0.00)	0/9 (0.00)	0/3 (0.00)	0/3 (0.00)	-
Age Strata 2	0/114 (0.00)	0/114 (0.00)	0/38 (0.00)	0/38 (0.00)	-
Age Strata 3	1/222 (0.45)	1/222 (0.45)	0/74 (0.00)	0/74 (0.00)	1.0000
Solicited AE (Day 0 to 7)
All ages	58/345 (16.81)	56/345 (16.23)	26/115 (22.61)	24/115 (20.87)	.2558
Age Strata 1	2/9 (22.22)	2/9 (22.22)	0/3 (0.00)	0/3 (0.00)	1.0000
Age Strata 2	9/114 (7.89)	8/114 (7.02)	5/38 (13.16)	5/38 (13.16)	.3128
Age Strata 3	47/222 (21.17)	46/222 (20.72)	21/74 (28.38)	19/74 (25.68)	.3726

*p-value measured for AEs related to vaccination.

Table 5. Distribution of solicited adverse events.

Solicited AEs	Vi-DT Group		Vi-TT Group		p-value^#
	n/N (%)	m	n/N (%)	m
All ages	58 (16.81)	105	26 (22.61)	39	.1635
Local AE	47 (13.62)	51	22 (19.13)	22	.1520
Pain/Tenderness	46 (13.33)	46	22 (19.13)	22	.1293
Erythema/Redness	1 (0.29)	1	0 (0.00)	0	1.0000
Swelling/Induration	2 (0.58)	2	0 (0.00)	0	1.0000
Pruritus	2 (0.58)	2	0 (0.00)	0	1.0000
Systemic AE	22 (6.38)	54	7 (6.09)	17	.9118
Fever	3 (0.87)	5	0 (0.00)	0	.5766
Headache^†	13 (3.87)	14	5 (4.46)	6	.7833
Fatigue^†	5 (1.49)	5	3 (2.68)	4	.4188
Myalgia^†	1 (0.30)	2	1 (0.89)	1	.4379
Lethargy	7 (2.03)	7	2 (1.74)	2	1.0000
Irritability^‡	0 (0.00)	0	0 (0.00)	0	NA
Nausea	4 (1.16)	4	2 (1.74)	2	.6427
Vomiting	2 (0.58)	2	0 (0.00)	0	1.0000
Arthralgia	2 (0.58)	2	0 (0.00)	0	1.0000
Diarrhea	4 (1.16)	4	0 (0.00)	0	.5763
Drowsiness	2 (0.58)	3	1 (0.87)	1	1.0000
Loss of appetite	4 (1.16)	4	1 (0.87)	1	1.0000
Chills	1 (0.29)	1	0 (0.00)	0	1.0000
Persistent crying^‡	0 (0.00)	0	0 (0.00)	0	NA
Rash*	0 (0.00)	0	0 (0.00)	0	NA
Nasopharyngitis*	1 (16.67)	1	0 (0.00)	0	1.0000

N: Number of total participants; n: Number of participants who reported events; m: Number of events.

%: percentages (100*n/N).

^#p-values for n/N comparisons of Vi-DT and Vi-TT groups.

*Only for MR vaccine recipients among the 9–15 months old

^†Only for age strata 2 and 3 those who are 2 y old and above.

^‡Only for age strata 1 those who are less than 2 y.

Table 6. Unsolicited adverse events.

Unsolicited AEs	Vi-DT Group		Vi-TT Group		p-value*
	n/N (%)	m	n/N (%)	m
Unsolicited AE (within 4 weeks)
All ages	16/345 (4.64)	38	3/115 (2.61)	7	.4280
Age Strata 1	3/9 (33.33)	9	0/3 (0.00)	0	.5091
Age Strata 2	5/114 (4.39)	15	2/38 (5.26)	5	1.0000
Age Strata 3	8/222 (3.60)	14	1/74 (1.35)	2	.4587

N: Number of total participants; n: Number of participants who reported events; m: Number of events.

%: percentages (100*n/N).

*p-values for n/N comparisons of Vi-DT and Vi-TT groups.

Table A1. GMT of anti-vi IgG ELISA response at week 4 for Dhulikhel Hospital – immunogenicity set.

Week 4 Post Vaccination	Vi-DT Group (Pooled Groups A+B+C)		Vi-TT Group		P-value^†
	N	GMT* (95% CI)	N	GMT* (95% CI)
All Ages	345	364.48 (321.84, 412.77)	115	321.30 (271.78, 379.83)	.2939
Age Strata1	9	307.35 (130.52, 723.73)	3	274.70 (94.27, 800.51)	.8071
Age Strata2	114	360.16 (302.88, 428.27)	38	475.83 (372.77, 607.39)	.0650
Age Strata3	222	369.26 (311.45, 437.80)	74	264.29 (212.74, 328.35)	.0172

*Geometric Mean Titers (unit: IU/ml).

^†The p-value for all ages was derived using an analysis of covariance model with group and age strata as covariates after log transformation. The p-value for each age strata was derived from two sample t-test after log transformation.

Table A2. Seroconversion rate of anti-vi IgG ELISA response at week 24 for Dhulikhel Hospital – immunogenicity set.

Week 24 Post Vaccination	Vi-DT Group (Pooled Groups A+B+C)		Vi-TT Group		P-value^†
	n/N	Seroconversion rate* (95% CI)	n/N	Seroconversion rate* (95% CI)
All Ages	314/317	99.05 (97.25, 99.68)	97/103	94.17 (87.87, 97.30)	.2396
Age Strata1	7/7	100.00 (64.57, 100.00)	3/3	100.00 (43.85, 100.00)	NA
Age Strata2	113/113	100.00 (96.71, 100.00)	37/38	97.37 (86.51, 99.53)	.2517
Age Strata3	194/197	98.48 (95.62, 99.48)	57/62	91.94 (82.47, 96.51)	.0209

N: number of total participants; n: number of participants seroconverted.

*Proportion of participants who had at least 4-fold rise anti-Vi antibody titers compared to baseline.

^†The p-value for all ages was derived using the generalized linear model for binomial distribution with group and strata as covariates. The p-value for each age strata was derived from Fisher’s exact test.