A randomized, dose-ranging assessment of the immunogenicity and safety of a booster dose of a combined diphtheria-tetanus-whole cell pertussis-hepatitis B-inactivated poliovirus-Hemophilus influenzae type b (DTPw-HBV-IPV/Hib) vaccine vs. co-administration of DTPw-HBV/Hib and IPV vaccines in 12 to 24 months old Filipino toddlers

Figures & data

Table 1. Composition of study vaccines

Antigen	Form 1	Form 1/2	Form 1/3	Control group
	DTPw-HBV-IPV/Hib formulation 1	DTPw-HBV-IPV/Hib formulation 2	DTPw-HBV-IPV/Hib formulation 3	DTPw-HBV/Hib (Zilbrix™ Hib)	IPV (Poliorix™)
Diphtheria toxoid	≥ 30 IU/ml	≥ 30 IU/ml	≥ 30 IU/ml	≥ 30 IU/ml	-
Tetanus toxoid	≥ 60 IU/ml	≥ 60 IU/ml	≥ 60 IU/ml	≥ 60 IU/ml	-
Bordetella pertussis antigen	≥ 4 IU	≥ 4 IU	≥ 4 IU	≥ 4 IU	-
Hepatitis B surface antigen	10 μg	10 μg	10 μg	10 μg	-
Polyribosyl ribitol phosphate	2.5 μg	2.5 μg	2.5 μg	2.5 μg	-
Poliovirus type 1 (Mahoney)	40 D units	19.60 D units	13.20 D units		40 D units
Poliovirus type 2 (MEF-1)	8 D units	3.92 D units	2.64 D units		8 D units
Poliovirus type 3 (Saukett)	32 D units	15.68 D units	10.56 D units		32 D units

All vaccines were manufactured by GSK Biologicals.

Table 2. Demographic characteristics of the total vaccinated cohort

		Form 1 n = 78	Form 1/2 n = 78	Form 1/3 n = 78	Control n = 78
Characteristic	Categories	Value/n (%)	Value/n (%)	Value/n (%)	Value/n (%)
Age (in months)	Mean	17.4	18.0	17.7	17.5
	SD	3.81	2.96	3.38	3.59
	Range	12–24	12–23	12–23	12–23
Gender	Female	37 (47.4)	31 (39.7)	35 (44.9)	40 (51.3)
	Male	41 (52.6)	47 (60.3)	43 (55.1)	38 (48.7)
Geographic ancestry	South East Asian	78 (100)	78 (100)	78 (100)	78 (100)

Form 1 received DTPw-HBV-IPV (full dose)/Hib vaccine; Form 1/2 received DTPw-HBV-IPV (1/2 dose)/Hib vaccine; Form 1/3 received DTPw-HBV-IPV (1/3 dose)/Hib vaccine; controls received DTPw-HBV/Hib Kft and IPV vaccines concomitantly; N, total number of subjects; value/n, value of considered parameter/number of subjects in a given category; SD, standard deviation.

Figure 1. Comparison between groups in the immune response to poliovirus types 1, 2 and 3 (ATP immunogenicity cohort): (A) difference in seroprotection rates between the control group and each DTPa-HBV-IPV/Hib formulation (Formulations 1–3); (B) GMT ratios (post divided by pre-vaccination titers) for anti-poliovirus types 1, 2 and 3. (A) The upper limits of the standardized asymptotic 95% CI on the group difference in the percentage of subjects with anti-poliovirus types 1, 2 and 3 titers ≥ 8 are ≤ 10 (predefined criteria for non-inferiority indicated by bold horizontal line); (B) The lower limits of the two-sided 95% CI on the geometric mean of the individual ratios (post- over pre-vaccination titers) for anti-poliovirus types 1, 2 and 3 antibodies are ≥ 2 (predefined criteria for immunogenicity indicated by bold horizontal line). Form 1 received DTPw-HBV-IPV_{(full dose)}/Hib; Form 1/2 received DTPw-HBV-IPV_{(1/2 dose)}/Hib; Form 1/3 received DTPw-HBV-IPV_{(1/3 dose)}/Hib; Controls received DTPw-HBV/Hib Kft + IPV.

Table 3. Seroprotection/seropositivity rates and antibody GMCs before and one month post-booster (ATP cohort for immunogenicity)

Antibody	Group	Pre-vaccination			Post-vaccination
		N	SP/S+	GMC/GMT	N	SP/S+	GMC/GMT
			% (95% CI)	Value (95% CI)		% (95% CI)	Value (95% CI)
Diphtheria	Form 1	78	88.5 (79.2; 94.6)	0.301 (0.237; 0.382)	78	100 (95.4; 100)	6.519 (5.460; 7.783)
	Form 1/2	78	88.5 (79.2; 94.6)	0.331 (0.258; 0.424)	78	100 (95.4; 100)	7.687 (6.112; 9.669)
	Form 1/3	78	88.5 (79.2; 94.6)	0.330 (0.264; 0.412)	78	100 (95.4; 100)	8.659 (7.132; 10.514)
	Control	77	84.4 (74.4; 91.7)	0.374 (0.276; 0.508)	77	100 (95.3; 100)	6.807 (5.231; 8.858)
Tetanus	Form 1	78	100 (95.4; 100)	0.776 (0.639; 0.942)	78	100 (95.4; 100)	26.120 (22.650; 30.121)
	Form 1/2	78	98.7 (93.1; 100)	0.766 (0.622; 0.944)	78	100 (95.4; 100)	31.047 (25.954; 37.139)
	Form 1/3	78	98.7 (93.1; 100)	0.833 (0.668; 1.038)	78	100 (95.4; 100)	31.054 (26.837; 35.934)
	Control	77	98.7 (93.0; 100)	0.932 (0.756; 1.149)	77	100 (95.3; 100)	24.402 (21.042; 28.298)
HBs	Form 1	78	82.1 (71.7; 89.8)	59.9 (40.3; 89.1)	78	98.7 (93.1; 100)	2713.4 (1846.9; 3986.2)
	Form 1/2	78	85.9 (76.2; 92.7)	46.9 (32.8; 67.2)	78	98.7 (93.1; 100)	2395.1 (1630.0; 3519.4)
	Form 1/3	78	79.5 (68.8; 87.8)	61.9 (42.2; 91.0)	78	100 (95.4; 100)	3992.8 (2747.2; 5803.1)*
	Control	77	90.9 (82.2; 96.3)	88.5 (60.7; 129.0)	77	100 (95.3; 100)	3484.3 (2452.2; 4950.8)
PRP	Form 1	78	35.9 (25.3; 47.6)	0.134 (0.109; 0.166)	78	98.7 (93.1; 100)	2.871 (1.797; 4.587)
	Form 1/2	78	34.6 (24.2; 46.2)	0.137 (0.110; 0.172)	78	97.4 (91.0; 99.7)	2.243 (1.520; 3.310)
	Form 1/3	78	38.5 (27.7; 50.2)	0.152 (0.118; 0.197)	78	91.0 (82.4; 96.3)	1.575 (1.065; 2.330)*
	Control	77	45.5 (34.1; 57.2)	0.171 (0.130; 0.226)	77	98.7 (93.0; 100)	3.305 (2.373; 4.603)
BPT	Form 1	76	65.8 (54.0; 76.3)	19.6 (16.4; 23.6)	76	100 (95.3; 100)	161.8 (143.6; 182.3)*
	Form 1/2	78	64.1 (52.4; 74.7)	20.1 (16.5; 24.5)	74	98.6 (92.7; 100)	182.9 (158.0; 211.9)
	Form 1/3	78	65.4 (53.8; 75.8)	18.9 (15.9; 22.4)	77	100 (95.3; 100)	211.0 (190.1; 234.2)
	Control	77	63.6 (51.9; 74.3)	19.5 (16.0; 23.9)	75	100 (95.2; 100)	194.7 (170.6; 222.4)
Polio	Form 1	78	97.4 (91.0; 99.7)	321.1 (231.2; 446.0)	78	100 (95.4: 100)	2218.4 (1786.3; 2755.1)*
type 1	Form 1/2	78	89.7 (80.8; 95.5)	219.1 (144.0; 333.6)	78	98.7 (93.1: 100)	1486.7 (1065.9; 2073.5)*
	Form 1/3	78	94.9 (87.4; 98.6)	296.6 (205.1; 428.8)	78	100 (95.4: 100)	1245.1 (1007.2; 1539.2)*
	Control	77	97.4 (90.9; 99.7)	296.9 (213.9; 412.1)	77	100 (95.3: 100)	3760.2 (2973.7; 4754.7)
Polio	Form 1	78	98.7 (93.1; 100)	186.8 (140.1; 249.2)	77	100 (95.3: 100)	1598.8 (1293.5; 1976.3)*
type 2	Form 1/2	78	96.2 (89.2; 99.2)	152.2 (111.8; 207.3)	78	100 (95.4: 100)	1056.4 (841.5; 1326.1)*
	Form 1/3	78	100 (95.4; 100)	183.4 (146.4; 229.7)	78	100 (95.4: 100)	966.5 (779.5; 1198.3)*
	Control	77	96.1 (89.0; 99.2)	148.0 (112.4; 194.9)	77	100 (95.3: 100)	2883.2 (2275.2; 3653.8)
Polio	Form 1	78	94.9 (87.4; 98.6)	74.5 (56.0; 99.0)	78	98.7 (93.1: 100)	2820.0 (2129.9; 3733.9)
type 3	Form 1/2	78	97.4 (91.0; 99.7)	82.1 (62.1; 108.6)	78	98.7 (93.1: 100)	2217.7 (1654.0; 2973.4)*
	Form 1/3	78	97.4 (91.0; 99.7)	102.1 (77.6; 134.4)	78	100 (95.4: 100)	1915.8 (1498.1; 2449.8)*
	Control	77	90.9 (82.2; 96.3)	79.1 (57.9; 108.1)	77	100 (95.3: 100)	3626.4 (2618.2; 5022.9)

Form 1 received DTPw-HBV-IPV _{(full dose)}/Hib vaccine; Form 1/2 received DTPw-HBV-IPV _{(1/2 dose)}/Hib vaccine; Form 1/3 received DTPw-HBV-IPV _{(1/3 dose)}/Hib vaccine; Controls received DTPw-HBV/Hib Kft and IPV vaccines concomitantly; SP/S+, seroprotection defined as concentration ≥ 0.1 IU/ml for diphtheria and tetanus, ≥ 10 mIU/ml for HBs, ≥ 0.15 μg/ml for PRP, ≥ 1:8 for poliovirus, seropositivity defined as ≥ 15 El.U/ml for BPT; GMC/GMT, geometric mean antibody concentration/titer, calculated for all subjects; N, number of subjects with available results; 95% CI, exact 95% confidence interval; *statistically significant difference post-vaccination between the indicated Form vs. the Control Form (the 95% CI on the adjusted GMC/GMT ratio excluded the value “1”).

Figure 2. Seroconversion rates for poliovirus types 1, 2 and 3 one month post-booster (ATP immunogenicity cohort). *Seroconversion was defined as post-booster antibody titer ≥ 1:8 in initially seronegative subjects, at least a 4-fold increase in post-booster titer in initially seropositive subjects, or a titer greater than the highest dilution tested [1:8192] in subjects with pre-booster antibody titers < 8192). Form 1 received DTPw-HBV-IPV_{(full dose)}/Hib; Form 1/2 received DTPw-HBV-IPV_{(1/2 dose)}/Hib; Form 1/3 received DTPw-HBV-IPV_{(1/3 dose)}/Hib; Controls received DTPw-HBV/Hib Kft + IPV.

Figure 3. Percentage of subjects reporting solicited local and general symptoms during the 8-d post-vaccination follow-up period (total vaccinated cohort). Grade 3 was defined as: Cried when limb is moved/spontaneously painful (pain); injection site diameter > 20 mm (redness/swelling); axillary temperature > 39.0°C (fever); prevented normal daily activities (irritability/fussiness, drowsiness); not eating at all (loss of appetite). Form 1 received DTPw-HBV-IPV_{(full dose)}/Hib; Form 1/2 received DTPw-HBV-IPV_{(1/2 dose)}/Hib; Form 1/3 received DTPw-HBV-IPV_{(1/3 dose)}/Hib; Controls received DTPw-HBV/Hib + IPV.