Immunogenicity and safety of a combined DTPa-IPV/Hib vaccine administered as a three-dose primary vaccination course in healthy Korean infants: phase III, randomized study

Figures & data

Table 1. Demographic characteristics (total vaccinated cohort).

	DTPa-IPV/Hib group N = 224	DTPa-IPV+ Hib group N = 227	Total N = 451
Age at dose 1 (weeks), mean (SD)	8.8 (1.1)	8.8 (1.1)	8.8 (1.1)
Female/male, %	43.3/56.7	50.7/49.3	47.0/53.0
Race*, n/%
Asian – East Asian	224 (100)	226 (99.6)	450 (99.8)

N, number of participants; n/%, number/percentage of participants in a given category; SD, standard deviation.

Infants in DTPa-IPV/Hib group received 3 doses of combined diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis and Haemophilus influenzae type b vaccine at 2, 4, 6 months of age and infants in DTPa-IPV+ Hib group received 3 concomitant doses of diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis vaccine and Haemophilus influenzae type b vaccine at 2, 4, 6 months of age.

*One participant from the DTPa-IPV+ Hib group had another heritage (not further specified).

Figure 1. Participant flow diagram.

N, number of participants in each group; TVC, total vaccinated cohort; ATP, according-to-protocol. Infants in DTPa-IPV/Hib group received 3 doses of combined diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis and Haemophilus influenzae type b vaccine at 2, 4, 6 months of age and infants in DTPa-IPV+ Hib group received 3 concomitant doses of diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis vaccine and Haemophilus influenzae type b vaccine at 2, 4, 6 months of age.

Table 2. Group differences in seroprotection/seropositivity rates and adjusted GMC ratio 1M post-dose 3 (ATP immunogenicity cohort).

	DTPa-IPV+ Hib group N = 217	DTPa-IPV/Hib group N = 213	Difference between groups (DTPa-IPV+ Hib minus DTPa-IPV/Hib)
Antibody	n (%)	n (%)	% (95% CI)
Anti-D	217 (100)	213 (100)	0.00 (−1.74–1.78)
Anti-T	217 (100)	213 (100)	0.00 (−1.74–1.78)
Anti-Polio 1	216 (100)	212 (100)	0.00 (−1.75–1.78)
Anti-Polio 2	211 (100)	204 (100)	0.00 (−1.79–1.85)
Anti-Polio 3	197 (99.0)	197 (99.5)	−0.50 (−3.14–1.89)
Anti-PRP	217 (100)	213 (100)	0.00 (−1.74–1.78)
	Adjusted GMC (EL.U/mL)		Adjusted GMC ratio (DTPa-IPV+ Hib over DTPa-IPV/Hib)
			Value (95% CI)
Anti-PT	56.2	54.3	1.04 (0.93–1.15)
Anti-FHA	134.6	124.2	1.08 (0.97–1.21)
Anti-PRN	134.4	124.9	1.08 (0.96–1.21)

M, month; ATP, according-to-protocol; N, maximum number of participants with available results; n (%), number (percentage) of participants with antibody concentrations above the specified cut-off; CI, confidence interval; EL.U/mL, ELISA units per milliliter; anti-D, anti-diphtheria toxoid; anti-T, anti-tetanus toxoid; PRP, polyribosyl-ribitol phosphate; PT, pertussis toxoid; FHA, filamentous hemagglutinin; PRN, pertactin; Adjusted GMC, geometric mean antibody concentration adjusted for baseline concentration.

Infants in DTPa-IPV/Hib group received 3 doses of combined diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis and Haemophilus influenzae type b vaccine at 2, 4, 6 months of age and infants in DTPa-IPV+ Hib group received 3 concomitant doses of diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis vaccine and Haemophilus influenzae type b vaccine at 2, 4, 6 months of age.

Bolded values indicate that the non-inferiority criteria (upper limits (ULs) of 95% confidence intervals (CIs) of group differences in seroprotection rates [DTPa-IPV+ Hib group minus DTPa-IPV/Hib group] for all antigens ≤ 10% and ULs of 95% CIs of GMC ratios [DTPa-IPV+ Hib group over DTPa-IPV/Hib group] for pertussis antigens ≤ 1.5) have been met.

Table 3. Seroprotection/seropositivity rates and GMCs/GMTs at pre-vaccination and 1M post-dose 3 (ATP immunogenicity cohort).

			DTPa-IPV/Hib group						DTPa-IPV+ Hib group
			Seroprotection/seropositivity						Seroprotection/seropositivity
Antibody		Time-point	N	n	%	95% CI	GMC/GMT	95% CI	N	n	%	95% CI	GMC/GMT	95% CI
Anti-D ≥ 0.1 IU/mL		Pre	213	29	13.6	9.3–19.0	0.058	0.055–0.061	217	30	13.8	9.5–19.1	0.060	0.056–0.064
		Post	213	213	100	98.3–100	8.096	7.520–8.717	217	217	100	98.3–100	8.692	8.125–9.298
Anti-T ≥ 0.1 IU/mL		Pre	213	64	30.0	24.0–36.7	0.081	0.072–0.090	217	76	35.0	28.7–41.8	0.091	0.080–0.103
		Post	213	213	100	98.3–100	10.259	9.654–10.902	217	217	100	98.3–100	12.421	11.599–13.301
Anti-Polio (≥ 8 ED50)	Type 1	Pre	211	104	49.3	42.4–56.2	9.5	8.3–11.0	216	89	41.2	34.6–48.1	9.4	8.0–11.0
		Post	212	212	100	98.3–100	328.8	289.8–373.1	216	216	100	98.3–100	372.7	323.8–428.9
	Type 2	Pre	211	119	56.4	49.4–63.2	10.8	9.4–12.5	214	108	50.5	43.6–57.4	8.8	7.7–9.9
		Post	204	204	100	98.2–100	340.6	295.4–392.6	211	211	100	98.3–100	400.2	347.6–460.7
	Type 3	Pre	211	41	19.4	14.3–25.4	5.5	5.0–6.1	216	31	14.4	10.0–19.7	4.9	4.5–5.3
		Post	198	197	99.5	97.2–100	377.7	322.3–442.6	199	197	99.0	96.4–99.9	465.3	390.3–554.7
Anti-PT (≥ 5 EL.U/mL)	PT	Pre	212	27	12.7	8.6–18.0	3.0	2.8–3.2	216	34	15.7	11.2–21.3	3.1	2.9–3.3
		Post	213	213	100	98.3–100	54.2	50.4–58.3	217	217	100	98.3–100	56.0	51.8–60.5
	FHA	Pre	211	170	80.6	74.6–85.7	10.5	9.3–12.0	214	178	83.2	77.5–87.9	11.7	10.3–13.3
		Post	213	213	100	98.3–100	125.0	115.4–135.4	217	217	100	98.3–100	134.2	124.2–145.0
	PRN	Pre	213	25	11.7	7.7–16.8	2.9	2.7–3.0	217	30	13.8	9.5–19.1	3.1	2.8–3.3
		Post	213	213	100	98.3–100	125.8	116.0–136.5	217	217	100	98.3–100	133.4	123.0–144.6
Anti-PRP	≥ 0.15 µg/mL	Pre	213	91	42.7	36.0–49.7	0.165	0.143–0.191	217	109	50.2	43.4–57.1	0.219	0.184–0.260
		Post	213	213	100	98.3–100	8.456	7.283–9.819	217	217	100	98.3–100	18.700	16.353–21.384
	≥ 1.0 µg/mL	Pre	213	14	6.6	3.6–10.8	0.165	0.143–0.191	217	30	13.8	9.5–19.1	0.219	0.184–0.260
		Post	213	208	97.7	94.6–99.2	8.456	7.283–9.819	217	217	100	98.3–100	18.700	16.353–21.384

M, month; ATP, according-to-protocol; N, number of participants with available results; n (%), number (percentage) of participants with concentration ≥ required threshold; GMC/GMT, geometric mean antibody concentration/titer; CI, confidence interval; EL.U/mL, ELISA units per milliliter; ED₅₀, median effective dose; IU/mL, international units per milliliter; Pre, blood sample collected before the first dose of the primary vaccination course; Post, blood sample collected after the third dose of the primary vaccination course; anti-D, anti-diphtheria; anti-T, anti-tetanus; PT, pertussis toxoid; FHA, filamentous hemagglutinin; PRN, pertactin; PRP, polyribosyl-ribitol phosphate.

The DTPa-IPV/Hib group received the combined DTPa-IPV/Hib vaccine at 2, 4 and 6 months of age.

The DTPa-IPV+ Hib group received the DTPa-IPV and Hib vaccines separately at 2, 4 and 6 months of age.

Table 4. Vaccine response rate to anti-PT, anti-FHA and anti-PRN antibodies 1M post-dose 3 (ATP immunogenicity cohort).

	% Vaccine response (95% CI)
Antibody	DTPa-IPV/Hib group (CI 95%)	DTPa-IPV+ Hib group (CI 95%)
Anti-PT	99.5 (97.4–100)	99.5 (97.4–100)
Anti-FHA	98.1 (95.2–99.5)	96.7 (93.4–98.7)
Anti-PRN	100 (98.3–100)	99.5 (97.5–100)

M, month; ATP, according-to-protocol; %, percentage of infants with vaccine response; CI, confidence interval; PT, pertussis toxoid; FHA, filamentous hemagglutinin; PRN, pertactin.

Infants in DTPa-IPV/Hib group received 3 doses of combined diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis and Haemophilus influenzae type b vaccine at 2, 4, 6 months of age and infants in DTPa-IPV+ Hib group received 3 concomitant doses of diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis vaccine and Haemophilus influenzae type b vaccine at 2, 4, 6 months of age.

Vaccine response was defined as an antibody concentration ≥ 5 EL.U/mL post-dose 3 for initially seronegative infants, or ≥ 1-fold increase the pre-vaccination antibody concentration for initially seropositive infants.

Figure 2. Incidence of solicited local and general symptoms reported up to 4 days post-vaccination (total vaccinated cohort).

Infants in DTPa-IPV/Hib group received 3 doses of combined diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis and Haemophilus influenzae type b vaccine at 2, 4, 6 months of age and infants in DTPa-IPV+ Hib group received 3 concomitant doses of diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis vaccine and Haemophilus influenzae type b vaccine at 2, 4, 6 months of age. The results are reported overall/dose. The error bars indicate 95% confidence intervals. Grade 3 were defined as adverse events preventing normal activity, pain upon limb movement or a spontaneously painful limb, redness and swelling >20 mm in diameter, a tympanic temperature >39.0°C, loss of appetite resulting in not eating at all, drowsiness that prevented normal activity, and irritability/fussiness resulting in crying that cannot be comforted.