Immunization with 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) according to different schedules in infants in South Africa: a phase III trial

Figures & data

Figure 1. Study design

OPV and measles vaccines were given as part of the national immunization program and were not considered as study vaccines; W: week; M: month; OPV: oral polio vaccine; HRV: human rotavirus vaccine; DTPw-HBV/Hib: diphtheriatetanus-whole cell pertussis-hepatitis B vaccine combined with lyophilized Haemophilus influenzae type b tetanus conjugate vaccine; PHiD-CV: 10-valent pneumococcal non-typeable H. Influenzae protein D conjugate vaccine; oral vaccination; intramuscular vaccination; blood sample. Note: blood samples taken at visits 8 and 9 were used for serological assessment of DTPw-HBV/Hib pre- and post-booster and of measles before and after administration of the second vaccine dose.

Table 1. Demographic characteristics (total vaccinated cohort)

	3 + 1 (N = 100)	3 + 0 (N = 100)	2 + 1 (N = 100)
Age
At visit 1 (SD), weeks	6.1 (0.41)	6.1 (0.35)	6.1 (0.29)
At visit 2 (SD), weeks	10.2 (0.56)	10.3 (0.58)	–
At visit 3 (SD), weeks	14.3 (0.69)	14.4 (0.73)	14.4 (0.65)
At PHiD-CV booster dose (SD), months	9.0 (0.20)	–	9.0 (0.10)
Gender
Female, n	58	50	47
Race
African heritage/African American, n	100	100	100

N: number of infants in each group; SD: standard deviation; n: number of infants in each category.

Figure 2. Participant Flow Diagram

TVC: total vaccinated cohort; ATP: according-to-protocol; N: number of children per group; n: number of children with the specified characteristic; AE: adverse event; SAE: serious adverse event.

Table 2. Immunogenicity assessed by GSK 22F ELISA for antipneumococcal antibodies and anti-protein D ELISA (ATP cohort for immunogenicity)

		% Children with IgG ≥0.2 µg/mL (95% CI)				GMC (µg/mL) (95% CI)
Age		3 + 1/3 + 0 pooled (N = 185–187)	3 + 1 (N = 92–93)	3 + 0 (N = 89–94)	2 + 1 (N = 96–97)	3 + 1/3 + 0 pooled (N = 185–187)	3 + 1 (N = 92–93)	3 + 0 (N = 89–94)	2 + 1 (N = 96–97)
Vaccine serotypes
1	6 weeks	19.8 (14.3–26.2)	23.7 (15.5–33.6)	16.0 (9.2–25.0)	20.6 (13.1–30.0)	0.08 (0.07–0.10)	0.10 (0.07–0.12)	0.07 (0.06–0.09)	0.08 (0.06–0.10)
	18 weeks	100 (98.0–100)	100 (96.1–100)	100 (96.2–100)	99.0 (94.4–100)	3.96 (3.53–4.44)	3.36 (2.91–3.88)	4.65 (3.91–5.53)	3.33 (2.85–3.88)
	9–10 months	89.8 (84.5–93.7)	88.2 (79.8–93.9)	91.4 (83.8–96.2)	89.7 (81.9–94.9)	0.68 (0.59–0.78)	0.56 (0.46–0.68)	0.83 (0.68–1.01)	0.52 (0.44–0.60)
	10–11 months		100 (96.1–100)	92.5 (85.1–96.9)	100 (96.3–100)		5.38 (4.47–6.48)	0.72 (0.58–0.88)	5.14 (4.42–5.97)
	24–27 months		73.9 (63.7–82.5)	62.2 (51.4–72.2)	67.0 (56.7–76.2)		0.42 (0.34–0.53)	0.28 (0.22–0.37)	0.33 (0.26–0.41)
4	6 weeks	15.5 (10.6–21.5)	16.1 (9.3–25.2)	14.9 (8.4–23.7)	10.3 (5.1–18.1)	0.06 (0.05–0.07)	0.06 (0.05–0.07)	0.06 (0.05–0.08)	0.05 (0.04–0.06)
	18 weeks	100 (98.0–100)	100 (96.1–100)	100 (96.1–100)	99.0 (94.4–100)	3.19 (2.80–3.64)	2.71 (2.28–3.21)	3.77 (3.09–4.60)	2.28 (1.90–2.75)
	9–10 months	94.6 (90.3–97.4)	94.6 (87.9–98.2)	94.6 (87.9–98.2)	94.8 (88.4–98.3)	1.00 (0.87–1.16)	0.89 (0.73–1.08)	1.13 (0.91–1.40)	0.65 (0.55–0.77)
	10–11 months		100 (96.1–100)	93.5 (86.5–97.6)	100 (96.3–100)		6.07 (5.09–7.24)	1.07 (0.86–1.34)	4.92 (4.16–5.81)
	24–27 months		72.8 (62.6–81.6)	59.3 (48.5–69.5)	69.1 (58.9–78.1)		0.44 (0.35–0.57)	0.33 (0.25–0.44)	0.34 (0.27–0.43)
5	6 weeks	15.0 (10.2–20.9)	15.1 (8.5–24.0)	14.9 (8.4–23.7)	11.3 (5.8–19.4)	0.07 (0.06–0.09)	0.07 (0.06–0.09)	0.07 (0.06–0.09)	0.07 (0.05–0.08)
	18 weeks	100 (98.0–100)	100 (96.1–100)	100 (96.2–100)	97.9 (92.7–99.7)	5.02 (4.49–5.62)	4.41 (3.79–5.13)	5.71 (4.84–6.75)	3.45 (2.85–4.16)
	9–10 months	97.8 (94.6–99.4)	98.9 (94.2–100)	96.8 (90.9–99.3)	95.9 (89.8–98.9)	1.27 (1.10–1.45)	1.02 (0.86–1.21)	1.57 (1.28–1.94)	0.99 (0.81–1.20)
	10–11 months		100 (96.1–100)	96.8 (90.9–99.3)	100 (96.3–100)		8.05 (6.70–9.66)	1.44 (1.16–1.77)	6.96 (5.89–8.22)
	24–27 months		85.9 (77.0–92.3)	83.3 (74.0–90.4)	84.5 (75.8–91.1)		0.72 (0.57–0.92)	0.45 (0.36–0.57)	0.52 (0.43–0.64)
6B	6 weeks	31.0 (24.5–38.2)	30.1 (21.0–40.5)	31.9 (22.7–42.3)	20.6 (13.1–30.0)	0.12 (0.10–0.14)	0.13 (0.10–0.16)	0.11 (0.08–0.14)	0.08 (0.06–0.10)
	18 weeks	84.4 (78.4–89.3)	79.6 (69.9–87.2)	89.2 (81.1–94.7)	82.5 (73.4–89.4)	0.83 (0.69–1.01)	0.65 (0.50–0.86)	1.06 (0.81–1.39)	0.57 (0.45–0.73)
	9–10 months	90.9 (85.8–94.6)	88.2 (79.8–93.9)	93.5 (86.5–97.6)	82.5 (73.4–89.4)	0.71 (0.61–0.83)	0.59 (0.47–0.74)	0.86 (0.70–1.06)	0.50 (0.42–0.60)
	10–11 months		93.5 (86.5–97.6)	95.7 (89.4–98.8)	97.9 (92.7–99.7)		2.05 (1.57–2.68)	0.93 (0.75–1.15)	1.98 (1.62–2.42)
	24–27 months		85.9 (77.0–92.3)	82.4 (73.0–89.6)	83.5 (74.6–90.3)		0.60 (0.47–0.77)	0.76 (0.56–1.03)	0.57 (0.44–0.74)
7F	6 weeks	34.4 (27.6–41.7)	35.5 (25.8–46.1)	33.3 (23.9–43.9)	35.1 (25.6–45.4)	0.13 (0.10–0.15)	0.15 (0.11–0.19)	0.11 (0.09–0.14)	0.12 (0.09–0.15)
	18 weeks	100 (98.0–100)	100 (96.1–100)	100 (96.2–100)	99.0 (94.4–100)	4.16 (3.72–4.64)	3.62 (3.12–4.19)	4.77 (4.06–5.60)	2.72 (2.30–3.22)
	9–10 months	100 (98.0–100)	100 (96.1–100)	100 (96.1–100)	95.8 (89.7–98.9)	1.55 (1.38–1.74)	1.40 (1.20–1.63)	1.72 (1.45–2.03)	1.01 (0.85–1.20)
	10–11 months		100 (96.1–100)	98.9 (94.2–100)	100 (96.3–100)		8.98 (7.63–10.56)	1.78 (1.49–2.13)	6.47 (5.59–7.50)
	24–27 months		97.8 (92.4–99.7)	87.9 (79.4–93.8)	95.9 (89.8–98.9)		1.08 (0.92–1.27)	0.67 (0.54–0.83)	0.84 (0.70–1.00)
9V	6 weeks	38.5 (31.5–45.9)	48.4 (37.9–59.0)	28.7 (19.9–39.0)	33.0 (23.8–43.3)	0.14 (0.11–0.18)	0.19 (0.14–0.25)	0.11 (0.08–0.14)	0.13 (0.10–0.18)
	18 weeks	100 (98.0–100)	100 (96.1–100)	100 (96.2–100)	94.8 (88.4–98.3)	3.96 (3.47–4.51)	3.04 (2.51–3.69)	5.13 (4.35–6.04)	2.05 (1.61–2.61)
	9–10 months	97.3 (93.8–99.1)	97.8 (92.4–99.7)	96.8 (90.9–99.3)	89.7 (81.9–94.9)	1.62 (1.40–1.86)	1.47 (1.20–1.81)	1.77 (1.44–2.17)	0.87 (0.70–1.09)
	10–11 months		100 (96.1–100)	97.8 (92.4–99.7)	96.9 (91.2–99.4)		9.55 (8.06–11.31)	1.96 (1.58–2.43)	6.51 (5.12–8.30)
	24–27 months		97.8 (92.4–99.7)	95.6 (89.1–98.8)	90.7 (83.1–95.7)		1.05 (0.86–1.28)	0.85 (0.68–1.06)	0.80 (0.64–1.00)
14	6 weeks	89.3 (84.0–93.3)	92.5 (85.1–96.9)	86.2 (77.5–92.4)	85.6 (77.0–91.9)	1.19 (0.98–1.44)	1.20 (0.92–1.56)	1.18 (0.89–1.55)	1.03 (0.79–1.34)
	18 weeks	100 (98.0–100)	100 (96.1–100)	100 (96.1–100)	97.9 (92.7–99.7)	4.51 (3.92–5.19)	3.85 (3.18–4.68)	5.27 (4.31–6.45)	2.51 (1.98–3.19)
	9–10 months	96.8 (93.1–98.8)	96.8 (90.9–99.3)	96.8 (90.9–99.3)	91.8 (84.4–96.4)	2.85 (2.39–3.40)	2.62 (2.04–3.35)	3.11 (2.41–4.01)	1.40 (1.07–1.83)
	10–11 months		98.9 (94.2–100)	93.5 (86.5–97.6)	96.9 (91.2–99.4)		7.33 (5.94–9.04)	2.60 (2.01–3.37)	5.08 (4.03–6.41)
	24–27 months		96.7 (90.8–99.3)	96.7 (90.7–99.3)	94.8 (88.4–98.3)		1.32 (1.07–1.64)	1.24 (0.96–1.61)	1.06 (0.83–1.36)
18C	6 weeks	37.4 (30.5–44.8)	39.8 (29.8–50.5)	35.1 (25.5–45.6)	35.1 (25.6–45.4)	0.13 (0.11–0.16)	0.13 (0.10–0.18)	0.13 (0.10–0.17)	0.11 (0.08–0.15)
	18 weeks	100 (98.0–100)	100 (96.1–100)	100 (96.2–100)	97.9 (92.7–99.7)	11.54 (9.85–13.53)	10.08 (8.25–12.31)	13.20 (10.31–16.90)	8.65 (6.44–11.60)
	9–10 months	100 (98.0–100)	100 (96.1–100)	100 (96.1–100)	94.8 (88.4–98.3)	3.42 (2.89–4.05)	3.07 (2.47–3.82)	3.80 (2.93–4.94)	3.40 (2.59–4.45)
	10–11 months		100 (96.1–100)	100 (96.1–100)	100 (96.3–100)		25.47 (21.75–29.83)	3.30 (2.55–4.27)	32.29 (26.43–39.45)
	24–27 months		97.8 (92.4–99.7)	90.1 (82.1–95.4)	100 (96.3–100)		1.93 (1.58–2.35)	0.80 (0.63–1.01)	2.44 (1.97–3.02)
19F	6 weeks	79.1 (72.6–84.7)	82.8 (73.6–89.8)	75.5 (65.6–83.8)	67.0 (56.7–76.2)	0.58 (0.48–0.70)	0.60 (0.47–0.77)	0.56 (0.42–0.74)	0.45 (0.34–0.60)
	18 weeks	100 (98.0–100)	100 (96.1–100)	100 (96.1–100)	97.9 (92.7–99.7)	9.78 (8.66–11.04)	8.75 (7.37–10.38)	10.93 (9.20–12.99)	6.90 (5.62–8.48)
	9–10 months	98.4 (95.4–99.7)	97.8 (92.4–99.7)	98.9 (94.2–100)	99.0 (94.4–100)	2.42 (2.10–2.80)	2.32 (1.91–2.82)	2.53 (2.04–3.15)	2.16 (1.74–2.69)
	10–11 months		98.9 (94.2–100)	97.8 (92.4–99.7)	99.0 (94.4–100)		8.88 (7.37–10.69)	2.60 (2.03–3.31)	9.47 (7.42–12.07)
	24–27 months		96.7 (90.8–99.3)	91.2 (83.4–96.1)	99.0 (94.4–100)		2.53 (1.91–3.34)	1.59 (1.15–2.20)	2.22 (1.74–2.84)
23F	6 weeks	36.9 (30.0–44.2)	38.7 (28.8–49.4)	35.1 (25.5–45.6)	19.6 (12.2–28.9)	0.14 (0.11–0.17)	0.16 (0.12–0.21)	0.12 (0.09–0.16)	0.08 (0.06–0.11)
	18 weeks	89.8 (84.5–93.7)	89.2 (81.1–94.7)	90.3 (82.4–95.5)	86.6 (78.2–92.7)	1.21 (1.00–1.46)	0.92 (0.72–1.19)	1.59 (1.21–2.09)	0.97 (0.74–1.27)
	9–10 months	84.9 (79.0–89.8)	82.8 (73.6–89.8)	87.1 (78.5–93.2)	78.4 (68.8–86.1)	0.70 (0.58–0.85)	0.55 (0.43–0.70)	0.90 (0.68–1.21)	0.43 (0.34–0.53)
	10–11 months		92.5 (85.1–96.9)	86.0 (77.3–92.3)	96.9 (91.2–99.4)		3.83 (2.84–5.15)	0.92 (0.68–1.23)	3.40 (2.67–4.33)
	24–27 months		76.1 (66.1–84.4)	72.2 (61.8–81.1)	71.1 (61.0–79.9)		0.51 (0.39–0.67)	0.53 (0.38–0.73)	0.52 (0.37–0.72)
Vaccine-related serotypes
6A	6 weeks	33.2 (26.5–40.4)	35.5 (25.8–46.1)	30.9 (21.7–41.2)	22.7 (14.8–32.3)	0.15 (0.12–0.18)	0.17 (0.13–0.23)	0.13 (0.10–0.16)	0.10 (0.08–0.13)
	18 weeks	29.6 (23.1–36.7)	28.0 (19.1–38.2)	31.2 (22.0–41.6)	24.7 (16.5–34.5)	0.13 (0.11–0.15)	0.12 (0.10–0.15)	0.13 (0.11–0.16)	0.11 (0.09–0.13)
	9–10 months	38.7 (31.7–46.1)	29.0 (20.1–39.4)	48.4 (37.9–59.0)	29.9 (21.0–40.0)	0.15 (0.12–0.18)	0.11 (0.09–0.14)	0.20 (0.15–0.27)	0.10 (0.08–0.13)
	10–11 months		63.4 (52.8–73.2)	51.6 (41.0–62.1)	68.0 (57.8–77.1)		0.36 (0.27–0.49)	0.21 (0.15–0.28)	0.36 (0.28–0.47)
	24–27 months		51.1 (40.4–61.7)	50.5 (39.9–61.2)	45.4 (35.2–55.8)		0.20 (0.15–0.27)	0.25 (0.18–0.36)	0.19 (0.14–0.26)
19A	6 weeks	59.9 (52.5–67.0)	61.3 (50.6–71.2)	58.5 (47.9–68.6)	58.8 (48.3–68.7)	0.29 (0.23–0.35)	0.29 (0.21–0.39)	0.28 (0.21–0.38)	0.27 (0.20–0.35)
	18 weeks	58.4 (50.9–65.6)	54.8 (44.2–65.2)	62.0 (51.2–71.9)	58.8 (48.3–68.7)	0.24 (0.20–0.29)	0.20 (0.16–0.25)	0.29 (0.23–0.38)	0.25 (0.20–0.32)
	9–10 months	49.5 (42.1–56.9)	46.2 (35.8–56.9)	52.7 (42.1–63.1)	50.5 (40.2–60.8)	0.20 (0.16–0.25)	0.17 (0.13–0.21)	0.24 (0.17–0.33)	0.19 (0.14–0.27)
	10–11 months		75.3 (65.2–83.6)	55.9 (45.2–66.2)	82.5 (73.4–89.4)		0.78 (0.57–1.07)	0.26 (0.19–0.37)	1.04 (0.72–1.49)
	24–27 months		66.3 (55.7–75.8)	64.0 (53.2–73.9)	64.9 (54.6–74.4)		0.53 (0.35–0.80)	0.41 (0.28–0.60)	0.58 (0.41–0.83)
Protein D
		% Children with Ab conc. ≥100 EL.U/mL (95% CI)				GMC (EL.U/mL) (95% CI)
	6 weeks	14.5 (9.8–20.4)	14.1 (7.7–23.0)	14.9 (8.4–23.7)	8.2 (3.6–15.6)	60.5 (56.2–65.0)	59.1 (54.0–64.7)	61.9 (55.1–69.5)	57.0 (51.8–62.7)
	18 weeks	100 (98.0–100)	100 (96.1–100)	100 (96.2–100)	97.9 (92.7–99.7)	3822.7 (3457.1–4226.8)	3431.8 (2955.1–3985.4)	4253.1 (3721.0–4861.4)	2240.0 (1871.0–2681.9)
	9–10 months	100 (98.0–100)	100 (96.1–100)	100 (96.1–100)	95.9 (89.8–98.9)	948.6 (841.2–1069.8)	827.7 (701.3–976.8)	1087.3 (914.7–1292.5)	520.9 (434.7–624.2)
	10–11 months		100 (96.1–100)	100 (96.1–100)	99.0 (94.4–100)		4576.5 (3938.2–5318.3)	930.4 (770.0–1124.2)	3141.0 (2619.0–3767.0)
	24–27 months		97.8 (92.4–99.7)	90.1 (82.1–95.4)	86.6 (78.2–92.7)		503.2 (421.0–601.5)	421.3 (334.2–531.1)	323.0 (255.6–408.1)

ELISA: enzyme-linked immunosorbent assay; ATP: according-to-protocol; IgG: immunoglobulin G; CI: confidence interval; GMC: geometric mean concentration; N: range of the numbers of infants with available results at each time point; Ab: antibody; EL.U: ELISA units; 6 weeks: preprimary vaccination; 18 weeks: 1 month postprimary vaccination; 9–10 months: 6 months postprimary vaccination (pre-booster in groups 2 + 1 and 3 + 1); 10–11 months: 7 months postprimary vaccination (1 month post-booster in groups 2 + 1 and 3 + 1); 24–27 months: 21 months postprimary vaccination (15 months post-booster in groups 2 + 1 and 3 + 1).

Table 3. Functional immune response assessed by opsonophagocytic activity assay (ATP cohort for immunogenicity)

		% Children with OPA titer ≥8 (95% CI)				GMT (95% CI)
Age		3 + 1/3 + 0 pooled (N = 169–185)	3 + 1 (N = 79–93)	3 + 0 (N = 76–92)	2 + 1 (N = 79–96)	3 + 1/3 + 0 pooled (N = 169–185)	3 + 1 (N = 79–93)	3 + 0 (N = 76–92)	2 + 1 (N = 79–96)
Vaccine serotypes
1	18 weeks	88.1 (82.6–92.4)	82.8 (73.6–89.8)	93.5 (86.3–97.6)	90.6 (82.9–95.6)	184.5 (143.2–237.7)	127.2 (86.2–187.8)	268.7 (196.7–366.9)	160.6 (117.8–218.8)
	9–10 months	50.5 (43.1–58.0)	41.3 (31.1–52.1)	60.0 (49.1–70.2)	43.2 (33.0–53.7)	20.5 (15.7–26.6)	14.1 (10.0–19.8)	30.0 (20.3–44.4)	14.9 (10.8–20.6)
	10–11 months		100 (96.0–100)	53.9 (43.0–64.6)	98.9 (94.2–100)		1014.8 (768.4–1340.3)	23.5 (16.1–34.4)	1003.6 (763.2–1319.8)
	24–27 months		46.1 (35.4–57.0)	30.6 (21.0–41.5)	39.6 (29.5–50.4)		22.8 (14.9–34.9)	12.3 (8.2–18.6)	13.9 (9.8–19.7)
4	18 weeks	100 (98.0–100)	100 (96.1–100)	100 (96.1–100)	97.9 (92.7–99.7)	1798.6 (1549.1–2088.3)	1711.9 (1367.7–2142.9)	1890.6 (1547.2–2310.2)	774.8 (596.7–1006.0)
	9–10 months	67.2 (59.8–74.1)	64.0 (53.2–73.9)	70.5 (59.8–79.7)	52.2 (41.5–62.7)	52.9 (38.3–73.1)	47.6 (30.2–74.8)	58.9 (36.8–94.3)	23.0 (15.0–35.2)
	10–11 months		98.9 (94.0–100)	82.8 (73.2–90.0)	100 (96.2–100)		2484.7 (1919.0–3217.1)	112.3 (70.8–178.1)	1717.6 (1406.0–2098.2)
	24–27 months		64.6 (53.3–74.9)	35.4 (25.0–47.0)	55.4 (44.1–66.3)		125.5 (69.1–228.2)	21.6 (12.4–37.5)	58.8 (33.0–105.0)
5	18 weeks	95.7 (91.7–98.1)	94.6 (87.9–98.2)	96.7 (90.8–99.3)	94.8 (88.3–98.3)	142.3 (117.9–171.8)	107.4 (81.8–141.0)	189.2 (147.0–243.5)	105.7 (81.6–136.8)
	9–10 months	63.9 (56.4–70.9)	56.2 (45.3–66.7)	71.4 (61.0–80.4)	66.0 (55.5–75.4)	24.6 (19.4–31.1)	18.2 (13.2–25.0)	33.0 (23.5–46.4)	21.7 (15.8–29.8)
	10–11 months		100 (96.0–100)	75.6 (65.4–84.0)	98.9 (94.2–100)		630.2 (447.5–887.7)	30.5 (21.8–42.5)	472.7 (343.5–650.5)
	24–27 months		61.4 (50.4–71.6)	34.9 (24.9–45.9)	55.1 (44.1–65.6)		19.5 (14.2–26.7)	8.6 (6.5–11.3)	13.3 (10.2–17.3)
6B	18 weeks	85.8 (79.9–90.5)	79.3 (69.6–87.1)	92.3 (84.8–96.9)	81.5 (72.1–88.9)	776.7 (548.3–1100.5)	499.5 (286.1–872.2)	1213.7 (808.2–1822.6)	361.2 (221.8–588.2)
	9–10 months	75.7 (68.7–81.8)	68.2 (57.4–77.7)	83.1 (73.7–90.2)	70.9 (60.1–80.2)	214.5 (146.2–314.5)	155.3 (86.5–278.8)	295.2 (179.5–485.4)	84.4 (49.6–143.6)
	10–11 months		92.0 (84.3–96.7)	84.9 (75.5–91.7)	94.7 (88.0–98.3)		1047.2 (679.3–1614.4)	261.5 (161.0–424.7)	945.9 (640.0–1398.2)
	24–27 months		67.5 (56.1–77.6)	72.2 (60.9–81.7)	62.7 (51.3–73.0)		116.6 (63.7–213.3)	87.2 (48.2–157.7)	55.9 (32.0–97.7)
7F	18 weeks	100 (98.0–100)	100 (96.1–100)	100 (96.1–100)	98.9 (94.3–100)	6355.7 (5354.5–7544.2)	5910.5 (4696.9–7437.6)	6834.5 (5280.8–8845.4)	2650.0 (2002.0–3507.9)
	9–10 months	100 (98.0–100)	100 (95.9–100)	100 (96.0–100)	98.9 (94.1–100)	2143.8 (1815.6–2531.3)	2257.7 (1738.2–2932.6)	2037.9 (1650.4–2516.5)	1364.1 (1002.9–1855.4)
	10–11 months		100 (95.9–100)	100 (96.0–100)	100 (96.2–100)		12,108.8 (9922.2–14777.4)	2741.1 (2173.7–3456.5)	6029.3 (4760.9–7635.6)
	24–27 months		100 (95.5–100)	100 (95.3–100)	100 (95.5–100)		6365.0 (5177.2–7825.4)	5601.1 (4334.9–7237.3)	5859.9 (4371.4–7855.2)
9V	18 weeks	98.9 (96.1–99.9)	97.8 (92.4–99.7)	100 (96.1–100)	94.8 (88.3–98.3)	1923.5 (1595.4–2319.2)	1672.2 (1243.6–2248.4)	2216.0 (1760.9–2788.8)	1068.2 (759.2–1503.0)
	9–10 months	94.9 (90.6–97.7)	94.3 (87.2–98.1)	95.6 (89.0–98.8)	79.8 (70.2–87.4)	494.8 (389.5–628.7)	520.3 (366.4–738.9)	471.2 (337.7–657.3)	190.1 (120.6–299.5)
	10–11 months		100 (96.0–100)	97.8 (92.2–99.7)	96.8 (91.0–99.3)		4250.1 (3493.4–5170.8)	492.3 (351.2–690.1)	2572.5 (1890.3–3500.8)
	24–27 months		96.5 (90.0–99.3)	90.5 (82.1–95.8)	91.0 (83.1–96.0)		1060.7 (761.2–1478.1)	412.3 (267.4–635.9)	465.7 (318.2–681.6)
14	18 weeks	97.8 (94.5–99.4)	95.7 (89.2–98.8)	100 (96.1–100)	80.0 (70.5–87.5)	2048.3 (1615.6–2596.8)	1902.7 (1300.9–2782.9)	2205.0 (1648.8–2948.7)	380.9 (228.1–636.0)
	9–10 months	93.1 (88.3–96.4)	95.3 (88.4–98.7)	91.0 (83.1–96.0)	73.3 (63.0–82.1)	362.1 (279.5–469.2)	440.5 (317.8–610.4)	300.4 (201.0–448.8)	83.2 (52.9–131.1)
	10–11 months		100 (95.9–100)	87.4 (78.5–93.5)	100 (96.2–100)		2180.0 (1781.9–2667.0)	280.0 (183.0–428.6)	1152.9 (910.6–1459.6)
	24–27 months		85.7 (76.4–92.4)	82.9 (72.5–90.6)	72.5 (61.4–81.9)		362.3 (229.7–571.6)	361.5 (213.2–613.2)	185.2 (105.8–324.1)
18C	18 weeks	99.5 (97.0–100)	98.9 (94.0–100)	100 (96.1–100)	97.8 (92.4–99.7)	1122.8 (951.1–1325.4)	1046.9 (802.6–1365.5)	1203.2 (981.2–1475.4)	1052.3 (777.7–1423.8)
	9–10 months	78.4 (71.6–84.2)	79.5 (69.6–87.4)	77.3 (67.1–85.5)	78.5 (68.8–86.3)	69.4 (52.4–92.0)	65.2 (43.5–97.8)	73.9 (49.5–110.2)	57.2 (39.2–83.5)
	10–11 months		100 (96.0–100)	77.8 (67.8–85.9)	98.9 (94.2–100)		1344.4 (1074.6–1681.9)	64.5 (44.1–94.3)	1441.3 (1111.7–1868.5)
	24–27 months		71.3 (60.0–80.8)	26.5 (17.4–37.3)	78.2 (67.4–86.8)		48.7 (30.4–78.1)	9.8 (6.6–14.5)	41.6 (27.3–63.3)
19F	18 weeks	98.9 (96.1–99.9)	98.9 (94.1–100)	98.9 (94.1–100)	92.6 (85.4–97.0)	576.5 (473.0–702.6)	511.9 (394.1–664.9)	649.3 (481.1–876.2)	275.9 (193.4–393.5)
	9–10 months	77.8 (71.0–83.6)	75.8 (65.7–84.2)	79.8 (69.9–87.6)	73.1 (62.9–81.8)	46.4 (36.1–59.8)	40.3 (28.3–57.2)	53.7 (37.2–77.6)	36.1 (25.2–51.8)
	10–11 months		95.5 (88.9–98.8)	77.3 (67.1–85.5)	92.6 (85.3–97.0)		730.8 (516.5–1034.1)	46.8 (31.6–69.5)	630.3 (422.9–939.5)
	24–27 months		74.4 (63.9–83.2)	61.0 (49.6–71.6)	69.4 (58.5–79.0)		52.5 (33.2–83.1)	28.2 (17.8–44.6)	47.6 (30.1–75.1)
23F	18 weeks	87.2 (81.4–91.7)	86.4 (77.4–92.8)	88.0 (79.6–93.9)	83.5 (74.3–90.5)	980.7 (689.0–1396.0)	864.1 (511.2–1460.6)	1107.0 (683.0–1794.0)	509.6 (306.8–846.6)
	9–10 months	58.6 (50.8–66.1)	54.8 (43.5–65.7)	62.4 (51.2–72.6)	42.7 (32.3–53.6)	77.7 (50.6–119.3)	59.9 (32.4–110.8)	100.5 (54.9–184.0)	35.2 (19.5–63.7)
	10–11 months		90.0 (81.9–95.3)	64.0 (52.9–74.0)	91.6 (84.1–96.3)		2144.8 (1312.5–3504.8)	83.6 (47.2–148.0)	1557.2 (1012.2–2395.7)
	24–27 months		42.5 (31.5–54.1)	46.2 (34.8–57.8)	48.8 (37.4–60.2)		69.7 (31.7–153.1)	92.7 (40.7–211.2)	103.5 (47.0–227.7)
Vaccine-related serotypes
6A	18 weeks	26.1 (19.9–33.2)	23.6 (15.2–33.8)	28.6 (19.6–39.0)	17.9 (10.8–27.1)	12.9 (9.5–17.5)	12.1 (7.8–18.9)	13.8 (9.1–20.9)	8.1 (5.8–11.3)
	9–10 months	27.2 (20.7–34.4)	22.4 (14.0–32.7)	31.8 (22.3–42.6)	21.6 (13.5–31.6)	13.6 (9.9–18.7)	11.2 (7.3–17.3)	16.5 (10.3–26.3)	10.0 (6.8–14.7)
	10–11 months		47.0 (35.9–58.3)	20.9 (12.9–31.0)	51.1 (40.5–61.5)		40.4 (22.9–71.4)	9.5 (6.5–14.0)	42.2 (25.5–69.9)
	24–27 months		35.4 (25.0–47.0)	22.8 (14.1–33.6)	34.2 (23.9–45.7)		20.5 (12.2–34.3)	15.3 (8.5–27.5)	19.0 (11.4–31.9)
19A	18 weeks	34.4 (27.6–41.8)	32.3 (22.9–42.7)	36.7 (26.8–47.5)	24.2 (16.0–34.1)	12.3 (9.6–15.7)	10.6 (7.7–14.7)	14.2 (9.7–20.8)	7.8 (5.9–10.2)
	9–10 months	15.7 (10.7–21.9)	12.5 (6.4–21.3)	18.9 (11.4–28.5)	10.8 (5.3–18.9)	6.4 (5.3–7.6)	5.7 (4.6–7.1)	7.1 (5.4–9.4)	5.1 (4.3–6.0)
	10–11 months		58.4 (47.5–68.8)	22.5 (14.3–32.6)	57.6 (46.9–67.9)		38.3 (24.1–60.9)	7.9 (5.7–10.9)	36.1 (22.3–58.3)
	24–27 months		47.5 (36.2–59.0)	35.4 (25.1–46.7)	43.2 (32.2–54.7)		25.1 (15.1–41.9)	14.5 (9.4–22.6)	16.8 (10.9–26.0)

OPA: opsonophagocytic activity; ATP: according-to-protocol; CI: confidence interval; GMT: geometric mean titer; N: range of the numbers of infants with available results at each time point; 18 weeks: 1 month postprimary vaccination; 9–10 months: 6 months postprimary vaccination (pre-booster in groups 2 + 1 and 3 + 1); 10–11 months: 7 months postprimary vaccination (1 month post-booster in groups 2 + 1 and 3 + 1); 24–27 months: 21 months postprimary vaccination (15 months post-booster in groups 2 + 1 and 3 + 1).

Figure 3. Kinetics of anti-pneumococcal antibody GMCs (ATP cohort for immunogenicity)

GMC: geometric mean concentration; ATP: according-to-protocol; W: weeks; M: months; 6W: pre-primary vaccination; 18W: 1 month post-primary vaccination; 9–10M: 6 months post-primary vaccination (pre-booster in groups 2+1 and 3+1); 10–11M: 7 months post-primary vaccination (1 month post-booster in groups 2+1 and 3+1); 24–27M: 21 months post-primary vaccination (15 months post-booster in groups 2+1 and 3+1). Note: Error bars indicate 95% confidence intervals. Data for the groups are slightly shifted for better visualization.

Figure 4. Kinetics of anti-pneumococcal OPA GMTs (ATP cohort for immunogenicity)

OPA: opsonophagocytic activity; GMT: geometric mean titer; ATP: according-to-protocol; W: weeks; M: months; 18W: 1 month post-primary vaccination; 9–10M: 6 months post-primary vaccination (pre-booster in groups 2+1 and 3+1); 10–11M: 7 months post-primary vaccination (1 month post-booster in groups 2+1 and 3+1); 24–27M: 21 months post-primary vaccination (15 months post-booster in groups 2+1 and 3+1). Note: Error bars indicate 95% confidence intervals. Data for the groups are slightly shifted for better visualization.

Figure 5. Solicited local and general symptoms (overall per dose; total vaccinated cohort)

N: number of doses (primary/booster). Vomiting and diarrhea were solicited due to co-administration of human rotavirus vaccine and were thus only solicited after visit 2 and visit 3 (i.e. interpretation of the overall/dose results has to be done with caution considering N being the sum of the 3 primary doses). The other general symptoms were solicited at visits 1, 2, and 3, even for the 2+1 group who did not receive PHiD-CV but DTPw-HBV/Hib, human rotavirus, and oral polio vaccines at visit 2. Note: Error bars indicate exact 95% confidence intervals.