Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine administered in a prime-boost regimen among Chinese infants: a randomized, double blind phase III clinical trial

Figures & data

Table 1. Baseline demographics of study population

Characteristics	Group T	Group C	Total	P
Age at first dose (days)	59.75 ± 10.42	59.45 ± 10.27	59.60 ± 10.34	.6136
Age at booster dose (months)	13.11 ± 0.61	13.11 ± 0.61	13.11 ± 0.61	.8571
Sex at first dose
Male	321 (53.50)	327 (54.50)	648 (54.00)	.7282
Female	279 (46.50)	273 (45.50)	552 (46.00)
Sex at booster dose
Male	277 (53.58)	281 (53.73)	558 (53.65)	.9613
Female	240 (46.42)	242 (46.27)	482 (46.35)
Body length at first dose (cm)	58.83 ± 2.69	58.80 ± 2.59	58.81 ± 2.64	.8698
Body length at booster dose (cm)	77.18 ± 2.87	77.00 ± 2.95	77.09 ± 2.91	.2985
Weight at first dose (kg)	5.88 ± 0.81	5.85 ± 0.76	5.87 ± 0.79	.4815
Weight at booster dose (kg)	10.12 ± 1.18	10.01 ± 1.17	10.06 ± 1.17	.1230
Axillary temperature before first dose (°C)	36.71 ± 0.23	36.71 ± 0.23	36.71 ± 0.23	.9799
Axillary temperature before booster dose (°C)	36.64 ± 0.32	36.65 ± 0.31	36.64 ± 0.31	.8319
Data are mean ± SD or n(%).

Figure 1. Screening, randomization, and inclusion in safety and immunogenicity analyses.

Table 2. Type-specific seropositive rates, GMC and GMI pre- and postprimary vaccination

Serotype	Group	Preprimary vaccination				Postprimary vaccination
		Seropositive rate n, % (95% CI)	P	GMC (95% CI)	P	Seropositive rate n, % (95% CI)	P	GMC (95% CI)	P	GMI (95% CI)	P
1	T	135,25.57 (21.90–29.51)	.1649	0.14 (0.12–0.16)	.0368	528, 100.0 (99.30–100.0)	.3185	5.90 (5.53–6.31)	<.0001	42.12 (35.42–50.08)	<.0001
	C	156,29.38 (25.53–33.45)		0.17 (0.15–0.20)		530,99.81 (98.96–100.0)		4.28 (4.02–4.56)		24.60 (21.21–28.53)
3	T	39,7.39 (5.30–9.96)	.6119	0.10 (0.08–0.11)	.2561	528, 100.0 (99.30–100.0)	<.0001	2.06 (1.96–2.16)	<.0001	21.62 (18.98–24.62)	<.0001
	C	35, 6.59 (4.63–9.05)		0.10 (0.09–0.12)		496,93.41 (90.95–95.37)		0.85 (0.80–0.89)		8.11 (7.18–9.16)
4	T	66,12.50 (9.80–15.63)	.5477	0.07 (0.06–0.08)	.0515	528, 100.0 (99.30–100.0)	.2496	4.88 (4.54–5.24)	<.0001	70.62 (58.18–85.73)	<.0001
	C	73,13.75 (10.93–16.97)		0.09 (0.07–0.10)		528,99.44 (98.36–99.88)		2.25 (2.12–2.39)		25.95 (21.93–30.69)
5	T	81,15.34 (12.37–18.70)	.5178	0.09 (0.08–0.11)	.0092	528, 100.0 (99.30–100.0)	.1343	2.79 (2.63–2.96)	<.0001	30.51 (25.60–36.36)	<.0001
	C	74,13.94 (11.10–17.18)		0.12 (0.11–0.14)		527,99.25 (98.08–99.79)		2.00 (1.89–2.12)		16.56 (14.23–19.26)
6A	T	223,42.23 (37.98–46.58)	.8171	0.22 (0.19–0.25)	.2446	523,99.05 (97.80–99.69)	.2521	4.35 (4.02–4.70)	.0038	19.81 (16.64–23.58)	.0218
	C	228,42.94 (38.68–47.27)		0.25 (0.22–0.28)		529,99.62 (98.65–99.95)		3.74 (3.49–4.00)		15.13 (13.02–17.59)
6B	T	377,71.40(67.34–75.22)	.9536	0.48(0.44–0.53)	.8761	525,99.43(98.35–99.88)	.7101	5.09(4.68–5.54)	.0001	10.49(9.22–11.95)	.0066
	C	380,71.56(67.52–75.37)		0.49(0.45–0.53)		527,99.25(98.08–99.79)		4.04(3.75–4.35)		8.24(7.34–9.26)
7 F	T	255,48.30(43.96–52.65)	.8757	0.29(0.26–0.32)	.4635	527,99.81(98.95–100.0)	.9968	5.60(5.27–5.95)	.0009	19.58(17.24–22.24)	.2656
	C	259,48.78(44.45–53.12)		0.30(0.27–0.33)		530,99.81(98.96–100.0)		6.54(6.11–7.00)		21.64(19.16–24.45)
9 V	T	292,55.30(50.95–59.60)	.9676	0.32(0.28–0.35)	.3977	527,99.81(98.95–100.0)	.9968	5.90(5.49–6.34)	<.0001	18.69(16.34–21.37)	<.0001
	C	293,55.18(50.84–59.46)		0.29(0.26–0.33)		530,99.81(98.96–100.0)		3.15(2.95–3.36)		10.71(9.32–12.31)
14	T	505,95.64(93.54–97.22)	.5166	1.48(1.35–1.62)	.9427	528, 100.0(99.30–100.0)	1.0000	21.72(19.86–23.76)	.0023	14.69(12.63–17.09)	.0733
	C	512,96.42(94.47–97.83)		1.47(1.35–1.60)		531,100.0(99.31–100.0)		18.06(16.71–19.52)		12.27(10.80–13.94)
18 C	T	282,53.41(49.05–57.73)	.7400	0.28(0.25–0.31)	.7550	522,98.86(97.54–99.58)	.5193	4.54(4.17–4.94)	.0002	16.31(13.89–19.15)	.0272
	C	289,54.43(50.08–58.72)		0.29(0.25–0.32)		527,99.25(98.08–99.79)		3.65(3.38–3.94)		12.76(11.01–14.79)
19A	T	503,95.27(93.09–96.91)	.9836	0.93(0.85–1.01)	.0723	528, 100.0(99.30–100.0)	1.0000	6.33(5.92–6.78)	<.0001	6.83(6.08–7.67)	<.0001
	C	506,95.29(93.13–96.93)		1.03(0.96–1.10)		531,100.0(99.31–100.0)		4.98(4.67–5.30)		4.84(4.37–5.36)
19 F	T	476,90.15(87.29–92.56)	.0401	0.81(0.75–0.87)	.5138	528, 100.0(99.30–100.0)	1.0000	10.95(10.23–11.71)	<.0001	13.50(12.18–14.96)	<.0001
	C	497,93.60(91.17–95.53)		0.84(0.79–0.89)		531,100.0(99.31–100.0)		5.43(5.12–5.77)		6.48(5.92–7.10)
23 F	T	265,50.19(45.84–54.54)	.4437	0.34(0.32–0.37)	.8197	527,99.81(98.95–100.0)	.9968	7.38(6.77–8.03)	<.0001	21.44(18.84–24.39)	<.0001
	C	279,52.54(48.20–56.86)		0.35(0.32–0.38)		530,99.81(98.96–100.0)		4.49(4.13–4.87)		12.85(11.22–14.71)

GMC = geometric mean concentration; IgG = immunoglobulin G; n = number of subjects with a determinate IgG antibody concentration for the given serotype;

Seropositive rates = percentage of IgG responders (IgG ≥0.35 µg/mL).

The P value in bold font means there is a significant difference between those two groups.

Table 3. Type-specific seropositive rates, GMC and GMI pre- and postbooster vaccination

Serotype	Group	Prebooster vaccination				Postbooster vaccination
		Seropositive rate n, % (95% CI)	P	GMC (95% CI)	P	Seropositive rate n, % (95% CI)	P	GMC (95% CI)	P	GMI (95% CI)	P
1	T	459,99.14(97.80–99.76)	1.0000	1.32(1.25–1.40)	.0507	463,100.0(99.21–100.0)	1.0000	8.15(7.64–8.68)	.0022	6.16(5.80–6.55)	<.0001
	C	452,99.34(98.09–99.86)		1.43(1.36–1.50)		455,100.0(99.19–100.0)		6.99(6.50–7.53)		4.90(4.62–5.21)
3	T	301,65.01(60.47–69.36)	.0001	0.44(0.42–0.47)	<.0001	463,100.0(99.21–100.0)	.2454	2.96(2.79–3.14)	<.0001	6.67(6.30–7.07)	<.0001
	C	238,52.31(47.61–56.98)		0.37(0.35–0.39)		453,99.56(98.42–99.95)		1.78(1.66–1.90)		4.78(4.54–5.03)
4	T	434,93.74(91.13–95.77)	.0144	0.96(0.90–1.03)	<.0001	463,100.0(99.21–100.0)	1.0000	6.40(5.94–6.89)	<.0001	6.66(6.23–7.11)	<.0001
	C	406,89.23(86.01–91.93)		0.74(0.70–0.78)		455,100.0(99.19–100.0)		3.95(3.65–4.27)		5.33(5.00–5.68)
5	T	449,96.98(94.98–98.34)	.5726	0.91(0.87–0.95)	.0389	463,100.0(99.21–100.0)	1.0000	4.18(3.95–4.43)	<.0001	4.59(4.39–4.81)	<.0001
	C	444,97.58(95.72–98.79)		0.85(0.82–0.89)		455,100.0(99.19–100.0)		3.18(2.97–3.40)		3.74(3.54–3.94)
6A	T	453,97.84(96.06–98.96)	.6608	1.35(1.28–1.44)	.0989	463,100.0(99.21–100.0)	.4956	8.45(7.83–9.13)	.0002	6.24(5.86–6.65)	.0033
	C	447,98.24(96.57–99.24)		1.26(1.19–1.34)		454,99.78(98.78–99.99)		6.89(6.38–7.44)		5.45(5.12–5.81)
6B	T	461,99.57(98.45–99.95)	1.0000	1.96(1.85–2.07)	.0092	463,100.0(99.21–100.0)	1.0000	13.41(12.43–14.47)	.0004	6.86(6.45–7.29)	.0314
	C	454,99.78(98.78–99.99)		1.76(1.66–1.86)		455,100.0(99.19–100.0)		10.93(10.05–11.89)		6.22(5.83–6.64)
7 F	T	454,98.06(96.34–99.11)	.0038	1.26(1.20–1.32)	<.0001	463,100.0(99.21–100.0)	1.0000	8.06(7.61–8.53)	.0114	6.42(6.03–6.83)	<.0001
	C	455,100.0(99.19–100.0)		1.97(1.87–2.08)		455,100.0(99.19–100.0)		7.19(6.72–7.69)		3.65(3.45–3.85)
9 V	T	455,98.27(96.62–99.25)	.0616	1.19(1.12–1.27)	.0004	463,100.0(99.21–100.0)	1.0000	10.42(9.72–11.17)	<.0001	8.73(8.21–9.29)	<.0001
	C	438,96.26(94.09–97.81)		1.02(0.96–1.09)		455,100.0(99.19–100.0)		5.68(5.27–6.11)		5.56(5.25–5.88)
14	T	463,100.0(99.21–100.0)	1.0000	5.23(4.92–5.56)	.0003	463,100.0(99.21–100.0)	1.0000	34.21(32.25–36.28)	<.0001	6.54(6.14–6.96)	<.0001
	C	455,100.0(99.19–100.0)		6.10(5.77–6.45)		455,100.0(99.19–100.0)		20.43(19.14–21.82)		3.35(3.15–3.56)
18 C	T	430,92.87(90.14–95.04)	.6491	0.89(0.83–0.95)	.1095	463,100.0(99.21–100.0)	.4956	5.97(5.61–6.36)	.0029	6.75(6.32–7.21)	<.0001
	C	426,93.63(90.97–95.69)		0.96(0.90–1.02)		454,99.78(98.78–99.99)		5.13(4.75–5.55)		5.37(5.06–5.70)
19A	T	461,99.57(98.45–99.95)	.4995	2.47(2.31–2.64)	.0497	463,100.0(99.21–100.0)	1.0000	18.74(17.52–20.05)	<.0001	7.58(7.07–8.14)	<.0001
	C	455,100.0(99.19–100.0)		2.25(2.09–2.41)		455,100.0(99.19–100.0)		12.95(12.04–13.94)		5.77(5.38–6.19)
19 F	T	463,100.0(99.21–100.0)	1.0000	3.04(2.86–3.23)	<.0001	463,100.0(99.21–100.0)	1.0000	19.77(18.55–21.07)	<.0001	6.51(6.08–6.97)	<.0001
	C	455,100.0(99.19–100.0)		2.22(2.10–2.35)		455,100.0(99.19–100.0)		9.95(9.28–10.67)		4.48(4.19–4.80)
23 F	T	461,99.57(98.45–99.95)	.1049	1.93(1.81–2.06)	.0032	463,100.0(99.21–100.0)	1.0000	10.54(9.83–11.31)	.3278	5.46(5.14–5.81)	<.0001
	C	448,98.46(96.86–99.38)		1.67(1.56–1.79)		455,100.0(99.19–100.0)		11.12(10.25–12.06)		6.66(6.22–7.13)

GMC = geometric mean concentration; IgG = immunoglobulin G; n = number of subjects with a determinate IgG antibody concentration for the given serotype;

Seropositive rates = percentage of IgG responders (IgG ≥0.35 µg/mL)

The P value in bold font means there is a significant difference between those two groups.

Table 4. Percentage of participants with OPA≥1:8 pre- and postprimary and booster vaccination

Serotype	Group	Preprimary vaccination		Postprimary vaccination		Prebooster vaccination		Postbooster vaccination
		Percentage n, % (95% CI)	P	Percentage n, % (95% CI)	P	Percentage n, % (95% CI)	P	Percentage n, % (95% CI)	P
1	T	4,3.88(1.07–9.65)	.7453	102,99.03(94.71–99.98)	1.0000	92,90.20(82.71–95.20)	.8931	102,100.0(96.45–100.0)	1.0000
	C	5,5.00(1.64–11.28)		99,99.00(94.55–99.97)		98,90.74(83.63–95.47)		108,100.0(96.64–100.0)
3	T	27,26.21(18.04–35.80)	.3821	103,100.0(96.48–100.0)	1.0000	102,100.0(96.45–100.0)	1.0000	102,100.0(96.45–100.0)	1.0000
	C	21,21.00(13.49–30.29)		100,100.0(96.38–100.0)		107,99.07(94.95–99.98)		108,100.0(96.64–100.0)
4	T	9,8.74(4.07–15.94)	.4455	103,100.0(96.48–100.0)	1.0000	102,100.0(96.45–100.0)	1.0000	102,100.0(96.45–100.0)	1.0000
	C	12,12.00(6.36–20.02)		100,100.0(96.38–100.0)		108,100.0(96.64–100.0)		108,100.0(96.64–100.0)
5	T	10,9.71(4.75–17.13)	.1998	103,100.0(96.48–100.0)	1.0000	101,99.02(94.66–99.98)	1.0000	102,100.0(96.45–100.0)	1.0000
	C	5,5.00(1.64–11.28)		100,100.0(96.38–100.0)		107,99.07(94.95–99.98)		108,100.0(96.64–100.0)
6A	T	33,32.04(23.18–41.96)	.6549	100,97.09(91.72–99.40)	.2465	101,99.02(94.66–99.98)	1.0000	101,99.02(94.66–99.98)	.4857
	C	35,35.00(25.73–45.18)		100,100.0(96.38–100.0)		107,99.07(94.95–99.98)		108,100.0(96.64–100.0)
6B	T	55,53.40(43.30–63.29)	.7324	103,100.0(96.48–100.0)	.4926	102,100.0(96.45–100.0)	.2470	102,100.0(96.45–100.0)	.1220
	C	51,51.00(40.80–61.14)		99,99.00(94.55–99.97)		105,97.22(92.10–99.42)		104,96.30(90.79–98.98)
7 F	T	31,30.10(21.45–39.92)	.5161	103,100.0(96.48–100.0)	1.0000	101,99.02(94.66–99.98)	.4857	102,100.0(96.45–100.0)	1.0000
	C	26,26.00(17.74–35.73)		100,100.0(96.38–100.0)		108,100.0(96.64–100.0)		108,100.0(96.64–100.0)
9 V	T	16,15.53(9.15–24.00)	.2382	103,100.0(96.48–100.0)	.4926	102,100.0(96.45–100.0)	1.0000	102,100.0(96.45–100.0)	1.0000
	C	10,10.00(4.90–17.62)		99,99.00(94.55–99.97)		108,100.0(96.64–100.0)		108,100.0(96.64–100.0)
14	T	72,69.90(60.08–78.55)	.3712	102,99.03(94.71–99.98)	1.0000	98,96.08(90.26–98.92)	.4347	102,100.0(96.45–100.0)	1.0000
	C	64,64.00(53.79–73.36)		100,100.0(96.38–100.0)		106,98.15(93.47–99.77)		108,100.0(96.64–100.0)
18 C	T	36,34.95(25.82–44.98)	.2865	102,99.03(94.71–99.98)	1.0000	102,100.0(96.45–100.0)	1.0000	102,100.0(96.45–100.0)	1.0000
	C	28,28.00(19.48–37.87)		99,99.00(94.55–99.97)		108,100.0(96.64–100.0)		108,100.0(96.64–100.0)
19A	T	42,40.78(31.20–50.90)	.0257	102,99.03(94.71–99.98)	1.0000	102,100.0(96.45–100.0)	1.0000	102,100.0(96.45–100.0)	1.0000
	C	26,26.00(17.74–35.73)		100,100.0(96.38–100.0)		107,99.07(94.95–99.98)		108,100.0(96.64–100.0)
19 F	T	34,33.01(24.06–42.97)	.0793	102,99.03(94.71–99.98)	1.0000	101,99.02(94.66–99.98)	.2132	102,100.0(96.45–100.0)	.2470
	C	22,22.00(14.33–31.39)		99,99.00(94.55–99.97)		103,95.37(89.53–98.48)		105,97.22(92.10–99.42)
23 F	T	20,19.42(12.28–28.38)	.9398	101,98.06(93.16–99.76)	.4404	100,98.04(93.10–99.76)	1.0000	101,99.02(94.66–99.98)	.6220
	C	19,19.00(11.84–28.07)		96,96.00(90.07–98.90)		105,97.22(92.10–99.42)		105,97.22(92.10–99.42)

The P value in bold font means there is a significant difference between those two groups.

Table 5. Overall profiles of adverse events after primary and booster vaccination

Event n (%)	Postprimary vaccination			Postbooster vaccination
	Group T (N = 600)	Group C (N = 600)	P	Group T (N = 517)	Group C (N = 523)	P
Serious adverse events	5(0.83)	13(2.17)	.0938	1(0.19)	2(0.38)	1.0000
Overall adverse events	458(76.33)	497(82.83)	.0064	207(40.04)	253(48.37)	.0073
Unsolicited adverse reactions	84(14.00)	68(11.33)	.1928	12(2.32)	12(2.29)	1.0000
Solicited adverse reactions	432(72.00)	479(79.83)	.0019	199(38.49)	249(47.61)	.0032
Grade 3	21(3.50)	22(3.67)	1.0000	11(2.13)	21(4.02)	.1049
Injection-site adverse reactions	262(43.67)	296(49.33)	.0561	97(18.76)	101(19.31)	.8745
Grade 3	17(2.83)	16(2.67)	1.0000	9(1.74)	13(2.49)	.5191
Redness	216(36.00)	256(42.67)	.0211	76(14.70)	88(16.83)	.3509
Grade 3	13(2.17)	15(2.50)	.8488	7(1.35)	10(1.91)	.6263
Pain	31(5.17)	18(3.00)	.0791	8(1.55)	12(2.29)	.4994
Induration	151(25.17)	129(21.50)	.1517	46(8.90)	37(7.07)	.3039
Grade 3	10(1.67)	5(0.83)	.2987	4(0.77)	7(1.34)	.5467
Rash	2(0.33)	2(0.33)	1.0000	1(0.19)	4(0.76)	.3738
Grade 3	0(0.00)	0(0.00)	1.0000	0(0.00)	1(0.19)	1.0000
Swelling	74(12.33)	146(24.33)	<.0001	39(7.54)	47(8.99)	.4315
Grade 3	9(1.50)	6(1.00)	.6049	4(0.77)	9(1.72)	.2639
Pruritus	0(0.00)	1(0.17)	1.0000	1(0.19)	1(0.19)	1.0000
Systemic adverse reactions	357(59.50)	388(64.67)	.0742	146(28.24)	199(38.05)	.0008
Grade 3	4(0.67)	6(1.00)	.7529	2(0.39)	8(1.53)	.1077
Decreased appetite	20(3.33)	23(3.83)	.7565	8(1.55)	5(0.96)	.4186
Fever	317(52.83)	357(59.50)	.0232	132(25.53)	185(35.37)	.0006
Grade 3	3(0.50)	4(0.67)	1.0000	2(0.39)	8(1.53)	.1077
Diarrhea	45(7.50)	50(8.33)	.6691	11(2.13)	10(1.91)	.8292
Grade 3	1(0.17)	1(0.17)	1.0000	0(0.00)	0(0.00)	1.0000
Cough	58(9.67)	58(9.67)	1.0000	3(0.58)	11(2.10)	.0558
Crying	86(14.33)	99(16.50)	.3374	17(3.29)	32(6.12)	.0396
Grade 3	0(0.00)	1(0.17)	1.0000	0(0.00)	0(0.00)	1.0000
Vomiting	19(3.17)	32(5.33)	.0850	2(0.39)	5(0.96)	.4516
Fatigue	23(3.83)	20(3.33)	.7565	2(0.39)	10(1.91)	.0375

For the computation of frequencies, the numerators were numbers of the subjects who occurred adverse events.

Table

CI	confidence interval
ELISA	enzyme-linked immunosorbent assay
GMC	geometric mean concentration
GMI	geometric mean increase
GMT	geometric mean titre
OPA	opsonophagocytic assays
FAS	full analysis set
PCV13	13-Valent pneumococcal conjugate vaccine
PPS	per-protocol set
SAE	serious adverse event
SS	safety set