药学学报

Serotype	PCV20-001	PCV20-002	PCV20-003	PCV20 (Pfizer)	P
1	10.5	10.3	10.4	10.2	0.970 0
3	10.5	10.4	10.7	10.3	0.911 6
4	11.6	11.3	11.5	11.5	0.962 2
5	11.0	11.3	11.0	11.0	0.955 6
6A	10.6	10.5	10.4	10.2	0.906 5
6B	10.0	10.2	9.6	9.8	0.698 4
7F	11.5	11.5	11.7	11.6	0.950 8
8	11.2	11.3	11.5	11.3	0.915 8
9V	11.1^*	11.1^*	10.9^*	9.8	0.004 2
10A	8.9	8.7	9.3	9.2	0.542 0
11A	10.9	10.8	10.9	10.7	0.955 2
12F	9.1	8.7	8.9	9.0	0.666 1
14	11.6	11.7	11.8	12.1	0.716 0
15B	9.9	9.8	10.2	10.0	0.870 7
18C	10.8	11.0	11.1	10.6	0.778 7
19A	9.9	9.6	10.0	9.9	0.900 4
19F	9.6	9.9	10.2	9.6	0.801 3
22F	10.7	10.9	10.9	10.8	0.980 1
23F	10.2	10.0	9.9	9.9	0.964 1
33F	10.1	10.4	10.4	10.4	0.967 3

Serotype

PCV20-001

PCV20-002

PCV20-003

PCV20 (Pfizer)

10.5

10.3

10.4

10.2

0.970 0

10.5

10.4

10.7

10.3

0.911 6

11.6

11.3

11.5

0.962 2

11.0

11.3

11.0

0.955 6

10.6

10.5

10.4

10.2

0.906 5

10.0

10.2

9.6

9.8

0.698 4

11.5

11.7

11.6

0.950 8

11.2

11.3

11.5

11.3

0.915 8

11.1^*

10.9^*

9.8

0.004 2

10A

8.9

8.7

9.3

9.2

0.542 0

11A

10.9

10.8

10.9

10.7

0.955 2

12F

9.1

8.7

8.9

9.0

0.666 1

11.6

11.7

11.8

12.1

0.716 0

15B

9.9

9.8

10.2

10.0

0.870 7

18C

10.8

11.0

11.1

10.6

0.778 7

19A

9.9

9.6

10.0

9.9

0.900 4

19F

9.6

9.9

10.2

9.6

0.801 3

22F

10.7

10.9

10.8

0.980 1

23F

10.2

10.0

9.9

0.964 1

33F

10.1

10.4

0.967 3

Serotype	PCV20-001	PCV20-002	PCV20-003	PCV20 (Pfizer)	P
1	10.5	10.3	10.4	10.2	0.970 0
3	10.5	10.4	10.7	10.3	0.911 6
4	11.6	11.3	11.5	11.5	0.962 2
5	11.0	11.3	11.0	11.0	0.955 6
6A	10.6	10.5	10.4	10.2	0.906 5
6B	10.0	10.2	9.6	9.8	0.698 4
7F	11.5	11.5	11.7	11.6	0.950 8
8	11.2	11.3	11.5	11.3	0.915 8
9V	11.1^*	11.1^*	10.9^*	9.8	0.004 2
10A	8.9	8.7	9.3	9.2	0.542 0
11A	10.9	10.8	10.9	10.7	0.955 2
12F	9.1	8.7	8.9	9.0	0.666 1
14	11.6	11.7	11.8	12.1	0.716 0
15B	9.9	9.8	10.2	10.0	0.870 7
18C	10.8	11.0	11.1	10.6	0.778 7
19A	9.9	9.6	10.0	9.9	0.900 4
19F	9.6	9.9	10.2	9.6	0.801 3
22F	10.7	10.9	10.9	10.8	0.980 1
23F	10.2	10.0	9.9	9.9	0.964 1
33F	10.1	10.4	10.4	10.4	0.967 3

Serotype

PCV20-001

PCV20-002

PCV20-003

PCV20 (Pfizer)

10.5

10.3

10.4

10.2

0.970 0

10.5

10.4

10.7

10.3

0.911 6

11.6

11.3

11.5

0.962 2

11.0

11.3

11.0

0.955 6

10.6

10.5

10.4

10.2

0.906 5

10.0

10.2

9.6

9.8

0.698 4

11.5

11.7

11.6

0.950 8

11.2

11.3

11.5

11.3

0.915 8

11.1^*

10.9^*

9.8

0.004 2

10A

8.9

8.7

9.3

9.2

0.542 0

11A

10.9

10.8

10.9

10.7

0.955 2

12F

9.1

8.7

8.9

9.0

0.666 1

11.6

11.7

11.8

12.1

0.716 0

15B

9.9

9.8

10.2

10.0

0.870 7

18C

10.8

11.0

11.1

10.6

0.778 7

19A

9.9

9.6

10.0

9.9

0.900 4

19F

9.6

9.9

10.2

9.6

0.801 3

22F

10.7

10.9

10.8

0.980 1

23F

10.2

10.0

9.9

0.964 1

33F

10.1

10.4

0.967 3

Serotype	2W	4W	6W	8W	9W	11W	P
1	8.9	10.7	10.2	10.1	9.2	9.2	0.001 0
3	7.3	8.0	8.1	8.3	8.0	7.9	0.035 9
4	6.5	8.1	8.2^*	8.5^*	7.9	7.8	0.000 1
5	8.9	9.4	9.7	10.6^*	11.0^*	10.3	<0.000 1
6A	6.9	8.2	9.6	10.6^*	10.8^*	11.0^*	<0.000 1
6B	6.7	7.9	8.8^*	9.1^*	8.7^*	8.8^*	<0.000 1
7F	7.2	9.7	11.8^*	11.8^*	11.0^*	11.0^*	<0.000 1
8	9.0	10.5	11.2^*	10.6	10.5	10.1	<0.000 1
9V	9.1	11.1	12.1^*	12.3^*	11.8	11.6	0.000 8
10A	6.3	7.0	8.0^*	8.1^*	8.0^*	8.1^*	<0.000 1
11A	9.3	11.4	11.7^*	12.0^*	10.7	10.5	<0.000 1
12F	7.7	8.1	7.8	8.1	7.5	7.7	0.524 6
14	7.1	8.3	9.7	10.5^*	10.3^*	10.1^*	<0.000 1
15B	7.1	9.4	9.9^*	10.1^*	9.5	9.8^*	0.000 2
18C	6.5	8.6	11.5^*	11.9^*	11.2^*	10.6	<0.000 1
19A	7.6	9.1	9.8^*	9.8^*	9.2	8.7	<0.000 1
19F	7.1	7.5	8.3	8.3	8.0	8.0	0.015 8
22F	7.5	8.4	9.0^*	8.7	8.0	8.3	0.002 1
23F	7.1	8.5	9.9^*	10.2^*	9.4	9.8	0.000 2
33F	10.3	11.5	12.2	12.3^*	12.0	12.0	0.000 2

Serotype

11W

8.9

10.7

10.2

10.1

9.2

0.001 0

7.3

8.0

8.1

8.3

8.0

7.9

0.035 9

6.5

8.1

8.2^*

8.5^*

7.9

7.8

0.000 1

8.9

9.4

9.7

10.6^*

11.0^*

10.3

<0.000 1

6.9

8.2

9.6

10.6^*

10.8^*

11.0^*

<0.000 1

6.7

7.9

8.8^*

9.1^*

8.7^*

8.8^*

<0.000 1

7.2

9.7

11.8^*

11.0^*

<0.000 1

9.0

10.5

11.2^*

10.6

10.5

10.1

<0.000 1

9.1

11.1

12.1^*

12.3^*

11.8

11.6

0.000 8

10A

6.3

7.0

8.0^*

8.1^*

8.0^*

8.1^*

<0.000 1

11A

9.3

11.4

11.7^*

12.0^*

10.7

10.5

<0.000 1

12F

7.7

8.1

7.8

8.1

7.5

7.7

0.524 6

7.1

8.3

9.7

10.5^*

10.3^*

10.1^*

<0.000 1

15B

7.1

9.4

9.9^*

10.1^*

9.5

9.8^*

0.000 2

18C

6.5

8.6

11.5^*

11.9^*

11.2^*

10.6

<0.000 1

19A

7.6

9.1

9.8^*

9.2

8.7

<0.000 1

19F

7.1

7.5

8.3

8.0

0.015 8

22F

7.5

8.4

9.0^*

8.7

8.0

8.3

0.002 1

23F

7.1

8.5

9.9^*

10.2^*

9.4

9.8

0.000 2

33F

10.3

11.5

12.2

12.3^*

12.0

0.000 2

Serotype	2W	4W	6W	8W	9W	11W	P
1	8.9	10.7	10.2	10.1	9.2	9.2	0.001 0
3	7.3	8.0	8.1	8.3	8.0	7.9	0.035 9
4	6.5	8.1	8.2^*	8.5^*	7.9	7.8	0.000 1
5	8.9	9.4	9.7	10.6^*	11.0^*	10.3	<0.000 1
6A	6.9	8.2	9.6	10.6^*	10.8^*	11.0^*	<0.000 1
6B	6.7	7.9	8.8^*	9.1^*	8.7^*	8.8^*	<0.000 1
7F	7.2	9.7	11.8^*	11.8^*	11.0^*	11.0^*	<0.000 1
8	9.0	10.5	11.2^*	10.6	10.5	10.1	<0.000 1
9V	9.1	11.1	12.1^*	12.3^*	11.8	11.6	0.000 8
10A	6.3	7.0	8.0^*	8.1^*	8.0^*	8.1^*	<0.000 1
11A	9.3	11.4	11.7^*	12.0^*	10.7	10.5	<0.000 1
12F	7.7	8.1	7.8	8.1	7.5	7.7	0.524 6
14	7.1	8.3	9.7	10.5^*	10.3^*	10.1^*	<0.000 1
15B	7.1	9.4	9.9^*	10.1^*	9.5	9.8^*	0.000 2
18C	6.5	8.6	11.5^*	11.9^*	11.2^*	10.6	<0.000 1
19A	7.6	9.1	9.8^*	9.8^*	9.2	8.7	<0.000 1
19F	7.1	7.5	8.3	8.3	8.0	8.0	0.015 8
22F	7.5	8.4	9.0^*	8.7	8.0	8.3	0.002 1
23F	7.1	8.5	9.9^*	10.2^*	9.4	9.8	0.000 2
33F	10.3	11.5	12.2	12.3^*	12.0	12.0	0.000 2

Serotype

11W

8.9

10.7

10.2

10.1

9.2

0.001 0

7.3

8.0

8.1

8.3

8.0

7.9

0.035 9

6.5

8.1

8.2^*

8.5^*

7.9

7.8

0.000 1

8.9

9.4

9.7

10.6^*

11.0^*

10.3

<0.000 1

6.9

8.2

9.6

10.6^*

10.8^*

11.0^*

<0.000 1

6.7

7.9

8.8^*

9.1^*

8.7^*

8.8^*

<0.000 1

7.2

9.7

11.8^*

11.0^*

<0.000 1

9.0

10.5

11.2^*

10.6

10.5

10.1

<0.000 1

9.1

11.1

12.1^*

12.3^*

11.8

11.6

0.000 8

10A

6.3

7.0

8.0^*

8.1^*

8.0^*

8.1^*

<0.000 1

11A

9.3

11.4

11.7^*

12.0^*

10.7

10.5

<0.000 1

12F

7.7

8.1

7.8

8.1

7.5

7.7

0.524 6

7.1

8.3

9.7

10.5^*

10.3^*

10.1^*

<0.000 1

15B

7.1

9.4

9.9^*

10.1^*

9.5

9.8^*

0.000 2

18C

6.5

8.6

11.5^*

11.9^*

11.2^*

10.6

<0.000 1

19A

7.6

9.1

9.8^*

9.2

8.7

<0.000 1

19F

7.1

7.5

8.3

8.0

0.015 8

22F

7.5

8.4

9.0^*

8.7

8.0

8.3

0.002 1

23F

7.1

8.5

9.9^*

10.2^*

9.4

9.8

0.000 2

33F

10.3

11.5

12.2

12.3^*

12.0

0.000 2

Sex	Group	Pre-immune	Days post-immune
Male	NC	20.5±0.5	22.6±0.7	26.0±1.1	28.1±1.5	31.7±2.2	34.6±2.3
T	20.6±0.6	22.7±0.7	26.6±1.3	27.7±1.7	32.8±2.3	35.5±2.3
Female	NC	21.5±0.7	22.2±0.8	24.2±0.8	25.2±1.5	26.0±1.5	27.4±1.5
T	21.4±0.5	22.8±0.9	24.8±1.1	24.9±1.8	26.4±1.3	27.3±1.3

Sex

Group

Pre-immune

Days post-immune

Male

20.5±0.5

22.6±0.7

26.0±1.1

28.1±1.5

31.7±2.2

34.6±2.3

20.6±0.6

22.7±0.7

26.6±1.3

27.7±1.7

32.8±2.3

35.5±2.3

Female

21.5±0.7

22.2±0.8

24.2±0.8

25.2±1.5

26.0±1.5

27.4±1.5

21.4±0.5

22.8±0.9

24.8±1.1

24.9±1.8

26.4±1.3

27.3±1.3

Sex	Group	Pre-immune	Days post-immune
Male	NC	20.5±0.5	22.6±0.7	26.0±1.1	28.1±1.5	31.7±2.2	34.6±2.3
T	20.6±0.6	22.7±0.7	26.6±1.3	27.7±1.7	32.8±2.3	35.5±2.3
Female	NC	21.5±0.7	22.2±0.8	24.2±0.8	25.2±1.5	26.0±1.5	27.4±1.5
T	21.4±0.5	22.8±0.9	24.8±1.1	24.9±1.8	26.4±1.3	27.3±1.3

Sex

Group

Pre-immune

Days post-immune

Male

20.5±0.5

22.6±0.7

26.0±1.1

28.1±1.5

31.7±2.2

34.6±2.3

20.6±0.6

22.7±0.7

26.6±1.3

27.7±1.7

32.8±2.3

35.5±2.3

Female

21.5±0.7

22.2±0.8

24.2±0.8

25.2±1.5

26.0±1.5

27.4±1.5

21.4±0.5

22.8±0.9

24.8±1.1

24.9±1.8

26.4±1.3

27.3±1.3

Sex	Group	Days post-immune
Male	NC	5.0±0.1	5.3±0.1	4.7±0.1	5.8±0.4	5.7±0.1
T	5.0±0.3	5.2±0.1	4.7±0.1	6.0±0.2	5.9±0.2
Female	NC	4.4±0.1	4.5±0.2	4.4±0.3	4.6±0.1	5.1±0.0
T	4.6±0.4	4.5±0.2	4.4±0.1	4.5±0.7	4.6±0.2

Sex

Group

Days post-immune

0-1

1-3

3-7

7-10

10-14

Male

5.0±0.1

5.3±0.1

4.7±0.1

5.8±0.4

5.7±0.1

5.0±0.3

5.2±0.1

4.7±0.1

6.0±0.2

5.9±0.2

Female

4.4±0.1

4.5±0.2

4.4±0.3

4.6±0.1

5.1±0.0

4.6±0.4

4.5±0.2

4.4±0.1

4.5±0.7

4.6±0.2

Sex	Group	Days post-immune
Male	NC	5.0±0.1	5.3±0.1	4.7±0.1	5.8±0.4	5.7±0.1
T	5.0±0.3	5.2±0.1	4.7±0.1	6.0±0.2	5.9±0.2
Female	NC	4.4±0.1	4.5±0.2	4.4±0.3	4.6±0.1	5.1±0.0
T	4.6±0.4	4.5±0.2	4.4±0.1	4.5±0.7	4.6±0.2

Sex

Group

Days post-immune

0-1

1-3

3-7

7-10

10-14

Male

5.0±0.1

5.3±0.1

4.7±0.1

5.8±0.4

5.7±0.1

5.0±0.3

5.2±0.1

4.7±0.1

6.0±0.2

5.9±0.2

Female

4.4±0.1

4.5±0.2

4.4±0.3

4.6±0.1

5.1±0.0

4.6±0.4

4.5±0.2

4.4±0.1

4.5±0.7

4.6±0.2

Test item	Time point	Male		Female
		9.9±2.2	8.9±1.5		4.6±1.6	7.2±2.3^**
End of recovery	9.1±3.2	9.4±1.6	5.1 ±1.6	5.5±1.4
RBC/10¹²·L^-1	End of dosing	8.16±0.34	8.18±0.33	7.42±0.25	7.40±0.22
End of recovery	8.67±0.40	8.75±0.34	7.70±0.31	7.64±0.29
Hemoglobin/g·L^-1	End of dosing	167±6	164±6	155±2	153±5
End of recovery	167±6	166±6	159±6	156±4
Hematocrit/%	End of dosing	43.4±1.3	43.1±1.7	40.8±0.6	40.1±1.3
End of recovery	43.9±2.3	43.3±1.2	41.6±1.0	41.4±1.5
Red blood cell distribution width/%	End of dosing	12.8±0.7	14.0±0.7^**	12.2±0.8	12.9±0.7
End of recovery	14.5±0.7	14.9±0.7	13.1±0.6	12.7±0.5
Monocyte/10⁹·L^-1	End of dosing	0.07±0.02	0.04±0.02^**	0.01±0.01	0 .02±0.01^*
End of recovery	0.06±0.03	0.06±0.03	0.01±0.01	0.02±0.01
Monocyte/%	End of dosing	0.8±0.2	0.5±0.2^*	0.2±0.1	0 .3±0.2
End of recovery	0.6±0.2	0.6±0.2	0.2±0.2	0.3±0.2
Eosinophils/10⁹·L^-1	End of dosing	0.22±0.10	0.16±0.12	0.02±0.02	0.06±0.04^**
End of recovery	0.22±0.10	0.38±0.38	0.05±0.04	0.12±0.26
Lymphocyte/10⁹·L^-1	End of dosing	7.72±1.66	7.13±1.41	3.85±1.34	5.99±2.00^*
End of recovery	7.24±2.71	7.13±0.93	4.13±1.49	4.33±1.14
Neutrophils/10⁹·L^-1	End of dosing	1.78±0.54	1.49±0.39	0.60±0.26	1.06±0.40^**
End of recovery	1.55±0.47	1.74±0.59	0.86±0.20	0.98±0.42
Platelet/10⁹·L^-1	End of dosing	847±100	891±68	910±200	929±46
End of recovery	855±90	745±120^*	847±60	727±187

Test item

Time point

Male

Female

9.9±2.2

8.9±1.5

4.6±1.6

7.2±2.3^**

End of recovery

9.1±3.2

9.4±1.6

5.1 ±1.6

5.5±1.4

RBC/10¹²·L^-1

End of dosing

8.16±0.34

8.18±0.33

7.42±0.25

7.40±0.22

End of recovery

8.67±0.40

8.75±0.34

7.70±0.31

7.64±0.29

Hemoglobin/g·L^-1

End of dosing

167±6

164±6

155±2

153±5

End of recovery

167±6

166±6

159±6

156±4

Hematocrit/%

End of dosing

43.4±1.3

43.1±1.7

40.8±0.6

40.1±1.3

End of recovery

43.9±2.3

43.3±1.2

41.6±1.0

41.4±1.5

Red blood cell distribution width/%

End of dosing

12.8±0.7

14.0±0.7^**

12.2±0.8

12.9±0.7

End of recovery

14.5±0.7

14.9±0.7

13.1±0.6

12.7±0.5

Monocyte/10⁹·L^-1

End of dosing

0.07±0.02

0.04±0.02^**

0.01±0.01

0 .02±0.01^*

End of recovery

0.06±0.03

0.01±0.01

0.02±0.01

Monocyte/%

End of dosing

0.8±0.2

0.5±0.2^*

0.2±0.1

0 .3±0.2

End of recovery

0.6±0.2

0.2±0.2

0.3±0.2

Eosinophils/10⁹·L^-1

End of dosing

0.22±0.10

0.16±0.12

0.02±0.02

0.06±0.04^**

End of recovery

0.22±0.10

0.38±0.38

0.05±0.04

0.12±0.26

Lymphocyte/10⁹·L^-1

End of dosing

7.72±1.66

7.13±1.41

3.85±1.34

5.99±2.00^*

End of recovery

7.24±2.71

7.13±0.93

4.13±1.49

4.33±1.14

Neutrophils/10⁹·L^-1

End of dosing

1.78±0.54

1.49±0.39

0.60±0.26

1.06±0.40^**

End of recovery

1.55±0.47

1.74±0.59

0.86±0.20

0.98±0.42

Platelet/10⁹·L^-1

End of dosing

847±100

891±68

910±200

929±46

End of recovery

855±90

745±120^*

847±60

727±187

Test item	Time point	Male		Female
		9.9±2.2	8.9±1.5		4.6±1.6	7.2±2.3^**
End of recovery	9.1±3.2	9.4±1.6	5.1 ±1.6	5.5±1.4
RBC/10¹²·L^-1	End of dosing	8.16±0.34	8.18±0.33	7.42±0.25	7.40±0.22
End of recovery	8.67±0.40	8.75±0.34	7.70±0.31	7.64±0.29
Hemoglobin/g·L^-1	End of dosing	167±6	164±6	155±2	153±5
End of recovery	167±6	166±6	159±6	156±4
Hematocrit/%	End of dosing	43.4±1.3	43.1±1.7	40.8±0.6	40.1±1.3
End of recovery	43.9±2.3	43.3±1.2	41.6±1.0	41.4±1.5
Red blood cell distribution width/%	End of dosing	12.8±0.7	14.0±0.7^**	12.2±0.8	12.9±0.7
End of recovery	14.5±0.7	14.9±0.7	13.1±0.6	12.7±0.5
Monocyte/10⁹·L^-1	End of dosing	0.07±0.02	0.04±0.02^**	0.01±0.01	0 .02±0.01^*
End of recovery	0.06±0.03	0.06±0.03	0.01±0.01	0.02±0.01
Monocyte/%	End of dosing	0.8±0.2	0.5±0.2^*	0.2±0.1	0 .3±0.2
End of recovery	0.6±0.2	0.6±0.2	0.2±0.2	0.3±0.2
Eosinophils/10⁹·L^-1	End of dosing	0.22±0.10	0.16±0.12	0.02±0.02	0.06±0.04^**
End of recovery	0.22±0.10	0.38±0.38	0.05±0.04	0.12±0.26
Lymphocyte/10⁹·L^-1	End of dosing	7.72±1.66	7.13±1.41	3.85±1.34	5.99±2.00^*
End of recovery	7.24±2.71	7.13±0.93	4.13±1.49	4.33±1.14
Neutrophils/10⁹·L^-1	End of dosing	1.78±0.54	1.49±0.39	0.60±0.26	1.06±0.40^**
End of recovery	1.55±0.47	1.74±0.59	0.86±0.20	0.98±0.42
Platelet/10⁹·L^-1	End of dosing	847±100	891±68	910±200	929±46
End of recovery	855±90	745±120^*	847±60	727±187

Test item

Time point

Male

Female

9.9±2.2

8.9±1.5

4.6±1.6

7.2±2.3^**

End of recovery

9.1±3.2

9.4±1.6

5.1 ±1.6

5.5±1.4

RBC/10¹²·L^-1

End of dosing

8.16±0.34

8.18±0.33

7.42±0.25

7.40±0.22

End of recovery

8.67±0.40

8.75±0.34

7.70±0.31

7.64±0.29

Hemoglobin/g·L^-1

End of dosing

167±6

164±6

155±2

153±5

End of recovery

167±6

166±6

159±6

156±4

Hematocrit/%

End of dosing

43.4±1.3

43.1±1.7

40.8±0.6

40.1±1.3

End of recovery

43.9±2.3

43.3±1.2

41.6±1.0

41.4±1.5

Red blood cell distribution width/%

End of dosing

12.8±0.7

14.0±0.7^**

12.2±0.8

12.9±0.7

End of recovery

14.5±0.7

14.9±0.7

13.1±0.6

12.7±0.5

Monocyte/10⁹·L^-1

End of dosing

0.07±0.02

0.04±0.02^**

0.01±0.01

0 .02±0.01^*

End of recovery

0.06±0.03

0.01±0.01

0.02±0.01

Monocyte/%

End of dosing

0.8±0.2

0.5±0.2^*

0.2±0.1

0 .3±0.2

End of recovery

0.6±0.2

0.2±0.2

0.3±0.2

Eosinophils/10⁹·L^-1

End of dosing

0.22±0.10

0.16±0.12

0.02±0.02

0.06±0.04^**

End of recovery

0.22±0.10

0.38±0.38

0.05±0.04

0.12±0.26

Lymphocyte/10⁹·L^-1

End of dosing

7.72±1.66

7.13±1.41

3.85±1.34

5.99±2.00^*

End of recovery

7.24±2.71

7.13±0.93

4.13±1.49

4.33±1.14

Neutrophils/10⁹·L^-1

End of dosing

1.78±0.54

1.49±0.39

0.60±0.26

1.06±0.40^**

End of recovery

1.55±0.47

1.74±0.59

0.86±0.20

0.98±0.42

Platelet/10⁹·L^-1

End of dosing

847±100

891±68

910±200

929±46

End of recovery

855±90

745±120^*

847±60

727±187

Test item	Time point	Male		Female
Alanine aminotransferase/U·L^-1	End of dosing	34±4	36±6		30±9	46±20^*
End of recovery	38±7	36±9	37±12	40±7
Aspartate aminotransferase/U·L^-1	End of dosing	113±29	127±21	121±25	140±32
End of recovery	148±24	148±26	121±34	118±43
Total protein/g·L^-1	End of dosing	61.81±2.33	62.36±2.48	71.26±4.13	73.59±5.91
End of recovery	59.70±3.45	60.84±2.33	71.46±5.45	71.91±4.33
Albumin/g·L^-1	End of dosing	27.85±0.83	28.53±1.41	36.55±3.70	38.46±4.48
End of recovery	28.80±1.53	28.21±0.63	39.86±4.41	40.39±3.23
Urea nitrogen/mmol·L^-1	End of dosing	4.68±0.46	4.70±0.55	4.72±0.50	5.22±0.72
End of recovery	5.58±0.61	4.83±0.41^**	5.72±0.71	5.78±0.70
Creatinine/μmol·L^-1	End of dosing	24.57±1.76	24.65±2.67	29.61±1.90	31.49±3.18
End of recovery	27.85±3.33	26.44±2.15	32.29±3.53	32.12±3.27
Uric acid/μmol·L^-1	End of dosing	144.36±12.56	147.83±16.01	159.39±25.29	156.66±18.31
End of recovery	158.64±15.71	158.61±27.38	157.65±22.63	147.53±9.84
Total cholesterol/mmol·L^-1	End of dosing	1.91±0.29	1.63±0.22^*	2.03±0.36	1.93±0.43
End of recovery	1.71±0.25	1.86±0.39	1.97±0.47	2.09±0.44
A/G ratio	End of dosing	0.82±0.06	0.84±0.07	1.05±0.10	1.10±0.14
End of recovery	0.94±0.06	0.87±0.05^*	1.26±0.14	1.28±0.11
K⁺/mmol·L^-1	End of dosing	5.05±0.12	5.19±0.18^*	4.44±0.23	4.51±0.28
End of recovery	5.27±0.25	5.17±0.31	4.62±0.29	4.37±0.17^*
Na⁺/mmol·L^-1	End of dosing	143.6±1.2	143.2±0.6	142.1±1.2	141.8±1.1
End of recovery	146.8±1.7	147.4±1.6	149.7±1.1	149.1±1.1
Cl^-/mmol·L^-1	End of dosing	102.5±1.1	103.7±1.3^*	104.2±1.2	103.9±2. 1
End of recovery	102.7±1.9	102.6±1.6	106.2±1.4	105.9±1.6

Test item

Time point

Male

Female

Alanine aminotransferase/U·L^-1

End of dosing

34±4

36±6

30±9

46±20^*

End of recovery

38±7

36±9

37±12

40±7

Aspartate aminotransferase/U·L^-1

End of dosing

113±29

127±21

121±25

140±32

End of recovery

148±24

148±26

121±34

118±43

Total protein/g·L^-1

End of dosing

61.81±2.33

62.36±2.48

71.26±4.13

73.59±5.91

End of recovery

59.70±3.45

60.84±2.33

71.46±5.45

71.91±4.33

Albumin/g·L^-1

End of dosing

27.85±0.83

28.53±1.41

36.55±3.70

38.46±4.48

End of recovery

28.80±1.53

28.21±0.63

39.86±4.41

40.39±3.23

Urea nitrogen/mmol·L^-1

End of dosing

4.68±0.46

4.70±0.55

4.72±0.50

5.22±0.72

End of recovery

5.58±0.61

4.83±0.41^**

5.72±0.71

5.78±0.70

Creatinine/μmol·L^-1

End of dosing

24.57±1.76

24.65±2.67

29.61±1.90

31.49±3.18

End of recovery

27.85±3.33

26.44±2.15

32.29±3.53

32.12±3.27

Uric acid/μmol·L^-1

End of dosing

144.36±12.56

147.83±16.01

159.39±25.29

156.66±18.31

End of recovery

158.64±15.71

158.61±27.38

157.65±22.63

147.53±9.84

Total cholesterol/mmol·L^-1

End of dosing

1.91±0.29

1.63±0.22^*

2.03±0.36

1.93±0.43

End of recovery

1.71±0.25

1.86±0.39

1.97±0.47

2.09±0.44

A/G ratio

End of dosing

0.82±0.06

0.84±0.07

1.05±0.10

1.10±0.14

End of recovery

0.94±0.06

0.87±0.05^*

1.26±0.14

1.28±0.11

K⁺/mmol·L^-1

End of dosing

5.05±0.12

5.19±0.18^*

4.44±0.23

4.51±0.28

End of recovery

5.27±0.25

5.17±0.31

4.62±0.29

4.37±0.17^*

Na⁺/mmol·L^-1

End of dosing

143.6±1.2

143.2±0.6

142.1±1.2

141.8±1.1

End of recovery

146.8±1.7

147.4±1.6

149.7±1.1

149.1±1.1

Cl^-/mmol·L^-1

End of dosing

102.5±1.1

103.7±1.3^*

104.2±1.2

103.9±2. 1

End of recovery

102.7±1.9

102.6±1.6

106.2±1.4

105.9±1.6

Test item	Time point	Male		Female
Alanine aminotransferase/U·L^-1	End of dosing	34±4	36±6		30±9	46±20^*
End of recovery	38±7	36±9	37±12	40±7
Aspartate aminotransferase/U·L^-1	End of dosing	113±29	127±21	121±25	140±32
End of recovery	148±24	148±26	121±34	118±43
Total protein/g·L^-1	End of dosing	61.81±2.33	62.36±2.48	71.26±4.13	73.59±5.91
End of recovery	59.70±3.45	60.84±2.33	71.46±5.45	71.91±4.33
Albumin/g·L^-1	End of dosing	27.85±0.83	28.53±1.41	36.55±3.70	38.46±4.48
End of recovery	28.80±1.53	28.21±0.63	39.86±4.41	40.39±3.23
Urea nitrogen/mmol·L^-1	End of dosing	4.68±0.46	4.70±0.55	4.72±0.50	5.22±0.72
End of recovery	5.58±0.61	4.83±0.41^**	5.72±0.71	5.78±0.70
Creatinine/μmol·L^-1	End of dosing	24.57±1.76	24.65±2.67	29.61±1.90	31.49±3.18
End of recovery	27.85±3.33	26.44±2.15	32.29±3.53	32.12±3.27
Uric acid/μmol·L^-1	End of dosing	144.36±12.56	147.83±16.01	159.39±25.29	156.66±18.31
End of recovery	158.64±15.71	158.61±27.38	157.65±22.63	147.53±9.84
Total cholesterol/mmol·L^-1	End of dosing	1.91±0.29	1.63±0.22^*	2.03±0.36	1.93±0.43
End of recovery	1.71±0.25	1.86±0.39	1.97±0.47	2.09±0.44
A/G ratio	End of dosing	0.82±0.06	0.84±0.07	1.05±0.10	1.10±0.14
End of recovery	0.94±0.06	0.87±0.05^*	1.26±0.14	1.28±0.11
K⁺/mmol·L^-1	End of dosing	5.05±0.12	5.19±0.18^*	4.44±0.23	4.51±0.28
End of recovery	5.27±0.25	5.17±0.31	4.62±0.29	4.37±0.17^*
Na⁺/mmol·L^-1	End of dosing	143.6±1.2	143.2±0.6	142.1±1.2	141.8±1.1
End of recovery	146.8±1.7	147.4±1.6	149.7±1.1	149.1±1.1
Cl^-/mmol·L^-1	End of dosing	102.5±1.1	103.7±1.3^*	104.2±1.2	103.9±2. 1
End of recovery	102.7±1.9	102.6±1.6	106.2±1.4	105.9±1.6

Test item

Time point

Male

Female

Alanine aminotransferase/U·L^-1

End of dosing

34±4

36±6

30±9

46±20^*

End of recovery

38±7

36±9

37±12

40±7

Aspartate aminotransferase/U·L^-1

End of dosing

113±29

127±21

121±25

140±32

End of recovery

148±24

148±26

121±34

118±43

Total protein/g·L^-1

End of dosing

61.81±2.33

62.36±2.48

71.26±4.13

73.59±5.91

End of recovery

59.70±3.45

60.84±2.33

71.46±5.45

71.91±4.33

Albumin/g·L^-1

End of dosing

27.85±0.83

28.53±1.41

36.55±3.70

38.46±4.48

End of recovery

28.80±1.53

28.21±0.63

39.86±4.41

40.39±3.23

Urea nitrogen/mmol·L^-1

End of dosing

4.68±0.46

4.70±0.55

4.72±0.50

5.22±0.72

End of recovery

5.58±0.61

4.83±0.41^**

5.72±0.71

5.78±0.70

Creatinine/μmol·L^-1

End of dosing

24.57±1.76

24.65±2.67

29.61±1.90

31.49±3.18

End of recovery

27.85±3.33

26.44±2.15

32.29±3.53

32.12±3.27

Uric acid/μmol·L^-1

End of dosing

144.36±12.56

147.83±16.01

159.39±25.29

156.66±18.31

End of recovery

158.64±15.71

158.61±27.38

157.65±22.63

147.53±9.84

Total cholesterol/mmol·L^-1

End of dosing

1.91±0.29

1.63±0.22^*

2.03±0.36

1.93±0.43

End of recovery

1.71±0.25

1.86±0.39

1.97±0.47

2.09±0.44

A/G ratio

End of dosing

0.82±0.06

0.84±0.07

1.05±0.10

1.10±0.14

End of recovery

0.94±0.06

0.87±0.05^*

1.26±0.14

1.28±0.11

K⁺/mmol·L^-1

End of dosing

5.05±0.12

5.19±0.18^*

4.44±0.23

4.51±0.28

End of recovery

5.27±0.25

5.17±0.31

4.62±0.29

4.37±0.17^*

Na⁺/mmol·L^-1

End of dosing

143.6±1.2

143.2±0.6

142.1±1.2

141.8±1.1

End of recovery

146.8±1.7

147.4±1.6

149.7±1.1

149.1±1.1

Cl^-/mmol·L^-1

End of dosing

102.5±1.1

103.7±1.3^*

104.2±1.2

103.9±2. 1

End of recovery

102.7±1.9

102.6±1.6

106.2±1.4

105.9±1.6

20价肺炎球菌结合疫苗的免疫原性及安全性研究

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尹珊珊 , 宋琳琳 , 任涛 , 刘兴 , 杨靖寰 , 郭龙静 , 李跃龙 , 邓海清 ^*

药学学报 | 专题报道: 糖疫苗的研究进展与发展趋势 2025,60(7): 2016-2023

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药学学报 |专题报道: 糖疫苗的研究进展与发展趋势 2025 , 60 (7) : 2016 -2023

20价肺炎球菌结合疫苗的免疫原性及安全性研究

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尹珊珊, 宋琳琳, 任涛, 刘兴, 杨靖寰, 郭龙静, 李跃龙, 邓海清^*

作者信息

北京民海生物科技有限公司, 结合疫苗新技术研究北京市重点实验室, 北京 102600

通讯作者:

邓海清, E-mail: denghaiqing@biominhai.com

作者简介:

^#共同第一作者.

作者贡献:

尹珊珊、宋琳琳负责实验工作、数据处理及文章撰写; 任涛负责疫苗制备及安全性研究; 刘兴、杨靖寰、郭龙静负责实验工作及数据汇总; 李跃龙负责图表整理及文章修改; 邓海清负责整体思路、文章修改。

Immunogenicity and safety of 20-valent pneumococcal conjugate vaccine

Shan-shan YIN, Lin-lin SONG, Tao REN, Xing LIU, Jing-huan YANG, Long-jing GUO, Yue-long LI, Hai-qing DENG^*

Affiliations

Beijing Key Laboratory for New Technology Research of Conjugate Vaccines, Beijing Minhai Biological Technology Co. Ltd., Beijing 102600, China

出版时间: 2025-07-12 doi: 10.16438/j.0513-4870.2025-0271

文章导航

摘要

收起

本研究旨在评价20价肺炎球菌结合疫苗 (20-valent pneumococcal conjugate vaccine, PCV20) 的免疫原性和安全性。利用ICR小鼠、SD大鼠建立不同的评价模型评价免疫原性及毒性反应。结果显示, 小鼠免疫原性试验显示3批20价肺炎球菌结合疫苗免疫3针后呈现较好的免疫原性; 大鼠免疫原性试验显示, 疫苗在首次给药后2周即诱导产生针对20种肺炎球菌血清型的抗体, 并在末次给药结束后3周仍维持一定水平, 具有较好的免疫持久性。疫苗在小鼠体内采用最大给药量法给药, 未见明显毒性反应。大鼠重复给药安全性试验显示注射部位局部刺激反应, 出现了病理改变, 在恢复期有所减轻; 给药期结束和恢复期结束时, 未见明显毒性反应、免疫毒性反应。研究表明, 在小鼠、大鼠模型中, 新型20价肺炎球菌结合疫苗展现出较好的免疫原性及安全性。所有实验动物的使用已获得北京民海生物科技有限公司实验动物伦理委员会批准 (批准号: 202309、202311)。

关键词

肺炎球菌 / 结合疫苗 / 免疫原性 / 安全性 / 小鼠 / 大鼠

Abstract

收起

This study aims to evaluate the immunogenicity and safety of the 20-valent pneumococcal conjugate vaccine (PCV20). Different evaluation models were established using ICR mice and SD rats to assess the immunogenicity and toxic reactions. The results showed that the immunogenicity test in mice demonstrated good immunogenicity for three batches of the 20-valent pneumococcal conjugate vaccine after three doses. The immunogenicity test in rats showed that the vaccine induced antibodies against 20 pneumococcal serotypes within 2 weeks after the first dose and maintained a certain level for 3 weeks after the final dose, indicating good immune persistence. The vaccine was administered to mice at the maximum dosage without any significant toxic reactions observed. The repeated-dose safety test in rats showed local irritation and pathological changes at the injection site, which were alleviated during the recovery period. No significant toxic reactions were observed at the end of the dosing period and the recovery period. Studies have shown that the novel 20-valent pneumococcal conjugate vaccine exhibits good immunogenicity and safety in mouse and rat models. The use of all experimental animals has been approved by the Ethics Committee of Laboratory Animal of Beijing Minhai Biological Technology Co. Ltd. (No. 202309, 202311).

Key words

Streptococcus pneumoniae / conjugate vaccine / immunogenicity / safety / mouse / rat

引用本文

尹珊珊, 宋琳琳, 任涛, 刘兴, 杨靖寰, 郭龙静, 李跃龙, 邓海清. 20价肺炎球菌结合疫苗的免疫原性及安全性研究. 药学学报, 2025 , 60 (7) : 2016 -2023 . DOI: 10.16438/j.0513-4870.2025-0271

Shan-shan YIN, Lin-lin SONG, Tao REN, Xing LIU, Jing-huan YANG, Long-jing GUO, Yue-long LI, Hai-qing DENG. Immunogenicity and safety of 20-valent pneumococcal conjugate vaccine[J]. Acta Pharmaceutica Sinica, 2025 , 60 (7) : 2016 -2023 . DOI: 10.16438/j.0513-4870.2025-0271

正文

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肺炎球菌 (Streptococcus pneumoniae) 是一种常见的病原体, 可导致肺炎、脑膜炎、中耳炎和菌血症等多种疾病, 尤其对儿童、老年人和免疫功能低下人群构成严重威胁^[1]。根据世界卫生组织的统计, 肺炎球菌感染每年导致全球数百万人死亡, 其中大多数发生在发展中国家^[2]。尽管抗生素治疗是主要的临床手段, 但随着抗生素耐药性的增加, 预防性疫苗的开发和应用显得尤为重要^[3]。

肺炎球菌疫苗主要包括多糖疫苗和多糖结合疫苗。多糖疫苗 (如23价肺炎球菌多糖疫苗, PPV23) 虽然覆盖范围广, 但对2岁以下儿童的免疫效果较差, 因其无法有效激活T细胞依赖性免疫反应^[4]。相比之下, 多糖结合疫苗通过将多糖抗原与载体蛋白结合, 能够诱导更强的免疫记忆和更持久的保护效果^[5]。近年来, 随着肺炎球菌血清型的多样化和流行病学的变化, 开发覆盖更多血清型的多价结合疫苗成为研究热点^[6], 据报道已有多个肺炎球菌结合疫苗如辉瑞公司的PCV20、默克公司的PCV15及PCV21使用范围覆盖至6周龄以上人群, 包含更多血清型的多价结合疫苗的接种从免疫原性、耐受性等临床结果也证明了可替代早期上市的结合疫苗PCV7、PCV13、PCV15及多糖疫苗PPV23等^[7-13]。目前国内仅有云南沃森、北京民海的PCV13获批上市, 尚未有更多价次肺炎结合疫苗成功上市。本文研究的20价肺炎球菌结合疫苗是一种新型疫苗, 包含已上市的13个血清型 (1、3、4、5、6A、6B、7F、9V、14、18C、19A、19F、23F) 和7个新增血清型 (8、10A、11A、12F、15B、22F、33F), 2021年肺炎球菌性疾病免疫预防专家共识^[14]中指出现有各种疫苗所包含血清型覆盖了中国在内各地大多数致病的血清型, PCV13覆盖约80%, PPV23覆盖>85%, 本研究除保留了已上市的13个血清型, 新增的7个型因其相对流行率较高, 广泛的地理分布, 以及与抗生素耐药、疾病严重程度的相关性等因素^[15]将其纳入20PCV, 旨在覆盖更多流行的肺炎球菌血清型, 以提供更广泛的保护。

与公司已上市的PCV13^[16,17]及其他公司上市产品^[8,10,18]比较, 公司研制的PCV20采用了先进的发酵技术、新的灭活方式, 根据血清型的差异改良了部分型别多糖的纯化方式, 降解多糖的制备也进行了更好的优化和精准控制, 采用破伤风类毒素和白喉毒素无毒突变CRM197双载体与不同型别的降解多糖结合, 再与磷酸铝吸附成为20价肺炎球菌结合疫苗。主要在以下几个关键环节与同类产品相比实现了优化或创新。① 多糖的制备: 纯化多糖的分子大小、杂质残留的一致性是基本前提, 为降解多糖的制备和质量控制奠定基础, 合适大小的降解多糖更有利于与载体蛋白结合及后期纯化, 同时也保证了免疫原性和批间一致性。从发酵培养过程、灭活及纯化方式调控多糖的合成及化学修饰; 在灭活、纯化过程根据血清型不同, 选择适合的方式保证多糖回收率和杂质去除率; 降解多糖利用高压均质的技术, 能够精准控制分子大小范围, 操作简单, 不破坏多糖重复单元结构, 避免了因化学降解导致抗原决定簇破坏而影响免疫原性。② 蛋白: 载体蛋白的质量控制和种类选择, 也是该疫苗的创新之处及未来临床结果有望凸显优势的设计关键点。与众多上市疫苗不同的是, 该疫苗多数血清型选择白喉毒素无毒突变体CRM197作为载体蛋白, 另有几个型别选择用破伤风类毒素作为载体蛋白。③ 结合方法: 型别不同, 结合方式不同, 主要基于结合物的结合效率、多糖蛋白比、放置稳定性、免疫原性等多方面综合评价, 选择了直接结合、间接结合及氨还原法等多个方式。④ 制剂制备: 在磷酸铝制备过程对于粒径的控制, 灭菌方式的选择及与结合物吸附条件均进行了摸索与论证。

疫苗的安全性和免疫原性是评价其临床应用价值的关键指标^[19], 基于上述的优化和创新, 本次研究通过系统的动物实验, 评估20价肺炎球菌结合疫苗免疫原性, 同时通过单次给药、重复给药等评价疫苗安全性。研究结果将为该疫苗的进一步开发和临床应用提供重要的科学依据。

材料与方法

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主要试剂 碱性磷酸酶标记的羊抗小鼠IgG抗体 (批号: 016M4761V)、碱性磷酸酶标记的羊抗大鼠IgG抗体 (批号: 081M6255V)、Tween 20 (批号: WXBD8211V); 显色底物 (批号: SLCG8427) 均购自Sigma公司; C多糖 (丹麦血清研究所; 批号: ACWPS3-1); 氯化钠 (批号: 20220829)、磷酸氢二钠 (批号: 20220520)、氯化钾 (批号: 20210922) 均购自国药集团; 氢氧化钠 (北京益利; 批号: 20220117)。

仪器 ELX808酶标仪 (美国BioTek公司); Pentra DX 120全自动血液分析仪 (法国ABX公司)、7100全自动生化仪 (日本日立公司)、Accuri^TM C6 plus流式细胞仪 (美国BD公司) 和组织病理学检查仪器均由第三方安全性评价研究中心提供, 并协助检验。

实验动物 SPF (specific pathogen free) 级ICR小鼠3～4周龄, 购自北京维通利华实验动物技术有限公司, 实验动物生产许可证号: SCXK (京) 2021-0006; SPF级SD大鼠雄性5～6周龄, 雌性6～7周龄购自北京维通利华实验动物技术有限公司, 实验动物生产许可证号: SCXK (京) 2021-0011。所有实验动物的使用已获得北京民海生物科技有限公司实验动物伦理委员会批准 (批准号: 202309、202311), 遵守相应的规范和要求。

供试品 PCV20 (批号: GR3621) 购自辉瑞投资有限公司; 其余制品由北京民海生物科技有限公司研发自制。

疫苗制备 北京民海生物科技有限公司研发自制, 具体制备流程如图1。各型别生产用肺炎球菌菌种经发酵、灭活、收获、根据不同型别采取不同纯化工艺纯化后冻干得到纯化多糖; 纯化多糖经过物理降解得到符合要求的降解多糖; 20个血清型的降解多糖采用3个不同结合工艺分别与载体蛋白 (破伤风类毒素或白喉毒素CRM197) 进行结合, 纯化得到单型结合物原液; 将单型结合物原液混合后加入磷酸铝佐剂等配制为半成品, 按规格要求进行分包装后即为疫苗成品。试验用对照疫苗PCV20 (批号: GR3621) 购自辉瑞投资有限公司。

小鼠免疫原性试验

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动物分组与免疫 ICR小鼠, SPF级, 50只, 每组10只。辉瑞PCV20 (批号GR3621)、3批民海PCV20、阴性对照 (氯化钠注射液), 共5组。实验组腹腔注射人用剂量 (每剂0.5 mL, 每剂中6B型多糖含量为4.4 μg, 其余型别均为2.2 μg) 的1/4, 小鼠于第0、14、28日免疫3次, 第35天取血。分离得到血清用于检测或保存于-20 ℃及以下待检。

血清抗体检查酶标板每孔加入包被液100 μL, 过夜; 血清样本稀释100倍后用含有肺炎球菌细胞壁C多糖的样品吸收液进行吸附, 吸附后的血清加入到包被好的酶标板中, 再倍比稀释后进行结合, 室温孵育后洗板, 加入碱性磷酸酶标记的二抗进行结合, 室温孵育后再次洗板, 加入显色底物进行显色反应, 酶标仪进行405 nm处的吸光度 (A) 值检测。

小鼠血清根据阴性对照的A值计算cut-off值, 以血清A值≥cut-off值所对应的稀释倍数为血清的抗体滴度 (稀释倍数小于100的按50进行计算), 将组内每只小鼠抗体滴度计算几何平均值, 再以2为底进行对数转换, 结果为血清抗体几何平均滴度 (geometric mean titer, GMT)。

大鼠免疫原性试验

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动物分组与免疫 SD大鼠, SPF级, 供试品组10只、阴性对照组10只, 雌雄各半。雄性5～6周, 雌性6～7周龄。供试品组、阴性对照组分别免疫20价肺炎球菌结合疫苗或氯化钠注射液 (0.9%), 剂量为每只大鼠0.5 mL (每次人用剂量为0.5 mL), 给药方式为肌肉注射, 左、右侧大腿后肢各0.25 mL, 连续注射5次, 每次间隔2周。供试品组、阴性对照组均在首次给药后第2、4、6、8、9周 (恢复期1周)、11周 (给药结束/恢复期3周) 分别采集动物血液样本1 mL, 共6次采血, 分离得到的血清于-20 ℃及以下保存, 进行抗体检测。

血清抗体检查酶标板每孔加入包被液100 μL, 过夜; 血清样本稀释100倍后用含有肺炎球菌细胞壁C多糖的样品吸收液进行吸附, 吸附后的血清加入到包被好的酶标板中, 再以3倍梯度稀释后进行结合, 室温孵育后洗板, 加入碱性磷酸酶标记的二抗进行结合, 室温孵育后再次洗板, 加入显色底物进行显色反应, 用酶标仪进行405 nm处A值检测。

大鼠血清根据阴性对照的A值计算cut-off值, 以血清A值≥cut-off值所对应的稀释倍数为血清的抗体滴度 (稀释倍数小于100的按50进行计算), 将组内每只大鼠抗体滴度计算几何平均值, 再以2为底进行对数转换, 结果为血清抗体GMT。

单次给药安全性试验 ICR小鼠40只, 雌雄各半, 3～4周龄。按体重和性别随机分为阴性对照组 (negative control group, 以下简称NC组)、供试品组 (treatment group, 以下简称T组), 分别肌肉注射氯化钠注射液 (0.9%)、20价肺炎球菌结合疫苗。供试品给药剂量为每只小鼠0.2 mL (每次人用剂量为0.5 mL)。给药后连续观察15天: 测定给药前、给药后第1、3、7、10和14天的小鼠体重; 测定给药后第0～1天、第1～3天、第3～7天、第7～10天、第10～14天的小鼠摄食量; 在给药后第15天进行大体解剖, 进行病理检查。

重复给药安全性试验 SD大鼠, 80只, 雌雄各半, 大鼠雄性5～6周龄; 雌性6～7周龄; 每组40只, 设定有NC组和T组, NC组肌肉注射给予每只0.5 mL的氯化钠注射液 (0.9%); T组肌肉注射给予每只0.5 mL 20价肺炎球菌结合疫苗; 每两周给药1次, 连续给药5次, 恢复期为3周。每天观察动物的毒性反应和注射部位的刺激反应, 每周测定动物的体重和摄食量, 在给药期结束和恢复期结束时, 测定血液学指标、血清生化指标等; 在给药期结束和恢复期结束时, 每组雌雄各10只大鼠实施安乐死, 进行大体解剖, 并进行组织病理学检查。

统计学分析 免疫原性数据采用方差分析或非参数检验进行比较; 安全性数据用均值 ± 标准差 (x±s) 的形式体现, 并用t检验进行统计分析。

结果

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1　免疫原性试验

1.1　小鼠免疫原性试验

将各型荚膜多糖特异性抗体的GMT进行了方差分析及组间对比, 结果显示, 所有型别在小鼠模型中均显示出了良好的免疫应答, 与辉瑞已上市的PCV20疫苗有较好的可比性。统计学分析发现, 多数型别之间差异无统计学意义, 但值得注意的是, 3批产品的9V型GMT均显著优于辉瑞已上市产品。对于在统计学上差异无统计学意义的型别, 进一步比较了GMT的绝对值, 结果显示, 3批产品中1型、3型、6A型、6B型、11A型和18C型的GMT绝对值均高于辉瑞已上市产品, 具体数据见表1, 证明了该疫苗在小鼠模型中与已上市同类产品具有较好的可比性, 进一步的结果还需要通过临床试验来验证。

1.2　大鼠免疫原性试验

将大鼠每次给药后2周采集的血清进行各型荚膜多糖特异性抗体含量检测, 共采血6次, 检测分析结果见表2。首次给药后2周, 针对各型肺炎球菌的抗体陆续被检出, 大部分型别在第3～5次 (首次给药后6～9周) 采血的抗体检测达到最高, 第6次采血 (首次给药后11周) 仍维持一定的抗体水平, 具有较好的持久性。各型别 (每组10只) 大鼠血清GMT结果显示, 在6次采血检测中各型别 (12F除外) 整体差异有统计学意义 (P < 0.05), 针对整体存在差异的型别再进一步进行多重比较, 大部分型别在首次给药后6～9周抗体水平与第1次采血 (首次给药后2周) 结果差异存在统计学意义。从各型血清滴度来看, 免疫两次疫苗后的所有动物抗体均达到了阳转, 随着针次增加, 有一定升高趋势, 并在一定时间内维持了较高抗体水平。值得注意的是, 12F型的抗体水平较低, 在小鼠模型中也存在该现象, 辉瑞上市产品该型别在动物体内抗体水平也较低。另外, 3、4、10A等型别在大鼠体内GMT值较小, 抗体水平较低, 这可能与相应型别在大鼠体内产生抗体能力不同或与检测系统的普适性存在一定关联, 需要更多的动物模型比较及针对个别型别检测方法的进一步优化。

2　安全性试验

2.1　单次给药安全性试验

采用最大给药量法, 每只小鼠肌肉注射给药0.2 mL (根据体重换算, 相当于临床拟用剂量的83～1 333倍) 后, 连续观察15天, 小鼠没有出现濒死或死亡, 也没有出现其他毒性反应。T组 (疫苗组) 雄性和雌性小鼠体重, 在给药后第1、3、7、10、14天同NC组比较均无统计学差异 (P > 0.05), 结果见表3。T组雄性小鼠的摄食量均值与NC组基本一致, 没有出现明显的异常变化; T组雌性小鼠的摄食量均值, 药后第10～14天与NC组比较, 略有降低; 其他时间点与NC组基本一致, 没有出现明显的异常变化, 结果见表4。病理学结果显示在给药后第15天进行大体解剖, T组小鼠各受检组织、器官均未产生肉眼可见的病理变化。

2.2　重复给药安全性试验

2.2.1　一般指标

整个试验期间, 各组大鼠均未出现明显毒副反应, 也无死亡; 在给药期结束时, T组大鼠注射部位肌肉及周围组织炎性细胞浸润, 坐骨神经周围组织炎性细胞浸润。在恢复期结束时, T组相较于给药期结束注射部位肌肉病变程度减轻、数量减少, 表明疫苗局部刺激是可逆的; 在给药期间、恢复期间动物体重变化差异无统计学意义。动物摄食量在给药期和恢复期两个组差异无统计学意义。

2.2.2　血液学指标

给药期结束时, T组雄性大鼠的红细胞分布宽度、单核细胞数量及百分率与NC组比较差异有统计学意义 (P < 0.01或P < 0.05), T组雌性大鼠的白细胞、淋巴细胞、单核细胞、嗜中性粒细胞和嗜酸性粒细胞数目与NC组比较差异有统计学意义 (P < 0.01或P < 0.05); 在恢复期结束时, T组雄性大鼠的血小板与NC组比较差异有统计学意义 (P < 0.05), 但在正常值范围内, 差异无生理学意义。此外, T组其他血液学各指标同NC组比较差异无统计学意义 (P > 0.05), 部分统计数据见表5。

2.2.3　血清生化指标

在给药期结束时, T组雄性大鼠总胆固醇、钾离子浓度和氯离子浓度与NC组比较差异有统计学意义 (P < 0.05); T组雌性大鼠丙氨酸氨基转移酶与NC组差异有统计学意义 (P < 0.05), 但在正常值范围内, 差异无生理学意义; 在恢复期结束时, T组雄性大鼠尿素氮、白球比与NC组比较差异有统计学意义 (P < 0.01或P < 0.05); T组雌性大鼠钾离子浓度与NC组比较差异有统计学意义 (P < 0.05), 但均在正常值范围内, 差异无生理学意义。此外, 其他各指标同NC组比较差异无统计学意义 (P > 0.05), 部分统计数据见表6。

2.2.4　病理性检查结果

在给药期结束和恢复期结束时, 各组解剖动物的脏器组织均未见毒性反应。部分病理性图片如图2。

讨论

收起

本研究通过一系列动物实验, 全面评价了20价肺炎球菌结合疫苗的安全性和免疫原性。在安全性方面, 单次给药和重复给药试验结果显示, 疫苗在最大给药量下 (至少为临床使用量的83倍) 未见明显的毒性反应。尽管在重复给药试验中, 注射部位出现了局部的肌肉坏死和炎性细胞浸润, 但在恢复期结束后, 病变程度显著减轻, 表明疫苗的局部刺激反应是可逆的。这一结果与既往研究报道的结合疫苗安全性特征一致^[20,21]。此外, 血液学、血清生化和病理学检查结果显示, 疫苗对主要脏器和免疫系统未产生显著毒性作用, 进一步支持了其良好的安全性^[22]。

在免疫原性方面, 小鼠模型中, 3次免疫后血清抗体滴度显示疫苗具有良好的免疫原性, 除9V型统计结果显示与辉瑞上市产品差异有统计学意义 (这可能与载体蛋白不同有关, 民海生物的9V型多糖与破伤风类毒素直接结合的方式), 其余型别差异均无统计学意义。这在公司已上市的PCV13的临床结果^[17]也得到证明, 加强免疫后的免疫原性显著优于辉瑞的产品。对于在统计学上差异无统计学意义的型别, 本研究进一步比较了GMT值。结果显示, 3批产品中1型、3型、6A型、6B型、11A型和18C型的GMT值均高于辉瑞已上市产品, 其余型别在小鼠模型中的免疫原性水平则相当。总体看来, 在小鼠模型上与辉瑞上市的PCV20比较, 免疫原性存在一定优势, 同时通过连续生产的3批产品证明了现有工艺的有效性和稳定性。本研究对多个型别 (如5、7F、10A、14、15B等) 的发酵过程、灭活方式、多糖纯化方法进行了创新性优化, 显著减少了蛋白质、核酸等残留物质^[23,24], 更精准控制了多糖的分子量和结构修饰等, 这些改良措施从源头至少为生产更加安全、有效的疫苗提供了坚实的理论基础。

在大鼠的免疫原性试验中, 首次给药后2周, 大鼠血清中即检测到针对20种肺炎球菌血清型的特异性抗体, 且多数型别随着针次的增加抗体水平逐渐上升, 在首次给药后6～9周抗体水平达到最高值, 并在第11周 (末次给药后3周) 仍维持一定水平。这一结果表明, 疫苗能够有效激活机体的免疫系统, 诱导产生持久的抗体反应。本次研究也发现不同型别的免疫反应各有不同, 不同血清型的抗体动力学存在一定差异, 这可能与抗原的特异性、免疫原性强弱、种属差异以及个体免疫反应的异质性有关^[25], 在较多临床试验报道也常有该现象^[8,16,26]。

本研究的PCV20选择双载体蛋白与不同型别血清型荚膜多糖结合, 这样在人体复杂的免疫程序中可以更大程度地避免载体蛋白启动效应或蛋白诱导的表位抑制效应 (carrier-induced epitope suppression, CIES)。研究显示^[27-29], 若存在白喉类毒素或破伤风类毒素初免导致体内预存相关抗体, 可能会增加或减弱多糖的免疫应答, 同时接种相同载体蛋白的结合疫苗也可能会因表位抑制效应引起多糖免疫应答水平的降低。相应的, 因多次重复接种结合疫苗, 也可能影响联合疫苗 (如包含白喉、破伤风在内的三联苗、四联苗、五联苗、六联苗等) 对应的抗原免疫原性。与公司已上市的PCV13相比, PCV20将原来的破伤风类毒素和白喉类毒素双载体变更为破伤风类毒素和白喉毒素CRM197双载体, 几个血清型选择使用破伤风类毒素, 其余多数型别选择无毒突变体CRM197作为载体, 在理论上大大减少了上述可能发生的现象。在小鼠和大鼠的免疫原性研究发现, 公司生产的PCV20有较好的免疫原性, 这个优势可能无法在现有的动物模型得以充分证明, 但在PCV13与其他厂家已上市同类产品临床试验比较中, 无论是免疫原性还是免疫持久性均展示了较好的可比性, 在多数型别呈现更好的有效性, 本制品从前期过程中纯化多糖和降解多糖的质量控制、载体蛋白的选择、结合工艺的优化与筛选、制剂技术的改良来看, 各个环节的关键质量属性得到较好的控制与评价, 理论上应呈现出更好的安全性和有效性^[30], 仍需在后续的临床试验中进一步验证。此外, 疫苗的长期保护效果、对不同人群的适用性以及与其他疫苗的联合使用策略仍需进一步研究^[31]。

总体来说, 本研究结果表明在小鼠和大鼠模型中均表现出良好的安全性和免疫原性, 为其进一步开发和临床应用奠定了坚实的基础。

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2025年第60卷第7期

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doi: 10.16438/j.0513-4870.2025-0271

接收时间：2025-03-12
首发时间：2026-09-20
出版时间：2025-07-12

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收稿日期：2025-03-12
修回日期：2025-05-16

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北京民海生物科技有限公司, 结合疫苗新技术研究北京市重点实验室, 北京 102600

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邓海清, E-mail: denghaiqing@biominhai.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Serotype	PCV20-001	PCV20-002	PCV20-003	PCV20 (Pfizer)	P
1	10.5	10.3	10.4	10.2	0.970 0
3	10.5	10.4	10.7	10.3	0.911 6
4	11.6	11.3	11.5	11.5	0.962 2
5	11.0	11.3	11.0	11.0	0.955 6
6A	10.6	10.5	10.4	10.2	0.906 5
6B	10.0	10.2	9.6	9.8	0.698 4
7F	11.5	11.5	11.7	11.6	0.950 8
8	11.2	11.3	11.5	11.3	0.915 8
9V	11.1^*	11.1^*	10.9^*	9.8	0.004 2
10A	8.9	8.7	9.3	9.2	0.542 0
11A	10.9	10.8	10.9	10.7	0.955 2
12F	9.1	8.7	8.9	9.0	0.666 1
14	11.6	11.7	11.8	12.1	0.716 0
15B	9.9	9.8	10.2	10.0	0.870 7
18C	10.8	11.0	11.1	10.6	0.778 7
19A	9.9	9.6	10.0	9.9	0.900 4
19F	9.6	9.9	10.2	9.6	0.801 3
22F	10.7	10.9	10.9	10.8	0.980 1
23F	10.2	10.0	9.9	9.9	0.964 1
33F	10.1	10.4	10.4	10.4	0.967 3

Serotype

PCV20-001

PCV20-002

PCV20-003

PCV20 (Pfizer)

10.5

10.3

10.4

10.2

0.970 0

10.5

10.4

10.7

10.3

0.911 6

11.6

11.3

11.5

0.962 2

11.0

11.3

11.0

0.955 6

10.6

10.5

10.4

10.2

0.906 5

10.0

10.2

9.6

9.8

0.698 4

11.5

11.7

11.6

0.950 8

11.2

11.3

11.5

11.3

0.915 8

11.1^*

10.9^*

9.8

0.004 2

10A

8.9

8.7

9.3

9.2

0.542 0

11A

10.9

10.8

10.9

10.7

0.955 2

12F

9.1

8.7

8.9

9.0

0.666 1

11.6

11.7

11.8

12.1

0.716 0

15B

9.9

9.8

10.2

10.0

0.870 7

18C

10.8

11.0

11.1

10.6

0.778 7

19A

9.9

9.6

10.0

9.9

0.900 4

19F

9.6

9.9

10.2

9.6

0.801 3

22F

10.7

10.9

10.8

0.980 1

23F

10.2

10.0

9.9

0.964 1

33F

10.1

10.4

0.967 3

Serotype	2W	4W	6W	8W	9W	11W	P
1	8.9	10.7	10.2	10.1	9.2	9.2	0.001 0
3	7.3	8.0	8.1	8.3	8.0	7.9	0.035 9
4	6.5	8.1	8.2^*	8.5^*	7.9	7.8	0.000 1
5	8.9	9.4	9.7	10.6^*	11.0^*	10.3	<0.000 1
6A	6.9	8.2	9.6	10.6^*	10.8^*	11.0^*	<0.000 1
6B	6.7	7.9	8.8^*	9.1^*	8.7^*	8.8^*	<0.000 1
7F	7.2	9.7	11.8^*	11.8^*	11.0^*	11.0^*	<0.000 1
8	9.0	10.5	11.2^*	10.6	10.5	10.1	<0.000 1
9V	9.1	11.1	12.1^*	12.3^*	11.8	11.6	0.000 8
10A	6.3	7.0	8.0^*	8.1^*	8.0^*	8.1^*	<0.000 1
11A	9.3	11.4	11.7^*	12.0^*	10.7	10.5	<0.000 1
12F	7.7	8.1	7.8	8.1	7.5	7.7	0.524 6
14	7.1	8.3	9.7	10.5^*	10.3^*	10.1^*	<0.000 1
15B	7.1	9.4	9.9^*	10.1^*	9.5	9.8^*	0.000 2
18C	6.5	8.6	11.5^*	11.9^*	11.2^*	10.6	<0.000 1
19A	7.6	9.1	9.8^*	9.8^*	9.2	8.7	<0.000 1
19F	7.1	7.5	8.3	8.3	8.0	8.0	0.015 8
22F	7.5	8.4	9.0^*	8.7	8.0	8.3	0.002 1
23F	7.1	8.5	9.9^*	10.2^*	9.4	9.8	0.000 2
33F	10.3	11.5	12.2	12.3^*	12.0	12.0	0.000 2

Serotype

11W

8.9

10.7

10.2

10.1

9.2

0.001 0

7.3

8.0

8.1

8.3

8.0

7.9

0.035 9

6.5

8.1

8.2^*

8.5^*

7.9

7.8

0.000 1

8.9

9.4

9.7

10.6^*

11.0^*

10.3

<0.000 1

6.9

8.2

9.6

10.6^*

10.8^*

11.0^*

<0.000 1

6.7

7.9

8.8^*

9.1^*

8.7^*

8.8^*

<0.000 1

7.2

9.7

11.8^*

11.0^*

<0.000 1

9.0

10.5

11.2^*

10.6

10.5

10.1

<0.000 1

9.1

11.1

12.1^*

12.3^*

11.8

11.6

0.000 8

10A

6.3

7.0

8.0^*

8.1^*

8.0^*

8.1^*

<0.000 1

11A

9.3

11.4

11.7^*

12.0^*

10.7

10.5

<0.000 1

12F

7.7

8.1

7.8

8.1

7.5

7.7

0.524 6

7.1

8.3

9.7

10.5^*

10.3^*

10.1^*

<0.000 1

15B

7.1

9.4

9.9^*

10.1^*

9.5

9.8^*

0.000 2

18C

6.5

8.6

11.5^*

11.9^*

11.2^*

10.6

<0.000 1

19A

7.6

9.1

9.8^*

9.2

8.7

<0.000 1

19F

7.1

7.5

8.3

8.0

0.015 8

22F

7.5

8.4

9.0^*

8.7

8.0

8.3

0.002 1

23F

7.1

8.5

9.9^*

10.2^*

9.4

9.8

0.000 2

33F

10.3

11.5

12.2

12.3^*

12.0

0.000 2

Sex	Group	Pre-immune	Days post-immune
Male	NC	20.5±0.5	22.6±0.7	26.0±1.1	28.1±1.5	31.7±2.2	34.6±2.3
T	20.6±0.6	22.7±0.7	26.6±1.3	27.7±1.7	32.8±2.3	35.5±2.3
Female	NC	21.5±0.7	22.2±0.8	24.2±0.8	25.2±1.5	26.0±1.5	27.4±1.5
T	21.4±0.5	22.8±0.9	24.8±1.1	24.9±1.8	26.4±1.3	27.3±1.3

Sex

Group

Pre-immune

Days post-immune

Male

20.5±0.5

22.6±0.7

26.0±1.1

28.1±1.5

31.7±2.2

34.6±2.3

20.6±0.6

22.7±0.7

26.6±1.3

27.7±1.7

32.8±2.3

35.5±2.3

Female

21.5±0.7

22.2±0.8

24.2±0.8

25.2±1.5

26.0±1.5

27.4±1.5

21.4±0.5

22.8±0.9

24.8±1.1

24.9±1.8

26.4±1.3

27.3±1.3

Sex	Group	Days post-immune
Male	NC	5.0±0.1	5.3±0.1	4.7±0.1	5.8±0.4	5.7±0.1
T	5.0±0.3	5.2±0.1	4.7±0.1	6.0±0.2	5.9±0.2
Female	NC	4.4±0.1	4.5±0.2	4.4±0.3	4.6±0.1	5.1±0.0
T	4.6±0.4	4.5±0.2	4.4±0.1	4.5±0.7	4.6±0.2

Sex

Group

Days post-immune

0-1

1-3

3-7

7-10

10-14

Male

5.0±0.1

5.3±0.1

4.7±0.1

5.8±0.4

5.7±0.1

5.0±0.3

5.2±0.1

4.7±0.1

6.0±0.2

5.9±0.2

Female

4.4±0.1

4.5±0.2

4.4±0.3

4.6±0.1

5.1±0.0

4.6±0.4

4.5±0.2

4.4±0.1

4.5±0.7

4.6±0.2

Test item	Time point	Male		Female
		9.9±2.2	8.9±1.5		4.6±1.6	7.2±2.3^**
End of recovery	9.1±3.2	9.4±1.6	5.1 ±1.6	5.5±1.4
RBC/10¹²·L^-1	End of dosing	8.16±0.34	8.18±0.33	7.42±0.25	7.40±0.22
End of recovery	8.67±0.40	8.75±0.34	7.70±0.31	7.64±0.29
Hemoglobin/g·L^-1	End of dosing	167±6	164±6	155±2	153±5
End of recovery	167±6	166±6	159±6	156±4
Hematocrit/%	End of dosing	43.4±1.3	43.1±1.7	40.8±0.6	40.1±1.3
End of recovery	43.9±2.3	43.3±1.2	41.6±1.0	41.4±1.5
Red blood cell distribution width/%	End of dosing	12.8±0.7	14.0±0.7^**	12.2±0.8	12.9±0.7
End of recovery	14.5±0.7	14.9±0.7	13.1±0.6	12.7±0.5
Monocyte/10⁹·L^-1	End of dosing	0.07±0.02	0.04±0.02^**	0.01±0.01	0 .02±0.01^*
End of recovery	0.06±0.03	0.06±0.03	0.01±0.01	0.02±0.01
Monocyte/%	End of dosing	0.8±0.2	0.5±0.2^*	0.2±0.1	0 .3±0.2
End of recovery	0.6±0.2	0.6±0.2	0.2±0.2	0.3±0.2
Eosinophils/10⁹·L^-1	End of dosing	0.22±0.10	0.16±0.12	0.02±0.02	0.06±0.04^**
End of recovery	0.22±0.10	0.38±0.38	0.05±0.04	0.12±0.26
Lymphocyte/10⁹·L^-1	End of dosing	7.72±1.66	7.13±1.41	3.85±1.34	5.99±2.00^*
End of recovery	7.24±2.71	7.13±0.93	4.13±1.49	4.33±1.14
Neutrophils/10⁹·L^-1	End of dosing	1.78±0.54	1.49±0.39	0.60±0.26	1.06±0.40^**
End of recovery	1.55±0.47	1.74±0.59	0.86±0.20	0.98±0.42
Platelet/10⁹·L^-1	End of dosing	847±100	891±68	910±200	929±46
End of recovery	855±90	745±120^*	847±60	727±187

Test item

Time point

Male

Female

9.9±2.2

8.9±1.5

4.6±1.6

7.2±2.3^**

End of recovery

9.1±3.2

9.4±1.6

5.1 ±1.6

5.5±1.4

RBC/10¹²·L^-1

End of dosing

8.16±0.34

8.18±0.33

7.42±0.25

7.40±0.22

End of recovery

8.67±0.40

8.75±0.34

7.70±0.31

7.64±0.29

Hemoglobin/g·L^-1

End of dosing

167±6

164±6

155±2

153±5

End of recovery

167±6

166±6

159±6

156±4

Hematocrit/%

End of dosing

43.4±1.3

43.1±1.7

40.8±0.6

40.1±1.3

End of recovery

43.9±2.3

43.3±1.2

41.6±1.0

41.4±1.5

Red blood cell distribution width/%

End of dosing

12.8±0.7

14.0±0.7^**

12.2±0.8

12.9±0.7

End of recovery

14.5±0.7

14.9±0.7

13.1±0.6

12.7±0.5

Monocyte/10⁹·L^-1

End of dosing

0.07±0.02

0.04±0.02^**

0.01±0.01

0 .02±0.01^*

End of recovery

0.06±0.03

0.01±0.01

0.02±0.01

Monocyte/%

End of dosing

0.8±0.2

0.5±0.2^*

0.2±0.1

0 .3±0.2

End of recovery

0.6±0.2

0.2±0.2

0.3±0.2

Eosinophils/10⁹·L^-1

End of dosing

0.22±0.10

0.16±0.12

0.02±0.02

0.06±0.04^**

End of recovery

0.22±0.10

0.38±0.38

0.05±0.04

0.12±0.26

Lymphocyte/10⁹·L^-1

End of dosing

7.72±1.66

7.13±1.41

3.85±1.34

5.99±2.00^*

End of recovery

7.24±2.71

7.13±0.93

4.13±1.49

4.33±1.14

Neutrophils/10⁹·L^-1

End of dosing

1.78±0.54

1.49±0.39

0.60±0.26

1.06±0.40^**

End of recovery

1.55±0.47

1.74±0.59

0.86±0.20

0.98±0.42

Platelet/10⁹·L^-1

End of dosing

847±100

891±68

910±200

929±46

End of recovery

855±90

745±120^*

847±60

727±187

Test item	Time point	Male		Female
Alanine aminotransferase/U·L^-1	End of dosing	34±4	36±6		30±9	46±20^*
End of recovery	38±7	36±9	37±12	40±7
Aspartate aminotransferase/U·L^-1	End of dosing	113±29	127±21	121±25	140±32
End of recovery	148±24	148±26	121±34	118±43
Total protein/g·L^-1	End of dosing	61.81±2.33	62.36±2.48	71.26±4.13	73.59±5.91
End of recovery	59.70±3.45	60.84±2.33	71.46±5.45	71.91±4.33
Albumin/g·L^-1	End of dosing	27.85±0.83	28.53±1.41	36.55±3.70	38.46±4.48
End of recovery	28.80±1.53	28.21±0.63	39.86±4.41	40.39±3.23
Urea nitrogen/mmol·L^-1	End of dosing	4.68±0.46	4.70±0.55	4.72±0.50	5.22±0.72
End of recovery	5.58±0.61	4.83±0.41^**	5.72±0.71	5.78±0.70
Creatinine/μmol·L^-1	End of dosing	24.57±1.76	24.65±2.67	29.61±1.90	31.49±3.18
End of recovery	27.85±3.33	26.44±2.15	32.29±3.53	32.12±3.27
Uric acid/μmol·L^-1	End of dosing	144.36±12.56	147.83±16.01	159.39±25.29	156.66±18.31
End of recovery	158.64±15.71	158.61±27.38	157.65±22.63	147.53±9.84
Total cholesterol/mmol·L^-1	End of dosing	1.91±0.29	1.63±0.22^*	2.03±0.36	1.93±0.43
End of recovery	1.71±0.25	1.86±0.39	1.97±0.47	2.09±0.44
A/G ratio	End of dosing	0.82±0.06	0.84±0.07	1.05±0.10	1.10±0.14
End of recovery	0.94±0.06	0.87±0.05^*	1.26±0.14	1.28±0.11
K⁺/mmol·L^-1	End of dosing	5.05±0.12	5.19±0.18^*	4.44±0.23	4.51±0.28
End of recovery	5.27±0.25	5.17±0.31	4.62±0.29	4.37±0.17^*
Na⁺/mmol·L^-1	End of dosing	143.6±1.2	143.2±0.6	142.1±1.2	141.8±1.1
End of recovery	146.8±1.7	147.4±1.6	149.7±1.1	149.1±1.1
Cl^-/mmol·L^-1	End of dosing	102.5±1.1	103.7±1.3^*	104.2±1.2	103.9±2. 1
End of recovery	102.7±1.9	102.6±1.6	106.2±1.4	105.9±1.6

Test item

Time point

Male

Female

Alanine aminotransferase/U·L^-1

End of dosing

34±4

36±6

30±9

46±20^*

End of recovery

38±7

36±9

37±12

40±7

Aspartate aminotransferase/U·L^-1

End of dosing

113±29

127±21

121±25

140±32

End of recovery

148±24

148±26

121±34

118±43

Total protein/g·L^-1

End of dosing

61.81±2.33

62.36±2.48

71.26±4.13

73.59±5.91

End of recovery

59.70±3.45

60.84±2.33

71.46±5.45

71.91±4.33

Albumin/g·L^-1

End of dosing

27.85±0.83

28.53±1.41

36.55±3.70

38.46±4.48

End of recovery

28.80±1.53

28.21±0.63

39.86±4.41

40.39±3.23

Urea nitrogen/mmol·L^-1

End of dosing

4.68±0.46

4.70±0.55

4.72±0.50

5.22±0.72

End of recovery

5.58±0.61

4.83±0.41^**

5.72±0.71

5.78±0.70

Creatinine/μmol·L^-1

End of dosing

24.57±1.76

24.65±2.67

29.61±1.90

31.49±3.18

End of recovery

27.85±3.33

26.44±2.15

32.29±3.53

32.12±3.27

Uric acid/μmol·L^-1

End of dosing

144.36±12.56

147.83±16.01

159.39±25.29

156.66±18.31

End of recovery

158.64±15.71

158.61±27.38

157.65±22.63

147.53±9.84

Total cholesterol/mmol·L^-1

End of dosing

1.91±0.29

1.63±0.22^*

2.03±0.36

1.93±0.43

End of recovery

1.71±0.25

1.86±0.39

1.97±0.47

2.09±0.44

A/G ratio

End of dosing

0.82±0.06

0.84±0.07

1.05±0.10

1.10±0.14

End of recovery

0.94±0.06

0.87±0.05^*

1.26±0.14

1.28±0.11

K⁺/mmol·L^-1

End of dosing

5.05±0.12

5.19±0.18^*

4.44±0.23

4.51±0.28

End of recovery

5.27±0.25

5.17±0.31

4.62±0.29

4.37±0.17^*

Na⁺/mmol·L^-1

End of dosing

143.6±1.2

143.2±0.6

142.1±1.2

141.8±1.1

End of recovery

146.8±1.7

147.4±1.6

149.7±1.1

149.1±1.1

Cl^-/mmol·L^-1

End of dosing

102.5±1.1

103.7±1.3^*

104.2±1.2

103.9±2. 1

End of recovery

102.7±1.9

102.6±1.6

106.2±1.4

105.9±1.6