Download BCG Vaccine

Post-marketing Surveillance of
BCG vaccination
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Outline
 Tuberculosis
 Bacille Calmette–Guérin (BCG) vaccine
 BCG vaccination program
 Differential diagnosis of BCG
 Surveillance of adverse events
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Taiwan
 Population: 23,499,404
 Health expenditures
constituted approximately 6-7
percent of the gross domestic
product (GDP)
 Universal health care
 National health insurance:
covers 99.6% population
 BCG vaccination, TB diagnosis
and treatment: Free of charge
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TAIWAN:
48.4
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BCG vaccine
 BCG is a live-attenuated vaccine derived from
Mycobacterium bovis invented in 1908 and first use in
humans in 1921
 Main BCG strains: the French Pasteur strain 1173P2, the
Danish (Copenhagen) strain 1131, Glaxo strain 1077 and
Tokyo strain 172
 BCG is given as an intradermal injection or puncture
 BCG prevents childhood progressive primary TB,
especially miliary TB and tuberculous meningitis
 WHO included BCG vaccination in the WHO Expanded
Program on Immunization in 1974
An apparatus used in
Japan
 Approximately 100 million newborn children receive BCG
annually
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BCG strains
Efficacy Safety
Behr, MA, Lancet Infectious Disease, 2:86-91, 2002
WHO policy on BCG vaccination
WHO BCG position paper, Weekly epidemiological record, 2004,79,25-40
High TB burden countries • a single-dose of BCG, all infants after birth
Symptomatic HIV or other
• infants should not be vaccinated
immunodeficiency states
Exposure to smear (+)
pulmonary TB
Low TB burden countries
• infants should complete IPT first
• Infants with high-risk of TB
• TST (-) older children
WHO revised BCG vaccination guidelines, Weekly epidemiological record, 2007, 21,193-196
Risk for HIV infection
• High prevalence of TB/HIV (HIV-uninfected children)
• Benefits (usually) outweigh risks
BCG vaccination policy by country
A: Universal BCG
B: Used to recommend universal BCG
C: BCG only for selected high-risk groups
Zwerling A, Behr MA, Verma A, Brewer TF, Menzies D, et al. (2011) The BCG World Atlas: A Database of Global BCG Vaccination Policies and
Practices. PLoS Med 8(3): e1001012. doi:10.1371/journal.pmed.1001012
http://journals.plos.org/plosmedicine/article?id=info:doi/10.1371/journal.pmed.1001012
Shift to selective BCG vaccination
• An efficient notification system must be in
place in addition to the following criteria:
– an average annual notification rate of smear-positive
pulmonary TB cases below 5 per 100 000; or
– an average annual notification rate of tuberculous
meningitis in children aged under five years below 1 per 10
million population during the previous five years; or
– an average annual risk of TB infection (ARTI) below 0.1%.
International Union Against Tuberculosis and Lung Disease. Criteria for discontinuation of vaccination programmes using
Bacille Calmette Guerin (BCG) in countries with a low prevalence of tuberculosis. Tubercle and Lung Disease 1994; 75:
179-181.
Estimated TB incidence rate, by age
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
<15
3.5
3.5
3.3
4.0
3.2
2.6
3.3
2.2
2.7
2.2
1.5
15-19
22.7
21.7
19.9
17.5
20.2
17.7
17.5
14.6
14.9
15.6
10.2
20-24
31.0
27.9
26.5
28.4
22.0
21.8
23.0
19.9
19.1
15.4
12.9
25-29
33.2
26.9
26.4
27.3
23.3
24.2
20.0
19.0
17.0
16.0
15.3
30-34
34.9
29.6
26.3
26.2
22.2
22.1
22.3
20.1
19.3
18.9
14.7
35-39
35.1
32.0
31.0
31.2
27.1
25.2
25.3
23.8
23.0
20.2
16.9
40-44
45.5
40.3
38.6
37.5
31.6
31.7
29.1
28.8
27.6
24.3
20.1
45-49
56.0
51.4
48.5
44.3
40.0
39.1
38.2
37.2
33.8
31.9
27.6
50-54
72.8
64.8
58.8
55.9
52.7
50.9
47.9
47.8
42.2
42.4
37.7
55-59
98.3
95.5
83.0
73.4
69.9
66.2
61.9
58.1
53.3
53.0
47.8
60-64 131.2
110.8
110.0
102.9
92.2
93.7
82.8
86.6
67.2
69.8
69.6
≧65
356.5
323.0
314.0
291.3
283.1
263.5
250.5
230.9
220.0
208.3
385.0
per 10,0000population
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BCG vaccination program in Taiwan
• Vaccination of
school
children with
negative TST
1951
1953
• BCG production
(Pasteur strain)
• Vaccination of
all newborns
and infants
1965
1979
• BCG production
(Tokyo 172
strain)
• Booster BCG
stopped in
1997
2001
BCG Vaccine
• Freeze-dried Tokyo 172 BCG
strain
• 0.05 mg/0.1ml intradermal
inoculation
• Inoculation site
– Left upper arm
• Contraindication
– Active TB
– Cellular immunity deficiency
– Acute fever, generalized skin lesion
Coverage rate (% )
Coverage of BCG immunization, 2002-2012
Birth cohort (year)
Tuberculous meningitis, birth cohort 2003-2008
TB meningitis
BCG vaccination
+
-
Incidence
(per 105)
+
4
1,244,240
0.32
-
3
19,668
15.25
•Approximately 1.6% of infants un-vaccinated
•The relative risk of TB meningitis in children with no BCG vaccination vs. children with
BCG vaccination is 47.4 times (10.6~212.0, p<0.001, Poisson)
2009-2013 Tuberculous meningitis: 7 cases
Data from national immunization information system (NISS) and NSNCD
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BCG adverse events
 Minor local adverse events
 injection site abscess
 lymphadenitis
 Severe complication
 suppurative lymphadenitis (100-1000
/million*)
 osteomyelitis/osteitis (1-700 /million*)
 Disseminated BCG infection (5 /million*)
severe combine immunodeficiency, Di-George
syndrome, interferon-γ receptor deficiency
* WHO statistic data
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Emerging Infectious Diseases, 15:9, 1525-1526, 2009
Taiwan active surveillance policy on
BCG vaccination
• A policy of enhanced childhood TB surveillance was
implemented in 2007
• Clinicians were advised to send clinical specimens to
Taiwan CDC for differential diagnosis of M. Bovis-BCG
for extrapulmonary TB patients <5 years of age
• TCDC strengthered active reporting and case
management system in the National TB registry
• TCDC/TFDA conduct close monitoring of vaccine quality
• Lab-confirmed cases are reviewed by the committe of
the vaccine injury compensation program
Diagnosis algorithm for identifying
BCG adverse events
Bacterial isolate
Paraffin-embedded specimen
Pus, Tissue, Gastric, CSF
Inactivation
Reporting
Non-MTBC
DNA isolation
Identification
1. IS6110 real-time PCR
2. -actin real-time PCR
MTBC
Differential diagnosis
M. bovis- BCG
1. Multiplex BCG PCR and sequencing
2. GenoType ® MTBC (isolate)
3. Spoligotyping (isolate)
4. Multiplex PCR in BCG sub-strains (isolate)
Reporting
Multiplex BCG
PCR failure
M. bovis family
pncA sequencing
Reporting
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pncA sequencing
Multiplex BCG PCR
M. Bovis family
MTBC
BCG
M. tuberculosis
Scorpio et al., 1997
M
1
2
3
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YEBOAH-MANU D. et al., 2001
Diagnosis of extra-pulmonary TB cases,
≦5 y/o, 2002-2015
Notification
Year
% Molecular
diagnosis of
EPTB cases
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
4
8
13
29
26
19
88
94
85
97
89
89
90
85
資料日期：截至2014/5/27
Case No. of
osteomyelitis
Case No. of soft Case No. of disseminated
tissue involvement
skin lesions
[Sample submitted
/BCG(+)]
[Sample submitted
/BCG(+)]
17 (1/1)
13 (2/2)
7 (-/-)
6 (3/1)
9 (3/3)
10 (2/2)
2 (2/1)
14 (14/9)
12 (12/10)
11 (11/4)
8 (8/7)
24 (24/19)
17(17/12)
21(20/12)
5
8
11 (1/1)
6 (1/1)
8
10 (1/1)
13 (11/1)
6 (6/1)
7 (6/1)
6 (6/3)
3 (3/3)
6 (6/3)
5(5/4)
7(7/4)
[Sample submitted
/BCG(+)]
1
2 (1/1)
1 (1/1)
1
2 (1/0)
1 (0/0)
1 (1/0)
2(1/0)
1(1/0)
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BCG adverse events, birth cohort 2005-2015
(per million population)
Birth
year
Osteomyelitis/
Soft tissue
Disseminated/
Immunization
Osteitis*
involvement skin involvement
No.
No. Incidence No. Incidence No. Incidence
Lymphadenitis
and/or injecting
site abscess
No. Incidence
Total
No.
Incidence
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
212,176
210,680
209,658
202,035
197,775
171,075
202,380
238,422
197,291
203,728
3
0
3
11
10
6
10
22
4
5
14.14
0.00
14.31
54.45
50.56
35.07
49.41
92.27
20.27
24.54
1
1
2
0
4
2
4
5
1
3
4.71
4.75
9.54
0.00
20.23
11.69
19.76
20.97
5.07
14.73
0
0
1
1
3
3
1
0
0
0
0.00
0.00
4.77
4.95
15.17
17.54
4.94
0.00
0.00
0.00
2
2
5
5
10
13
21
16
14
14
9.43
9.49
23.85
24.75
50.56
75.99
103.77
67.11
70.96
68.72
6
3
11
17
27
24
36
43
19
22
28.28
14.24
52.47
84.14
136.52
140.29
177.88
180.35
96.30
107.99
2015
211,133
0
0.00
0
0.00
0
0.00
4
18.95
4
18.95
資料日期：截至2016/1/27
*WHO annual report, 2000 : 1-700 cases/million
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Vaccine injury compensation program (VICP)
• Case:
• 38 patients identified
• 30 claimed
surveillance
• Incidence: (per million)
• 2002-2006: 3.68
• 2008-2012: 30.1
•
Chiu, NC, et al. EID, 21:3, 539-540, 2015
No immunodeficiency or
other underlying conditions
Inoculation age and osteomyelitis/osteitis onset
Chiu, NC, et al. EID, 21:3, 539-540, 2015
Less than one month
More than one month
less than five months
More than five months
65
19
0
No. of BCG vaccination
(1989-2014 birth cohort)
3,964,050
1,562,013
120,243
Incidence (per 1,000,000)
16.40
12.16
0
Time of vaccination
Case no. of
osteomyelitis/osteitis (softtissue infection)
Data from TCDC NIIS system as of Nov. 27, 2015
New policy
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Conclusion
 We found no association between cases and
vaccine batches, inoculation age, underlying
disease, or other intracellular microorganism
infection among cases with osteomyelitis
/osteitis.
 Comprehensive surveillance system could help
(1) reducing unnessary contact investigations
and LTBI treatment; (2) improving treatment and
care.
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Thank you for your attention!
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