1. Post-marketing Surveillance of BCG vaccination 1

2. 2 Outline  Tuberculosis  Bacille Calmette–Guérin (BCG) vaccine  BCG vaccination program  Differential diagnosis of BCG  Surveillance of adverse events

3. 3 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

4. TAIWAN: 48.4 TAIWAN: 48.4 4

5. 5 BCG vaccine  BCG is a live-attenuated vaccine derived from Mycobacterium bovis invented in 1908 and first use in humans in 1921 the French Pasteur strain 1173P2, the Danish (Copenhagen) strain 1131, Glaxo strain 1077 and Tokyo strain 172  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  Approximately 100 million newborn children receive BCG annually An apparatus used in Japan

6. BCG strains Efficacy Safety Behr, MA, Lancet Infectious Disease, 2:86-91, 2002

7. WHO policy on BCG vaccination a single-dose of BCG, all infants after birth High TB burden countries infants should not be vaccinated Symptomatic HIV or other immunodeficiency states infants should complete IPT first Exposure to smear (+) pulmonary TB Infants with high-risk of TB TST (-) older children Low TB burden countries Risk for HIV infection High prevalence of TB/HIV (HIV-uninfected children) Benefits (usually) outweigh risks WHO BCG position paper, Weekly epidemiological record, 2004,79,25-40 WHO revised BCG vaccination guidelines, Weekly epidemiological record, 2007, 21,193-196

8. BCG vaccination policy by country 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 A: Universal BCG B: Used to recommend universal BCG C: BCG only for selected high-risk groups

9. 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.

10. 20052006200720082009201020112012201320142015 <153.5 3.34.03.22.63.32.22.72.21.5 15-1922.721.719.917.520.217.717.514.614.915.610.2 20-2431.027.926.528.422.021.823.019.919.115.412.9 25-2933.226.926.427.323.324.220.019.017.016.015.3 30-3434.929.626.326.222.222.122.320.119.318.914.7 35-3935.132.031.031.227.125.225.323.823.020.216.9 40-4445.540.338.637.531.631.729.128.827.624.320.1 45-4956.051.448.544.340.039.138.237.233.831.927.6 50-5472.864.858.855.952.750.947.947.842.242.437.7 55-5998.395.583.073.469.966.261.958.153.353.047.8 60-64131.2110.8110.0102.992.293.782.886.667.269.869.6 ≧ 65 385.0356.5323.0314.0291.3283.1263.5250.5230.9220.0208.3 per 10,0000population 10

11. BCG vaccination program in Taiwan Vaccination of school children with negative TST 1951 BCG production (Pasteur strain) 1953 Vaccination of all newborns and infants 1965 BCG production (Tokyo 172 strain) 1979 Booster BCG stopped in 1997 2001

12. 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 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

13. Coverage of BCG immunization, 2002-2012 Birth cohort (year) Coverage rate (% )

14. Tuberculous meningitis, birth cohort 2003-2008 + - Incidence (per 10 5 ) + 4 1,244,240 0.32 - 3 19,668 15.25 BCG vaccination TB meningitis Data from national immunization information system (NISS) and NSNCD 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) 14 2009-2013 Tuberculous meningitis: 7 cases

15. 15 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

16. Emerging Infectious Diseases, 15:9, 1525-1526, 2009

17. 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

18. 18 Bacterial isolate Identification 1. IS6110 real-time PCR 2.  -actin real-time PCR 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 Non-MTBC MTBC Paraffin-embedded specimen Pus, Tissue, Gastric, CSF DNA isolation Diagnosis algorithm for identifying BCG adverse events M. bovis family pncA sequencing Multiplex BCG PCR failure Reporting Inactivation

19. Multiplex BCG PCR M 1 2 3 4 YEBOAH-MANU D. et al., 2001 BCG MTBC pncA sequencing Scorpio et al., 1997 M. Bovis family M. tuberculosis

20. Diagnosis of extra-pulmonary TB cases, ≦ 5 y/o, 2002-2015 資料日期：截至 2014/5/27 20 Notification Year % Molecular diagnosis of EPTB cases Case No. of osteomyelitis Case No. of soft tissue involvement Case No. of disseminated skin lesions [Sample submitted /BCG(+)] 2002417 (1/1)51 2003813 (2/2)8- 2004137 (-/-)11 (1/1)2 (1/1) 2005296 (3/1)6 (1/1)- 2006269 (3/3)81 (1/1) 20071910 (2/2)10 (1/1)1 2008882 (2/1)13 (11/1)- 20099414 (14/9)6 (6/1)- 20108512 (12/10)7 (6/1)2 (1/0) 20119711 (11/4)6 (6/3)- 2012898 (8/7)3 (3/3)1 (0/0) 20138924 (24/19)6 (6/3)1 (1/0) 201490 17(17/12)5(5/4)2(1/0) 201585 21(20/12)7(7/4)1(1/0)

21. BCG adverse events, birth cohort 2005-2015 (per million population) 資料日期：截至 2016/1/27 Birth year Immunization No. Osteomyelitis/ Osteitis* No. Incidence Soft tissue involvement No. Incidence Disseminated/ skin involvement No. Incidence Lymphadenitis and/or injecting site abscess No. Incidence Total No.Incidence 2005212,176314.1414.7100.00 29.43628.28 2006210,68000.0014.7500.00 29.49314.24 2007209,658314.3129.5414.77 523.851152.47 2008202,0351154.4500.0014.95 524.751784.14 2009197,7751050.56420.23315.17 1050.5627136.52 2010171,075635.07211.69317.54 1375.9924140.29 2011202,3801049.41419.7614.94 21103.7736177.88 2012238,4222292.27520.9700.00 1667.1143180.35 2013197,291420.2715.0700.00 1470.961996.30 2014203,728524.54314.7300.00 1468.7222107.99 2015211,13300.000 0 418.954 21 *WHO annual report, 2000 : 1-700 cases/million

22. Vaccine injury compensation program (VICP) Case: 38 patients identified 30 claimed Incidence: (per million) 2002-2006: 3.68 2008-2012: 30.1 No immunodeficiency or other underlying conditions surveillance Chiu, NC, et al. EID, 21:3, 539-540, 2015

23. Inoculation age and osteomyelitis/osteitis onset Chiu, NC, et al. EID, 21:3, 539-540, 2015 Time of vaccination Less than one month More than one month less than five months More than five months Case no. of osteomyelitis/osteitis (soft- tissue infection) 65190 No. of BCG vaccination (1989-2014 birth cohort) 3,964,0501,562,013120,243 Incidence (per 1,000,000) 16.4012.160 Data from TCDC NIIS system as of Nov. 27, 2015

24. 24 New policy

25. 25 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.

26. 26 Thank you for your attention!