BCG (Bacille Calmette Guérin) General Overview

Tuberculosis & Chest Service Public Health Services Branch Centre for Health Protection Department of Health Hong Kong SAR

Tuberculosis

April 1993: WHO declared TB as a global emergency

GLOBAL PROBLEM

PREVALENCE OF TB INFECTION 1.7 BILLION

PREVALENCE OF TB CASES 16-20 MILLION

ANNUAL INCIDENCE OF TB 8 MILLION

ANNUAL DEATHS FROM TB 3 MILLION

1 Global Plan to Stop TB STOP TB Strategy (2006-2015) Launched in 2006 by WHO with six DOTS Strategy components:

1. Pursuing high-quality DOTS expansion and enhancement Goals/ Targets: 2. Addressing TB/HIV, MDR-TB and other challenges – Millennium Development Goal (MDG) 6 • Target 8: halt and begin to reverse the 3. Contributing to health system incidence of TB by 2015 strengthening 4. Engaging all care providers – Targets linked to MDGs: 5. Empowering people with TB, and • By 2005 : communities ≥ – Case detection rate 70% 6. Enabling and promoting research – Treatment success rate ≥85% • By 2015 : – ↓TB prevalence & death rates by 50% (relative to 1990) • By 2050 – eliminate TB (1/1,000,000)

2 TB notification in Hong Kong (1952 - 2009)

800

700

600 2009 TB notification rate = 76.6 per 100,000 (provisional figures) 500

400

300

200 N otification rate (per 100,000)

100

0 Year 1 9 5 2 1 9 5 6 1 9 6 0 1 9 6 4 1 9 6 8 1 9 7 2 1 9 7 6 1 9 8 0 1 9 8 4 1 9 8 8 1 9 9 2 1 9 9 6 2 0 0 0 2 0 0 4 2 0 0 8

3 Countries in Western Pacific Region (WHO Classification) (for Adaptation of the DOTS Strategy)

• Group 1: high TB burden • Mainland China

• Group 2: intermediate TB burden and good health infrastructure • Hong Kong * • Singapore, Japan, Malaysia, Macao, Brunei, Korea

• Group 3: Pacific Island Countries (PIC) with populations smaller than 1 million

• Group 4: Industrialised countries with low TB burden and low incidence • Australia, New Zealand

CONTROL OF TUBERCULOSIS IN HONG KONG Strategies

- Case finding: passive vs active - Effective chemotherapy: DOTS - Treatment of latent TB infection (preventive treatment or chemoprophylaxis) - BCG vaccination - (Health education)

4 MDR-TB and XDR-TB • MDR-TB (multidrug-resistant TB) ( 耐多藥結核病) • resistant to at least H (isoniazid) and R (rifampicin) • XDR-TB (extensively drug-resistant TB) ( 廣泛耐藥性結核病): – (Oct 06 WHO definition) resistant to • any fluoroquinolone, and • at least one of the 3 injectable second-line drugs (capreomycin, kanamycin, and amikacin), • in addition to MDR-TB

• Global figures [WHO 2007 estimation] : • MDR-TB: 490,000 • XDR-TB: 40,000

Cavity

5 Miliary TB

BCG (Bacille Calmette-Guérin)

• Development: – 1908: Nocard isolated a strain – known as “Lait Nocard”, which caused bovine tuberculous mastitis – 1921: after 13 years of successive subculturing the strain by Albert Calmette and Camille Guérin first developed BCG • Produced by several laboratories round the world – different strain: different viability, immunogenicity, reactogenicity, and residual virulence Now: four main strains accounting for >90% of current vaccines: - French Pasteur strain 1173P2 (international reference strain) - Danish (Copenhagen) strain 1131 - Glaxo strain 1077 - Tokyo strain 172 • 1921 : Oral BCG vaccine – Contaminated with virulent TB bacillus in 1929 in Germany 72 deaths among 251 vaccinated children • 1927 : Intradermal BCG • 1939 : Multiple puncture vaccination • 1948 : WHO and UNICEF: encouraged BCG vaccination campaigns all over the world • 1974 : WHO launched EPI • At present: nearly 100 million children vaccinated with BCG every year

6 BCG (Bacille Calmette-Guérin) • Efficacy: – Several clinical trials (after 1930): • efficacy between 0 and 80% • Largest trial in Madras: no protection – Case control studies • Efficacy between 16 and 73% • Protection for pulmonary TB: 10 to 66% • Protection for TBM and miliary TB: consistently high, >50% – Meta-analyses • Protection for TBM and miliary TB: 72 to 100%, with a summary estimate of 86% • Protection for all forms of TB: summary estimates: – 51% (RCT, randomised controlled trial) – 50% (case-control studies) • Protection for pulmonary TB: – Heterogeneous – Several RCTs: -88 and 79%

Estimates of BCG efficacy against different forms of TB and leprosy, from clinical trials (CT), case control (CC), cohort (COH) and household contact studies (HH).

(Fine PEM et al. WHO/V&B/99.23; 1999:1-42)

7 BCG (Bacille Calmette-Guérin)

• Hypothesis for heterogeneity in protective efficacy:

– Biological variability of BCG vaccine due to different strains – Exposure to environmental mycobacteria • Higher efficacy rates if far away from the equator (with low or no prevalence of EM) • Meta-analysis: 41% of the discrepancy in the estimated efficacy is due to latitude – Route of infection • Protective if the disease results from primary infection (TBM, disseminated TB) • Lower if exogenous reinfection – Other factors • Related to use of the vaccine: viability, dose, route of administration • Host factors: nutritional status, other infections, genetic aspects

Results of meta-analyses on BCG efficacy (TB Manual 2006) Target disease Efficacy (95% CI) Remarks Reference

TB at all sites 74% (62-83%) 4 RCTs in newborns and Colditz GA 1995 infants TB at all sites 52% (38-64%) 9 Case control studies in Colditz GA 1995 newborns and infants Death 65% (12-86%) 5 RCTs in newborns and Colditz GA 1995 infants Meningeal TB 64% (30-82%) 5 Case control studies in Colditz GA 1995 newborns and infants Disseminated TB 78% (58-88%) 3 Case control studies in Colditz GA 1995 newborns and infants Laboratory confirmed 83% (58-93%) 3 Case control studies in Colditz GA 1995 TB newborns and infants Meningeal TB and 86% (65-95%) All ages, 7 RCTs Rodrigues LC 1993 disseminated TB Disseminated TB 75% (61-84%) All ages, 6 case control Rodrigues LC 1993 studies Colditz GA 1994 Overall TB risk 51% (30-66%) All ages Brewer TF 2000 Colditz GA 1994 Overall TB death 71% (47-84%) All ages Brewer TF 2000

8 Meta-analysis on childhood TBM and miliary TB (Bourdin B. Lancet 2006)

In 2002, estimations:

• 100.5 million BCG vaccinations given to infants

• TB meningitis: 29729 cases prevented ≡ 3435 vaccinations to prevent 1 case

• MiliaryTB: 11486 cases prevented ≡ 9314 vaccinations to prevent 1 case

• US$2-3 per dose • US$206 (150-272) per year of healthy life gained

BCG (Bacille Calmette-Guérin)

• Length of protective efficacy

– According to literature, protective efficacy decreases with time – Study in UK by MRC between 1950 and 1970: • First 5 years: protection around 84% • Between 10 and 15 years: 59% (Hart PD 1977) – Study in US: • 77% decreasing to 52% during a 6-decade follow up (Aronson NE 2004) – Study in Brazil: • protection by neonatal vaccination against all forms of TB lasts for 15 to 20 years (Barreto ML 2005) – Meta-analysis (1998) • Efficacy wanes with time, lasts probably no longer than 15 years

9 BCG Previous Vaccination Policies

1. At birth • WHO EPI

2. Once in childhood or adolescence • E.g., UK (targeted vaccination for those at greatest risk)

3. Repeated/booster BCG vaccination • Not recommended now.

4. No routine BCG vaccination • E.g., US: BCG only for selective use among high risk individuals

BCG • Revaccination

– Some countries (Russia, Portugal, Chile, Hungary) used repeated BCG vaccination – based on assumption that protection decreases with time.

– Hungary (1959): reported decrease in TB incidence after use of revaccination introduced (methodology flaw?)

– Chile, Finland, Malawi, Brazil, Japan – no evidence for efficacy of a second dose

– WHO recommends use of one dose of BCG vaccine against TB only; booster dose has no proven additional protective effect (WHO 1995)

10 BCG (Bacille Calmette-Guérin) • Study in HK: – Revaccination of school children did not confer further protection against TB – RR = 1.28 (95% CI = 0.92 – 1.77)

• ACI (Advisory Committee on Immunisation of DH in HK (2000): – BCG for all newborns in HK – For children under age 15 and residing in HK, and who have never had BCG vaccination before, direct BCG vaccination is recommended and prior TST is not required – Local BCG revaccination programme for primary school children in HK stopped in 2000

11 BCG (Bacille Calmette-Guérin)

• BCG vaccine supplied by DH free of charge to HA & private hospitals • Danish 1331 (intradermal injection) (Statens Serum Institut)

• In turn, statistics are provided to DH on coverage of BCG vaccination in newborns. • BCG: – Intradermally at the insertion of deltoid on the left arm

12 120

100 BCG vaccination coverage

60 Percentage

Infant mortality rate 20 (All causes) Infant mortality rate (TB) 0 1952 1956 1960 1964 1968 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008

Year

BCG for HCW in Hong Kong (TB Manual 2006) (HA Task force 2003) (ACI 2004)

• In Hong Kong, the bulk of the population has received BCG vaccination at some point in time.

• In health care settings, a comprehensive infection control programme should be the priority and routine vaccination of HCW is not recommended .

• Nevertheless, for HCW who have never received BCG before, they should be counselled on the risks and benefits associated with BCG vaccination, as well as the possible roles of tuberculin surveillance and treatment of LTBI.

• Under special high risk circumstances , e.g., situations with a high risk of exposure to MDR-TB, BCG may be considered for previously unvaccinated individuals who are tuberculin tested to be negative and are thus likely to be free of past TB infection.

13 BCG (Bacille Calmette-Guérin) • Administration: – Oral vaccine • requires a much higher dose • Effective dose difficult to control as some mycobacteria are inactivated by gastric acid • Reports of cervical lymphadenopathy and middle ear infection – Subcutaneous injection • Should be avoided as it may produce large abscesses – Percutaneous injection • Spread vaccine over left arm • Heat-sterilised number 3 straight suture needle: 20 times (4 rows of 5 punctures) – Intradermal: • Delivered dose better controlled • More effective in inducing tuberculin reaction

14 15 BCG (Bacille Calmette-Guérin)

• BCG scar

– BCG vaccination leaves a typical scar • high sensitivity and specificity of the scar as an indicator of previous BCG vaccination – 17 – 25% do not have a scar – No evidence of association between scar and protection vs TB – Size of scar: • Bears a correlation with PPD response before vaccination • Smaller scar associated with a small BCG dose • Larger with increase in number of doses

Tuberculin Skin Test and BCG

• Positive TST (delayed type hypersensitivity) – Does not mean immunity induced by BCG (CMI cellular mediated immunity) – Induration >15 mm more related to TB infection than BCG vaccination – Tuberculin reactivity after vaccination decreases with time – Tuberculin response lower after neonatal BCG vaccination than after postneonatal vaccination

• IGRA (interferon-gamma release assay) – (QuantiFERON TB Gold Test, Tspot TB test) – Specific tests and not confounded by BCG

16 BCG (Bacille Calmette-Guérin)

Adverse reactions: • Local reactions to BCG vaccines: – Superficial scar in most recipients – ↑chance of keloid (esp if near acromion process) – Rarely ulceration and regional LN enlargement • Severe reactions: – Osteitis – Disseminated infection is rare and only occurs in patients with impaired immunity

Classification of BCG Disease (Hesseling AC et al. Clin Infect Dis 2006)

Category Description

Local BCG disease A local process at the site of vaccination. This includes any of the following BCG infection site abscess conforming to EPI definitions: ≧10 mm X 10 mm Severe BCG scar ulceration

Regional disease Involvement of any regional lymph nodes or other regional lesions beyond the vaccination site: ipsilateral axillary, supraclavicular, cervical and upper arm glands. Lymph node involvement must conform to EPI definition and may include enlargement, suppuration and fistula formation.

Distant disease Involvement of any site beyond a local or regional ipsilateral process. This includes any of the following: BCG confirmed from at least 1 distant site beyond the vaccination site, e.g. pulmonary secretions (gastric aspirate, tracheal aspirate), cerebrospinal fluid, urine, osteitis, and distant skin lesion.

Disseminated disease BCG confirmed from >1 remote site, as described under distant disease, and/or from at least 1 blood or bone marrow culture.

BCG IRIS Defined as BCG disease that presents in an HIV-infected child within 3 months after the initiation of highly active antiretroviral therapy (HAART) with/without immunological or viral proof of immune reconstitution

EPI, Expanded Programme on Immunization EPI criteria for local or regional BCG disease: (1) Ipsilateral LN ≧15 X 15 mm; (2) Suppurative ipsilateral axiallry lymphadenitis; (3) Injection site abscess of ≧10 mm; (4) Nonresolving BCG papule

17 Adverse events of BCG vaccination

• Ulcers at vaccination site: – Inappropriate application, e.g, • Subcutaneous injection • Excessive dose • Secondary contamination at puncture site

18 Lawrence CM, Summerly ME. Keloid formation after BCG vaccination. The Practitioner. 1982;226:326-328.

19 Adverse events of BCG vaccination • BCG lymphadenitis – Prospective study of two million vaccinations (1979-81) estimated risk to be 0.387 per 1000 for infant (age <1) – [Other studies of regional suppurative lymphadenitis: incidence of 0.1 per 1000 to 5 per 1000 vaccinated children in some developing countries.] – Among 6000 reported cases, majority occurred within first 5 months after vaccination – Factors: • Vaccine strain (e.g., more reactogenic Pasteur strain, less reactogenic Glaxo strain) • Total number of viable and non-viable bacilli in the vaccine preparation • Dose of BCG given • Age of person receiving the vaccine (more common among newborns than older children) – Treatment: • No consensus • Antimicrobial (erythromycin/ INH) to no treatment • Uncomplicated cases generally resolve spontaneously on observation

Adverse events of BCG vaccination

• Osteitis: – Incidence of 0.6 to 46 cases per one million vaccinated children

20 Adverse events of BCG vaccination

• Disseminated infection: – Rare, may result in death – Incidence ranges from 0.19 to 1.56 per one million vaccinees – Esp in children with congenital or acquired immunodeficiency who are mistakenly vaccinated

Major contraindications to BCG vaccination

• Relative or temporary in some literature: – BW < 2 kg – Skin reactions at the vaccination site – Severe diseases – Use of immunosuppresants – Febrile condition

• Absolute – Acquired or congenital immunodeficiencies

21 BCG VACCINATION FOR THE HIV-INFECTED

• BCG – live attenuated bacterial vaccine – not to be given to AIDS patient

• Diagnosis of HIV infection in newborns – Difficult (maternal Ab passively transferred to infant in utero) – Need sophisticated and costly investigations [e.g., direct demonstration of the HIV virus (HIV DNA, HIV RNA and p24 antigens)]

• WHO Revised BCG vaccination guidelines for infants at risk for HIV infection (Wkly Epidemiol Rec 2007;83:193-6) – ‘For infants who are already HIV infected when vaccinated with BCG vaccine, the benefits of potentially preventing severe TB are outweighed by the risks associated with the use of BCG vaccine’.

“The use of BCG Vaccine in HIV Infected Patients” (SCAS) (Nov 2009)

Recommendations:

• Recommend against BCG vaccination in all HIV- infected patients.

• For HIV-exposed infants, a delayed approach is recommended – vaccination is delayed in those known to have been exposed to HIV in utero or during birth, until HIV is ruled out (mostly within 6 months by nucleic acid amplification tests)

22 BCG (Bacille Calmette-Guérin)

• Other uses: – Immune modulator: • Treatment of some neoplasms (e.g., bladder cancer) – Leprosy • Efficacy ranging from 20% to 80% • Some studies show that BCG offers greater protection against leprosy than TB – Buruli Ulcer • M. ulcerans infection – Protection against: • Ancylostomiasis and other helminth infections – Atopy: • Decrease in frequency of atopy among children vaccinated with BCG

New Vaccine Development

• Limited and controversial efficacy of BCG • Deciphering of the whole genome of M. tuberculosis (Nature 1998)

• Approaches: – Live attenuated vaccine: by deleting the gene responsible for virulence – Subunit vaccine – DNA vaccine

23 Chapter 15 BCG vaccination

Professional Manual 2006 (available for download at www.info.gov.hk/tb_chest)

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