BCG: Past, Present and Future
Nwora Lance Okeke, MD, MPH August 24, 2016 Disclosures
• Nothing to disclose Overview
• Introduction and History • Current Use • Effectiveness • Non-vaccine uses of BCG
Edmond Nocard (1850-1903)
Albert Calmette (1863-1933) Camille Guerin (1872-1961)
Courtesy of Wellcome Library, London, the Pasteur Institute, Phototheque Biu Sante Paris Early Timeline
1882: Koch identifies M. tuberculosis as cause of human disease 1900: Calmette and Guerin discover that “tubercle bacilli” can be attenuated using ox bile 1902: Virulent strain of mycobacterium isolated from cows with mastitis by Nocard 1908: Strain obtained by Nocard cultured up by Calmette and Guerin for the next 11 years 1913: first trials on cattle interrupted by WWI 1919: successfully inoculated attenuated bacilli in guinea pigs, rabbits, horses and cattle without progressive disease 1921: first trial in humans First Human Trials
• 1921-1928: 115,000 infants administered oral BCG with zero vaccine- associated complications • Sample of 8,076 children vaccinated, mortality 4.6% • Unvaccinated children “living under the same conditions” was 16-25% • Romania: 50% decreased mortality among vaccinated children (n = 80,000) • Sweden: 2.3% mortality in vaccinated, 9.5% among unvaccinated (n = 4,009) • New York (1930): TB associated mortality • 0.8% among vaccinated children (n = 208) • 8% among vaccinated children (n = 350)
Proc R Soc Med 1931 (11): 1481-90 UNESCO, 2013 Timeline • Early 1930s: switch to intradermal administration • Late 1940s: Increase in TB cases associated with WWII; WHO adopts BCG for widespread administration among at-risk individuals • 1950: Large Public Health Trials • Culture heterogeneity? • Environmental Mycobacteria?
Chengalpattu Trial
• Trial organized by Indian Ministry of Health and US Public Health Service, WHO • At 7.5 years of follow up, no protective efficacy provided by either of the vaccine strains
World Health Organ Tech Rep Ser. 1980;651:1-21. What is bacille Calmette-Guerin?
• Mycobacterium bovis • Member of the mycobacterium tuberculosis family • Cause of approximately 1.5% of pulmonary TB outside Africa • Higher incidence of extrapulmonary manifestations due to oral ingestion as primary mode of inoculation • PZA monoresistance • Clinically indistinguishable from Mtb disease
Bacille de Calmette et Guerin
• M.bovis attenuated with ox bile • Subcultured 230 times over 13 years • Loss of virulence to all animals tested • First mass-produced by the Pasteur Institute in 1931 • Other major producers: • Glaxo/Danish strain • Tokyo • Montreal • OncoTICE Immunogenicity of BCG
• No surrogate marker to quantify immune response to BCG • Vaccine-induced T-cell proliferation, IFN-gamma, TNF or IL-2 release have not been directly correlated with protection against TB • No demonstrable difference in immunogenicity between strains
Clin Infect Dis. 2014;58(4):470.
Administration of BCG
• 0.1mg/mL x 1 dose with 27 gauge needle • Intradermal or MPP • Neonatal administration recommended in most high-prevalence regions • Papule by 2 weeks • Pustule by 6 weeks • Scar by 3 months • Booster dosing? Who gets BCG?
• Neonates in countries with moderate to high-incidence of TB • Annual average rate of smear positive TB > 5 per 100,000 • Average rate of TB meningitis of > 1 per 100,000 in children over 5 • Average annual risk of TB > 0.1% • ? Healthcare workers in high-incidence countries who have not been vaccinated • ? Persons exposed to MDR-TB
World Health Organization PLoS Med 8(3): e1001012. BCG Worldwide
• One billion children in over 180 countries • Given to about 100 million children worldwide every year Does it work? Trial Year Conducted Vaccinated/Unvaccinated Saskatchewan 1933-1948 306/303 Native American 1935-1998 1551/1447 Chicago Infants 1937-1960 5426/4128 Turtle and Rosebud Infants 1938-1946 123/139 Chicago Infants (TB HH) 1941-1953 311/250 Ida B. Wells Housing Project 1942-1956 699/625 US Mental Health 1944-1948 20/15 Illinois Mentally 1947-1959 531/494 Handicapped Georgia 1947-1967 2498/2341 Puerto Rico Children 1949-1968 50634/27338 Madanapelle 1950-1971 5069/5803 Georgia/Alabama 1950-1970 16913/17854 UK MRC 1950-1970 20800/13300 African Gold Miners 1965-1968 8317/7997 Haiti 1965-1968 641/340 Chingleput 1968-1983 73459/364004 Bombay Infants 1976 396/300 Agra 1988 1259/1259
Clinical Infectious Diseases 2014;58(4):470–80 Trial Year Conducted Vaccinated/ RR (95% CI) Unvaccinated Saskatchewan 1933-1948 306/303 0.20 (0.06, 0.69) Native American 1935-1998 1551/1447 Chicago Infants 1937-1960 5426/4128 0.34 (0.19,0.60) Turtle and Rosebud 1938-1946 123/139 0.40 (0.13, 1.25) Infants Chicago Infants (TB 1941-1953 311/250 0.28 (0.08, 1.02) HH) Ida B. Wells Housing 1942-1956 699/625 Project US Mental Health 1944-1948 20/15 Illinois Mentally 1947-1959 531/494 Handicapped Georgia 1947-1967 2498/2341 Puerto Rico Children 1949-1968 50634/27338 Madanapelle 1950-1971 5069/5803 Georgia/Alabama 1950-1970 16913/17854 UK MRC 1950-1970 20800/13300 African Gold Miners 1965-1968 8317/7997 Haiti 1965-1968 641/340 Chingleput 1968-1983 73459/364004 Bombay Infants 1976 396/300 0.62 (0.35,1.07) Agra 1988 1259/1259 Trial Year Conducted Vaccinated/ RR (95% CI) Unvaccinated Saskatchewan 1933-1948 306/303 0.20 (0.06, 0.69) Native American 1935-1998 1551/1447 Chicago Infants 1937-1960 5426/4128 0.34 (0.19,0.60) Turtle and Rosebud 1938-1946 123/139 0.40 (0.13, 1.25) Infants Chicago Infants (TB 1941-1953 311/250 0.28 (0.08, 1.02) HH) Ida B. Wells Housing 1942-1956 699/625 Project US Mental Health 1944-1948 20/15 Illinois Mentally 1947-1959 531/494 Handicapped Georgia 1947-1967 2498/2341 Puerto Rico Children 1949-1968 50634/27338 0.72 (0.57,0.90) Madanapelle 1950-1971 5069/5803 Georgia/Alabama 1950-1970 16913/17854 UK MRC 1950-1970 20800/13300 African Gold Miners 1965-1968 8317/7997 Haiti 1965-1968 641/340 Chingleput 1968-1983 73459/364004 Bombay Infants 1976 396/300 0.62 (0.35,1.07) Agra 1988 1259/1259 0.40 (0.19, 0.83) Trial Year Conducted Vaccinated/ RR (95% CI) Unvaccinated Saskatchewan 1933-1948 306/303 0.20 (0.06, 0.69) Native American 1935-1998 1551/1447 Chicago Infants 1937-1960 5426/4128 0.34 (0.19,0.60) Turtle and Rosebud 1938-1946 123/139 0.40 (0.13, 1.25) Infants Chicago Infants (TB 1941-1953 311/250 0.28 (0.08, 1.02) HH) Ida B. Wells Housing 1942-1956 699/625 Project US Mental Health 1944-1948 20/15 0.26 (0.01,6.36) Illinois Mentally 1947-1959 531/494 1.40 (0.57,3.42) Handicapped Georgia 1947-1967 2498/2341 Puerto Rico Children 1949-1968 50634/27338 0.72 (0.57,0.90) Madanapelle 1950-1971 5069/5803 0.81 (0.52,1.26) Georgia/Alabama 1950-1970 16913/17854 0.92 (0.56,1.53) UK MRC 1950-1970 20800/13300 African Gold Miners 1965-1968 8317/7997 0.63 (0.39,1.00) Haiti 1965-1968 641/340 0.11 (0.01,0.91) Chingleput 1968-1983 73459/364004 1.05 (0.88, 1.25) Bombay Infants 1976 396/300 0.62 (0.35,1.07) Agra 1988 1259/1259 0.40 (0.19, 0.83) Trial Year Conducted Vaccinated/ RR (95% CI) Unvaccinated Saskatchewan 1933-1948 306/303 0.20 (0.06, 0.69) Native American 1935-1998 1551/1447 0.26 (0.20,0.33) Chicago Infants 1937-1960 5426/4128 0.34 (0.19,0.60) Turtle and Rosebud 1938-1946 123/139 0.40 (0.13, 1.25) Infants Chicago Infants (TB 1941-1953 311/250 0.28 (0.08, 1.02) HH) Ida B. Wells Housing 1942-1956 699/625 0.15 (0.01, 2.87) Project US Mental Health 1944-1948 20/15 0.26 (0.01,6.36) Illinois Mentally 1947-1959 531/494 1.40 (0.57,3.42) Handicapped Georgia 1947-1967 2498/2341 1.25 (0.28, 5.58) Puerto Rico Children 1949-1968 50634/27338 0.72 (0.57,0.90) Madanapelle 1950-1971 5069/5803 0.81 (0.52,1.26) Georgia/Alabama 1950-1970 16913/17854 0.92 (0.56,1.53) UK MRC 1950-1970 20800/13300 0.22 (0.16, 0.31) African Gold Miners 1965-1968 8317/7997 0.63 (0.39,1.00) Haiti 1965-1968 641/340 0.11 (0.01,0.91) Chingleput 1968-1983 73459/364004 1.05 (0.88, 1.25) Bombay Infants 1976 396/300 0.62 (0.35,1.07) Agra 1988 1259/1259 0.40 (0.19, 0.83) Trial Year Conducted Vaccinated/ RR (95% CI) Unvaccinated Native American 1935-1998 1551/1447 0.26 (0.20,0.33) Chicago Infants 1937-1960 5426/4128 0.34 (0.19,0.60) Puerto Rico Children 1949-1968 50634/27338 0.72 (0.57,0.90) Madanapelle 1950-1971 5069/5803 0.81 (0.52,1.26) Georgia/Alabama 1950-1970 16913/17854 0.92 (0.56,1.53) UK MRC 1950-1970 20800/13300 0.22 (0.16, 0.31) African Gold Miners 1965-1968 8317/7997 0.63 (0.39,1.00) Chingleput 1968-1983 73459/364004 1.05 (0.88, 1.25) Bombay Infants 1976 396/300 0.62 (0.35,1.07) Agra 1988 1259/1259 0.40 (0.19, 0.83) Trial Criteria Metaregression RRR (95% CI)
Infants (n = 5) 0.41 (0.29,0.56)
School Aged Children, non-stringent TST (n = 2) 0.59 (0.35,1.01)
School Aged Children, stringent TST (n = 4) 0.26 (0.18,0.37)
Other Ages, non-stringent TST (n = 4) 0.81 (0.55,1.22)
Other Ages, stringent TST (n = 3) 0.88 (0.59,1.31) Trial Criteria Metaregression RRR (95% CI)
Done at 0-20 degrees latitude 0.78 (0.58, 1.05)
Done at 20-40 degrees latitude 0.68 (0.48,0.95)
Done at 40+ degree latitude 0.32 (0.22,0.46)
Clin Infect Dis 2014;58(4):470–80 BCG Vaccine Efficacy
• Overall Risk Reduction of Pulmonary TB : 50% (Range 0-80%) • Overall Risk Reduction of Meningeal and Miliary TB in Children: 85% • Protective efficacy against M. leprae, M. ulcerans and invasive MAC
Does it work?
• Protection of children in high-incidence TB countries against military and meningeal TB • Perhaps some protective benefit against pulmonary TB IF administered before TB (or environmental mycobacteria) exposure • Strain of vaccine makes no difference WHO Position
• “BCG vaccine has a documented protective effect against meningitis and disseminated TB in children. It does not prevent primary infection and, more importantly, does not prevent reactivation of latent pulmonary infection, the principal source of bacillary spread in the community. The impact of BCG vaccination on transmission of Mtb is therefore limited.” • “..optimal utilization of BCG is encouraged”
World Health Organization, 2004 WHO Recommendations
• All infants as soon as possible after birth in countries with high TB burden • Adults not previously vaccinated in close contact with persons with known MDR Mtb CDC Guidelines
• Not recommended for routine use in the United States • Three exceptions: • Children exposed to persons who have TB and cannot be treated • Children exposed to person with INH and RIF resistant-TB • HCW with prolonged exposure to persons with MDR-TB
CDC, 2011 BCG and TST • If a TST is ≥ 10mm in a person previously vaccinated with BCG, SUSPECT TB INFECTION • CDC Guidelines: • TST ≥ 10mm considered positive if: – The vaccinated person is a contact of another person who has infectious TB, particularly if the infectious person has transmitted M. tuberculosis to others – The vaccinated person was born or has resided in a country in which the prevalence of TB is high – The vaccinated person is exposed continually to populations in which the prevalence of TB is high (e.g., some health care workers, employees and volunteers at homeless shelters, and workers at drug-treatment centers)
Klinik BTP BCG and Non-muscle Invasive Bladder Cancer
• 1976: Morales et al. reported resolution of superficial bladder tumor in 9 patients who received intradermal and intravesical BCG (Dose: 120mg once weekly for 6 weeks) • 1982: Brosman et al. reported similar efficacy without intradermal dosing in patients with recurrent superficial bladder cancer • Dose: 120mg weekly x 6 weeks, 120mg q 2 weeks x 12 weeks, 120mg monthly x 2 years • 0/26 recurrences in BCG group; 9/23 recurrences in thio-tepa group at 24 wks
J Urol 1976;116:180-3 J Urol 1982;128:27-30 BCG for Superficial Bladder Cancer
• Metanalysis of 25 RCT, 4767 patients • OR for Recurrence: 0.61 (0.46,0.80) • OR for Recurrence (TUR + BCG v. TUR alone): 0.35 (0.20,0.59) • BCG superior to all other intravesical agents • Consensus Recommendations • 6 weeks of weekly induction starting 2-6 weeks post TURBT • 3-weekly doses q 6 months thru 36 months • 81mg Connaught strain (Theracys®) OR 50mg of Tice strain (OncoTICE®) retained for 2 hours • Adjuvant for high-grade tumors only Sanofi Pasteur
Urology 67 (6), 2006 Nat Rev Urol. 2015 Apr;12(4):225-35 How does it work?
• BCG antigenicity • Overwhelming inflammatory response • ↑CD4 T-cells, macrophages • ↑inflammatory cytokines • ↑ IFN-gamma • Direct suppression of tumor cells by BCG?
Complications of Intravesical BCG
• Common • Cystitis (67%) • Fever (25%) • Hematuria (23%) • Flu-Like Illness (15%) • Severe (<1%) • Prostatitis • Pneumonitis • Sepsis • Lumbar Osteomyelitis • AAA (18 cases reported)
Clin Infect Dis. 2000;31 Suppl 3:S86. Other medical uses of BCG
• Autologous tumor cells + BCG for stage II colon cancer • Intralesional BCG for melanoma Conclusion
• BCG vaccine confers some protection against pulmonary TB, but when and where to use it remains unclear • If BCG vaccinated and positive TST, likely LTBI • Vaccination policies vary widely globally • Role of BCG on decreasing burden of tuberculosis worldwide is limited • Better vaccines are needed Questions or Comments?