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Present and future of the tuberculosis (BCG) vaccine Xavier Sáez-Llorens, MD Professor of Paediatrics, University of Panama, Panama City & Head of Infectious Diseases, Hospital del Niño, Panama City, Panama


Problems in the management of TBC 10% of infected persons will develop TBC in their lifetime; in AIDS patients, rate of incidence of TBC is 4–8% per year Less than 20% of all TBC cases have access to Directly Observed Treatment Short- course (DOTS). 80% of cases are recorded in the developing world Multi-drug resistance of M. tuberculosis is increasing worldwide


Current BCG vaccine (II) Reactogenicity: BCGitis common (normal course) 1–2% develop SC abscesses and/or satellite lymph nodules axillar adenitis 3:10,000 osteitis rare dissemination 1:1 million Potential interference with purified protein derivative (PPD) interpretation, especially within 1–2 years after BCG and when multiple doses given


Recommendations for BCG use Give BCG at birth in countries with endemic disease Give a second BCG dose at age 10 years in countries with high rate of disseminated or meningeal TBC during adolescence or early adulthood Give BCG to selected high-risk persons living in non-endemic countries (minorities, immigrants, refugees) Uninfected healthcare personnel attending TBC cases? HIV-infected individuals with normal CD4?


Recommendations for BCG vaccination in the USA Not for routine immunisation schedules or TBC control programmes Consider BCG for a young child with negative PPD, who is continually exposed to untreated or ineffectively treated patients, especially if dealing with MDR strain Consider BCG for healthcare workers on an individual basis


The ideal vaccine against TBC Few adverse events Good protection in animal models Prevention of infection and disease Only one dose/few doses needed Oral or aerosol administration Durable immunogenicity No problems with PPD interpretation Temperature and time stability Inexpensive No interference with other vaccines


Trial designs Pre-infection in endemic areas Vaccinating newborns at high risk for early infection and disseminated or meningeal disease (5-year study period) Postinfection in endemic areas Vaccinating PPD-reactive healthy adults in areas with a high reactivation rate (~3% per year) (5-year study period) Pre-infection in different regions of the world Vaccinating uninfected children or adults in endemic and non-endemic areas to assess infection and disease (15–20-year study period) Total population trial Vaccinating a large, epidemiologically well-characterised population and performing a combined assessment


Factors that may affect PPD results Type of result Possible causes False positive Other mycobacteria BCG vaccination False negative Anergy Recent TBC infection Very young age (< 6 months) Live-virus vaccination Overwhelming TBC disease


Better PPD ‘Cloning of an M. tuberculosis gene encoding a purified derivative protein that elicits strong TBC-specific, delayed-type hypersensitivity’ DPPD: potent, delayed-type hypersensitivity to TBC infection in animals and humans tested to date Coler RN et al. J Infect Dis 2000;182:224–33


DNA vaccines (I) ‘Immunogenicity and protective efficacy of a TBC DNA vaccine’ DNA encoding the Ag85 protein or the hsp60 molecule is very encouraging in mouse and guinea pig models Huygen K et al. Nat Med 1996;2:893–8


DNA vaccines (II) ‘The immunogenicity of single and combination DNA vaccines against TBC’ Proteins MPT-63 and MPT-83 are more immunogenic than BCG in the mouse pulmonary TBC model Morris S et al. Vaccine 2000;18:2155–63


Attenuated strain of M. tuberculosis ‘Search for new TBC vaccines’ Mutant purC M. tuberculosis offers significant protection in the guinea pig TBC model Gicquel B. Bull Acad Natl Med 1999;183;53–61


Oral BCG ‘Mucosal bacille Calmette-Guérin vaccination of humans inhibits delayed-type hypersensitivity to purified protein derivative, but induces mycobacteria-specific interferon gamma responses’ Hoft DF et al. Clin Infect Dis 2000;30:S217–22


Inactivated vaccine of M. vaccae (I) ‘Safety and immunogenicity of a five-dose series of inactivated M. vaccae vaccination for the prevention of HIV-associated TBC’ Waddell RD et al. Clin Infect Dis 2000;30:S309–15


Inactivated vaccine of M. vaccae (II) ‘Immunotherapy with M. vaccae in patients with newly diagnosed pulmonary TBC treated with standard chemotherapy: a randomised, clinical trial in Durban, South Africa’ NO BENEFIT WAS FOUND Durban Immunotherapy Trial Group. Lancet 1999;354:116–9

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