tbc

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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

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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

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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

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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?

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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