TY - JOUR
T1 - A recombinant attenuated Mycobacterium tuberculosis vaccine strain is safe in immunosuppressed simian immunodeficiency virus-infected infant macaques
AU - Jensen, Kara
AU - Ranganathan, Uma Devi K.
AU - Van Rompay, Koen K.A.
AU - Canfield, Don R.
AU - Khan, Imran
AU - Ravindran, Resmi
AU - Luciw, Paul A.
AU - Jacobs, William R.
AU - Fennelly, Glenn
AU - Larsen, Michelle H.
AU - Abel, Kristina
PY - 2012/8
Y1 - 2012/8
N2 - Many resource-poor countries are faced with concurrent epidemics of AIDS and tuberculosis (TB) caused by human immunodeficiency virus (HIV) and Mycobacterium tuberculosis, respectively. Dual infections with HIV andM. tuberculosis are especially severe in infants. There is, however, no effective HIV vaccine, and the only licensed TB vaccine, the Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine, can cause disseminated mycobacterial disease in HIV-infected children. Thus, a pediatric vaccine to prevent HIV andM. tuberculosis infections is urgently needed. We hypothesized that a highly attenuatedM. tuberculosis strain containing HIV antigens could be safely administered at birth and induce mucosal and systemic immune responses to protect against HIV and TB infections, and we rationalized that vaccine safety could be most rigorously assessed in immuno-compromised hosts. Of three vaccine candidates tested, the recombinant attenuatedM. tuberculosis strain mc 26435 carrying a simian immunodeficiency virus (SIV) Gag expression plasmid and harboring attenuations of genes critical for replication (panCD and leuCD) and immune evasion (secA2), was found to be safe for oral or intradermal administration to non-SIV-infected and SIV-infected infant macaques. Safety was defined as the absence of clinical symptoms, a lack of histopathological changes indicative ofM. tuberculosis infection, and a lack of mycobacterial dissemination. These data represent an important step in the development of novel TB vaccines and suggest that a combination recombinant attenuatedM. tuberculosis-HIV vaccine could be a safe alternative to BCG for the pediatric population as a whole and, more importantly, for the extreme at-risk group of HIV-infected infants.
AB - Many resource-poor countries are faced with concurrent epidemics of AIDS and tuberculosis (TB) caused by human immunodeficiency virus (HIV) and Mycobacterium tuberculosis, respectively. Dual infections with HIV andM. tuberculosis are especially severe in infants. There is, however, no effective HIV vaccine, and the only licensed TB vaccine, the Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine, can cause disseminated mycobacterial disease in HIV-infected children. Thus, a pediatric vaccine to prevent HIV andM. tuberculosis infections is urgently needed. We hypothesized that a highly attenuatedM. tuberculosis strain containing HIV antigens could be safely administered at birth and induce mucosal and systemic immune responses to protect against HIV and TB infections, and we rationalized that vaccine safety could be most rigorously assessed in immuno-compromised hosts. Of three vaccine candidates tested, the recombinant attenuatedM. tuberculosis strain mc 26435 carrying a simian immunodeficiency virus (SIV) Gag expression plasmid and harboring attenuations of genes critical for replication (panCD and leuCD) and immune evasion (secA2), was found to be safe for oral or intradermal administration to non-SIV-infected and SIV-infected infant macaques. Safety was defined as the absence of clinical symptoms, a lack of histopathological changes indicative ofM. tuberculosis infection, and a lack of mycobacterial dissemination. These data represent an important step in the development of novel TB vaccines and suggest that a combination recombinant attenuatedM. tuberculosis-HIV vaccine could be a safe alternative to BCG for the pediatric population as a whole and, more importantly, for the extreme at-risk group of HIV-infected infants.
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U2 - 10.1128/CVI.00184-12
DO - 10.1128/CVI.00184-12
M3 - Article
C2 - 22695156
AN - SCOPUS:84864572318
SN - 1556-6811
VL - 19
SP - 1170
EP - 1181
JO - Clinical and Vaccine Immunology
JF - Clinical and Vaccine Immunology
IS - 8
ER -