A recombinant attenuated Mycobacterium tuberculosis vaccine strain is safe in immunosuppressed simian immunodeficiency virus-infected infant macaques.
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 and M. 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 and M. tuberculosis infections is urgently needed. We hypothesized that a highly attenuated M. 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 immunocompromised hosts. Of three vaccine candidates tested, the recombinant attenuated M. tuberculosis strain mc(2)6435 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 of M. 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 attenuated M. 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.
Department of Microbiology and Immunology and Center for AIDS Research, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Kara
K
Jensen
Uma Devi K
UD
Ranganathan
Koen K A
KK
Van Rompay
Don R
DR
Canfield
Imran
I
Khan
Resmi
R
Ravindran
Paul A
PA
Luciw
William R
WR
Jacobs
Glenn
G
Fennelly
Michelle H
MH
Larsen
Kristina
K
Abel
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D007271:Injections, Intradermal; D008251:Macaca; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000472:pathogenicity; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity; D032581:Tuberculosis Vaccines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000235:genetics; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics
D018449:SAIDS Vaccines; D032581:Tuberculosis Vaccines; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic