Efficacy and safety of live attenuated persistent and rapidly cleared Mycobacterium tuberculosis vaccine candidates in non-human primates.
Tuberculosis (TB) remains a global health burden for which safe vaccines are needed. BCG has limitations as a TB vaccine so we have focused on live attenuated Mycobacterium tuberculosis mutants as vaccine candidates. Prior to human studies, however, it is necessary to demonstrate safety in non-human primates (NHP). In this study, we evaluate the safety and efficacy of two live attenuated M. tuberculosis double deletion vaccine strains mc(2)6020 (DeltalysA DeltapanCD) and mc(2)6030 (DeltaRD1 DeltapanCD) in cynomolgus macaques. In murine models, mc(2)6020 is rapidly cleared while mc(2)6030 persists. Both mc(2)6020 and mc(2)6030 were safe and well tolerated in cynomolgus macaques. Following a high-dose intrabronchial challenge with virulent M. tuberculosis, mc(2)6020-vaccinates were afforded a level of protection intermediate between that elicited by BCG vaccination and no vaccination. BCG vaccinates had reduced tuberculosis-associated pathology and improved clinical scores as compared to saline and mc(2)6030 vaccinates, but survival did not differ among the groups.
Larsen
Michelle H
MH
Albert Einstein College of Medicine, Bronx, NY 1461, USA. larsen@aecom.yu.edu
Biermann
Karolin
K
Chen
Bing
B
Hsu
Tsungda
T
Sambandamurthy
Vasan K
VK
Lackner
Andrew A
AA
Aye
Pyone Pyone
PP
Didier
Peter
P
Huang
Dan
D
Shao
Linyun
L
Wei
Huiyong
H
Letvin
Norman L
NL
Frothingham
Richard
R
Haynes
Barton F
BF
Chen
Zheng W
ZW
Jacobs
William R
WR
D000818:Animals; D001500:BCG Vaccine / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics; D001835:Body Weight; D002097:C-Reactive Protein / Q000032:analysis; D002262:Carboxy-Lyases / Q000235:genetics; D017353:Gene Deletion; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008168:Lung / Q000473:pathology; D008252:Macaca fascicularis; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity*; D012720:Severity of Illness Index; D016019:Survival Analysis; D014376:Tuberculosis / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000009:adverse effects* / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000009:adverse effects / Q000276:immunology; D037521:Virulence Factors / Q000235:genetics
D001500:BCG Vaccine; D001426:Bacterial Proteins; D032581:Tuberculosis Vaccines; D014613:Vaccines, Attenuated; D037521:Virulence Factors; D007371:Interferon-gamma; D002097:C-Reactive Protein; D002262:Carboxy-Lyases; C489813:LysA protein, Mycobacterium tuberculosis