Differential immune responses and protective efficacy induced by components of a tuberculosis polyprotein vaccine, Mtb72F, delivered as naked DNA or recombinant protein.
Key Ags of Mycobacterium tuberculosis initially identified in the context of host responses in healthy purified protein derivative-positive donors and infected C57BL/6 mice were prioritized for the development of a subunit vaccine against tuberculosis. Our lead construct, Mtb72F, codes for a 72-kDa polyprotein genetically linked in tandem in the linear order Mtb32(C)-Mtb39-Mtb32(N). Immunization of C57BL/6 mice with Mtb72F DNA resulted in the generation of IFN-gamma responses directed against the first two components of the polyprotein and a strong CD8(+) T cell response directed exclusively against Mtb32(C). In contrast, immunization of mice with Mtb72F protein formulated in the adjuvant AS02A resulted in the elicitation of a moderate IFN-gamma response and a weak CD8(+) T cell response to Mtb32c. However, immunization with a formulation of Mtb72F protein in AS01B adjuvant generated a comprehensive and robust immune response, resulting in the elicitation of strong IFN-gamma and Ab responses encompassing all three components of the polyprotein vaccine and a strong CD8(+) response directed against the same Mtb32(C) epitope identified by DNA immunization. All three forms of Mtb72F immunization resulted in the protection of C57BL/6 mice against aerosol challenge with a virulent strain of M. tuberculosis. Most importantly, immunization of guinea pigs with Mtb72F, delivered either as DNA or as a rAg-based vaccine, resulted in prolonged survival (>1 year) after aerosol challenge with virulent M. tuberculosis comparable to bacillus Calmette-Guérin immunization. Mtb72F in AS02A formulation is currently in phase I clinical trial, making it the first recombinant tuberculosis vaccine to be tested in humans.
Skeiky
Yasir A W
YA
Corixa Corp., Seattle, WA 98104, USA. yskriky@aeras.org
Alderson
Mark R
MR
Ovendale
Pamela J
PJ
Guderian
Jeffrey A
JA
Brandt
Lise
L
Dillon
Davin C
DC
Campos-Neto
Antonio
A
Lobet
Yves
Y
Dalemans
Wilfried
W
Orme
Ian M
IM
Reed
Steven G
SG
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000138:chemical synthesis; D001483:Base Sequence; D004269:DNA, Bacterial / Q000008:administration & dosage; D005260:Female; D006168:Guinea Pigs; D007109:Immunity; D007114:Immunization / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000235:genetics; D020815:Polyproteins / Q000138:chemical synthesis / Q000276:immunology / Q000627:therapeutic use; D015996:Survival Rate; D032581:Tuberculosis Vaccines / Q000008:administration & dosage* / Q000737:chemistry; D014397:Tuberculosis, Pulmonary / Q000517:prevention & control / Q000628:therapy; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic
D000276:Adjuvants, Immunologic; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D020815:Polyproteins; D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic