Sterilizing immunity: New opportunities for rational TB vaccine design

Sher, Alan; Flynn, JoAnne L.

doi:10.1084/jem.20210454

Cited by 1 publication

(2 citation statements)

References 16 publications

(19 reference statements)

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“…Recent studies showed that intravenous (iv) immunization of non-human primates with BCG confers sterilizing immunity against challenge with virulent Mtb (7,9,10), although only a modest improvement in protection was observed in the mouse challenge model (11).…”

Section: Introductionmentioning

confidence: 99%

“…The route of vaccination triggers different immune responses and is therefore an important factor in immunization studies (7-9). Recent studies showed that intravenous (iv) immunization of non-human primates with BCG confers sterilizing immunity against challenge with virulent Mtb (7, 9, 10), although only a modest improvement in protection was observed in the mouse challenge model (11).…”

Section: Introductionmentioning

confidence: 99%

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Intravenous Immunization with Triple Auxotrophs ofMycobacterium tuberculosis: A novel vaccine strategy against tuberculosis

Vilchèze,

Rajagopalan,

Jacobs

2024

Preprint

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Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious cause of mortality worldwide despite widespread use of the BCG vaccine and the availability of sterilizing pharmacopoeia. Recent research indicates that the intravenous administration of BCG confers sterilizing immunity against Mtb pulmonary challenge in non-human primates. However, while BCG is relatively safe, complications such as disseminated BCGosis have been observed in immunocompromised individuals. Double auxotrophic mutants of Mtb lacking the ability to synthesize leucine and pantothenate are safe and sterilized in immunocompromised mice and SIV-infected Rhesus macaques. We examined how immunization with a Mtb triple auxotrophic strain, mc27902, which cannot synthesize leucine, pantothenate, and arginine, protects immunocompetent mice from a virulent Mtb infection. The route of immunization was a crucial factor for protection with mc27902 with intravenous immunization being 100 times more effective in protecting immunocompetent mice from Mtb challenge when compared to conventional subcutaneous vaccination with BCG. To further increase the safety of the attenuated auxotroph for vaccine purposes, the type VII secretion system Esx1 responsible for BCG attenuation was deleted in mc27902. When tested by prime-boost immunization of immunocompetent mice followed by aerosol challenge with virulent Mtb, mc27902 Δesx1 provided similar protection to mc27902. This robust protection against Mtb infection conferred by mc27902 and mc27902 Δesx1 in a mouse model paves the way for new TB vaccine development using highly attenuated, auxotrophic Mtb strains.

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Section: Introductionmentioning

confidence: 99%