Dietary pyridoxine controls efficacy of vitamin B6-auxotrophic tuberculosis vaccine bacillus Calmette-Guérin ΔureC::hly Δpdx1 in mice.

[severe combined immunodeficiency]

The only tuberculosis (TB ) vaccine in use today , bacillus Calmette-Guérin (BCG ), provides insufficient protection and can cause adverse events in immunocompromised individuals , such as BCGosis in HIV (+) newborns . We previously reported improved preclinical efficacy and safety of the recombinant vaccine candidate BCG ΔureC ::hly , which secretes the pore-forming listeriolysin O of Listeria monocytogenes . Here , we evaluate a second -generation construct , BCG ΔureC ::hly Δpdx 1 , which is deficient in pyridoxine synthase , an enzyme that is required for biosynthesis of the essential cofactor vitamin B 6 . This candidate was auxotrophic for vitamin B 6 in a concentration-dependent manner , as was its survival in vivo . BCG ΔureC ::hly Δpdx 1 showed markedly restricted dissemination in subcutaneously vaccinated mice , which was ameliorated by dietary supplementation with vitamin B 6 . The construct was safer in severe combined immunodeficiency mice than the parental BCG ΔureC ::hly . A prompt innate immune response to vaccination , measured by secretion of interleukin-6 , granulocyte colony-stimulating factor , keratinocyte cytokine , and macrophage inflammatory protein-1 α , remained independent of vitamin B 6 administration , while acquired immunity , notably stimulation of antigen-specific CD 4 T cells , B cells , and memory T cells , was contingent on vitamin B 6 administration . The early protection provided by BCG ΔureC ::hly Δpdx 1 in a murine Mycobacterium tuberculosis aerosol challenge model consistently depended on vitamin B 6 supplementation . Prime-boost vaccination increased protection against the canonical M . tuberculosis H 37 Rv laboratory strain and a clinical isolate of the Beijing /W lineage . We demonstrate that the efficacy of a profoundly attenuated recombinant BCG vaccine construct can be modulated by external administration of a small molecule . This principle fosters the development of safer vaccines required for immunocompromised individuals , notably HIV (+) infants .Mycobacterium tuberculosis can synthesize the essential cofactor vitamin B 6 , while humans depend on dietary supplementation . Unlike the lipophilic vitamins A , D , and E , water-soluble vitamin B 6 is well tolerated at high doses . We generated a vitamin B 6 auxotroph of the phase II clinical tuberculosis vaccine candidate bacillus Calmette-Guérin ΔureC ::hly . The next -generation candidate was profoundly attenuated compared to the parental strain . Adaptive immunity and protection in mice consistently depended on increased dietary vitamin B 6 above the daily required dose . Control of vaccine efficacy via food supplements such as vitamin B 6 could provide a fast track toward improved safety . Safer vaccines are urgently needed for HIV-infected individuals at high risk of adverse events in response to live vaccines .