Lymph node targeting of BCG vaccines amplifies CD4 and CD8 T-cell responses and protection against Mycobacterium tuberculosis

Abstract

Vaccination with Mycobacterium bovis BCG provides limited protection against pulmonary tuberculosis and a risk of dissemination in immune-compromised vaccinees. For the development of new TB vaccines that stimulate strong T-cell responses a variety of strategies is being followed, especially recombinant BCG and attenuated M. tuberculosis. The objective of the current study was to test potential benefits of vaccination through direct lymph-node targeting of wildtype BCG; the recommended route of vaccination with BCG is intradermal. C57BL/6 mice were immunised with BCG by intradermal, subcutaneous or intralymphatic injections. Cellular immune responses and protection against M. tuberculosis were determined. Intralymphatic vaccination was 100–1000 times more effective in stimulating BCG-specific immune responses than intradermal or subcutaneous immunisation. Intralymphatic administration stimulated high frequencies of mycobacterium-specific lymphocytes with strong proliferating capacity and production of TNF-α, IL-2, IL-17 and, especially, IFN-γ secretion by. CD4 and CD8 T cells. Most importantly, intralymphatic vaccination with 2×103CFU BCG induced sustained protection against M. tuberculosis in intratracheally challenged C57BL/6 mice, whereas subcutaneous vaccination with 2×105CFU BCG conferred only a transient protection. Hence, direct administration of M. bovis BCG to lymph nodes demonstrates that efficient targeting to lymph nodes may help to overcome the efficacy problems of vaccination with BCG.