Modulation of protection against Mycobacterium tuberculosis by adjuvants that elicit different T cell responses. (166.18)

The use of an adjuvant within a vaccine can influence and direct the immune response to enable a desired outcome. A T helper 1 (Th1) response, including antigen-specific production of interferon-gamma (IFN-γ), is needed to protect against Mycobacterium tuberculosis. A successful subunit vaccine should include not only an appropriate antigen but also a proper adjuvant to ensure that a Th1 mediated cellular response is induced. Only a few adjuvants have been approved for use in human vaccines such as Alum and oil-in-water (o/w) based emulsions, including MF59 (Novartis), AS03 (GSK Biologics), AF03 (Sanofi) and liposomes (Crucell). These adjuvants primarily induce humoral responses. A new adjuvant in approved products is AS04, which combines the TLR-4 agonist monophosphoryl lipid A (MPL) with Alum. In this study we combine our candidate TB vaccine, ID93, with a synthetic TLR-4 agonist, glucopyranosyl lipid adjuvant (GLA) mixed with a stable o/w emulsion (SE). Both SE and GLA-SE induce potent cellular responses when combined with ID93 in mice. ID93/GLA-SE induced multifunctional CD4+ Th1 cell responses (IFN-γ, TNF-α, IL-2) in mice and protected both mice and guinea pigs against M. tuberculosis. In contrast, ID93/SE in the absence of GLA induced IL-5 and provided no protection, as assessed by bacterial burden, survival, and pathology. These results demonstrate the importance of properly formulating subunit vaccines with effective adjuvants for use against TB.