New TB vaccine strategy builds lung immunity to stop reactivation

Tuberculosis remains a global threat in part because many people carry a latent infection that can later reactivate into active, contagious disease. To slow the TB epidemic, researchers need vaccines that not only prevent initial infection but also stop latent infections from progressing to active illness. Steven C. Derrick and colleagues used a mouse tuberculosis (TB) latency model to test several candidate vaccines for that exact purpose: could a vaccine prevent reactivation of a latent infection? The team also tested promising candidates in an acute aerosol infection model to see how well they control a fresh lung infection. From this set of experiments the researchers identified one particularly encouraging regimen, which they called BAA, that performed strongly in both the latency and acute models. By studying the immune cells in the lungs before and after challenge, Derrick’s group aimed to map the kinds of responses a vaccine needs to generate — information that could help guide the design of better TB vaccines and reveal immune markers, or correlates, of protection.

The most promising regimen combined several specific components. Mice were given BCG formulated in adjuvant (Adj) (dimethyl dioctadecyl-ammonium bromide (DDA) plus D-(+)-Trehalose 6,6’-Dibehenate (TDB)) with rEsat-6 delivered subcutaneously (SC), followed by an intranasal (IN) administration of an adenovirus construct expressing a fusion of Esat-6 (E6) and antigen-85B (Ag85B) (AdE6-85B). This vaccine regimen was designated BAA. In the latency model BAA consistently prevented reactivation in 75 - 100% of immunized animals. In the acute aerosol infection model BAA produced a consistent 2 – 3 log10 mycobacterial CFU reduction in the lungs relative to nonimmunized mice (Naïve), and it was significantly more protective than BCG or BCG+Adj controls. Immune analysis showed higher pre-challenge frequencies of CD4+ tissue resident memory (T_RM) T cells (CD69+ PD-1+ CXCR3+) and CD4+ populations bearing CD153 and P2X7R in lungs of BAA-immunized mice. After infection lungs also harbored significantly higher frequencies of multifunctional CD4+ T cells expressing IL-17A and TGFβ or IL-17A, TGFβ and IFN-γ compared with controls.

These findings point to a possible blueprint for vaccines that stop latent TB from becoming active disease and that limit early bacterial growth in the lungs. The BAA regimen appears to work in part by seeding the lungs with CD4+ T_RM cells before exposure and by generating multifunctional CD4+ T cells after infection — immune cell types linked here to protection. Because correlates of protective immunity in TB have been unclear, identifying markers such as CD69+ PD-1+ CXCR3+ T_RM cells, CD153 and P2X7R on CD4+ cells, and multifunctional IL-17A/TGFβ/IFN-γ–producing CD4+ cells is an important advance. If these markers reliably track with protection, they could help researchers compare vaccine candidates more quickly and design regimens that specifically promote the lung-resident and multifunctional responses seen with BAA. Ultimately, Derrick and colleagues’ work suggests that vaccines focused on establishing the right lung T cell populations could reduce reactivation and better control acute TB infections.