Abstract
Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), causes 1.8M deaths annually. The current vaccine, BCG, has failed to eradicate TB leaving 25% of the world’s population with latent Mtb infection (LTBI), and 5–10% of these people will reactivate and develop active TB. An efficient therapeutic vaccine targeting LTBI could have an enormous impact on global TB incidence, and could be an important aid in fighting multidrug resistance, which is increasing globally. Here we show in a mouse model using the H56 (Ag85B-ESAT-6-Rv2660) TB vaccine candidate that post-exposure, but not preventive, vaccine protection requires low vaccine antigen doses for optimal protection. Loss of protection from high dose post-exposure vaccination was not associated with a loss of overall vaccine response magnitude, but rather with greater differentiation and lower functional avidity of vaccine-specific CD4 T cells. High vaccine antigen dose also led to a decreased ability of vaccine-specific CD4 T cells to home into the Mtb-infected lung parenchyma, a recently discovered important feature of T cell protection in mice. These results underscore the importance of T cell quality rather than magnitude in TB-vaccine protection, and the significant role that antigen dosing plays in vaccine-mediated protection.
Highlights
One fourth of the world’s population is estimated to harbor latent Mycobacterium tuberculosis (Mtb) infection (LTBI), of which 5–10% will eventually develop active and transmittable tuberculosis (TB) [1, 2]
We observed that a wide range of high and low vaccine doses were protective in a preventive murine TB model, but similar high vaccine doses were detrimental to post-exposure vaccine protection
While a broad range of H56 vaccine antigen doses were protective in prophylactic vaccination, only a narrow range of lower doses were protective in post-exposure vaccination
Summary
One fourth of the world’s population is estimated to harbor latent Mycobacterium tuberculosis (Mtb) infection (LTBI), of which 5–10% will eventually develop active and transmittable tuberculosis (TB) [1, 2]. This constitutes an enormous reservoir of potential TB disease, and developing a vaccine that can prevent reactivation in LTBI individuals would greatly impact the global TB burden [3]. Evidence suggests a protective immune response against infection with Mtb is derived mainly from IFN-γ-producing Th1 cells that activate infected macrophages, since CD4-deficient, IFN-γ- and inducible nitric oxide synthase (iNOS)-KO mice are highly susceptible to Mtb infection compared to wild-type strains [9,10,11,12]. The last 10–20 years of research has shown that TB immunity is not as straightforward as previously understood, with some studies even suggesting that classical Th1-derived cytokines are not necessary for protection [13, 14]
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