The Role of Innate Immunity in the Acquisition of Sterile Protection against TB Infection

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Tuberculosis (TB) is a major global health problem. Vaccines are the most powerful instruments for limiting the morbidity and mortality of infectious diseases, so the development of highly protective TB vaccines is one of the highest priorities in public health. Bacille de Calmette et Guérin (BCG), the only TB prophylactic vaccine licensed, is 80% effective against extra-pulmonary TB infection (extra-PTBI), but has variable efficacy against PTBI, the site of primary TB infection1-7. BCG generates TB-specific adaptive cell-mediated immunity (aCMI), which is thought to be essential to its strong protective effect against extra-PTBI. However, BCG, and new vaccine candidates that generate more robust aCMI than BCG, remain poorly protective against PTBI8,9, suggesting that aCMI is a poor correlate of protection against primary TB infection. Additional evidence that aCMI may not provide protection against primary TB infections is that: 1) 10 to 20% of individuals with aCMI measured by tuberculin skin test (TST) or interferon γ release assay (IGRA) develop active disease; 2) 20% of individuals heavily exposed to smear-positive highly infectious PTBI maintain a negative TST or IGRA, yet do not develop infection; 3) effective treatment of TB infection leads to loss of aCMI in many cases, suggesting that aCMI is maintained by antigen persistence. Thus, aCMI may control reactivation of latent TB infection (LTBI), while other immunologic mechanism/s confer sterile protection against TB. Innate CMI (iCMI) mediated by natural killer (NK), γδ T and NK T (NKT) cells has been documented against M. tuberculosis (Mtb) and BCG ex vivo10-21. Although iCMI effectors do not meet criteria for canonical immunologic memory, persistence of memory-like iCMI has been clearly demonstrated against viruses, tumors and other immunogens22-29. Recent evidence suggests that BCG administration and Mtb infection also elicit memory-like iCMI11-14,30. We hypothesized that Mtb memory-like iCMI is a mechanism of sterile protection against Mtb infection thus preventing LTBI. An important corollary is that TB-specific iCMI will provide a robust measure for vaccine-induced protection, which is much needed for the development of highly efficacious TB vaccines.  Using samples collected in the Cohort For TB Research By The Indo-US Medical Partnership Multicentric Prospective Observational Study (C-TRIUMPh; full protocol description can be found in Appendix 2) at the Byramjee Jeejeebhoy Govt. Medical College (BJMC), Pune, India, together with a prospective cohort to be enrolled in the US, we will investigate TB-specific iCMI as a mechanism of protection against LTBI, and the extent to which iCMI can be elicited by BCG vaccination.


Aim 1: To identify the Mtb iCMI characteristics that differentiate LTBI- from LTBI+ adults with high exposure to smear-positive PTBI.

Hypothesis: LTBI- individuals highly exposed to TB have more robust Mtb memory-like iCMI than LTBI+ and TB unexposed individuals.
Using Cytometry time of flight (CyTOF) technology and systems biology analytical tools designed for large datasets, we will measure a large array of NK, NKT, [small gamma small delta] T and mucosal-associated invariant T (MAIT) cell responses to ex-vivo Mtb antigenic stimulation and analyze the differences between a subset of LTBI- and LTBI+ adults highly exposed to smear-positive PTBI. The most significant independent differences will be used to build a smaller flow cytometry panel that will be used to test the remaining LTBI- and LTBI+ highly TB-exposed adults.

Aim 2. To characterize the Mtb-specific iCMI generated by BCG administration.

Hypothesis: Compared with LTBI- individuals highly exposed to TB, BCG administration generates memory-like iCMI to Mtb of lower magnitude and/or restricted to a fraction of the vaccine recipients.
We will recruit adults who received BCG and had negligible exposure to TB and compare their Mtb iCMI with that of highly TB-exposed LTBI- adults using the tools described in AIM 1.
The results of this study have the potential to shift the paradigm for immune protection against Mtb infection by substituting and/or adding iCMI to aCMI as long term protective responses and, thereby, to revolutionize the field of TB vaccine development. The study will provide added value to C-TRIUMPh by using already collected peripheral blood mononuclear cells (PBMC) to accomplish its immunologic goals. We will also leverage the NIH efforts to develop advanced immunologic capacity at BJMC.   


University of Colorado Denver, Aurora, CO