Abstract
Lack of an effective vaccine results in 9 million new cases of tuberculosis (TB) every year and 1.8 million deaths worldwide. Although many infants are vaccinated at birth with BCG (an attenuated M. bovis), this does not prevent infection or development of TB after childhood. Immune responses necessary for prevention of infection or disease are still unknown, making development of effective vaccines against TB challenging. Several new vaccines are ready for human clinical trials, but these trials are difficult and expensive; especially challenging is determining the appropriate cellular response necessary for protection. The magnitude of an immune response is likely key to generating a successful vaccine. Characteristics such as numbers of central memory (CM) and effector memory (EM) T cells responsive to a diverse set of epitopes are also correlated with protection. Promising vaccines against TB contain mycobacterial subunit antigens (Ag) present during both active and latent infection. We hypothesize that protection against different key immunodominant antigens could require a vaccine that produces different levels of EM and CM for each Ag-specific memory population. We created a computational model to explore EM and CM values, and their ratio, within what we term Memory Design Space. Our model captures events involved in T cell priming within lymph nodes and tracks their circulation through blood to peripheral tissues. We used the model to test whether multiple Ag-specific memory cell populations could be generated with distinct locations within Memory Design Space at a specific time point post vaccination. Boosting can further shift memory populations to memory cell ratios unreachable by initial priming events. By strategically varying antigen load, properties of cellular interactions within the LN, and delivery parameters (e.g., number of boosts) of multi-subunit vaccines, we can generate multiple Ag-specific memory populations that cover a wide range of Memory Design Space. Given a set of desired characteristics for Ag-specific memory populations, we can use our model as a tool to predict vaccine formulations that will generate those populations.
Highlights
An estimated 9 million new cases of tuberculosis (TB) are reported annually (WHO, 2014)
We asked which properties intrinsic to those antigens are important in determining amounts and types of memory T cells generated, i.e., location in Memory Design Space
Despite modern advances to induce large and long-lasting populations of antigenspecific memory T cells, there is no efficacious vaccine against M. tuberculosis or several other infections requiring cell-mediated immunity
Summary
An estimated 9 million new cases of tuberculosis (TB) are reported annually (WHO, 2014). This number could be an underestimate by a factor of almost 2 due to difficulties diagnosing individuals with latent infection and those living in remote areas of developing countries (WHO, 2014). Vaccines are a critical component of the effort to stop TB due to the asymptomatic nature of latent infection and that initial symptoms of active diseases are shared by many pulmonary infections. Would either prevent an initial infection from taking hold or would prevent existing latent TB infections from progressing to active disease, reducing risk of reactivation (Karp et al, 2015)
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