Assessing vaccine-mediated protection in an ultra-low doseMycobacterium tuberculosismurine model

Abstract

Despite widespread immunization with Bacille-Calmette-Guerin (BCG), the only currently licensed tuberculosis (TB) vaccine, TB remains a leading cause of mortality globally. There are many TB vaccine candidates in the developmental pipeline, but the lack of a robust animal model to assess vaccine efficacy has hindered our ability to prioritize candidates for human clinical trials. Here we use a murine ultra-low dose (ULD) Mycobacterium tuberculosis (Mtb) challenge model to assess protection conferred by BCG vaccination. We show that BCG confers a durable reduction in lung bacterial burdens, curbs Mtb dissemination to the contralateral lung, and prevents detectable infection in a small percentage of mice. These findings are consistent with the ability of human BCG vaccination to mediate protection, particularly against disseminated disease, in specific human populations and clinical settings. Overall, our findings demonstrate that the ultra-low dose Mtb infection model can measure distinct parameters of immune protection that cannot be assessed in conventional dose murine infection models and could provide an improved platform for TB vaccine testing.

Attenuated Mycobacterium tuberculosis vaccine protection in a low-dose murine challenge model

“…These data corroborate other recent work showing that BCG reduces detectable infection and disseminated infection in addition to traditional bacterial load measurements, although these studies required substantially larger numbers of mice due to the lower protective efficacy of BCG. 19 , 20 Therefore, the capacity of ΔLprG to abrogate detectable infection and disseminated infection with relatively small group sizes may provide an experimentally tractable model for assessing potent vaccines such as ΔLprG, including facilitating mechanistic studies evaluating immune molecules and subsets in mediating defined aspects of protection.…”

“…Indeed, BCG provides long-term bacterial control in the low-dose model, in contrast to the short-lived protection observed after 100 CFU challenge. 20 Use of challenge strain barcoding 18 , 20 and analysis of spleen and other sites of dissemination like draining lymph nodes could provide a more granular understanding of vaccine protection. In addition, future studies could assess the contributions of myeloid and T cell subsets as well as the cytokines identified in our correlates analysis for their potential roles as regulators of ΔLprG vaccine protection in the low-dose model.…”

“… 18 Moreover, additional studies in this model found that BCG immunization improved long-term control of bacterial loads, prevented dissemination of barcoded bacilli to contralateral lung, and reduced the proportion of mice with detectable infection, although these studies required large numbers of mice due to the low protective efficacy of BCG. 19 , 20 In this study, we evaluated the protective efficacy of BCG and the more potent live attenuated ΔLprG vaccine candidate in the low-dose model. 5 , 6 Compared to BCG, ΔLprG yielded protection from detectable infection in a substantial subset of mice and anatomic containment in all animals with breakthrough infection.…”

Key advances in vaccine development for tuberculosis—success and challenges

“…With this ULD model, a blood RNA signature was identified that could predict the severity of TB disease in NHP. Recently, the ULD mouse model was used to evaluate the protective efficacy of BCG vaccination, with the important finding that BCG could prevent infection in some of mice 119 . Therefore, the ULD model could represent an important advance in the use of mice to model TB vaccine responses.…”

Animal models for COVID-19 and tuberculosis

“…The major caveat of the C57BL/6 model lies in the lack of human-like pathology. Of note, application of ultra-low dose infection (ULD) ( 56 ) may render these mice amenable for pathology studies ( 57 ). Upon ULD, mice develop single, structured lesions upon inhalation of 1-3 Mtb CFU of the laboratory strain H37Rv.…”