Protection and Long-Lived Immunity Induced by the ID93/GLA-SE Vaccine Candidate against a Clinical Mycobacterium tuberculosis Isolate

Abstract

dMycobacterium tuberculosis HN878 represents a virulent clinical strain from the W-Beijing family, which has been tested in small animal models in order to study its virulence and its induction of host immune responses following infection. This isolate causes death and extensive lung pathology in infected C57BL/6 mice, whereas lab-adapted strains, such as M. tuberculosis H37Rv, do not. The use of this clinically relevant isolate of M. tuberculosis increases the possibilities of assessing the long-lived efficacy of tuberculosis vaccines in a relatively inexpensive small animal model. This model will also allow for the use of knockout mouse strains to critically examine key immunological factors responsible for long-lived, vaccine-induced immunity in addition to vaccine-mediated prevention of pulmonary immunopathology. In this study, we show that the ID93/glucopyranosyl lipid adjuvant (GLA)-stable emulsion (SE) tuberculosis vaccine candidate, currently in human clinical trials, is able to elicit protection against M. tuberculosis HN878 by reducing the bacterial burden in the lung and spleen and by preventing the extensive lung pathology induced by this pathogen in C57BL/6 mice.T he development of an effective Mycobacterium tuberculosis vaccine, and increased availability of novel drugs targeting drug-resistant strains, would significantly contribute to decreasing the continuing spread of this global disease. Nine million people were estimated to have contracted tuberculosis (TB) in 2013, with 1.5 million deaths occurring annually (1). Overall, 3.5% of new cases and 20.5% of previously treated cases are multidrugresistant (MDR) TB (1), although this can be as high as 35% and 75%, respectively, in central Asian countries. The Beijing lineage of TB has been associated with a number of MDR TB outbreaks (2-6) and accounts for approximately 13% of isolates worldwide (7). The Beijing lineage itself has expanded more rapidly than other lineages (8); this may be due to the higher virulence of modern strains compared with phylogenetically older sublineages (9-11). The clinical isolate, HN878, is a representative strain from the W-Beijing lineage. The HN878 isolate has been studied in mice to characterize the infectivity and pathogenicity of this virulent clinical strain of M. tuberculosis (12)(13)(14). These same studies have provided insight into the role of the immune response generated to this pathogen in animals and humans and how the immune response to HN878 contributes to the pathology induced following infection with this isolate. Mice infected with the hypervirulent HN878 strain have increased type I interferon (IFN) expression in the lung and decreased Th1 immunity (12), and HN878 infection in IFN-␣/␤R-deficient mice results in decreased bacterial growth (13). In humans, a type I IFN-␣ molecular signature, expressed by a population of isolated neutrophils, was observed in patients with active TB (15). More recently, analysis using a whole-genome microarray approach showed a similar type I interferon molecular signa...

New insights into the mycobacterial PE and PPE proteins provide a framework for future research

“…PPE62 is reported to be a surface accessible heme‐binding protein, which is not strictly required for virulence of M. tuberculosis (Mitra et al , ). The PPE‐MPTR protein PPE42 is an immunogenic protein that is part of the ID93 subunit vaccine candidate (Bertholet et al , ; ; Baldwin et al , ).…”

“…However, especially the PPE proteins contain many predicted and experimentally validated antigenic epitopes. Important examples of immunogenic PPE proteins include the PPE‐SVP protein PPE18, which is part of M72/AS01E subunit vaccine candidate (Meeren et al , ) and the PPE‐MPTR protein PPE42, which is a part of the subunit vaccine ID93 (Bertholet et al , ; ; Baldwin et al , ). Furthermore, immune responses to PE and PPE proteins also play a large role in designing whole‐cell vaccines.…”

New Genome-Wide Algorithm Identifies Novel In-Vivo Expressed Mycobacterium Tuberculosis Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine Profiles

“…Following this disappointing outcome, the field has been reconsidering the design of future TB vaccines15, including new efforts towards better rationalized and comprehensive antigen selection approaches, both in pre-clinical16 and clinical studies17181920.…”

Identification of New Features from Known Bacterial Protective Vaccine Antigens Enhances Rational Vaccine Design

“…The findings in this study can be translated into a predictive framework with different approaches to improve existing methods and achieve better identification and validation of novel PAgs. Even though traditional rule-based prediction has been successful in multiple studies ( 6 , 9 ) and also applied in many tools ( 12 – 14 ), this type of “all-or-nothing” selection might fail to capture the relationship among different criteria ( 16 ). For example, a potential cytoplasmic or cytoplasmic membrane PAg would be immediately discarded from a study that includes surface-exposing SCL as one of the criterion.…”

“…This finding led to the approval of the first MenB vaccine, Bexsero, for use in the Europe ( 7 ), and United States ( 8 ). The success of Bexsero is a milestone for rational vaccine design and RV has also been applied in vaccine prediction against other challenging pathogens such as Mycobacterium tuberculosis ( 9 ).…”