TY - JOUR
T1 - Identification and evaluation of novel protective antigens for the development of a candidate tuberculosis subunit vaccine
AU - Stylianou, Elena
AU - Harrington-Kandt, Rachel
AU - Beglov, Julia
AU - Bull, Naomi
AU - Pinpathomrat, Nawamin
AU - Swarbrick, Gwendolyn M.
AU - Lewinsohn, Deborah A.
AU - Lewinsohn, David M.
AU - McShane, Helen
N1 - Funding Information:
H.M. is a Wellcome Senior Clinical Research Fellow (grant number 095780/Z/11/Z). This project was funded in part by FP7 grant NEWTBVAC (project number 241745) and also received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 643381. The antigens and peptide pools provided by the D. A. Lewinsohn laboratory have been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services, under contract no. HHSN272200900053C and HHSN266200400081C. E.S., R.H.-K., J.B., N.B., and N.P. performed the experiments, and G.M.S. provided necessary experimental material. E.S. and H.M. designed the experiments and interpreted the data with contribution from D.A.L. and D.M.L. E.S. wrote the manuscript with input from G.M.S., D.A.L., D.M.L., and H.M. All authors had access to the data and approved the manuscript before it was submitted. The Aeras TB Vaccine Foundation, a nonprofit organization, has licensed technology from OHSU of which David M. Lewinsohn and Deborah A. Lewinsohn are inventors and which is used in this research. In addition, OHSU, David M. Lewinsohn, and Deborah A. Lewinsohn have a financial interest in and Gwendolyn M. Swarbrick is an employee of ViTi, a company that may have a commercial interest in the results of this research and technology. These potential individual and institutional conflicts of interest have been reviewed and managed by OHSU. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2018 American Society for Microbiology.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - The development of a vaccine against tuberculosis (TB), a disease caused by Mycobacterium tuberculosis, is urgently needed. The only currently available vaccine, M. bovis BCG, has variable efficacy. One approach in the global vaccine development effort is focused on boosting BCG using subunit vaccines. The identification of novel antigens for inclusion in subunit vaccines is a critical step in the TB vaccine development pathway. We selected four novel mycobacterial antigens recognized during the course of human infection. A replication-deficient chimpanzee adenovirus (ChAdOx1) was constructed to express each antigen individually, and these vectors were evaluated for protective efficacy in murine M. tuberculosis challenge experiments. One antigen, PPE15 (Rv1039c), conferred significant and reproducible protection when administered alone and as a boost to BCG vaccination. We identified immunodominant epitopes to define the protective immune responses using tetramers and intravascular staining. Lung parenchymal CD4+ and CD8+ CXCR3+ KLRG1- T cells, previously associated with protection against M. tuberculosis, were enriched in the vaccinated groups compared to the control groups. Further work to evaluate the protective efficacy of PPE15 in more stringent preclinical animal models, together with the identification of further novel protective antigens using this selection strategy, is now merited.
AB - The development of a vaccine against tuberculosis (TB), a disease caused by Mycobacterium tuberculosis, is urgently needed. The only currently available vaccine, M. bovis BCG, has variable efficacy. One approach in the global vaccine development effort is focused on boosting BCG using subunit vaccines. The identification of novel antigens for inclusion in subunit vaccines is a critical step in the TB vaccine development pathway. We selected four novel mycobacterial antigens recognized during the course of human infection. A replication-deficient chimpanzee adenovirus (ChAdOx1) was constructed to express each antigen individually, and these vectors were evaluated for protective efficacy in murine M. tuberculosis challenge experiments. One antigen, PPE15 (Rv1039c), conferred significant and reproducible protection when administered alone and as a boost to BCG vaccination. We identified immunodominant epitopes to define the protective immune responses using tetramers and intravascular staining. Lung parenchymal CD4+ and CD8+ CXCR3+ KLRG1- T cells, previously associated with protection against M. tuberculosis, were enriched in the vaccinated groups compared to the control groups. Further work to evaluate the protective efficacy of PPE15 in more stringent preclinical animal models, together with the identification of further novel protective antigens using this selection strategy, is now merited.
KW - Mycobacterium tuberculosis
KW - Tuberculosis
KW - Vaccines
KW - Viral vectors
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U2 - 10.1128/IAI.00014-18
DO - 10.1128/IAI.00014-18
M3 - Article
C2 - 29661928
AN - SCOPUS:85050107942
VL - 86
JO - Infection and Immunity
JF - Infection and Immunity
SN - 0019-9567
IS - 7
M1 - e00014-18
ER -