On September 3, 2015, the 2015 Fall meeting of the Biomarkers and Correlates Working Group (BCWG) was held in Rockville, Maryland. Tuberculosis (TB) experts from around the world (including TBVI experts) attended to discuss and make recommendations for the TB vaccine community regarding studies needed to better define biomarkers or correlates for risk of TB infection or disease, protection induced by vaccination, and endpoints for clinical trials.
Updates were given on the Human Challenge Model, the TB Vaccine Accelerator, and the mycobacterial growth inhibition assay (MGIA):
- The Human Challenge Model Consortium consists of partners from Albert Einstein College of Medicine, Cornell University, Harvard University, Imperial College London, and Rutgers University. Dr. Eric Rubin from Harvard University, a Co-Principal Investigator of the study, gave updates with Dr. Michelle H. Larsen, a Co-Principal Investigator from Albert Einstein College of Medicine. The goal of the consortium is to develop a clinically attenuated challenge strain that can be used in humans to evaluate the efficacy of TB vaccine candidates. Within two years, the research team hopes to create a challenge strain that can be tested in animals. The challenge strain must replicate in the host to induce an immune response, but also be cleared from the host after a defined period of time to keep the host safe and for researchers to examine memory responses. The challenge strain will be developed de novo marker-free due to the regulatory follow-up needed from the start.
- The TB Vaccine Accelerator includes four integrated projects: 1a) proof-of-concept (POC) for antibody-mediated protection against Mycobacterium tuberculosis (Mtb) infection, 1b) POC for CD1-mediated protection against infection, 2a) New Riley model facility and 2b) a pilot study to test non-human primates to guinea pig transmission. Dr. Nathalie Cadieux, the Manager of Project 1a, informed the BCWG that many technical hurdles still remain to show that passive transfer of antibodies protect against natural transmission in guinea pigs. The team will meet in October 2015 to discuss alternatives offered by the BCWG around these challenges.
- Dr. D. Branch Moody, the Principal Investigator of Project 1b from Brigham and Women’s Hospital and Harvard Medical School, provided an update on the POC for CD-1 mediated protection against infection. In this study, TbAd (1-tuberculosinyladenosine) is an MTB-specific molecule that is being investigated as a marker for detecting TB disease in humans. TbAd is a shed-abundant molecule detectable in peripheral tissue and seems chemically stable. The research team plans to measure the percentage of clinical TB strains with TbAd in Peru as a next step to determine whether it can be used as a disease marker in either serum or urine.
- The MGIA Working Group currently involves partners from Aeras, Center for Biologics Evaluation and Research within the US Food and Drug Administration, Colorado State University, London School of Hygiene & Tropical Medicine (LSHTM), and Oxford University. The assay measures bacterial growth and may be a useful tool to assess vaccine efficacy. Dr. Helen Fletcher, Senior Lecturer in Immunology at the LSHTM and Dr. David Hokey, Senior Director of Immunology and Animal Studies at Aeras, presented on the status of the assay development. Researchers are standardizing the assay between laboratories and are currently optimizing the MGIA in mice to inform gating decisions for TB vaccine candidates. The goal is to move the assay into non-human primates (NHPs) and humans. The team intends to optimize the assay to MTB and is exploring the development of a positive control for the assay.
The BCWG received organisational updates from the Dr. Willem Hanekom, the Deputy Director of TB Vaccines at the Bill & Melinda Gates Foundation, who is also a BCWG member.
- The Gates Foundation kicked-off the Collaboration for TB Vaccine Discovery (CTVD) in July 2015. The CTVD aims to facilitate early data exchange among the research community to identify priorities and strategic opportunities for execution; funding for execution, however, will not be offered through CTVD. CTVD currently includes five research communities, which are open to non-Gates Foundation-funded projects, and each community will meet 3-4 times per year prior to the annual CTVD meeting in the summer of 2016. The research communities are: Donor unrestricted T-cells, Aerosol vaccination, Whole cell vaccines, B cells/antibodies, and NHPs. CTVD will also offer services for Gates Foundation-funded projects where Aeras will serve as the product development partner. Many current BCWG agenda items will eventually be incorporated into the existing CTVD research communities so the BCWG can focus more on clinical immunology to inform the upstream space. CTVD’s application to fund the Visiting Scientist Program (VSP) is currently available online.
- Dr. Robert Seder, Chief of the Cellular Immunology Section at the National Institute of Allergy and Infectious Diseases and also a BCWG member, is a member of CTVD’s NHP Research Community and presented the community’s research plan, which was discussed at the July CTVD meeting. The plan involves increasing the global capacity for NHP studies using better technology, prioritizing scientific questions, and using the global capacity for NHP studies to answer questions strategically to make clinical decisions. The NHP Research Community hopes to use CTVD to gather and generate compelling NHP data to bring in new funding, and to also serve as a resource to inform NHP study design for projects regardless of project funding. The community understands that expanding NHP challenge study capacity needs to be done in parallel with expanding the testing capacity of smaller, less expensive animal models to ensure that NHP facilities are used on the most promising candidates and delivery strategies.
Topics of Interest
The relevance of immunodominance to TB antigen selection was also discussed at the BCWG.
- Dr. David Lewinsohn, Professor at Oregon Health & Science University, discussed the challenge of defining immunodominance across populations due to variability. The discussion suggested that it may be best for researchers to look for sub-dominant or cryptic epitopes within dominant antigens in diverse human populations, and to use methods to enhance the breadth of the vaccine candidate’s response against these epitopes. Different NHP study designs were proposed to help TB researchers identify the epitopes that are initially seen in the lung during TB infection.
The BCWG serves as a resource and advisory board to the broader TB vaccine research and development (R&D) community. Members represent nine different academic, governmental, non-profit, and private institutions from the USA, Europe, and Africa involved in the conduct and funding of pre-clinical and clinical TB vaccine research. The BCWG meets at least twice a year to discuss study designs or other topics of interest related to biomarkers and correlates. Agenda items are welcome from the TB vaccine community. Suggested topics for the 2016 Spring Meeting may be sent to Esther Lau (firstname.lastname@example.org) by January 31 for consideration.