On March 25th, 2015 – a day after the world commemorated the progress we’ve made against tuberculosis (TB), the 2015 Spring Meeting of the Biomarkers and Correlates Working Group (BCWG) was held. TB experts from around the world, among others TBVI’s Prof. Tom Ottenhoff, discussed and made recommendations for the TB vaccine community regarding the studies needed to better define biomarkers or correlates for risk of TB infection or disease, protection induced by vaccination, and endpoints for clinical trials.
At the 2015 Spring Meeting, updates were given on the Prevention of Infection (POI) clinical trial, the mycobacterial growth inhibition assay (MGIA), the CD1 arm of the TB Vaccine Accelerator, and the Human Challenge Model.
- The POI trial is being conducted among adolescents without any evidence of latent TB infection in the Western Cape Province of South Africa. This Phase 2 study started enrolling in 2014 and aims to evaluate H4:IC31, a vaccine candidate jointly developed by Statens Serum Institut, Sanofi Pasteur, and Aeras, and its ability to prevent Mycobacterium tuberculosis (Mtb) infection compared to placebo and BCG revaccination. Designing a clinical trial using infection as the primary endpoint, as measured by the QuantiFERON® TB Gold In-Tube test (QFT), is a major shift from previous TB vaccine R&D efforts focused on preventing TB disease. The point estimate of efficacy target for this trial is a 50% reduction of QFT conversion among H4:IC31 recipients compared to the placebo by 2017.
- 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, and Oxford University. The assay measures bacterial growth and may be a useful tool to assess vaccine efficacy. Researchers are currently attempting to optimize the peripheral blood mononuclear cell (PBMC) MGIA in the mouse, but achieving reproducibility of the assay has been challenging. The assay is being standardized to BCG, since standardizing it to Mtb would prove to be a resource challenge when being used in the field.
- The TB Vaccine Accelerator includes four integrated projects: 1a) proof-of-concept (POC) for antibody-mediated protection against 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. The BCWG received an update from Dr. D. Branch Moody, the Principal Investigator of project 1b from Brigham and Women’s Hospital and Harvard Medical School. Model Mtb lipid antigens have been selected and are being synthesized along with the CD1 reagents; the antigens and reagents will be made available to the TB vaccine community when synthesis is complete. Responding CD-1 restricted T-cells following Mtb exposure will be monitored using human tetramers, which will be ready for antigen loading soon. Aeras offered leukaphoresis samples from adults in the USA before and after BCG vaccination to test the tetramers. Lipid immunization studies in guinea pigs will begin in July 2015, but whether the immunizations will need an adjuvant component is still unknown.
- The Human Challenge Model Consortium consists of partners from Albert Einstein College of Medicine, Cornell University, Harvard University, Imperial College London, and Rutgers University. The BCWG received an update from Dr. Eric Rubin from Harvard University, a Co-Principal Investigator of the study along with Dr. Sarah Fortune from Harvard University and Dr. Michelle H. Larsen from Albert Einstein College of Medicine. The Consortium is attempting to generate attenuated Mtb strains which will clear in humans after a specified period of time so that they can be used to challenge human volunteers who previously received TB vaccine candidates in TB vaccine human challenge clinical trials. Using human challenge methodology to evaluate TB vaccine candidates in humans would directly inform human immune responses to the candidates. Clearly, ethical and safety concerns regarding the challenge Mtb strains will need to be considered as the strains are developed and prior to their first use in humans. Different routes of infection (e.g., aerosol vs. skin), for instance, still need to be tested in animals to inform the reversion, replication, and pathology of the modified challenge strain and to develop the appropriate reporter tools.
The BCWG received organizational updates from the TuBerculosis Vaccine Institute (TBVI) and the Bill & Melinda Gates Foundation (BMGF).
- TBVI is a European not-for-profit foundation supporting R&D efforts for new TB vaccines that are accessible and affordable to all people. It launched TBVAC2020 in January 2015, which aims to diversify the TB vaccine pipeline by introducing innovative approaches and to select the most promising candidates by portfolio management. TBVAC2020 consists for 40 partners, including seven partners outside of Europe, and is funded through December 2018. The project includes seven work packages involving discovery R&D, preclinical, and early clinical development. Dr. Thomas H. Ottenhoff, a member of TBVI and of the BCWG, emphasized that the goals put forth by TBVAC2020 will only be realized through successful global partnerships not only with USA and countries in Europe, but also with countries with high burden of TB, such as Brazil, Russia, India, China, and South Africa.
- Dr. Willem Hanekom is the Deputy Director of TB Vaccines at the BMGF and also a BCWG member. He held a question and answer session at the BCWG regarding the BMGF’s TB Vaccine Strategy, which was recently revised in 2014. The strategy has received a widely positive response from BMGF’s global partners and emphasizes up-stream discovery while fostering greater innovation, collaboration, and coordination within the TB vaccine landscape. The BMGF hopes to introduce the Collaboration for TB Vaccine Discovery (CTVD) in July 2015 to promote early data sharing among investigators affiliated with the foundation, thereby facilitating idea and knowledge exchange to ultimately accelerate and improve TB vaccine research quality.
Topics of Interest
Three topics of interest were discussed at the BCWG: whole mycobacteria cell vaccines for TB, antigen selection, and biobanks.
- Despite having six whole mycobacteria cell vaccines for TB in the global clinical pipeline in Phase 1, 2a, and 3 trials, the TB vaccine community still does not have a method to differentiate these candidates or to select the most promising candidate for further testing and development. The BCWG suggested using gene expression profiling to differentiate the immune mechanism and efficacy potential of the whole mycobacteria cell vaccine candidates being tested. Conducting gene expression profiling on the whole blood or PBMC specimens of clinical trial participants who have received these vaccines may illuminate whether the vaccine candidates are eliciting similar immune responses, thereby allowing researchers to differentiate candidates by immune mechanisms. Gene expression profiling will also take into consideration responses to non-protein antigens and non-classical immune responses to antigens that may be contributing to vaccine-induced protection but are ignored in current testing paradigms.
- As a follow-up to the question Aeras posed at the January 2015 “Host Response to TB” Keystone Symposium in Santa Fe, New Mexico, the BCWG discussed whether there is enough evidence to recommend changing any of the antigens Aeras is currently using in its antigen cassettes. The BCWG agreed that there was insufficient data to recommend a change at this time, and that the TB vaccine community needed to better understand how antigens contribute to an overall immune correlate of protection against Mtb infection or TB disease. The role of vectors and adjuvants are also important determinants of immune responses to antigens, which will need to be considered when evaluating antigens for inclusion in vaccine candidates.
- Lastly, the BCWG deliberated on questions related to the creation and maintenance of biobanks for the TB vaccine community. It was decided that Aeras will work with its clinical trial partners to organize and advertise the legacy specimens remaining from past clinical trials by the end of 2015. Aeras, however, is also collecting specimens from current clinical trials specifically for biobank purposes and will be made available for use to the TB vaccine R&D community. While the importance of having a biobank of specimens from vaccine clinical trials is recognized as a valuable asset, maintaining and governing biobanks involve many logistical challenges. The BCWG decided to solicit feedback for this endeavor from the European TB community through Prof. Tom Ottenhoff from TBVI.
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 2015 Fall Meeting in September may be sent to Esther Lau (firstname.lastname@example.org) by July 31 for consideration.