RePORT Meeting day 2: We travel back to BMC

This morning we were back at the Marriott in Newton for day two of the inaugural RePORT meeting. I took the Green Line out to the Riverside station and a quick hotel shuttle brought me to the Marriott. It actually is possible to live without a car in the Boston area! Today’s morning lecturers included the following individuals:

  • Steve Reed from IDRA talked about developmental paths for an ID93/GLA-SE TB vaccine candidate.
  • Umesh Shaligram from the Serum Institute of India talked about the recombinant BCG vaccine, VPM1002. He also talked about BCG and bladder cancer (1, 2).
  • Ed Nardell discussed TB reinfection and his research with guinea pigs in South Africa. He also talked about the potential TIPI trial, a BCG vaccine for humanitarian health workers with IGRA conversions as an outcome. During the Q&A, Jerry Ellner spoke about the Pine Street Inn TB homeless shelter outbreak which occurred down the street from BMC, and how TB reinfection had been discovered.
  • Morten Ruhwald from Denmark talked about the H56 vaccine trial.
  • Lew Schraeger from AERAS spoke about the post MVA-85A vaccine era, as we are essentially back to the drawing board with TB vaccines. He focused on the Louis Picker from Oregon State’s research with CMV vectored vaccines. He also invited Ford von Reyn from Dartmouth up to the microphone to talk about the DAR901 study. DAR901 has a lot of potential.
  • Bob Husson talked about urinary protein biomarkers.
  • Branch Moody discussed lipid biomarkers, for example tuberculosinyladenosine (TbAd)

We then took a shuttle to BMC and on the way I had the opportunity to catch up with Jeff Tornheim, an ID fellow at Hopkins who is working on TB research in India with Amita Gupta. We had a nice discussion about the potential of whole genome sequencing for drug resistance. We also talked about the challenges facing TB vaccines. At BMC in the afternoon, there were several more speakers:

  • Jerry Ellner gave a gracious introduction to Barry Bloom, who then presented a fantastic lecture about TB immunology with a special focus on Vitamin D.
  • Robert Wilkinson discussed transcriptomics and TB-IRIS .
  • Susan Dorman talked about clinical trials. She focused on surrogate markers like EBA and adaptive clinical trial design. She also spoke about BDQ, delamanid, PA-824, linezolid, dosing of levofloxacin, meropenem + clavulanate, etc.. She also talked about treatment shortening of DS-TB (get rid of ethambutol, or increase doses of rifampin/rifapentine/PZA).
  • A Q&A about TB Drugs was led by Susan Dorman, Carole Mitnick, Mercedes Becerra, and Bob Horsburg. Carrying out clinical trials for TB is very difficult and real world DR-TB treatment is completely different than a clinical trial. In programmatic conditions, patients don’t do as well as they do in a clinical trial (LTFU, etc). I asked the panel about measuring drug levels (like Chuck Pelloquin’s lab at the University of Florida does) and they thought ideally that would be important for DR-TB management of all patients (but it is rarely done).  We need to know which patients we should be most concerned about, and check their drug levels. The issue is not only exposures and pharmacokinetics, but pharmacodynamics and MIC. In which patients can we overcome apparent drug resistance by thoughtful dosing strategies? Rifampin is amenable to fingerstick blood level testing. If we had drugs with a wide toxic-therapeutic ratio, we would be fine. But the drugs we have for DR-TB, have a narrow ratio. Give a bit too much, they get toxic. So we need levels. Also, we may be under-dosing obese patients.  Finally, for high dose INH as well as injectibles in DR-TB, drug levels are very important.
  • Megan Murray described her research from Lima, Peru about community-based TB transmission.
  • James Collins from MIT talked about bioengineering approaches to TB drugs.
  • Igor Kramnik spoke about small molecules that regulate macrophage responses to interferon gamma.
  • Samuel Behar gave a great lecture about the TB vaccines and T cells. Afterwards, I asked him about the CMV vector vaccines and also the DAR901 study that Lew Schraeger and Ford von Ryan had highlighted earlier in the day. Dr. Behar responded saying that we have numerous strategies that elicit T cells. They differ on what kind of T cells, or how many T cells, but all of them in animal models often provide a similar degree of protection. The problem isn’t necessarily with the T cell, it may be with the evasion of antigen presentation by the bacteria. You can have 100x more T cells, or only MH1 restricted T cells, but will have the same problem. You select against the cells that are presenting antigen. There is a subset of infected cells that are resistant to recognition.
  • Eric Rubin gave a funny and informative lecture about TB genetics.
  • I left the day thinking that it is extremely unlikely that we will be able to treat our way out of the DR-TB epidemic. Treatment is very difficult. Diagnostics are better than before with Xpert, but drugs are toxic and not that effective, requiring prolonged regimens. We need shorter treatment regimens but that isn’t happening anytime soon. Lack of coordination in the supply chain leads to stockouts and patients are often lost to follow-up. Even if patients aren’t lost, often they don’t absorb the drugs well and we rarely check drug levels. Because of weak national TB programs, M&E is often lacking. We need an effective TB vaccine, but the scientific challenges are huge. And beyond a TB vaccine we need much more attention on reducing nosocomial transmission, using FAST, natural ventilation, UVGI, etc.   There’s lots of work ahead. I really hope the funders would make a commitment to giving more money to researchers like Louis Picker, Samuel Behar and Ford von Reyn. We desperately need an effective TB vaccine!
  • One comment, from my friend/colleague Dr. Ruvandhi Nathavitharana: “I’m perhaps biased but although we have come a long way with diagnostics, with 3 million missed TB cases annually, there is still much to do to ensure that the advances lead to a clinical impact. The major gaps in linkage to care should also not be underestimated although I agree that developing an effective TB vaccine must be a priority. I found the discussion about thoughtful trial design given the constraints in terms of outcomes and funding was particularly insightful.”
  • Finally, the RePORT team has a new paper out in CID.
Back at the Marriott
Back to Newton
Boston Medical Center
Boston Medical Center
Pine Street Inn (homeless shelter) where there was a famous TB outbreak ~20 years ago. I'd like to explore the history of this outbreak someday if I have time.
Pine Street Inn (homeless shelter) where there was a famous TB outbreak ~20 years ago. I’d like to explore the history of this outbreak someday if I have time.

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