Designing a New TB Vaccine Using Software Assisted Antigen Comparison

Designed to Cure

A series of mycobacterium tuberculosis colonies in culture. By Dr. George Kubica at the Center for Disease Control, via Wikimedia Commons.

A series of mycobacterium tuberculosis colonies in culture. By Dr. George Kubica at the Center for Disease Control, via Wikimedia Commons.

Tuberculosis is a disease that most immunologists and cellular biologists will be familiar with. As a bacterium, m. tuberculosis is notable for its ability to take root in human hosts for long periods of time, exhibiting extreme genetic variability, drug resistance, stealth and ultimately lethality.1 Because of this, TB is a global health problem, and despite the presence of a vaccine, there’s still no end in sight.2  

The current standard for prophylactic therapy is the BCG vaccine, which while distributed broadly, has an extremely variable efficacy.3 It’s clear that a better solution is needed–and that solution, explored via software, might be extremely counterintuitive, according to a new paper published in Nature Communications.4

Beating BCG

It’s important to note that the authors of the new paper aren’t alone in arguing in favor of abandoning BCG as the primary vaccine for TB.5 In fact, since roughly 2005, researchers and clinicians have agreed that BCG is largely a legacy vaccine which should be deprecated in favor of something else.6

As noted by the authors of the new research, the problem is that BCG is hard to beat when it comes to safety. When dealing with live vaccines, there’s always a risk of host illness–except in the case of BCG, which might make its intended bovine host sick, but can only act as an immunogenic non-threat to humans. Regulators have so far been loath to trial live TB vaccines in healthy volunteers for fear of creating infections in the healthy, though there have been a couple of exceptions experimenting with comparisons between the BCG vaccine and its prospective replacement, MTBVAC.7 MTBVAC claims to have a number of advantages over the BCG vaccine, but a lively ongoing scientific debate exists as to which should be the first line prophylactic in crisis areas and why.  

What Will MTBVAC Prove?

The authors of the new paper join the discussion on the side of MTBVAC, arguing that as safety concerns regarding a live virus are managed, providing the immune system with a vaccine that is extremely close to what it might encounter in the field make up for the risks. Indeed, the authors of the new study sought to poke major holes in the idea that the BCG vaccine can remain viable in the changing face of TB whatsoever, given that several core TB antigens are effectively absent from the BCG vaccine’s repertoire of immunity.

The authors’ core conclusions explain quite a bit about the variability of the BCG vaccine’s efficacy while also providing insights that could easily be integrated via software into the next iteration of MTBVAC. The picture is somewhat complicated by the fact that most study participants have been exposed to the BCG vaccine before exposure to the new vaccine candidates, however.

This means that in order to bring the authors’ insights on specific antigen immunogenicity to bear, researchers must:

  • Sequence the epitopes responsible for immunogenicity on the BCG bacteria
  • Sequence the epitopes responsible for immunogenicity on the TB bacteria
  • Determine which immunogenic epitopes are not present on both bacteria
  • Determine which immunogenic BCG epitopes are not necessary for an immunogenic response to live-attenuated TB
  • Determine whether host genetics can invoke desensitization of immune response when exposed first to immunogenic BCG epitopes then subsequent attenuated live TB epitopes
  • Determine whether host genetics alter the dose-response curve of live attenuated TB or BCG, and by what mechanism

In short, this is a project for software to manage. There’s little debate that a live attenuated TB vaccine like MTBVAC will replace the outdated BCG vaccine, but vaccine researchers will need a software platform that enables them to keep track of host genetics, bacterial genetics, vaccine formulations, adjuvants, and immunogenic epitopes.

Honing In On the TB Vaccine Panacea

Simply keeping track of all a vaccine comparison’s moving parts isn’t enough to close the loop and form a new and super effective vaccine, however. Each immunogenic antigen on both of the extant vaccines must be compared in their immunogenicity quantitatively in the light of an array of potential host genetic profiles. This means that the data sets brought to bear on creating the next-generation TB vaccine will have to use the insights outlined in the Nature paper and unite them with similar insights culled directly from the field, from live samples of dominant TB strains.

TB vaccine research thus must juggle further exploration into the already-deployed vaccine, effective development of the new vaccine, and adaptive response to the changing environment outside the laboratory of living TB. As the authors of the nature paper note, keeping up with the capabilities of TB in the wild is critical because of the rate of change that TB is capable of–in one instance, totally new reactive behavior was observed, which would dash certain vaccine development efforts if it became more widespread.8 That’s quite a lot of data to keep on the same plate, and researchers won’t be able to even approach the issue of new TB vaccine formulation without a software suite that can keep up with the demands of the field.

Designed to Cure is the antigen comparison and vaccine development platform that the researchers of the future will use to develop prophylactics that make the best of old and pair it with new insights. Designed to Cure enables your team to track thousands of bacterial strains, vaccine formulations, adjuvants, host genetics, epitope profiles, and more. Contact us today to find out how you can use Designed to Cure to unify immunogenicity profiles with live feedback and help rid the world of TB.

  1.  “Identification Of A Virulence Gene Cluster Of Mycobacterium Tuberculosis By Signature-Tagged Transposon Mutagenesis.” October 1999, https://www.ncbi.nlm.nih.gov/pubmed/10564470?dopt=Abstract&holding=npg.
  2.  “Global Tuberculosis Report 2016.” 2016, http://www.who.int/tb/publications/global_report/en/.
  3. “Variation In Protection By BCG: Implications Of And For Heterologous Immunity.” November 1995, http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(95)92348-9/abstract.
  4.  “Reactogenicity To Major Tuberculosis Antigens Absent In BCG Is Linked To Improved Protection Against Mycobacterium Tuberculosis.” May 2017, https://www.nature.com/articles/ncomms16085#abstract.
  5. “Genome Plasticity Of BCG And Impact On Vaccine Efficacy.” January 2007, http://www.pnas.org/content/104/13/5596.
  6. “New Live Mycobacterial Vaccines: The Geneva Consensus On Essential Steps Toward Clinical Development.” May 2005, http://www.sciencedirect.com/science/article/pii/S0264410X05003336?via%3Dihub.
  7.  “Safety OF Human Immunisation With A Live-Attenuated Mycobacterium Tuberculosis Vaccine: A Randomised, Double-Blind, Controlled Phase I Trial.” November 2015, http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(15)00435-X/fulltext.
  8. “Phagosomal Rupture By Mycobacterium Tuberculosis Results In Toxicity And Host Cell Death.” February 2012, http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1002507.