Thursday, October 09, 2014

Tuberculosis vaccines- Story so far


   As has been argued by me in this blog every now and then, Tuberculosis is one of the major research question of global medical concern. One one hand there is an increasing problem of increasing antibiotic resistance, necessity to come up with new antibiotics and non adherence to treatment, on the other hand there is a great deal of need to come up with a better vaccine. BCG represents one of the finest vaccine in terms of the number of people administered, but also the safety factor. As I have already discussed in one of my earlier post there is a great demand for design of new vaccine approach for TB. Read my previous post here and here. There are many different TB vaccines in literature. Many of them are currently undergoing clinical trials in various phase. It is nearly out of scope of this post to talk about every type out there in R&D. So, I will elaborate on a few that looks promising (but data is awaited).

  The most talked about candidate is modified Vaccinia Ankara virus expressing antigen 85A famously known as MVA85A. The vaccine was developed by researchers at Oxford. The idea behind the development was the understanding that TH1-type cellular immune response probably has good protection correlates. Mycobacterium tuberculosis antigen 85 occurs in different types- 85A, 85B and 85C. Their function is maintenance of cell integrity of the cell wall by catalyzing the transfer of mycolic acids to the cell wall arabinogalactan and synthesis of cord factor (Trehalose dimycolate). The initial work showed promising response in people primed with BCG. The interferon response was good. However, a placebo-controlled phase 2b trial, showed a very poor outcome, with a efficacy of 17·3% which is too less to be useful.

Table 1: Vectored vaccines for TB.
     Several vaccine preparations using the Antigen 85A has been tried without much success. The current interest is focussed on MVA85A-IMX313 (Link). This is a candidate TB vaccine MVA85A with the carrier protein IMX313. IMX313 is a small DNA sequence fused to an antigen gene. This fused antigen is can auto-assemble into a heptamer, which is more readily identified by the immune system.

Table 2: Recombinant vaccines for TB
   Recombinant vaccines have also attracted wide attention. The widely talked about include rBCG DureC:Hly, rBCG30 and Aeras-422. rBCG DureC:Hly or more commonly known as VPM 1002, is a BCG Danish, subtype Praguen that expresses membrane-perforating listeriolysin (hly) of Listeria monocytogenes and is devoid of urease C (ΔureC hly+ BCG). The vaccine is thought to provide a balanced Th1-Th17 cytokine levels.

Table 3: Sub-unit vaccines
    The next group of vaccines include subunit vaccines. Several different proteins have been found to be important and attempts are made to create conjugates with carrier molecules for a potential candidate vaccine. Table 3 is a list of pursued vaccines in this category. Most of the listed vaccines are in phase 1 or 2 trial and intended to be used as booster vaccine.

     There are many other potential candidates that I could think of. Each with a slightly different combination and approach. The question that commonly arises is how about the modern technology of DNA vaccines. Of course that also has been tried. Some well known examples include- Ag85-Flt3 DNA; rBCG-Flt3, CFP-10 DNA, HSP65 and IL-12 HVJ-liposome, Six-gene cocktail and IL-12 etc.

     Another vaccine that is gaining popularity as a therapeutic vaccine is Ruti. It consists of detoxified liposomal fragments of Mycobacterium tuberculosis now being developed by the biotech company Archivel Farma. The vaccine induces long-term memory T-cell responses to multiple TB antigens with good tolerance. Currently Phase III is planned.

    So many vaccines in pipeline?? Why haven't we been able to develop a vaccine? The answer is the current vaccine design approach for TB at least, is a trial and error approach. There is virtually no data on the possible correlates of immune protection. That makes the development process still harder. Moreover, the current research is directed towards developing a booster or secondary vaccine which can support BCG, not a replacement. Oh yes, we need to know a lot more of TB biology if we want to start search all over again. So, the story so far is that, new vaccines are on scene, but none has reached the finished line yet...
McShane H, Pathan AA, Sander CR, Keating SM, Gilbert SC, Huygen K, Fletcher HA, & Hill AV (2004). Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nature medicine, 10 (11), 1240-4 PMID: 15502839

Desel C, Dorhoi A, Bandermann S, Grode L, Eisele B, & Kaufmann SH (2011). Recombinant BCG ΔureC hly+ induces superior protection over parental BCG by stimulating a balanced combination of type 1 and type 17 cytokine responses. The Journal of infectious diseases, 204 (10), 1573-84 PMID: 21933877

Hoft DF, Blazevic A, Abate G, Hanekom WA, Kaplan G, Soler JH, Weichold F, Geiter L, Sadoff JC, & Horwitz MA (2008). A new recombinant bacille Calmette-Guérin vaccine safely induces significantly enhanced tuberculosis-specific immunity in human volunteers. The Journal of infectious diseases, 198 (10), 1491-501 PMID: 18808333

Ly, L., & McMurray, D. (2008). Tuberculosis: vaccines in the pipeline Expert Review of Vaccines, 7 (5), 635-650 DOI: 10.1586/14760584.7.5.635

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