Month: April 2014

Recombinant BCG: tuberculosis vaccine Patented in accordance with 35 USCS § 101

 

The Bacille Calmette-Guerin (BCG) vaccine is a great example of an entity derived from nature being used in a new and resourceful way. I have written a  research paper on TB and after re-reading it, I realized how much the recombination of M. bovis relates to the 35 USCS § 101, especially because it was successfully patented. (http://www.google.com/patents/US8361482) The information below is from the United States Code of Service and my research paper respectively.

The Law:

“Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title [35 USCS §§ 1 et seq.].”

Background on Mycobacterium tuberculosis:

Mycobaceterium tuberculosis (MTB) is a species that belongs to the family Mycobacteriaceae, and the  genus Mycobacterium, which is actually the only genus in the Mycobacteriaceae family. There are about 71 known species of Mycobacterium and they are divided into categories based on their colony morphology, biochemical properties, and growth rate. Growth rate is the property used to divide these species into two populations: slow and rapid growers. Rapid growth is defined as colony presentation within 7 days. Interestingly, slow growers tend to be more pathogenic for humans than the rapid growers are. Some of the species that are categorized as slow growers are: M.leprae, M. ulcerans, M. avium and M. tuberculosis. Although these species differ in many ways, all members of the Mycobacterium genus are gram positive, rod-shaped and non-motile.

Antibiotic Resistance:

Mycobacteria are particularly resistant to beta-lactam antibiotics such as penicillin and ampicillin, which target peptidoglycan cell wall synthesis. This resistance is not only attributed to the impermeability of the mycobacteria cell membrane but also to beta-lactamases that are intrinsically encoded for in the bacterial chromosome. However, drugs such as streptomycin, isoniazid, and rifampin have been shown to be quite effective against this microbe. Streptomycin is an antibiotic that inhibits protein synthesis. Rifampin inhibits nucleic acid synthesis and isoniazid, which is also known as isonicotinylhydrazine (INH) is an organic molecule that is activated by the microbe and inhibits the production of mycolic acid, an essential component of its bacterial cell wall.Although this has led to advancements in TB treatment, widespread use of these antibiotics has worsened antibiotic resistance. However, MTB drug resistance is not a new occurrence. On the contrary, it has been an issue for almost seventy years.

History of Resistance:

In the 1940s it was found that after just a few months of streptomycin treatment four-fifths of the patients were experiencing antibiotic resistance. A decade later, “combination therapy” was the new method of treatment. This therapy entailed the use of three drugs. This three-drug regimen was quite pragmatic. Theoretically, the probability of the bacterium developing resistance against all three different antibiotics is much lower than the probability that the bacterium will develop resistance against just one antibiotic. A nine-month combinatorial treatment of rifampin, streptomycin and isoniazid was shown to cure nearly all the patients treated.These results demonstrate the effectiveness of combination therapy. However, drug therapy can be just as quickly rendered ineffective, at it can effective. Unfortunately, multidrug-resistant MTB (Mdr) has already arisen, particularly against rifampin and isoniazid. Yet, there is a silver lining; the rediscovery of a drug called Pyrazinamide (PZA) in the 1980s reduced the period of treatment time for TB from nine-months, to six-months making patient compliance a bit easier. PZA may also help combat moderately dormant forms of TB by acting as an artificial analog to a compound known as nicotinamide. Nicotinamide is a vitamin that is needed for many important biological processes, particularly NAD synthesis. Exactly how PZA inhibits bacterial growth is poorly understood.

Treatment Today (BCG):

Unfortunately, due to the risk of resistance with antibiotic treatment, other means of treatment must coincide with antibiotic use. Scientists have developed an attenuated vaccine in order to treat/prevent PTB.  When creating an attenuated vaccine one takes a pathogen and infects a different host with it until the fitness of the pathogen is no longer optimal in the vaccinated host. Once this occurs, the virus can no longer cause disease. In this case M.bovis, a bacterium that causes bovine TB and can also cause disease in humans, is the attenuated strain used to prevent TB infection. The vaccine used for TB treatment is known as BCG, which stands for Bacille Calmette-Guerin after the two scientists who created it in 1921. An M. bovis isolate was taken from a cow suffering from mastitis, which is inflammation of breast tissue, and then the isolate was attenuated for about 13 years, ensuring that the strain was no longer virulent in the host.This vaccine has been shown to be clinically effective against the primary progression of  PTB.

The Vaccine’s Drawbacks:

However, there are some drawbacks associated with use of this vaccine. The polymorphism involved in M. bovis gene expression may result in varying degrees of efficacy against TB. For example, during a study done by the World Health Organization (WHO) in 1993 (out of 129 cases)  infants were vaccinated with either the “Paris-type” vaccine or the “Glaxo” vaccine. Those that received the Paris-type vaccine were 40% less likely to contract TB. Both vaccines contained M.bovis but because of the slight differences in gene expression one was less effective than the other. This can be problematic when trying to consistently treat TB worldwide. Another caveat is exposure to environmental mycobacteria or UV light can render the BCG vaccine ineffective. Currently, steps are being made to develop a new TB vaccine that will be more consistent and effective.

References:

  •  Brogden, Kim A., Minion, F.C., et al.(2007). Virulence Mechanisms of Bacterial Pathogens. Washington, DC: ASM Press
  • Koneman, E., Procop G. et al (2006). Koneman’s Color Atlas and Textbook of  Diagnostic Microbiology (6th e.d.). Philadelphia: Lipincott Williams & Wilkins. 4. Novartis Foundation.(1998). Genetics and Tuberculosis. Chichester, England: John Wiley & Sons.
  • Ratledge, Colin., Dale, Jeremy.(1999). Mycobacteria: Molecular Biology and Virulence. Malen, MA: Blackwell Science.
  • Tibayrenc, Michel.(2007). Encyclopedia of Infectious Diseases. Hoboken, New Jersey: John Wiley & Sons.
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