Nature Biotechnology | Trade Secrets

Synthetic Vaccines

Traditional and novel forms of vaccines.

Traditional and novel forms of vaccines.

Birgit Schmidt

In 2010 scientists from the JCVI announced the creation of the first bacterial cell controlled by a chemically synthesized genome1. The ‘synthetic’ cell was mycoplasma, a bacterium with an exceptionally small genome of less than 1 million base pairs and without a cell wall. Carole Lartigue, one of the co-authors of that landmark paper, later returned to the National Research Institute for Agriculture (INRA) in Bordeaux, France, to continue working on Mycoplasma. In fact Mycoplasma is not just a beautiful model organism for synthetic genomics. Their small genomes make them also a great model for systems biology, a work that was spearheaded by Luis Serrano at CRG in Barcelona2, 3, 4, who characterized Mycoplasma in a quantitative manner to apply this knowledge to do a rational engineering for novel applications. Some mycoplasma, however, are pathogens affecting both human and farm animals (Table 1). The mycoplasma infections not only cause animal suffering and death, but also lead to epidemics, resulting in production delays, lower food-conversion rates and an overall decreasing efficiency and profit for farmers.

Table 1: Main mycoplasma infections of farm animals

Animal Mycoplasma species Disease Existing vaccines
Cattle   M. bovis Mastitis, Pneumonia, Arthritis Inactivated (not effective)
M. mycoides subsp mycoides Contagious bovine pleuropneumonia (CBPP) attenuated
Pig M. hyopneumoniae Respiratory disease Inactivated
Poultry   M. gallisepticum Chronic respiratory disease (CRD), sinusitis Inactivated
M. synoviae Arthritis, respiratory disease Inactivated
Sheep/goat M. agalactiae Contagious agalactiae, mastitis, pneumonia, arthritis none
M. ovipneumoniae Atypical pneumonia none
M. capricolum (subsp. capripneumoniae) Contagious caprine pleuropneumonia (CCPP) none

 

In the European H2020 funded project MycoSynVac (2015-2020), CRG together with INRA, the global healthcare leader MSD Animal Health, and other partners across Europe, are now working on the first synthetic biology-derived animal vaccine. Traditionally, bacterial vaccines are made from simply inactivated or attenuated pathogens, which are deployed to ‘train’ the immune system of the host. In many Mycoplasma species, however, these vaccines don’t work really well, because the inactivated pathogens don’t attach, for example, to the host epithelial cells, thus failing to trigger an appropriate immune reaction.

The goal of MycoSynVac is not just a mere attenuated pathogen, but a reprogrammed organism that has to be, so to say, ‘semi-infectious.’ In other words, the reprogrammed microbe should be able to ‘inhabit’ the host, to attach to host epithelial cells in the respiratory tract, but then refrain from causing cell damage and inflammatory response because the virulence factors had been removed5.

Re-programming this behaviour requires not only a deep understanding of the pathogenic life cycle and its cause on a genetic level6, but also reliable bioinformatics models7 and precise gene editing tools for Mycoplasma8,9.

Mycosynvac is also developing extra layers of safety with newly developed biosafety control circuits built into the vaccine. These and other challenges don’t exactly make this vaccine a low-hanging fruit, but when considering the impact and scope of a successful product, it immediately seems worthwhile. The reasons are manifold:

(A) The market for animal products and animal vaccines is huge, with M. hyopneumoniae vaccines alone currently topping $150 million annually.

(B) For many pathogens there is either no vaccine available or they don’t work very well, so new applications are in high demand.

(C) The designed vaccines will be based on a standardized ‘chassis’ that can hold several different types of pathogenic epitopes (the surface molecules necessary for the protective immune responses), so development of the next vaccine(s) will be much easier and faster.

(D) Making it easier to engineer novel vaccines will also allow for a systematic replacement of antibiotics in agriculture. Antibiotics in farming industry is already a serious concern in the surge of antimicrobial resistance (AMR) and so-called ‘superbugs’ (multi-resistant pathogens) affecting animals and humans alike. Vaccines as tools to reduce AMR have historically been under-recognized in these discussions, even though their effectiveness in reducing disease and AMR is well documented10.

(E) Last but not least, once approved for farm animals, the next goal will be synthetic biology vaccines for human infections with an even bigger market and impact.

Markus Schmidt

References:

  1. http://science.sciencemag.org/content/329/5987/52
  2. http://science.sciencemag.org/content/326/5957/1268
  3. http://science.sciencemag.org/content/326/5957/1235
  4. http://science.sciencemag.org/content/326/5957/1263
  5. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137354
  6. http://genomea.asm.org/content/4/2/e00263-16.long
  7. https://www.frontiersin.org/articles/10.3389/fcimb.2017.00031/full
  8. http://pubs.acs.org/doi/pdf/10.1021/acssynbio.5b00196?src=recsys
  9. http://pubs.acs.org/doi/abs/10.1021/acssynbio.6b00379
  10. https://www.nature.com/articles/nm.4465

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