Algae-based oral recombinant vaccines

Journal Article.pdf

In this journal article, the authors present to us plant-based vaccines as a real solution to impacting worldwide death rate due to infectious diseases. Infectious diseases directly account for 25% of deaths in the world. Traditional vaccines are expensive to administer from all points of view, let it be from availability, infrastructural, development, and medical personal availability. Furthermore, this high associated cost of vaccine delivery hinders the development of new vaccines for diseases that could be prevented.

The added value of plant-based vaccines is that it is orally administered and thus elicits both mucosal and systemic immunity. Additionally, they avoid the associated high costs, the need for trained medical personnel, reduce the risks of infections associated with syringes utilization and improved safety compared to traditional recombinant vaccine since there is no risk of infections by mammalian pathogens. It was estimated that the cost of plant-produced vaccines might be as much as a thousand times less than traditional vaccine production.

However, plant-based vaccines have still not made it through licensing except for one product, a veterinary injectable vaccine against Newcastle disease virus in poultry made from purified antigen expressed in cultured tobacco cells. This is explained by the low yield of the protein, less than 1% total soluble protein (TSP) in lettuce, tomato, potato, and tobacco. Even with the help of improved techniques in recombinant viral vectors or Agrobacterium mediated transformation, the end product has still a low yield and is unstable (uneven expression across the plant).

Plant-based vaccines are still the subjects of many researches as plant cells are attractive for oral vaccines. Their rigid cell walls protect the antigen through the stomach into the intestines so that they can access the gut-associated lymphoid tissue. Unfortunately, the inedible tobacco plants have proven to be the highest-yielding plant in the land species.

Green microalgae has recently attracted the interest of many industries. It has proven to be a very competent protein production platform even when dealing with complex proteins.  It has also showed that it can yield product as high as 10% TSP with a sophisticated cellular folding machinery. It has already been used to produce full-length human antibodies with varying expression rate.

The advantages conferred by those unicellular green algae are many. They have all the qualities of plant systems and numerous unique ones over terrestrial plant as vaccine production manufactory.  Indeed, the utilization of algae allows for rapid biomass accumulation and the entirety of the biomass is utilized for target protein production without having to waste energy on supporting tissue that do not produce the target protein or can’t be harvested. The authors also remind us of the importance of the fact that algae are not restricted by season, soil fertility and cross contamination risks. Furthermore, they can easily be grown in enclosed bioreactor for higher yield production, withstand long storage period at room temperature when dried, and can endure the harsh conditions of the stomach such as low pH with low antigen degradation, making them the perfect host to produce edible vaccines.

Algae have been used as vaccine production host in the past with some success. It was discovered that codon optimization was critical for high yield and for the oral administration to be effective, the antigen had to be fused to a known mucosal adjuvant such as the beta subunit of cholera toxin (CTB). During a pre-clinical trial, mice were fed freeze-dried algae for 5 weeks and 80% of them survived a lethal challenge with Staphylococcus aurea that killed all control mice within 48hrs.

The authors summarize all the algae produced vaccine up to this day and enumerate the progresses that have been done on algae research; however, the predominant problem is still the low yield of target gene. It is important to note that all those experiments were done for the most part on the same alga model organism C. reinhardtii, and that we are still in early research phase of algae produced vaccines (less than 11 years). The authors also remind us that the advances made on this model organism can be readily applied to other organisms more suited for mass vaccine production. Furthermore, algae have proved to be having a complex folding machinery for heavily disulfide-bonded proteins and are reliable—keep in mind there is no glycosylation machinery in algal chloroplasts.

There is no doubt in the authors’ minds that algae are the right hosts to produced complex vaccine antigens, and that this point was proven repeatedly in the past. For the authors, it is a question of fine-tuning the method. Indeed, even though CTB is the favored adjuvant, fusion of the protein with this adjuvant has been suggested to impair CTB’s activity. This led to many other adjuvants being researched for oral administration. The authors suggest that future work should be directed into finding the proper antigen adjuvant fusion combination as well as optimization the expression levels.

For the authors the future of algae produced vaccine is not to be questioned, but defined and refined. Indeed, given the low associated costs and logistical requirements, the authors go as far as stating that plant or algal production may be the only available option for large scale inexpensive and efficient vaccination. The authors call for investors and the pharmaceutical industry as well to seriously consider this avenue and give it the attention it deserves.

What do you think?

Y.S.H.

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