Plant-Based Vaccine Manufacturing

Nicotiana. Source openi.nlm.nih.govAs visitors to this site know, the development of new methods to cultivate viruses for vaccine use has been an important part of the history of vaccines. From living, complex organisms such as humans and cows, to chicken eggs, to tissue explants, to mammalian cells in culture, various hosts have been used at different stages of technological development to produce vaccine material. Now, recombinant technology, like cell culture technology before it, is changing the way vaccines are made as plants are being programmed to produce antigens for vaccines.

Last week, College of Physicians Director and CEO George M. Wohlreich, MD, and I made a visit to a unique research facility in Newark, Delaware, last week to see first-hand the future of vaccines. Fraunhofer USA’s Center for Molecular Biotechnology built this 14,000 square foot plant-based vaccine research and manufacturing facility, funded partly by grants from the Defense Advanced Research Projects Agency (DARPA). DARPA has an interest in accelerating vaccine development and manufacture for infectious agents that threaten national security. A plant-based platform has the potential to produce vaccine faster than conventional methods.

After a meeting with CMB’s executive director Vidadi Yusibov, PhD, we toured a very clean, artificially lit “greenhouse” where we saw cultivation of Nicotiana benthamiana, a small herbaceous plant native to Australia. Hundreds of plants were in different stages of growth, from just germinated seeds to mature plants ready to be moved on to the next stage of production. The plants are not grown in soil, which might introduce pathogens, but in an alternative growth medium that provides a relatively pathogen-free, matted, adherent substrate (important for the next step).

In the next room the gene for the target antigen is introduced into the plant via a common soil bacterium. CMP uses Agrobacterium, into which a gene for the target antigen (for example, an influenza protein) is inserted. The Agrobacteria proliferate in culture and are then suspended in solution. The Nicotiana are placed into a tabletop machine that looks something like a small oven: the stems and leaves of the plants are immersed upside down in the Agro-containing solution (a reason why a relatively matted growth medium is preferred: it won’t disintegrate or fall into the water). The machine creates a vacuum, forcing gases out of the plants (visible as bubbles escape). When the vacuum is broken, the Nicotiana take in the Agro solution. The plants are turned right side up and moved to another growth room to recover. Over the next several days, Agro infects the plants, and the plant cells consequently churn out the influenza protein as directed by the gene carried by Agro.

Harvest comes next: we saw a room with equipment adapted from the food-processing industry where the plant matter is processed and the antigen extracted. Further purification and treatment follow, and the target antigen is included in a vaccine candidate. ClinicalTrials.gov lists two CMB trials, both for influenza vaccines, though CMB has other vaccines (among them, malaria and anthrax) in earlier phases of research.

To have practical implications, any small-scale vaccine production system needs to be able to be used on a national or global scale. Another part of the complex houses a larger, automated growing facility that demonstrates the potential of scale up of this platform to commercial production.

For more reading on plant-based vaccine manufacturing, see this Wired.com article on the topic as well as this article from Plant Cell Reports (2011).

Many thanks to Fraunhofer USA’s Center for Molecular Biotechnology for hosting us at their facility.