Vaccine Manufacturing Process – an overview
Vaccine manufacturing comprises several stages (1). In the first step, the antigen inducing the immune response is produced. Since viral antigens are normally presented by the native virus, vaccine manufacturing has historically depended on virus growth in cultured primary cells, continuous cell lines or chicken eggs (depending on the tropism) for the production of whole viral particles. Moreover, the growth of bacteria-specific viruses in bacteria grown in bioreactors can be employed for the manufacturing of bacteriophages for Phage-Display (6) and more recently for the development of bacterial vaccines (7).
Nowadays further development of recombinant protein production technology allows expression of the isolated antigenic peptide in organisms such as bacteria, yeasts and mammalian cell lines, increasing consistency of upstream and downstream processes.
In a second step, the viral particles are collected and further processed. Non-attenuated viruses may need to be inactivated through chemical or physical methods, but generally no further purification is required. Recombinant proteins on the other hand require further purification steps (downstream) including ultrafiltration and column chromatography.
In its final step, the vaccine is formulated by adding adjuvant, stabilizers, and preservatives as needed. The adjuvant enhances the immune response against the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials.
Vaccine manufacturing is evolving. Cultured mammalian cells are expected to become increasingly important over conventional options that use chicken eggs (5). Vaccine manufacturing is relying on mammalian cells due to greater productivity and low incidence of problems with contamination versus vaccine manufacturing using eggs (1). Recombinant technology that produces genetically detoxified vaccine is expected to grow in popularity for the production of bacterial vaccines that use toxoids (1). Combination vaccines are expected to reduce the quantities of antigens they contain, and thereby decrease undesirable interactions, by using pathogen-associated molecular patterns.
There are many cost pressures when manufacturing vaccines. Producing a vaccine in eggs has been the historical practice with vaccine manufacturing using cell lines being a more recent endeavor. Having a critical cell number, producing the most vaccine possible, and reducing variables or tedious downstream activities is a must for vaccine manufacturing.
While some manufacturers have successfully produced vaccines for decades, others have faltered or failed, and relatively little information is available in the literature on the challenges, complexity and cost of vaccine manufacturing (1).
Outcomes can vary widely due to the nearly infinite combinations of biological variability in basic starting materials, the microorganism itself, the environmental condition of the microbial culture, the knowledge and experience of the manufacturing technician, and the steps involved in the purification processes (1).
Regulatory authorities license not only a specific biological entity, but also the processes by which that entity is produced, tested, and released for use. Subtle changes in the production process may alter the final product and change its purity, safety, or efficacy.
Many vaccine patents protect the manufacturing process rather than the antigen that is produced by the process. Emphasis on process development is a major success factor in being first to market with new biopharmaceuticals and inadequate process development is often implicated in late stage product development failures. Anyone looking to develop a new vaccine must keep commercial production in mind to help stop late stage product development failures. An emphasis on process development is a major factor to accelerate time to market. Serum free media helps to reduce variables and provide a consistent performing product for vaccine manufacturing. Moving away from serum use increases reproducibility and viral titers. Using a serum free medium that is also protein free faciliites easier downstream processing which reduces workload and costs which are increasing concerns in vaccine manufacturing. Getting rid of the high cost of serum, large processing time for egg based cultures, and providing a regulatory friendly product for easy insertion into any vaccine manufacturing workflow are all benefits of using serum free media for vaccine production.
Lonza has developed a variety of media that can be used for vaccine manufacturing. Whether using insect cells, MDCK cells or Vero cells Lonza has many serum free media options that will enable successful vaccine manufacturing that aid in reducing costs, reducing variables, and providing a regulatory friendly product for many vaccine manufacturing processes. If serum remains a vital part of your vaccine manufacturing workflow, Lonza’s portfolio of classical media has been widely used in a variety of applications. If recombinant viral proteins are the desired product for your vaccine manufacturing workflow, Lonza employs a variety of products for protein production.
References:
- Plotkin, S. Robinson, J. Cunningham, G. et al. The complexity and cost of vaccine manufacturing – An overview. Vaccine, Volume 35, Issue 33, 24 July 2017. Pg 4064-4071
- https://www.vaccines.gov
- https://www.who.int/topics/vaccines/en/
- https://www.news-medical.net/health/What-are-Vaccines.aspx
- Simmons NL: Cultured monolayers of MDCK cells: a novel model system for the study of epithelial development and function. Gen Pharmacol 1982, 13(4):287-291
- Frenzel A, Schirrmann T, Hust M. Phage display-derived human antibodies in clinical development and therapy. MAbs. 2016 Oct;8(7):1177-1194.
- Domingo-Calap P, Georgel P, Bahram S. Back to the future: bacteriophages as promising therapeutic tools. HLA. 2016 Mar;87(3):133-40.