Application of bioreactor technology for cell culture-based viral vaccine production: Present status and future prospects

Abstract

Bioreactors are widely used in cell culture-based viral vaccine production, especially during the coronavirus disease 2019 (COVID-19) pandemic. In this context, the development and application of bioreactors can provide more efficient and cost-effective vaccine production to meet the global vaccine demand. The production of viral vaccines is inseparable from the development of upstream biological processes. In particular, exploration at the laboratory-scale is urgently required for further development. Therefore, it is necessary to evaluate the existing upstream biological processes, to enable the selection of pilot-scale conditions for academic and industrial scientists to maximize the yield and quality of vaccine development and production. Reviewing methods for optimizing the upstream process of virus vaccine production, this review discusses the bioreactor concepts, significant parameters and operational strategies related to large-scale amplification of virus. On this basis, a comprehensive analysis and evaluation of the various process optimization methods for the production of various viruses (SARS-CoV-2, Influenza virus, Tropical virus, Enterovirus, Rabies virus) in bioreactors is presented. Meanwhile, the types of viral vaccines are briefly introduced, and the established animal cell lines for vaccine production are described. In addition, it is emphasized that the co-development of bioreactor and computational biology is urgently needed to meet the challenges posed by the differences in upstream production scales between the laboratory and industry.

Keywords: COVID-19; bioreactor; cell culture; computational biology; process optimization; viral vaccine production.

FIGURE 1

Overview the upstream culture process of viral vaccines. (A) Development and scale-up of a cell culture bioreactor. The left plot shows a small-scale bioreactor, which can contain cell lines, microcarriers, virus vectors, and viruses. The right plot shows an engineering grade bioreactor that can be produced on a large scale at one time. (B) Virus produced by cell lines in a bioreactor. The types of viruses produced by cell culture in a bioreactor mentioned in this review, including SARS-CoV-2, Influenza Virus, Tropical Virus, Enterovirus, and Rabies Virus. (C) Vaccine production based on large-scale virus culture. Bioreactors are mainly used to produce inactivated vaccines, live attenuated vaccines, and several subtypes of vaccines (including protein subunit vaccines, virus-like particles vaccines, and replicating viral vector vaccines).

FIGURE 2

Process definition in bioreactor and its result influence in celluar environment. (A) Bioreactors can preset important parameter values through four strategies (pH Control Srategy, dO2 Control Strategy, Temperature Control strategy, pressure control strategy). The output of the process includes physical and chemical parameters such as pH, solubility of different gases, temperature, osmotic pressure, shear force and so on. Different process definitions have a great influence on the cellular environment. (B) Different celluar environment will lead to different growth states of cells. Good cell state and higher cell concentration can produce more virus titers. But the replication and release of the virus can also lead to cell death. Meanwhile, the accumulation of waste from cell metabolism will affect the celluar environment. The state of the cellular environment ultimately determines the formation and quality of the product.