Reacting to a Pandemic: Innovations in Vaccine Development

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SARS-CoV-2 vaccine development statistics

Figure 1: SARS-CoV-2 candidate vaccines in the preclinical and clinical evaluation phases

Vaccine research, development, and production are multifaceted endeavors. The industry faces a constant need for new methods to increase speed, yield, and product stability — and to produce new vaccines cost-effectively to ensure a stable supply chain.

Long before the COVID-19 pandemic, other viral infections such as influenza and rabies already challenged the world and caused millions of deaths (1). Since the 18th century, vaccination has proven to be the most (and in many cases, the only) successful route to elimination of such diseases. For years, experts have warned of underlying concern regarding the possible emergence of a truly deadly virus strain on a level with the 1918 “Spanish Flu” influenza outbreak that caused ~50 million deaths around the world. That catastrophic possibility became real in 2020 with the appearance and pandemic spread of the SARS-CoV-2 virus — now responsible for over 66 million cases of COVID-19 worldwide, including over 1.5 million deaths in its first year alone (2).

The estimated value of the global vaccine market (excluding veterinary vaccines) in 2018 was $US26 billion, which is predicted to grow substantially by 2030 (3). In terms of doses, that represents an increase since 2017 of about 20% to 3.5 billion. The increase is attributable to a growing world population, international vaccination programs, and efforts by organizations such as the World Health Organization (WHO). This trend brings new challenges in terms of vaccine manufacturing, transportation, storage, and distribution. Newly developed nucleic-acid–based vaccines — especially those based on messenger RNA (mRNA) — are very temperature unstable. Such products need to be transported and stored at temperatures that can be as low as –80 °C (for RNA-based products).

Innovations in Development
Traditionally, viruses for vaccines (e.g., influenza) have been grown in embryonated hen’s eggs. New challenges introduced by the current pandemic have encouraged and catalyzed innovations in the field of vaccine development. In recent years, the industry has recognized an advantage in mammalian cell-culture systems as a promising alternative to egg-based vaccine production. Cell lines can be cultured to large quantities in stirred-tank bioreactors, allowing for much shorter lead times, a more controlled production process, and a higher grade of reproducibility through standardization, with automation and parallel control of multiple units. Cell-culture–based vaccine development benefits from the flexibility and scalability of a well-established biopharmaceutical bioreactor cell-culture infrastructure, which reduces costs and knowledge transfer. For example, Vero cells can be cultivated successfully in stirred-tank bioreactors (4).

There is no single gold-standard methodology to develop a new vaccine. The right path depends on the level of information that is available when research begins. Has a virus been identified clearly, or only the disease it causes? Are researchers still trying to figure out that cause? On a basic level, if the virus is not known, then research starts with screening infected patients and sequencing the viral genome. If a virus or its components are known already and that information is widely available, then development of a new vaccine can start straight away with identification of a number of product candidates.

The current pandemic sparked a worldwide joint effort to find a vaccine against SARS-CoV-2, with more than 160 projects in the preclinical phase and more than 50 products already in clinical phases in under a year after the new virus first was sequenced (Figure 1). Neither funding availability nor country borders mattered as large companies joined forces with smaller ones to innovate through this development process. The most promising vaccine candidates — some available already at the end of 2020 — have resulted from such collaborations.

Figure 2: Advanced technologies in upstream bioprocessing enhance the efficiency of vaccine development.

Single-Use Flexibility
Single-use bioprocess solutions come in a broad range of options, from small research and development (R&D) sizes to large-scale biomanufacturing systems. These already are well established in the larger biologics industry, as well as in vaccine development and production. This makes cleaning equipment redundant while enabling fast adaption of processes to react quickly to new market demands.

Process Intensification: The vaccine development transition from egg-based processes to cell-culture–based manufacturing takes advantage of the world’s installed bioreactor base and established cell-culture workflows. Intensification of this process is similar to that for monoclonal antibody (MAb) products: Cell lines and media need to be optimized, and the best modes of production need to be established.

With the recent development of nucleic-acid–based vaccines, the role of automation in R&D is increasing further. Screening processes for discovery of new vaccine candidates have enhanced throughput and reproducibility significantly, as have molecular and cell-biological testing with instruments such as automated pipetting devices. Automation not only intensifies existing production workflows, but it also standardizes data management and documentation, which are critical to highly regulated environments such as the pharmaceutical industry.

The decision to automate a process must be considered carefully because not every process is equally suited for automation. Initial capital expenditures in new systems, software, and training of personnel must be evaluated beforehand. Those investments most likely will be compensated for over time, but standardized step-by-step processes are best and should be implemented in established technologies where it makes sense to do so. The molecular steps of vaccine development — from production in stirred-tank bioreactors to testing of final products — are well suited to automation. That is especially true for newly developed nucleic-acid vaccines — and particularly relevant in the trend toward larger-scale processes and market demands.

Ready to Go
Advancing single-use and automation technologies can accelerate vaccine development and production. Stirred-tank bioreactors represent a key technology needed on the journey through developing and producing a new vaccine. These are optimal tools for each step in upstream biology, enabling parallel control of several bioreactors for efficient and reproducible optimization of different process parameters. Vaccine product quality will benefit greatly from process engineers’ ability to program automated responses such as feeding cycles and pH control adjustments. Large systems available on the market already are suitable to operate in current good manufacturing practice (CGMP) environments for vaccine production.

1 Past Pandemics. WHO Regional Office for Europe: Copenhagen, Denmark, December 2020;

2 WHO Coronavirus Disease (COVID-19) Dashboard. World Health Organization: Geneva, Switzerland, December 2020;

3 Global Vaccine Market Report. World Health Organization: Geneva, Switzerland, 2019;

4 Kiesslich S, Kamen AA. Vero Cell Upstream Bioprocess Development for the Production of Viral Vectors and Vaccines. Biotechnol. Adv. 44, 15 November 2020: 107608;

David Solbach is scientific communications manager bioprocess for Eppendorf AG, Bioprocess Center, Rudolf-Schulten-Straße 5, 52428 Jülich, Germany;

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