Move toward cell-based manufacturing signals opening in vaccine market

Published: 3-Feb-2017

Global investments and initiatives by governmental and non-governmental organisations are bringing considerable growth to the vaccines and vaccination market

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In 2016, revenue within the industry hit an all-time high of more than $467 million and is projected to reach up to $769.4 million by 2022, at a compound annual growth rate of 10.5%.1 Across the seven major markets (7MM) of the US, France, Germany, Italy, Spain, the UK and Japan, the vaccine market has been predicted to increase from $3.1 billion last year to $4.3 billion in 2025.2

Global vaccine manufacturing is even brighter. A $6 billion market in 2000 has skyrocketed to $33 billion in 2014 … with no signs of slowing.3

Consistent growth, attributed to both the seasonality of vaccines and the need created by an unpredictable epidemic, has created a highly competitive market wherein 80% of global vaccine sales stem from five companies. This is compounded by the fact that a limited number of companies enter the market because of the strict international standards of quality control established by the World Health Organization (WHO), in which a lack of competition creates a pendulum swinging between supply and demand.4

This is especially true in the global influenza vaccine market, in which the scalability to reach pandemic levels of infection prevention remains questionable, as seen with H1N1 for influenza in 2009.

New technologies and advances in research are causing a diversification between vaccine manufacturing methods, creating new opportunities for pharmaceuticals and bioprocessing firms to enter the market. For the last 70 years, the virus load necessary for the production of vaccines was amassed using hen eggs; that is, the virus is replicated in several eggs and then transferred to many more eggs for further replication. But this technique is falling out of fashion as cell-based methods of replication (after growing the virus in a hen egg, the virus is transferred to cell lines) have shown many benefits compared with egg-based methods.

However, as “vaccine production is one of the most heavily regulated industries in the pharmaceutical sector, with tough margins to meet,” these benefits have not necessarily outweighed the building costs and validation necessary to retrofit a facility for cell-based manufacturing.5 However, with new research into cell-based production, there may be a changing of the tide.


The influenza virus is one of the most important human pathogens. Annually, the virus infects 3–5 million people, with deaths from infection falling somewhere between 250,000 and 500,000. Influenza is also a major cause of acute respiratory infection.6 A global increase in preventable healthcare, as well as the “introduction of new vaccines, entry of new players, rising R&D investments, evolving government policies and infrastructure projects are set to further boost the market’s growth.”7

The transition to the cell-based production of influenza vaccines, owing to its ubiquity and greater regulatory scrutiny, could be the tipping point between old and new. The proven efficacy and safety of egg-based methods makes it a tougher pill to swallow for well-established pharmaceutical and manufacturing firms. Why face new regulatory hurdles and the cost of retrofitting or building a new facility that is capable of cell culture work?

This line of thinking is perhaps why only one cell-based vaccine for influenza has been approved for human use by FDA.8 Even though research shows numerous benefits to cell-based vaccines, as of November 2016, more than 90% of all vaccines currently in trial are manufactured using egg-based methods.9

Cell-based vaccines

Egg-based methods to produce vaccines face several limitations. The ability to secure enough vaccine-quality eggs to manufacture the influenza vaccine for the world’s population “is a daunting, probably impossible task. An influenza outbreak among poultry is a serious possibility that would decrease the availability of vaccine-quality eggs.”8

Furthermore, although lab-based strains tend to grow very well inside eggs, wild-type influenza strains still need to be optimised to grow properly in eggs. The 2012–2013 flu season saw a wild-type strain mutate in egg-based models, causing the influenza vaccine produced to not match the predominant strain — something that could have been prevented in cell-based methods.8

According to WHO, the benefits of cell-culture-derived vaccines are numerous. Most importantly, cell-based methods:

  • protect against avian flu outbreak that could decimate the availability of vaccine-worthy eggs
  • permit the growth of all influenza viruses (even wild-type strains)
  • reduce vaccine production time
  • make animal-component-free production feasible.10

Despite the countless benefits, cell-based vaccines still face many obstacles in terms of production optimisation. For example, even though cell-based production shows greater homology after amplification, wild-type influenza strains still need to be adapted to grow in cells. In general, the growth of different virus strains is dependent on the cell line, and the optimal cell line for growth of the influenza virus may be different from the cell lines currently used.11 Lastly, as viruses hijack the host cell and demand nutritional changes, finding a medium that provides sufficient nutrients for the cells remains a constant hurdle to production, and may require novel methods to overcome.10

Process intensification

Process intensification for vaccine production is of great value to the industry at large. At the moment, there is extensive research, both in industry and academia, into the proper cell line to fit the right bioprocessing technique. Current research has led WHO to recommend the use of suspension cells over adherent cell-based culture, because suspension cells deliver a higher yield and purity at a lower cost.10 Bioreactors, either stainless steel or single-use, show many benefits when compared with static cultures or roller bottle technology. Of the two, single-use systems require less turnaround between batches because of the cleaning and the validation of stainless steel bioreactors, which can be costly, time consuming and delay manufacturing runs.5 Despite this, and the fact that stainless steel bioreactors have more upfront costs, they are capable of producing, much higher yields.10

To meet the rising demand in the influenza vaccine market, which works on much shorter timescales than other vaccine sectors, moving away from conventional batch cultivation and toward a fed-batch, perfusion or continuous batch cultivation system may be necessary. Research shows that fed-batch and perfusion techniques could deliver 10–100 fold increases in production. But these processes are also rife with both defective interfering particles (DIPs), which can greatly reduce virus titres, and antigenic shifts in the virus population, which are inherent mutations in the protein structures of the virus to evade the host’s immune response. For these reasons, vaccine production to date has lagged behind the high cell density production of other products that meet FDA’s good manufacturing practice (cGMP) requirements, such as protein produced with CHO cells. Regardless of these setbacks, the move toward high cell density is probable, and both fed-batch and perfusion methods should likely be used to meet this goal.

Lastly, to aid in process intensification, new experimental results show that a time-dose infusion of insulin before cell infection by the influenza virus increases cell density by accelerating cell reproduction; infusion of insulin after infection can improve overall virus yields. Preliminary experimental results indicate that this process shows scalability.12


Because of strict regulation, the seasonality of influenza and the unpredictability of epidemics, vaccine manufacturing has been controlled by a select few, but this is beginning to change. The gradual move away from egg-based vaccine production is creating new opportunities for entry into the global vaccine market. New research in process intensification of these cell-based methods using fed-batch and perfusion single-use or steel bioreactors has shown promise, but there are several hurdles to overcome. Furthermore, a time-dose infusion of insulin before and after infection has been shown to increase cell density and virus yields.


  1. Occams Business Research and Consulting, Global Vaccines and Vaccination Market Insights, Opportunity, Analysis, Market Shares and Forecast 2016–2022: (2016).
  2. GlobalData Healthcare, PharmaPoint: Seasonal Influenza Vaccines – Global Drug Forecast and Market Analysis to 2025: (2016).
  5. F. Tapia, et al., “Bioreactors for High Cell Density and Continuous Multistage Cultivations: Options for Process Intensification in Cell Culture-Based Viral Vaccine Production,” Appl Microbiol. Biotechnol. 100(5), 2121–2132 (2016).
  6. D. Shin, et al., “Comparison of Immunogenicity of Cell- and Egg-Passaged Viruses for Manufacturing MDCK Cell Culture-Based Influenza Vaccines,” Virus Research 204, 40–46 (2015).
  7. RNCOS E-Services Private Limited, Global Influenza Vaccine Market Outlook 2022: (2016).
  8. P.C. Soema, et al., “Current and Next Generation Influenza Vaccines: Formulation and Production Strategies,” European Journal of Pharmaceutics and Biopharmaceutics 94, 251–263 (2015).

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