The traditional method of manufacturing vaccines for influenza involves infecting hens’ eggs with the virus, then harvesting and purifying the large amounts of virus that they produce as a result. It’s time-consuming and expensive, requiring large specialized facilities for production. With the advent of genetic engineering and decades of improvement in protein production through cell-line engineering and industrial culture, it was only a matter of time before the vaccine industry saw the real value in modern biomanufacturing instead (1, 2). In addition to cost savings, as Ernst & Young authors wrote in a February 2015 BPI special report, “Genetically engineered vaccines hold the promise of increasing safety, reducing reactogenicity, and improving immunogenicity” (1).
Universal Approach Shows Promise
An international team of scientists have designed a new generation of “universal” influenza vaccines that could help protect against most (88%) known flu strains worldwide (95% of known US strains) with a single dose. UK universities in Lancaster and Aston collaborated with Complutense in Spain to apply ground-breaking computational techniques in design of this vaccine (study reported in the journal Bioinformatics).
Derek Gatherer (Lancaster University) said, “Every year we choose a recent strain of flu as the vaccine, hoping that it will protect against next year’s strains. We know that this method is safe and that it works reasonably well most of the time. However, sometimes it doesn’t work — as in the H3N2 vaccine failure in winter 2014–2015 — and even when it does, it is immensely expensive and labor-intensive. These yearly vaccines give us no protection at all against potential future pandemic flu.”
Previous pandemics in 1918, 1957, and 1968 caused millions of deaths. Even today, WHO reports that annual flu epidemics kill up to half a million people around the world. Gatherer continued, “It doesn’t have to be this way. Based on our knowledge of the flu virus and the human immune system, we can use computers to design the components of a vaccine that gives much broader and longer-lasting protection.”
Pedro Reche (Complutense University of Madrid) explained, “A universal flu vaccine is within reach. The components of this vaccine would be epitopes, short flu-virus fragments already known to be recognized by the immune system. Our collaboration has found a way to select epitopes reaching full population coverage.”
Darren Flower (Aston University) added, “Epitope-based vaccines aren’t new, but most reports have no experimental validation. We have turned the problem on its head and use only previously tested epitopes. This allows us to get the best of both worlds, designing a vaccine with a very high likelihood of success.”
The team is actively seeking partners in the pharmaceutical industry to synthesize their vaccine for a laboratory proof-of-principle test. Based on work described in a 2011 BPI supplement article, perhaps BiondVax Pharmaceuticals in Israel would be interested (3).
Smaller Companies Carving Out Space
The market for seasonal influenza vaccines has been dominated by big pharma; soon it could see smaller companies such as Protein Sciences Corporation and Mitsubishi Tanabe Pharma increase their presence across the competitive landscape. Research and consulting firm GlobalData reported last year that Sanofi, GlaxoSmithKline, MedImmune (AstraZeneca), Novartis, and Seqiris (CSL Limited) have provided most commercially available vaccines over the past decade. Smaller companies such as Mylan have entered the competitive landscape but so far have been unable to acquire a significant market share across the seven major markets (7MM): the United States, France, Germany, Italy, Spain, the United Kingdom, and Japan.
Christopher Pace (GlobalData’s director of infectious diseases) explains: “2015 brought about changes in the influenza vaccines space. Novartis fully retreated from the market by selling its vaccine portfolio to CSL Limited (creating Seqiris), leaving only four established companies to compete for the majority of market share in the 7MM. AstraZeneca has tried to remain competitive by continuing to market FluMist as a premium product, focusing on the benefits of a nasal spray over existing standard intramuscular injectable vaccines. However, a recent decision by the US Centers for Disease Control and Prevention to recommend against its use will significantly alter the pediatric seasonal influenza vaccine market, leaving current or future players to exploit the drug’s potential marginalization.”
With Flucelvax and Fluad, Seqirus (CSL) is the only big-pharma player with a marketed quadrivalent vaccine from cell culture and an adjuvanted seasonal influenza vaccine, both of which are posited as offering superior efficacy over standard vaccines. GSK also has a strong presence in the global market with its flagship product, Fluarix Tetra, which is directly competing with the leading franchise (Sanofi’s Fluzone quadrivalent on the US market and Vaxigrip in Europe).
Pace concludes: “Smaller players such as Protein Sciences Corporation, Mitsubishi Tanabe Pharma, and Novavax will expand the use of cell culture manufacturing methods to increase their presence in the seasonal influenza vaccines market. Quadrivalent cell-culture–based seasonal influenza vaccines are likely to capture at least 25% of the 7MM market share by 2025, although it is unlikely that Sanofi, CSL Limited/Seqirus, and GSK will lose their market leadership.”
Challenges Remain
Protein Sciences’ Flublok product recently faced an obstacle with partners UMN Pharma and Astellas in Japan, however. Japanese regulators turned away their submission for this vaccine from cell culture, causing the collaboration (since 2010) to dissolve. Exclusive licensee of the product for Japan, UMN regrets that the companies cannot work together toward its success there.
After a successful phase 3 trial, Astellas submitted a marketing application to Japanese health authorities in May 2014. When they canceled its review, Astellas withdrew the application. But UMN Pharma believes that the agency “ignored or did not understand” the product’s evidence of “superior safety and efficacy.” That company believes that it is possible to reapply.
UMN’s license from Protein Sciences covers Japan, China, Korea, Hong Kong, Taiwan, and Singapore. And through another joint venture it plans to manufacture the vaccine for the US market. Meanwhile, Protein Sciences remains committed to its technology (4, 5). Along with an increasing number of other industry experts, the company believes that cell culture is the future of vaccine manufacturing (6–11).
References
1 Lagerwij A, et al. The Path to Vaccine Profitability: Robust Supply Chains Could Help Pave the Way. BioProcess Int. 13(2) 2015: I1–I9.
2 Scott C. Vaccine Development and Production: Disease and Pandemic Research, Discovery, and Innovation. BioProcess Int. 13(2) 2015: I10–I15.
3 Ben-Yedidia T, Rudolph W. Development of a Universal Influenza Vaccine. BioProcess Int. 9(8) 2011: S46–S49.
4 Price A. New Technologies to Meet the Challenge of Pandemic Influenza. BioProcess Int. 9(8) 2011: S40–S45.
5 Gottlieb T, Hassin S, Ben-Yedidia T. Preparedness Ahead of Pandemic Outbreaks. BioProcess Int. 11(9) 2013: S20–S25.
6 Angelastro MP, et al. Centers for the Innovation in Advanced Development and Manufacturing. BioProcess Int. 13(11) 2015: 47–48.
7 Madeline B, et al. Culturing a Duck ES-Derived Cell Line in Single-Use Bioreactors: A Rapid, Efficient, and Cost-Effective Vaccine Manufacturing System Based on Suspension Culture. BioProcess Int. 13(3) 2015: S26–S33.
8 Rader RA, Langer ES. Bioprocess Advances Drive Vaccine Manufacturing in Developing Countries. BioProcess Int. 12(2) 2014: 10–15.
9 Moncaubeig F. Simpler and More Efficient Viral Vaccine Manufacturing. BioProcess Int. 11(9) 2013: S1–S3.
10 Gottlieb T, Hassin S, Ben-Yedidia T. Preparedness Ahead of Pandemic Outbreaks. BioProcess Int. 11(9) 2013: S20–S25.
11 Kaisermayer C, Magnusson A-C, Tscho J. Scale-Up of Adherent Vero Cells Grown on Cytodex™ Microcarriers Using WAVE Bioreactor™ Systems. BioProcess Int. 11(7) 2013: 15–17.
Alison Center is editorial assistant, and Cheryl Scott is cofounder and senior technical editor of BioProcess International, PO Box 70, Dexter, OR 97431; 1-646-957-8879; cscott@bioprocessintl.com; www.bioprocessintl.com.