"When we think of the major threats to our national security, the first to come to mind are nuclear proliferation, rogue states and global terrorism. But another kind of threat lurks beyond our shores, one from nature, not humans – an avian flu pandemic." - Barack Obama
The common cold and flu are both caused by viral infection, but by different types of viruses. The common cold is caused by various viruses including the most common rhinoviruses. On the other hand, flu is caused by influenza viruses. In January 2013, the US Centers for Disease Control and Prevention reported that on the first week of January, 7.3% of the US deaths were caused by pneumonia and flu. Influenza viruses can spread so easily by patients’ cough, sneeze, talk, or even touch. Indeed, seasonal influenza causes tens of millions of respiratory illnesses and up to a half a million deaths worldwide each year .
We became more worried after the incidents such as the SARS outbreak and avian influenza, which warned us about the dangers of evolving viruses of animal origin. It is possible that a new evolved influenza virus can result in a pandemic with millions of casualties through human-to-human transmission. The most important way of reducing the risk of flu infection we learned from school is "washing hands well". However, a more effective measure we can take to prevent seasonal flu is getting vaccinated every year. There are two types of vaccines, the flu shot and the nasal spray flu vaccine, the former being more widely used . The latter contains weakened yet live flu viruses, thus being restricted to only young and healthy people. .
Flu shots are inactivated viruses that are injected with a needle. It is produced by approved process that employs fertilized chicken eggs . Flu vaccine production starts with injecting virus inoculum to the fertilized egg, which is then incubated for viruses to multiply. After collecting the fluid, viruses are inactivated by treating with formalin. The fluid containing inactivated viruses then undergoes extensive filtration and concentration steps. At the end, ultrafiltration is performed to obtain the final purified inactivated viruses . Thus, a series of unit operations including filtration, centrifugation, and ultrafiltration are conducted in automated and optimized manner for the large-scale production of inactivated viruses as flu vaccine. This process resembles the petrochemical refinery process, which is an optimized process of many unit operations that allow conversion of crude oil to various useful chemicals and fuels.
For the protection of people, either rich or poor, from flu infection, rapid and efficient production of flu vaccine of high quality at low cost is very important. The current method of using many different chicken eggs, that are not homogenous, does not make much sense to chemical engineers. Chemical engineers who have successfully established petrochemical refinery processes have expanded their expertise to include biochemical engineering. Many processes for the production of recombinant proteins by cultivation of mammalian cells as well as downstream processes for their purification have successfully been developed . Thus, cell culture engineering can be used as a quality controlled large-scale production platform using a well-defined cell line and fully defined standard culture medium. Also, this method does not require extensive time required for egg preparation and can be initiated quickly .
For cell culture, the selection of cell line is important. In the case of flu vaccine production, the MDCK cells from Madin-Darby canine kidney have most widely been employed as they yield large number of influenza viruses . Biochemical engineers have developed efficient methods of cell culture. Many mammalian cells are anchorage dependent; that is, they need a surface to grow on. Engineers were able to adopt techniques used in chemical reaction engineering processes to develop microcarrier culture system, packed-bed bioreactor system, and hollow fiber membrane bioreactor system for the cultivation of such anchorage-dependent cells . For cell culture-based production of flu vaccine, bioreactor is not the only equipment needed. Many other equipments including culture medium tank, sterilization system, and recovery-purification equipments need to be optimally designed and operated along with cell culture bioreactor. Thus, again, the whole process of cell culture-based flu vaccine production relies on chemical engineering process design and operation.
If we think of a bigger picture, what are the things to be considered? First, influenza viruses vary in hundreds of types and they continuously evolve, making it technically impossible to prepare all possible flu vaccines. Second, once infected, there are only a few antiviral drugs such as Tamiflu and Symmetrel for possible cure, but without guarantee due to the emergence of viruses increasingly resistant to these drugs . Are there better ways of identifying the flu viruses earlier on and developing better strategies for rapidly manufacturing vaccines and drugs?
Over the last decade, recombinant antibodies have become blockbuster drugs because of their specific targeting and efficiency when treating diseases. Thus, it is natural to think of the possibility to cure flu with antibodies. Indeed, human monoclonal antibodies against influenza viral surface protein have been discovered, and were found to neutralize the flu viruses by blocking their fusion with the host cell receptors . Large-scale manufacturing of recombinant antibodies is also possible by cell culture engineering. Therefore, engineers' role in designing the process for production and purification of antibodies is becoming increasingly important. Recently, chemical engineers at University of Texas Austin developed an accessible and scalable technology for the high-throughput sequenc¬ing of antibodies from individual human B lymphocytes , which is expected to improve our understanding on the spectrum of antibodies in our body, and consequently develop better therapeutic antibodies against influenza virus in the near future.
In addition to the important roles of engineers in discovering and manufacturing flu vaccines and therapeutics, advances are being made in vaccine delivery as well. No one likes needle injection. Engineers have developed microneedle delivery of vaccines, which is painless, by combining engineering disciplines of modeling and simulation on drug release profiles together with nanotechnology to design and manufacture microneedles . Drugs or vaccines coated on or encapsulated in the microneedles can be delivered into the skin without pain.
Engineers have also contributed to the early detection of influenza. Typically, influenza outbreak is monitored by collecting virologic and clinical data such as influenza-like illness at the clinic. The U.S. Centers for Disease Control and Prevention collects national and regional data through such surveillance systems, which inevitably causes 1-2 week reporting lag. After two weeks, it is usually too late to prevent the wide spread of flu. Engineers developed a very interesting surveillance system based on Google web search. By processing hundreds of billions of individual searches from the Google web search logs , they were able to generate much more rapid and comprehensive models for influenza outbreak. This simple idea came from that people, when they have flu symptoms, tend to search the web for words like "influenza complication", "cold remedy", "general influenza symptoms", "antiviral medication", and "specific influenza symptom". .
In summary, early detection, prevention through vaccination, and efficient therapy upon infection are important to avoid influenza pandemic. Chemical engineers and biochemical engineers have contributed significantly to the rapid large-scale manufacturing of better vaccines and neutralizing antibodies, while computer engineers are utilizing big data to develop a better surveillance system.
What lies in the future? Currently, the global health authorities are predicting what types of influenza virus will prevail each year so that fertilized eggs are prepared for manufacturing the corresponding vaccines. In the future, more rapid and accurate prediction of influenza virus type will be possible thanks to the rapid and inexpensive DNA/RNA sequencing. Based on the accurate identification of virus types, chemical engineers will be able to rapidly manufacture vaccines at large-scale. Also, for those who are already infected, suitable antibodies will be developed and administered to neutralize flu viruses. In the future, flu vaccines might be available in the supermarket in a patch form so that people can buy and put it on their skin for microneedle-based vaccine delivery. In collaboration with medical doctors and biological scientists, engineers will continue to contribute significantly to fight back against evolving influenza viruses.
 Ginsberg, J. et al. "Detecting influenza epidemics using search engine query data", Nature 457: 1012-1014 (2009).
 Matthews, J.T. "Egg-base production of influenza vaccine: 30 years of commercial experience", The Bridge (National Academy of Engineering), 17-24 (Fall 2006).
 Clark, D.S. and Blanch, H.W. "Biochemical Engineering", Marcel Dekker (1997).
 Rappuoli, R. "Cell-culture-based vaccine production: technological options", The Bridge (National Academy of Engineering), 25-30 (Fall 2006).
 Genzel, Y. et al. "MDCK and Vero cells for influenza virus vaccine production: a one-to-one comparison up to lab-scale bioreactor cultivation", Applied Microbiology and Biotechnology 88: 461-475 (2010).
 Sun, B. et al. "Production of influenza H1N1 vaccine from MDCK cells using a novel disposable packed-bed bioreactor", Applied Microbiology and Biotechnology 97: 1063-1070 (2013).
 Heuer A.H. "Engineering and vaccine production for an influenza pandemic", The Bridge (National Academy of Engineering), 3-4 (Fall 2006).
 Friesen, R.H.E. et al. "New class of monoclonal antibodies against severe influenza: prophylactic and therapeutic efficacy in ferrets", Plos One, 5: e9106.
 DeKosky, B.J. et al. "High-throughput sequencing of the paired human immunoglobulin heavy and light chain repertoire", Nature Biotechnology, 31: 166-169(2013).
 Kim, Y.C. et al. "Microneedles for drug and vaccine delivery", Advanced Drug Delivery Reviews, 64: 1547-1568 (2012).