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Volume 2009 Supplement, Issue 6
The industry and government must collaborate to develop robust technologies and quicker, more flexible manufacturing approaches for vaccine development.
Although the worldwide response to the swine flu outbreak of early 2009 has shown that we have come closer to being prepared for future flu pandemics, emerging diseases and new influenza strains still present a tremendous threat, with the potential for disastrous effects to global health and both local and global economies. A major limiting factor in preparedness is still the ability to manufacture an adequate number of vaccine doses, in a short period of time and in the right location, when an outbreak occurs. The following article discusses current developments and what could be done in the future from a technology and policy perspective to improve our capability to cope with pandemics.
Each year, approximately 15 million deaths are directly caused by infectious diseases. The secondary effects of infections cause millions more. Two of the major killers are malaria and HIV, but influenza also represents a significant risk. In September 2008, the World Bank issued a report estimating that a flu pandemic of similar scope to that seen in 1918 could kill 71 million people worldwide and cost the global economy more than $3 trillion.1 Although this is a worst-case scenario based on past experiences, the differences in transmission and severity shown by the outbreaks of avian flu in South-East Asia in 2003 and this year's swine flu have highlighted how unpredictable such a virus can be.
Although the effects of each pandemic will vary greatly, depending on the nature and severity of the disease, the threat applies to all corners of the globe, from major capital cities to rural areas of developing countries. In addition, pathogenic viruses such as HIV and influenza mutate rapidly, which is why the HIV virus we encounter today is very different from the strain that first emerged in the 1980s. Consequently, resistance to the antiviral drugs in circulation develops very quickly and as the speed of development of new treatments lags behind, we are left increasingly exposed to the effects of infection. If we also take into account the fact that infectious diseases are the second leading cause of death globally, then it is clear that we must have a robust strategy in place to address the threat of a pandemic.
One of the best ways to combat the spread of infectious disease is through the implementation of an immunization program. Immunization has eradicated smallpox, reduced the global incidence of polio by 99%, and dramatically decreased many other causes of illness and death.2 Countries around the world are now looking to vaccines and immunization as the way forward, and the World Health Organization (WHO) Department of Immunization, Vaccines and Biologicals has set for itself the goal of attaining "a world in which all people at risk are protected against vaccine-preventable diseases."3
Over the past eight to nine years, and especially since the SARS and avian flu outbreaks, many governments have concentrated their efforts on developing preparedness plans. Increased stockpiles of vaccines and antiviral drugs, finance set aside for vaccine development and research, and a focus on education of the public—all played their part in ensuring that when swine flu emerged earlier this year, we were more prepared. There is still a huge gap, however, between the level of vaccine availability and demand, and we still have a long way to go before we have the technology, manufacturing capacity, and responsiveness required to combat a pandemic on a scale based on the 1918 incident. Because vaccination is a key element in pandemic preparedness, what more could we do to ensure that the next global pandemic has as little impact as possible, both socially and economically?
Although we are prepared for the next flu pandemic with stockpiles of antivirals and vaccines, these projects tend to be localized, with some countries holding enough to cover their own population and others falling well short. However, even those countries with large, carefully stored reserves of antivirals may not be protected in the event of an outbreak because of increasing viral resistance to currently available medicines.
In addition, stockpiling of vaccines relies on being able to predict which virus, and which particular strain of that virus and with which traits, will strike next. Therefore, our biggest future pandemic threat comes from new emerging diseases and virus strains, which we know nothing about. In the case of the 2009 swine flu pandemic, many doses of vaccines were rendered useless because they were targeted at the avian flu strain H5N1, demonstrating that even here we need to adapt our approach. Also, vaccines are often relatively unstable because of their complexity, more so than any other class of biopharmaceuticals, and therefore, are difficult to transport and store becasuse they require controlled temperature conditions.
Developing a rapid response capability is one way, and some argue the best way, to overcome the problems associated with stockpiling and being unable to predict what will cause the next pandemic. A rapid response would enable the production of a suitable, effective, and safe vaccine as close to the outbreak as possible, both in terms of time and geography.
Currently, the investment required for a dedicated flu vaccine factory—from commissioning to validation—could run as high as $600 million for 50 million doses, depending on the vaccine technology used, and the time taken to build and start production could be as long as six years.4 In addition, although our existing vaccine manufacturing capacity is greater than it was a few years ago, we are still far from being able to produce sufficient vaccines to supply the whole world. We may be able to ramp up production to meet demand if given time, but in reality, in the event of a serious pandemic we would have neither the time nor capacity to cover even a small percentage of the world.
To address this problem, suppliers have been working hard to develop platform and manufacturing process tools that could support novel ways of vaccine production, which would enable facilities to be rapidly deployed and set up as and where needed. A flexible platform process is currently under development on which any vaccine could theoretically be produced rapidly and in any given location.
Another option is a mobile manufacturing facility, which involves the use of small-scale, modular manufacturing units that are able to work according to cGMP standards. Each unit could contain a flexible manufacturing structure, which is sufficiently adaptable to produce the particular vaccine required. Although such modular units are still in development, much of the technology contained in them is already established and widely used in the industry. Ready-to-use product platforms are ideally suited for these mobile units because they cut time spent on cleaning between runs and are prevalidated, radically shortening the manufacturing time.
Borders are often closed in a pandemic, which would mean that a community could not rely on cross-border provisions and must have independent vaccine supplies. Also, large countries such as India, China, and the US have widely dispersed populations, often with very remote locations, and therefore would suffer greatly from the problems associated with transportation and storage of vaccines. Mobile manufacturing units would overcome these problems by allowing localized production to tackle an outbreak of disease in an affected country or region. The local manufacturing approach also contributes to long-term investment, creating local capacity, and helping to develop local skills and education, offering poorer countries the facility to manufacture their own vaccine rather than buying in from an outside supplier. However, vaccine-manufacturing solutions must also meet the specific local needs and consider restraints typical in a certain region, i.e., the availability of services such as water, which is vital in vaccine manufacture.
With all of these solutions, it is essential to have a standardized approach and develop solutions that are validated and comply with all safety requirements. To achieve this, countries could benefit from working with a global company that also has the experience and infrastructure to work with partners locally.
Although vaccine production methods are constantly improving, there are still many hurdles to overcome. The biggest limiting factor we currently face is the lack of sophisticated technology for rapid vaccine manufacture. One good example is the production method of influenza vaccines that still uses chicken eggs. This is widely considered to be an archaic system with a range of drawbacks including the logistics of egg procurement and a slow production process. As a result, production is shifting toward mammalian cell-based production and new technologies such as virus-like particles. Suppliers are working hard to develop new tools that will not only support existing production methods, but also push them forward to ensure that manufacturing capability is available when the methods are ready.
In addition to significant levels of investment in vaccine-production processes, another area of focus for improving future ability to survive pandemic threats and mutating pathogens is in the research and development of universal vaccines. The universal vaccine approach may improve the chances of marginalizing pandemic diseases. There are many companies attempting to rise to this challenge.
In the near future, it is also hoped that a "template" vaccine will be available that is easily adaptable when a new strain or new mutation arises. Although such template vaccines hold great promise, we are still far from having access to any technology that will protect us from our biggest potential threat—emerging diseases. These are pathogens of which we presently have no knowledge about and which would not behave in the same way as those we have been studying.
Because we cannot know for sure what we might face in the future, investment in education is incredibly important. From informing the general public about how to prevent the spread of viruses and giving them the necessary knowledge to exert pressure on the authorities to facilitate preparedness, to building scientists' knowledge and ensuring the relevant expertise is available to run manufacturing facilities, it is crucial that both industry and government bodies work together for the future.
For a country or region to be fully prepared, all stakeholders including government bodies, industry, and healthcare providers, must work together and coordinate their efforts. When swine flu emerged earlier this year in Mexico, it made evident the instrumental role the WHO has played over the past years by ensuring all countries had a preparedness plan in place. The WHO also has the important task of supporting the worldwide pandemic response infrastructure, ensuring access to data is available, coordinating stockpiling of drugs, and overseeing communications between stakeholders.
Ensuring that all populations have access to safe vaccines and the corresponding level of supporting education are two important steps that must be achieved in the move toward true pandemic preparedness. Global companies have essential technological expertise and the required infrastructure to support governments and vaccines manufacturers so that everything possible is done to protect the global population from pandemic threats.
Over the last few years, there has been improvement in the global level of preparedness and the ability to respond to global pandemic threats. This has been manifested in a united response that has been evident during the current swine flu pandemic. However, no stakeholders can afford to be complacent and there is a need to continue and enhance investment in developing technologies such as template vaccines and quicker, more flexible manufacturing approaches. Moreover, the next pandemic could be the next-generation HIV, malaria, or an unidentified emerging disease, which would be even more difficult to tackle, so investment in the ability to react quickly is vital.
Developing true partnerships between governments, manufacturers, suppliers, and scientists is critical to create and support systems that will enable appropriate response to any emerging global threat to human health.
CATARINA FLYBORG is an enterprise solutions leader and DARIA DONATI, PhD, is a vaccine initiative marketing manager, both at GE Healthcare, Uppsala, Sweden, +46.18.612.1636, firstname.lastname@example.org
1. Burns A, van der Mensbrugghe D, Timmer H. Evaluating the economic consequences of avian influenza. World Bank Report; 2008 Sept.
2. GAVI Fund. Washington, DC. Available from: http://www.gavialliance.org/about/in_technologies. [cited 2009 Sep 3].
3. World Health Organization. Geneva. Available from: http://www.who.int/immunization/en/. [cited 2009 Sep 3]
4. Robinson JM. An Alternative to the scale-up and distribution of pandemic influenza vaccine. BioPharm Int. Advances in vaccine development and manufacturing. 2009 suppl;22(1):12–20.