Current egg-based manufacturing methodologies for the production of influenza vaccines are slow and have an inherent lag period
from variant identification to vial. In addition, seasonal influenza variants are predicted up to 12 months in advance by
the World Health Organization but may only be confirmed five to six months before a vaccine reaches the market. Vaccine manufacturers
have little time to produce and stockpile the selected candidates, and often have to manufacture one or more vaccine strains
in advance at risk of the preferred strains altering. There is a need for a more flexible and rapid production methodology
to produce cheap and effective influenza vaccines with minimal notice for pandemic variants. A new approach to combat this
threat is required. There are several technologies in early development that may offer a more viable solution to the pandemic
threat, such as the use of microbial-derived production processes and platform virus-like particle manufacturing strategies
to alleviate some of these constraints and lead to a more rapid response time.
As of June 2009, the World Health Organization updated the status of the current outbreak of influenza A H1N1 swine flu (Figure
1) to a global pandemic, highlighting the requirement for a cheap, effective prophylactic vaccine and manufacturing strategy
to raise the current state of preparedness for such situations. In 1918, one such influenza pandemic swept the globe and an
estimated 50–100 million people died as a direct consequence. This historical data suggests that a similar flu pandemic in
the modern era would affect 30% of the global population (approximately 2 billion) and an estimated 60 million individuals
(1%) would die.1 Combating the virus poses some significant and difficult challenges. Because the virus is an RNA virus, the lack of proof
reading capability when the virus replicates can cause the virus to mutate and combine genetic material with another virus
serotype resulting in variant forms, which may cross the species barrier wwAny vaccine must be specific to the current common
strains of influenza virus to be effective; most vaccines are trivalent meaning they contain three inactivated virus strains
to further increase the vaccine's efficiency and to overcome minor drifts in the virus morphology. Seasonal variants are predicted
up to six months in advance with scientists selecting the virus strain and subtype that is most likely to protect against
the virus in the first quarter of the year. Production of the vaccine by infecting live hen eggs, or more recently cells in
culture, then begins and may take up to six months. The current production rate globally is approximately 300 million doses
for each 6-month cycle in ideal conditions, providing vaccinations for only 5% of the global population.2
(EDEN BIODESIGN LTD)
There are several anti-viral drugs on the market, such as Roche's Tamiflu (oseltamivir phosphate), which can be used as an
effective treatment for H1N1 influenza patients but have a different mode of action than a viral antigen vaccine. Tamiflu's
mode of action is to prevent the release of the viral particles from infected cells, reducing the severity and duration of
the infection; this is invaluable in reducing infection and controlling the spread of the disease but it has no prophylactic
properties whatsoever. It has been estimated that Tamiflu production will be at 110 courses for 2009 alone.3
Figure 1. Images of H1N1 influenza virus. Image taken in the Centers for Disease Control and Prevention Influenza Laboratory2
Vaccination—Supply and Demand
The original licensed influenza vaccines were inactivated versions of a mixture of three influenza strains produced by an
egg-based manufacturing process. To give an idea of scale, on average, between one and two eggs are needed to produce one
dose of vaccine. During the production process itself, fertile hen eggs are infected with the candidate influenza strain and
incubated for several days. The vaccine is purified from the allantoic fluid of virus-infected chick embryos by a combination
of tangential flow filtration (TFF), density centrifugation, and, more recently, by anion exchange column chromatography.
The virus is also chemically inactivated through formaldehyde or β-propiolactone treatment at some point during processing.
More recently, licensed inactivated influenza vaccines are made in mammalian cell culture and purified by more modern techniques.
The major hurdle facing the manufacturers for the production of a pandemic vaccine is the time of production with the entire
production process for a season's influenza vaccine taking an average of six months. The challenge to the vaccine producers
is to develop a production process with a rapid turnaround time with minimal notice to combat a pandemic threat.
There are many approaches that may be taken for the development and production of a vaccine. An attractive prospect is the
use of platform production systems which, in turn, would offer significant advantages for the production of pandemic vaccines,
significantly reducing the lead in and production times and ultimately time to patient once the virus serotype has been identified.
This approach will also allow for strategic manufacturing sites to be at a state of operational readiness for the production
of the vaccine candidate with minimal notice. One such approach is the use of a microbial system for the production of virus-like
particle (VLP) based vaccines.