Influenza vaccines are made by inoculating live flu virus into fertilized chicken eggs, then purifying and inactivating the
resulting egg-adapted virus to produce trivalent inactivated virus, or TIV. TIVs represent the majority of the currently licensed
and marketed flu vaccines worldwide. In addition, there is the recently licensed egg-derived live attenuated influenza vaccine
(LAIV) produced by MedImmune.
Given the February-to-September time constraint, vaccine manufacturers have approximately six months to develop, manufacture,
and release millions of doses of trivalent vaccine. In practice, this short timeline necessitates that manufacturers speculate
on likely strains each year, so they can commence production of at least one, and probably two, strain-specific bulk antigens
in advance of knowing actual strain requirements. This tight schedule leaves little or no time to optimize and validate the
production process for the new virus strain. Consequently, the purification stream used for egg-derived flu vaccine involves
a trade-off between the need to specifically purify the antigens from the crude egg harvest and the need to have a process
that is not so specific that it no longer works if the properties of the HA and NA antigens change due to drifting or shifting.
This trade-off does not lend itself to a stringent purification stream with predictable yields.
Although manufacturing capacity has been growing and the uptake of seasonal vaccination has increased, demand has outstripped
capacity. Early assumptions were that the global capacity of around 300 million doses per annum could be tripled in a pandemic
situation by producing only a monovalent rather than a trivalent vaccine. These assumptions have been modified by the recognition
that low natural immunity in the population to a new virus may require a high dose, possibly in a boost regimen. Switching
from seasonal flu capacity, built to meet elective seasonal vaccination in developed countries, is also grossly insufficient
for potential global needs. Indeed, two of the last three pandemics originated in the Far East, where avian flu is most prevalent
and where the cost of vaccines can be prohibitive. Antigen-sparing approaches, notably through the use of adjuvants, may enable
reduced unit dosage, which could, in turn, increase vaccine coverage from a given manufacturing facility.
The substantial shortfalls in the current process have sparked development of alternative non-egg–based manufacturing systems,
primarily cell-culture flu vaccines such as those developed by Novartis and Solvay (produced in Madin-Darby canine kidney
[MDCK], cells) and by Sanofi-Pasteur and Crucell (using Crucell's PerC.6 human cell line). For these cell-culture–derived
vaccines, the live flu virus is used to infect cells in culture. Once the viral infection has propagated through the cells,
the live virus is harvested and inactivated in much the same way as in conventional egg-based flu vaccines. These systems
rely on being able to generate a seed stock of live virus to use throughout the production campaign. If an avian-flu-type
pandemic breaks out, it has been predicted that the live flu strain(s) will require higher containment levels than are normal
during vaccine production. This could limit total available manufacturing capacity to those manufacturers that possess the
required contained facilities. (The WHO web site, , contains numerous articles on the subject of biosafety risk assessments for avian flu and other pandemic influenzas.)
Several alternative approaches that do not rely on live virus seed stocks have been developed in recent years. These use the
genetic sequences that code for virus surface antigens rather than the live virus itself. The genetic sequences are propagated
in a form that does not produce infectious virus and does not require high containment manufacturing facilities. The time
required to produce these strain-specific genetic sequences for the commencement of a manufacturing campaign is typically
weeks to months shorter than the time required for laying down a live viral seed stock. This genetic manipulation approach
should therefore reduce annual timelines to clinic and market. The genetic approach is also expected to lead to marketed products
that will be less expensive to manufacture than cell-culture flu vaccines, while also being potentially easier to transfer
and license at additional manufacturing sites, should the need arise.