Abstract
The H5N1 avian influenza A and 2009 influenza A (H1N1) pandemics have highlighted the critical importance of embryonated hen
eggs as a manufacturing platform for vaccines. We discuss the implications of recombinant viral vectors that can express proteins
in embryonated chicken eggs and their potential impact on manufacturing with this long-established platform. New recombinant
protein expression AdCEV vectors offer a pragmatic approach to increasing the efficiency, utility, and safety of manufacturing
in eggs. Their use is complementary to the single-use downstream processing systems and risk-based quality assurance that
are leading to dramatic reductions in the cost of multi-use manufacturing facilities for recombinant biopharmaceuticals. This
system also offers a safe and economical manufacturing process that addresses the urgent needs of influenza pandemic preparedness,
especially for low and middle income countries (LMICs).
Dimitri Vervitsiotis, Getty Images
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Fertilized hen eggs have been used in vaccine manufacturing for over 50 years. They are the original single-use bioreactors—inexpensive,
easily scaleable, and environmentally friendly.More human vaccines are manufactured in embryonated eggs than in any other
biological substrate, with more than 250 million doses of inactivated seasonal influenza vaccine distributed to 100 countries
annually. Vaccines for yellow fever and many veterinary vaccines are also routinely made in eggs.1
Nevertheless, large-scale flu vaccine production in eggs poses many challenges such that significant investments have been
directed toward developing cell culture-based alternatives. These new platforms, which include recombinant mammalian cell
culture, plant-based vaccines, and E. coli and other microbial-based production systems, have made significant progress, but the best of these efforts are still several
steps away from meeting the needs of large-scale, annual influenza prophylaxis.2,3
Given this situation, eggs are likely to remain the most important production platform for flu vaccine production for the
foreseeable future. Yet, the narrow economic margins of annual flu vaccine development, licensure, and mass production are
a serious challenge to pandemic flu vaccine preparedness, which must be based on the same production capacity used for seasonal
flu vaccine production. Yields of inactivated flu vaccine can range from 1–3 doses per egg, depending on the strain, although
the seasonality of the industry in temperate regions can leave production capacity idle for half the year.1
The World Health Organization strategy for pandemic vaccine supply calls for the establishment of an economically sustainable
base of annual flu vaccine production around the world that can provide surge capacity in the event of a pandemic like the
current 2009 influenza A (H1N1) pandemic.4 The need for increased flu immunization is especially important in low and middle income countries (LMICs) where flu prophylaxis
is minimal or absent. Efforts are being aimed at stretching the existing egg-based vaccine supply through use of adjuvants
and improved recovery of immunogens from eggs.
Here, we examine the potential impact of new recombinant vector technologies on influenza vaccine production and the wider
implications of such technology for global health. Egg-based manufacturing as presented here is comprised of three interacting
processes: a molecular process that takes place in the egg, a manufacturing process consisting of upstream and downstream
activities that manipulate unit eggs, and an operational process that encompasses the spatial, temporal, and economic organization
of egg-based vaccine manufacturing. The potential impact of the model AdCEV/egg platform on each of these organizational levels
is discussed.
