Cell-Culture–Based Manufacturing: Meeting the Challenge of 21st Century Influenza - Influenza vaccines traditionally required yearly redevelopment to address changes in flu strains. With breakth


Cell-Culture–Based Manufacturing: Meeting the Challenge of 21st Century Influenza
Influenza vaccines traditionally required yearly redevelopment to address changes in flu strains. With breakthrough technologies, however, the variables of yearly redevelopment can be reduced—accelerating time to market while reducing costs.

BioPharm International

When the genetic approach is used to produce purified recombinant HA proteins to incorporate into a vaccine (such as Protein Science's FluBlØk recombinant vaccine, containing trivalent HA antigen made in insect cells), there is a risk that the change in HA strain will lead to altered behavior of the protein in the purification process. In this regard, the PowderMed vaccine that involves inoculation with DNA coding for the HA antigens, rather than the HA antigen proteins themselves, has an advantage, because the purification of DNA should vary little with changes in strain. Another approach that could reduce the potential for variability in production quality involves engineering fusion proteins in which only the HA region varies, while the rest of the fusion protein remains the same. This could be exploited as the basis for chromatographic or membrane purification techniques.

Immunobodies Influenza Vaccine

One of the genetic products in development is based on ImmBio's ImmunoBodies platform technology. The product originated from oncology work conducted by Scancell Ltd that ImmBio adapted for anti-infective applications. The resulting HA–Fc fusion protein vaccine uses baculovirus vectors that are genetically engineered to carry the DNA sequence of chosen HA molecules that are fused to the DNA sequence of the Fc portion of human immunoglobulin. (A more detailed explanation of this platform technology is available at http://www.immbio.com/platforms/immunobodies/.) The vectors are used to infect insect cells in culture, causing the cells to produce a protein containing the combined HA antigen sequence and the Fc protein. The fusion protein can be isolated using the same methods used for isolating monoclonal antibodies to yield a highly purified protein for injection.

Due to the presence of its Fc portion, the fusion protein targets dendritic cells, leading to stimulation of T-cell mediated response as well as an antibody response to the HA portion (as is normally seen with conventional vaccines). The combined response should provide protection not only at commencement of infection, when antibodies can bind to influenza virus outside cells, but also at the subsequent stage of viral replication. Infected cells express some viral antigens on their surface and the T-cell response induced by the fusion protein will stimulate their destruction, thus halting the virus' ability to further replicate.

Choice of System

In developing its fusion protein expression system, ImmBio used the following key criteria to select from among four main choices for the expression of a recombinant protein (i.e., bacterial cells such as Escherichia coli, yeast, insect cells, and mammalian cells):

  • Speed: Can it meet the annual production cycle or respond to an emergent pandemic?
  • Functionality: Does the system express an efficacious product? (The HA requires correct folding, and the Fc requires glycosylation for receptor binding.)
  • Cost: How does the cost compare to current marketed influenza vaccines?
  • Availability: Are scaled-up manufacturing facilities and regulatory experience available?

Table 1. The rating process that was used by ImmBio to identify the baculovirus expression system as the system of choice
From this rating process (Table 1) the baculovirus expression system was identified as the system of choice.

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