Vaccines Incorporating Toll-Like Receptor Ligands - Attaching the HA antigen to a TLR can produce a strong immunogenic response and can be produced quickly and easily in E. coli. - BioPharm

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Vaccines Incorporating Toll-Like Receptor Ligands
Attaching the HA antigen to a TLR can produce a strong immunogenic response and can be produced quickly and easily in E. coli.


BioPharm International Supplements


Application in M2e


Figure 3. Influenza M2e vaccine: mice vaccinated with 0.3 or 3.0 μg of globular head fusion protein are protected 100% from death following a challenge with virus that kills 90% of nave mice
This technology has also been applied to both seasonal and pandemic influenza vaccines. Two distinct, but complementary, vaccines are currently in development. The first is based on the highly conserved ectodomain of the viral M2 ion channel protein (M2e). M2e is a 24 amino acid extension of M2 protruding through the membrane of the virus and the infected cell. Antibodies raised against the M2e sequence have been shown to reduce the rate of spread of influenza virus in culture and to protect mice from a lethal challenge of virus. The M2e sequence is highly conserved across the H1, H2, and H3 serotype viruses that have infected humans over the past 90 years.7,9 It is also well-conserved in the avian serotypes, suggesting that a cocktail of three or four M2e vaccines could provide broad protection against any influenza virus. A significant advantage of such an approach would be that the vaccine would not have to change on an annual basis, unlike the current influenza vaccine strategies.


Figure 4a. Influenza STF2.1HA vaccine efficacy: 0.3 μg provide 90–100% protection against a challenge dose of virus that kills 90% of nave mice
M2e as a peptide is poorly-immunogenic and ineffective, even when delivered at high doses on aluminum-containing adjuvants. Four copies of M2e head-to-tail mixed with flagellin, rather than fused, are also ineffective. However, fusing four head-to-tail copies of the human consensus M2e sequence to the C-terminus of flagellin creates a highly potent M2e vaccine. Doses of 0.3 μg provide 90–100% protection against a challenge dose of virus that kills 90% of nave mice (Figure 4, unpublished data),10 reinforcing the value of coupling a TLR ligand to an antigen. The first study of M2e in man, funded by the Gates Foundation, has been completed and it was found that the vaccine is highly immunogenic at low doses.

Application in Hemagglutinin


Figure 4b and 4c. Low doses of PR8 STF2.HA subunit protect mice against challenge with homologous virus
Another application of this technique has been in the major antigen of the virus, hemagglutinin (HA), one of the two predominant proteins on the viral surface. HA binds to sialic acid sugars on the surface of cells, and therefore, is a prime target for the immune system. Virus-neutralizing antibody raised by natural infection is known to be directed to the area of HA around the sialic acid binding site, and can thus prevent binding and block infection.11 Viruses that have mutations in the HA gene in the region of the sialic acid binding site have an infectious advantage over their neighbors, and thus can dominate the population (a primary reason the influenza vaccine needs to be updated every year).


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