Tandem Core

What is tandem core?

In order to explain the technology, we must first consider the structure of the hepatitis B virus (HBV). In common with all other viruses, nucleic acid is covered by a protein shell for protection. It is this shell that is of most interest. In the case of HBV, there are two shell proteins, called core and surface. In the diagram, the viral nucleic acid is shown in red, the core protein in blue and the surface antigen in yellow.

Both of these shell proteins have the unusual property of being able to form virus like particles (VLP). This means that many copies of either core or surface can coalesce to form a large structure that resembles a virus, but does not contain any nucleic acid. As far as the immune system is concerned, this is a threat, but in reality, it is perfectly safe since it cannot replicate like a real virus. VLPs can, therefore, be used as vaccines since they are safe and stimulate strong anti-viral immune responses. Indeed, several new major vaccines exploit this property, eg Gardasil™ and Cervarix™.

What is so special about core protein?

Both core and surface can form VLP and, indeed, surface VLP is the basis of the current vaccine for HBV. However, core protein has even more unique features since it is highly immunogenic (can stimulate the immune system). Furthermore, it is also capable of carrying other proteins on its surface. This then confers immunogenicity to the carried proteins as well as the core itself. The secret to this ability lies in the structure of core. Two core molecules pair spontaneously and form a unique ‘spike’, represented by the helical regions shown in the diagram. At the tip of these spikes lies the major insertion region (MIR) which is the optimal site into which other targets can be added. When 90-120 of these pairs, or dimers, join together, a VLP is formed, which looks remarkably like a virus.

Why is it useful?

As stated above, core is extremely good at generating immune responses. This is most likely due to the presence of conserved sequences which activate the immune system directly (Toll like receptors or TLRs). Furthermore, since core can carry other proteins on its spike, strong immunity can be generated to these inserts too. Therefore, a vaccine based on core could, potentially, raise immunity to targets which do not normally initiate a response.

But there is a problem: when very large or hydrophobic (water hating) molecules are inserted into the MIR, the pair of core molecules tends to fall apart. If this happens, then no VLP forms and subsequently no immune response is generated.

What is the solution?

If large inserts effectively “push” the core molecules apart, it was reasoned that physically tying them together should overcome this limitation. This was carried out by Professor Dave Rowlands at Leeds University, who made a genetic construct of two core molecules tied together by a flexible linker. The tandem core molecule, it still immunogenic, still forms VLP butcannot fall apart when large molecules are added because the cores are effectively “nailed” together.

Remarkably, when tandem core is “loaded” with targets from other viruses, it still physically resembles a virus. This means the immune system attacks it as expected and, at the same time, learns to protect against whatever targets have been placed in the VLP. Below is an electron micrograph showing a real tandem core.

HBVGFP_surface1

How does it differ from other vaccines?

Other VLP vaccines tend to be specific for a disease. For example, Engerix-B is a VLP made from hepatitis B, and is thus the vaccine for HBV. However, in the case of tandem core, we can insert sequences for a variety of targets and so can make vaccines for multiple diseases.

What are you using it for?

We currently have active programmes in a number of diseases including influenza, malaria, hepatitis and several others: read more about our research and development.