Introduction

iQur is focused on liver disease. Chronic liver disease is now the fifth commonest cause of death in the UK and the second commonest cause of death in middle aged men. Of the three commonest causes of liver disease (alcohol, obesity and viral hepatitis B and C), viral hepatitis affects over 500 million people worldwide. Prevention of infection with Hepatitis B virus (HBV) and Hepatitis A virus (HAV) are major public health goals of all developed and emerging countries, strongly supported by the WHO.

iQur is concentrating its therapeutic research and development on a vaccine platform based on exploiting the immune stimulant properties of Hepatitis B core. iQur’s patented Tandem Core Technology  (TCT) relies on the linkage of two HBV core molecules to form a stable backbone that combines to form virus like particles.  Insertion of target antigens into the TCT produces a vaccine that combines the immune alert signal provided by the HBV core with targeting of the immune response to the inserted vaccine antigen.

This technology can be used to generate immune responses against infectious pathogens including viruses, bacteria and parasites such and malaria, agents used in biodefence, anima pathogens and cancer associated antigens.

Having established proof of concept in a small animal model, iQur is refining it lead candidate vaccine. This is a combined anti-HBV and anti-HAV prophylactic vaccine.  The advantages of this vaccine over competitors is lower cost  of goods and greater efficacy.

Tandem core technology is a breakthrough with a number of unique features:      

• Platform technology. Capable of rapid insertion of new antigenic targets with minimal changes required to the construct.
• Broad applicability. This vaccine approach could be adapted to treat and prevent infectious diseases, cancers and immune mediated disorders such as Influenza, “bird flu” viral hepatitis, cervical cancer, melanoma and rheumatoid arthritis.
• It is highly immunogenic. It may be possible to release a vaccine which only needs one or two injections rather than the current multiple protocols, e.g. HBV.
• It has two insertion sites. Many current vaccines rely on a single antigen and would benefit from a multi-valent approach, e.g. RTS S which is a single HBV surface-malaria sporozoite construct. Alternatively, it may be possible to target two viruses simultaneously, e.g. HAV & HBV.
• Strong IP. The intellectual property has been licensed from a granted patent at the University of Leeds.

Background:      Hepatitis B (HBV) core protein is well known to be a profound immune stimulator (immunogenic) and has been used in a number of experimental vaccines. When an HBV core protein is conjugated to a hitherto non-immunogenic target, strong immune responses can be generated against both components. Core protein, as its name suggests, resides within the virus and hence, when it is exposed to the immune system it forms a powerful immune stimulant. Therefore, when used as a vaccine, very strong responses are elicited. The individual core proteins assemble into organised “virus-like particles” (VLP) further increasing their immunogenicity.

Using HBV core antigen as a carrier for non-immunogenic antigens is not new, however, our system is unique because it relies on the genetic conjugation of two core proteins, generating a “tandem-core” protein. Cores 1 and 2 both have insertion sites for antigens of our choice. Therefore, it is possible that two antigens can be made immunogenic at the same time, thus greatly enhancing the potency of our potential vaccine.

                    Proof of concept:           In order to examine this concept, we have used an HBV tandem core construct, expressing Green Fluorescent Protein (GFP) (a jelly-fish protein) inserted at the first site. We demonstrated that tandem-cores expressing GFP protein gave off green fluorescence proving that not only was this large protein inserted into the cores but also the whole construct assembled in the correct shape (conformation) to elicit  antibody (B-cell) responses that rely on 3-dimensional structure. GFP allowed us to examine conformation directly because it only fluoresces when it is correctly folded. This was indeed the case.

             Three groups of mice were vaccinated with (a) saline (b) “empty” tandem core (c) tandem-core expressing one GFP molecule. After 14 days strong antibody responses were detected to core protein in (b) and (c) and to GFP alone in (c). This was as predicted and proves that the tandem-core construct was capable of generating an antibody response to both the vector (core) and insert (GFP). Furthermore, this was detected after only a single administration; current vaccines for HBV usually require three or more injections. We also expect that T-cell responses will be generated over time.

NB: T-cell immunity is generated by the breaking down of proteins into linear peptides and is thus not dependent on the 3D structure of a protein. However, T-cell immunity is ideal for combating infected cells (antigen inside the cell) whereas B-cell (antibody) immunity can prevent cell to cell spread (antigen outside the cell). An ideal vaccine would stimulate both arms of the immune system.