ImmBioVax™

One of ImmBio’s two technology platforms, “ImmBioVax”, is based on the recent significant discovery that a family of proteins called “heat shock proteins” (“hsps”) have a pivotal role in the normal immune response to infections. Under certain circumstances, including those found during infection, hsps will form complexes with pathogenic antigens (hspCs). The antigen-laden hspCs are targeted directly to dendritic cells (DCs), the antigen presenting cells (“APCs”) of the immune system. The DCs then ‘present’ these antigens to the rest of the immune system, to mount the ‘adaptive’ response - including the production of killer T-cells and antibodies against that pathogen. ImmBio’s ImmBioVax™ technology utilises pathogen-derived hspCs as vaccines against infectious disease caused by the pathogen.

ImmBioVax™ vaccines provide a safer approach than other vaccines because they incorporate the factors that specifically target the antigen to the immune system and stimulate the immune response without the need for adjuvants. Importantly, they elicit polyclonal immunity without the use of either the whole live pathogen or the genetic material from the pathogen, this eliminating the risk of pathogen mutation.
In short, ImmBio's technology utilises the immune system’s own antigen capture and activation mechanisms to elicit the most effective immune response against the pathogen.

Major advances in the approaches include:

• A high level of efficacy, including against strain variation and against antibiotic resistance, through the efficient and appropriate presentation of multiple antigens
• The scope for use in a prime or boost regimen, including in situations where other approaches confer only limited or waning protection but where a second dose is ineffective
• An approach which in large parts mirrors the normal course of infection without use of an adjuvant, and is expected to provide an excellent safety profile

Given the importance of biomanufacturing processes to biological products such as ImmBioVax vaccines, ImmBio, along with a number of collaborators, have extensively worked on design, control, assays and functional specifications. In addition to specific IP, ImmBio has significant know-how relating to both upstream and downstream processes and assay design. Regulatory agency input is sought to assess CMC acceptability of bioprocess design.

The basic science behind ImmBioVax

The human body is equipped with a powerful and sophisticated system of defence against harmful pathogens - the immune system. The proper functioning of the immune response to invading pathogens is prompt, appropriate and self-limiting. It also retains a "memory" of pathogens encountered, enabling more rapid responses to future invasion. Consequently a number of vaccines are already available, each of which builds a specific defence capability, through mechanisms which mimic (but not replicate) infection, ahead of any potential contact with the relevant matching pathogen.

The immune response is essentially composed of two phases:

• An initial ‘innate’ response that is a generalised, fast response to any pathogen.
• A subsequent ‘adaptive’ response that is specific to the invading pathogen.

The innate response is mediated by genes that are inherited in the germ line and is typified by inflammation. The adaptive response is mediated by genes that are specifically re-arranged in effector cells of the immune system, namely the T and B-lymphocytes, forming pathogen-specific molecules (e.g. antibodies produced by B-cells). Until recently, knowledge of the immune system has almost exclusively been around the pathogen-specific adaptive immune response. However, the key role of the innate response in the control of the adaptive phase is now being appreciated and is the basis of the evolution of ‘immunology’ into the emerging science of ‘immunobiology’.

The diagram above sets out the key stages in an immunological response, described in the following narration:

1. The most important defence mechanism against infections is the role of the immune system in the labelling and eradication of invading pathogens. T-cells are the key players in the immune response as illustrated in AIDS, which results from the loss of T-cells due to HIV infection. T-cells can either act directly (killer T-cells) or induce B-cells to produce antibody (helper T-cells).
2. However, T-cells only see antigens when shown them by professional Antigen Presenting Cells (APCs), the most efficient of which is the Dendritic Cell (DC). DCs capture the pathogen’s antigens and load them onto their surfaces, thus enabling them to activate specific T-cells that recognise the presented antigens. DCs are the most efficient APC’s as they don’t just show T-cells antigens, but also tell them what to do.
   
   Thus DCs control the cellular immune response. Consequently the key for successful vaccines is to develop effective methods for loading DCs with antigens.
   
   Conventional vaccines use Adjuvants to stimulate uptake of co-formulated antigens. This non-specific stimulation of DCs is both inefficient and raises safety concerns. DNA vaccines aims to achieve the uptake of expressed protein by DCs or more recently, the direct expression of DNA in DCs - both are inefficient for loading DCs.
3. The biology of the immune system reveals what DCs are normally designed to see. At the start of an immune response, conserved features (e.g. bacterial cell wall or viral RNA) are recognised by cells of the “innate” immune system (e.g. macrophages). This leads to the release of signals that mediate inflammation (notably pro-inflammatory cytokines).
   The pathogen can be a microbe (bacteria or fungi), virus or parasite.
4. Inflammation induces stress response in pathogens that result in the enormous up-regulation of genes for a specific family of proteins, termed Heat Shock Proteins (hsps). The normal role of hsps is to “chaperone” the correct folding of other proteins; their ubiquitous increase during stress is thus a protective response that reflects the pathogen’s need to re-fold its proteins when the stress is removed.
5. Consequently hsps produced by pathogens are normally found complexed with antigens from the pathogen (hspCs).
6. HspCs containing complexed pathogen antigens are efficiently captured by DCs.
7. Dendritic cells take antigens complexed in hspCs and load them onto MHC-molecules which are then displayed on their surfaces, thus enabling them to efficiently stimulate specific T-cells that see these antigens.

Thus, in a normal immune response to pathogen infection, DCs capture antigens in the form of  pathogen-derived hspCs.  ImmBio’s novel ImmBioVax™ approach is to produce hspC-enriched vaccines from stressed bacteria, which will be actively taken up by APCs – specifically DCs – hence eliciting a cellar immunological response.