Traditional vaccines have been using whole dead bacteria, viruses or sub-units as target vaccine antigens – these approaches have over the years been improved and most technologies are using some form of a viral vector as a combination of adjuvant and delivery of vehicle for one or more specific protein sequences derived from the target. These naturally occurring proteins or even shorter fragments of proteins are in principle based on a quite similar vaccine delivery technology because they all leave for the immune system on its own to choose what epitopes are the best targets. In the vast majority of cases, the most immunodominant domains will be picked out instead of the specific signature domains where the target bacteria or virus are most vulnerable.
Bionor has for the last 2 decades focused on developing technologies that can identify and point out common, conserved, short protein fragments/peptides (the vulnerable spots) that can guide the immune system directly to these key vaccine antigen targets.
The goal is to use such preselected targets to induce specific immune responses for either prevention or treatment.
In particular, for challenging vaccines like Mycobacteria, HIV, HCV, Herpes or multi-season Flu vaccine, the vulnerable spots will normally be short amino acid sequences, which in addition are likely to be less immunogenic. In order to circumvent such challenges, Bionor has applied its know-how and peptide technologies to modify and make these vaccine antigen targets visible and immunogenic for the immune system.
These technologies also include selection, modeling and design of vaccine antigens that can elicit immune responses to human ligands.
The Bionor approach for vaccine development
Bionor’s vaccine approach is to engage both arms of the immune system to seek out and hit one or more selected target(s) on a bacterium or a virus where it is assumed to be most vulnerable or even tag/block a (human) cell ligand.
In an antibody response, microbes or infected cells are “tagged” by antibodies for attack by other parts of the immune system or they are neutralized directly.
In a cell-mediated immune response, white blood cells (T-cells) are activated to effectively seek out and kill a virus-infected cell.
In order to do that, Bionor vaccines are using modified peptides (small protein fragments) combined with an appropriate adjuvant to drive such targeted responses either towards antibody-responses (including Th2) or T-cell / Cell-mediated responses supported by Th1.
For HIV in particular, researchers have discovered several conserved regions on several viral proteins. Today we know that some of these forms such vulnerable spots and are the targets for Bionor’s vaccines.
Why use peptides?
Vaccines against new and challenging diseases such as HIV requires a detailed understanding of the strengths and limitations of the various vaccine technologies in order to make the best approach and choice of technology to circumvent the challenges. Peptide-based vaccine antigens with modified antigenic expression are beyond doubt the best suitable technology today with respect to flexibility to combine detailed target analyses with modeling, design, and synthesis for construction/adaption of antigens in such a way that even small peptides can become visible and immunogenic. The key is to identify and circumvent the natural “hiding mechanisms” for the vulnerable spots.
Summarized; vaccines which have turned out to be challenging to develop would benefit from a peptide-based vaccine approach. This approach will allow for tailor-made directing and boosting the immune system towards one or more of the specifically selected vaccine antigens in a robust and cost-effective way.
How are the peptide selected?
From the analyses of genetic sequences of proteins of for example a virus, Bionor identifies certain regions on one or several virus proteins with a set of predefined characteristics such as the likelihood for mutations within a specific peptide domain. When such a non-changing / conserved/low mutating domain have been identified and deemed likely represent a critical properties /functions for the virus by the researchers, such domains will be selected for further analyses, modeling and design as possible vaccine antigens.
Why are the peptides modified?
When a conserved region has been identified and selected, the peptides are modified by various amino acid substitutions/modification to become visible for the immune system and enhance their potential to induce an effective immune response. This peptide selection and modifications are based on a peptide modeling and design platform technology well suited to address viruses that constantly “mutate” (changes), such as with HIV.
How can the peptide-vaccines be delivered?
Peptide vaccines can be delivered intra-dermally, subcutaneously, intra-muscularly or even nasally. New delivery technologies have now made all these delivery routes available for modern vaccines. The choice of route will to some extent depend on what type of response one is seeking and the adjuvant used.
Bionor has also successfully completed a pilot nasal immunization study using and an Oil in Water adjuvant together with Vacc-4x.
Intradermal delivery technologies have become available and are being used in other products currently on the market.
How can non-toxic peptides be immunogenic?
Peptides are part of what we digest every day and are as such not immunogenic alone but co-administered with a suitable danger-signaling adjuvant they will be immunogenic. Part of the vaccine technologies includes a selection of adjuvant and route of administration to mount high, long-lasting immune responses.
Bionor has extensive experience to make peptides immunogenic when such vaccine peptides are combined with adjuvants like Alumn, Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), Oil in Water adjuvants or Water in Oil adjuvants.
For example the Vacc-4x peptides (T-cell vaccine) have been made immunogenic by applying the following principles; peptides designed for eliciting Cell-mediated/CTL responses are normally delivered to APCs / dendritic cells through “intradermal” injection (within the top layer of the skin) in combination with an adjuvant (supporting /danger signaling agent, which can enhance the effect) that helps stimulate a cellular response. The adjuvant GM-CSF has been used for Vacc-4x. It is injected intradermally at the same site as the vaccine because of its known effects on dendritic cell maturation and migration. Dendritic cells are targeted because they are plentiful in the skin and their job is to find and respond to foreign material/organisms and are the most potent antigen-presenting cells.
In the same way antibody, vaccines like Vacc-C5 designed for development of robust antibody responses against peptides must follow the standard route of preclinical and clinical development to demonstrate immunogenicity. This means the peptide vaccine antigens need to be dose escalated together with an appropriated danger signaling adjuvant and delivered via either the intradermal, subcutaneous or another suitable delivery route.