HIV Vaccine London 2 nd August 2011

1. HIV Vaccine London 2nd August 2011

2. SEEK is a drug-discovery group that uses a pioneering scientific and commercially-driven approach to create breakthrough medicines which address major diseases in order to radically improve human health. 2nd August 2011

3. Low versus high mutation • Viruses such as chicken pox have a low level of mutation so people obtain long-term immunity from exposure to the virus • Previous exposure to HIV does not provide long-term protection because the virus mutates regularly • Vaccines are developed to mimic the disease, tricking the immune system to react as if it had encountered the actual virus in order to develop memory against part of the disease • For highly-mutating viruses, this does not work as memory is formed against the variable regions 2nd August 2011

4. Antibody vaccine approaches • Previously-attempted HIV vaccines use irradiated viruses or parts of the envelope proteins such as Gag • These vaccines stimulate the immune system to produce antibodies against these envelope or surface proteins 2nd August 2011

5. Current vaccine approaches (2) • Antibodies attach to the virus via some of the surface proteins. Once attached the virus is destroyed, creating memory antibodies 2nd August 2011

6. Problem with current approaches • Certain proteins of the HIV virus mutate regularly, particularly those on the surface, therefore memory antibodies created against the previous proteins are ineffective against the new proteins • This is why no vaccine for HIV has been successful to date 2nd August 2011

7. Replication of Virus • If the virus is not destroyed by antibodies, it will enter certain immune cells where it will hijack the cells’ machinery, in order to replicate • Once virus numbers reach a critical level, the person will contract HIV 2nd August 2011

8. Cellular Mechanisms • When a virus enters a cell, it breaks down into peptides, some of which are exported to the cell surface via molecules called HLAs 2nd August 2011

9. T cell mediated immune response • T cells form the second line of defence of the immune system. They recognise internal peptides presented by HLAs on the surface of cells • Each T cell will only interact with a specific HLA/peptide combination 2nd August 2011

10. T cell mediated immune response (2) • The more a peptide is presented by HLAs, the more memory T cells are generated that recognise the peptide. The more memory T cells that recognise a peptide, the stronger the immune response to that peptide • Mutating viruses tend to produce more variable peptides. Hence, the majority of newly-created T cells are directed towards the highly-variable peptides, which mutate regularly. This is how the virus evades this arm of the immune system 2nd August 2011

11. In order to overcome the variable surface proteins, scientists targeted the internal proteins of the virus, which are less variable, or contain more “conserved” regions • These whole proteins are too large to make synthetically, therefore, scientists delivered them to cells in the form of DNA via a vector, to get the cells to make these proteins • Protein expression levels are difficult to control and the vector used to deliver the DNA tends to favour the cells it was designed to infect, which can cause difficulties such as tolerance induction T cell vaccine approaches 2nd August 2011

12. T cell vaccine approaches (2) • The immune system is left to choose which peptides from the whole proteins to memorise • The immune system produces the most memory cells against those virus peptides that are most abundantly presented on surfaces of cells. These tend to be the most variable peptides 2nd August 2011

13. SEEK’s approach • By examining over 5600 protein sequences from HIV -1 and HIV-2 known isolates from all clades, certain parts or regions of the viruses’ proteins that are conserved have been identified • SEEK identified the most highly-binding and reactive of these conserved regions to form the basis of the antigen for its vaccine 2nd August 2011

14. Explanation of SEEK’s approach • A vaccine made using these binding and reactive conserved regions of the virus proteins would enter cells and be presented in large volumes to the T cells, via the HLAs on the cells’ surfaces • Certain of the conserved peptides that SEEK uses in its vaccine are placed on the cells’ surfaces during the life cycle of the HIV virus, enabling B cells (or antibodies) to bind to these 2nd August 2011

15. Explanation of SEEK’s approach (2) • This approach dictates to the immune system which peptides to memorise • By doing so, it does not allow the normal evading mechanisms of the virus, or whole proteins of the virus, to trick the immune system into remembering the variable peptides 2nd August 2011

16. Immune response • Significant numbers of memory T cells are now created against these constant peptides, as more would be presented on the surface of cells by the HLAs • Significant numbers of B cells (or antibodies) are now created against these constant peptides, that are placed on the cells surfaces during the HIV life cycle 2nd August 2011

17. Immune response (2) • In naturally-occurring infection, these constant peptides would have to compete with other peptides for space within the limited number of HLAs on a cells’ surfaces, resulting in fewer of the desired memory T cells being produced • In naturally-occurring infection, the constant peptides that are placed on the cell surface during the HIV life-cycle are so few that not enough B cells (or antibodies) can form against them. Hence, they are never able to out-number the virus, rendering them ineffective 2nd August 2011

18. Implication of SEEK’s vaccine • SEEK’s vaccine would generate sufficient T cells and B cells against conserved peptides and hence would be effective against all clades of the HIV virus that are known • This should provide long-term protection before exposure as well as therapeutic benefit after exposure to HIV 2nd August 2011

19. SEEK’s manufacturing approach • A vaccine based on constant peptides can be manufactured in chemical plants • This allows the vaccine to be made in large quantities and at a low cost • Such a vaccine can resolve the problem of treating a large number of people in low-income countries, for whom the cost of anti-retroviral treatments is prohibitive 2nd August 2011

20. SEEK’s antigen selection method • The use of a proprietary computer algorithm has allowed the identification of these constant peptides, making the development of the vaccine feasible • This technology can also be applied to the identification of vaccines for other highly-mutating viruses • SEEK has identified vaccine candidates using this technology against Flu, Hepatitis B & C, Rotavirus A, mosquito-borne diseases and others 2nd August 2011