HIV Vaccine London 2 nd August 2011

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. 2 nd August 2011

Low versus high mutation 2 nd August 2011 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

Antibody vaccine approaches 2 nd August 2011 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

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

Problem with current approaches 2 nd August 2011 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

Replication of Virus 2 nd August 2011 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

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

T cell mediated immune response 2 nd August 2011 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

T cell mediated immune response (2) 2 nd August 2011 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

T cell vaccine approaches 2 nd August 2011 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 (2) 2 nd August 2011 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

SEEK’s approach 2 nd August 2011 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

Explanation of SEEK’s approach 2 nd August 2011 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

Explanation of SEEK’s approach (2) 2 nd August 2011 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

Immune response 2 nd August 2011 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

Immune response (2) 2 nd August 2011 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

Implication of SEEK’s vaccine 2 nd August 2011 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

SEEK’s manufacturing approach 2 nd August 2011 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

SEEK’s antigen selection method 2 nd August 2011 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