Flu Universal VaccineLondon5th 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.

5th August 2011

Low versus high mutation

5th 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 flu does not provide long-term protection because the virus mutates seasonally

• 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

Current vaccine approach

5th August 2011

• Existing influenza vaccines use a weakened strain of the current year’s virus

• These vaccines stimulate the immune system to produce antibodies as the first line of defence

Current vaccine approach (2)

5th 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 approach

5th August 2011

• Certain proteins of the influenza virus mutate from year to year, particularly those on the surface, therefore, memory antibodies developed from prior years’ exposure are ineffective in dealing with the current year’s virus

• This is why annual flu vaccination is necessary and why a vaccine for the pandemic cannot be developed until the strain of the virus is characterised

Replication of Virus

5th August 2011

• Since the virus is not destroyed by antibodies, it enters lung cells where it hijacks the cells’ machinery in order to replicate

• Once the virus population reaches a critical level, the person will contract the flu

Cellular Mechanisms

5th 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 immunity

5th 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 immunity (2)

5th August 2011

• The more a peptide is presented by HLAs, the more memory T cells are generated that recognise that 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 highly-variable peptides, which change seasonally. This is how the virus evades this arm of the immune system

New vaccine approach

5th 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

New vaccine approach (2)

5th 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

5th August 2011

• By examining every human and animal influenza A and B strain that has existed over the past 60yrs, certain parts or regions of the viruses’ proteins that are conserved in all strains have been identified

• SEEK identified the most highly-binding and reactive of these conserved regions to form the basis of the antigens in its vaccine

Explanation of SEEK’s approach

5th August 2011

• A vaccine made using these binding and reactive conserved regions of the virus proteins, the peptides would enter cells and be presented in large volumes to the T cells via the HLAs on the cells surfaces

Explanation of SEEK’s approach (2)

5th 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

5th August 2011

• Significant numbers of memory T cells are now created against these constant peptides, as more are presented on the surfaces of the cells by the HLAs

Immune response (2)

5th August 2011

• In natural-occurring infection, these constant peptides would have to compete with other peptides for space within the limited number of HLAs on cells’ surfaces, resulting in fewer of the desired memory T cells being produced

Implication of SEEK’s vaccine

5th August 2011

• SEEK’s vaccine would eliminate the need for both annual and pandemic vaccinations

• The constant peptides found in all animal and human influenza viruses, represented in the vaccine, create sufficient numbers of memory T cells to destroy enough of the cells containing the virus, preventing the contraction of flu

• Due to the large number of conserved regions used in the vaccine, the statistical chance of all the regions mutating is negligible and, if certain ones mutated, the virus would be unable to enter lung cells and would no longer be flu

Current vaccine production

5th August 2011

• Traditional vaccine production involves growing the virus strain in chicken eggs

• A limited supply of eggs, and a shortage of factories, limits the maximum production to 350 million doses per annum

• Given the time to manufacture, and time to vaccinate, most people could not be protected in a pandemic

SEEK’s manufacturing approach

5th August 2011

• A vaccine based on constant peptides can be manufactured in chemical plants

• Such a vaccine can be made and administered in large quantities, prior to a pandemic, thereby protecting a large proportion of the population

SEEK’s antigen selection method

5th 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 HIV, Hepatitis B & C, Rotavirus A, mosquito-borne diseases and others