HIV Vaccine
London
2nd August 2011
SEEK is a drug-discovery group that uses a pioneeringscientific and commercially-driven approach to createbreakthrough medicines which address major diseasesin order to radically improve human health.
2nd August 2011
Low versus high mutation
2nd August 2011
• Viruses such as chicken pox have alow level of mutation so people obtainlong-term immunity from exposure tothe virus
• Previous exposure to HIV does notprovide long-term protection becausethe virus mutates regularly
• Vaccines are developed to mimic thedisease, tricking the immune system toreact as if it had encountered the actualvirus in order to develop memoryagainst part of the disease
• For highly-mutating viruses, this doesnot work as memory is formed againstthe variable regions
Antibody vaccine approaches
2nd August 2011
• Previously-attempted HIVvaccines use irradiated viruses orparts of the envelope proteins suchas Gag
• These vaccines stimulate theimmune system to produceantibodies against these envelopeor surface proteins
Current vaccine approaches (2)
2nd August 2011
• Antibodies attach to the virus viasome of the surface proteins. Onceattached the virus is destroyed,creating memory antibodies
Problem with current approaches
2nd August 2011
• Certain proteins of the HIV virusmutate regularly, particularly thoseon the surface, therefore memoryantibodies created against theprevious proteins are ineffectiveagainst the new proteins
• This is why no vaccine for HIVhas been successful to date
Replication of Virus
2nd August 2011
• If the virus is not destroyed byantibodies, it will enter certainimmune cells where it will hijackthe cells’ machinery, in order toreplicate
• Once virus numbers reach acritical level, the person willcontract HIV
Cellular Mechanisms
2nd August 2011
• When a virus enters a cell, it breaks down into peptides, some of which areexported to the cell surface via molecules called HLAs
T cell mediated immune response
2nd August 2011
• T cells form the second line ofdefence of the immune system.They recognise internal peptidespresented by HLAs on the surfaceof cells
• Each T cell will only interact with aspecific HLA/peptide combination
T cell mediated immune response (2)
2nd August 2011
• The more a peptide is presentedby HLAs, the more memory T cellsare generated that recognise thepeptide. The more memory T cellsthat recognise a peptide, thestronger the immune response tothat peptide
• Mutating viruses tend to producemore variable peptides. Hence, themajority of newly-created T cellsare directed towards the highly-variable peptides, which mutateregularly. This is how the virusevades this arm of the immunesystem
T cell vaccine approaches
2nd August 2011
• In order to overcome thevariable surface proteins,scientists targeted the internalproteins of the virus, which areless variable, or contain more“conserved” regions
• These whole proteins are toolarge to make synthetically,therefore, scientists deliveredthem to cells in the form of DNAvia a vector, to get the cells tomake these proteins
• Protein expression levels aredifficult to control and the vectorused to deliver the DNA tends tofavour the cells it was designedto infect, which can causedifficulties such as toleranceinduction
T cell vaccine approaches (2)
2nd August 2011
• The immune system is left tochoose which peptides from thewhole proteins to memorise
• The immune system producesthe most memory cells againstthose virus peptides that are mostabundantly presented on surfacesof cells. These tend to be themost variable peptides
SEEK’s approach
2nd August 2011
• By examining over 5600 proteinsequences from HIV -1 and HIV-2known isolates from all clades,certain parts or regions of theviruses’ proteins that areconserved have been identified
• SEEK identified the most highly-binding and reactive of theseconserved regions to form thebasis of the antigen for its vaccine
Explanation of SEEK’s approach
2nd August 2011
• A vaccine made using thesebinding and reactive conservedregions of the virus proteins wouldenter cells and be presented inlarge volumes to the T cells, via theHLAs on the cells’ surfaces
• Certain of the conserved peptidesthat SEEK uses in its vaccine areplaced on the cells’ surfaces duringthe life cycle of the HIV virus,enabling B cells (or antibodies) tobind to these
Explanation of SEEK’s approach (2)
2nd August 2011
• This approach dictates to theimmune system which peptides tomemorise
• By doing so, it does not allow thenormal evading mechanisms of thevirus, or whole proteins of thevirus, to trick the immune systeminto remembering the variablepeptides
Immune response
2nd August 2011
• Significant numbers of memoryT cells are now created againstthese constant peptides, as morewould be presented on thesurface of cells by the HLAs
• Significant numbers of B cells(or antibodies) are now createdagainst these constant peptides,that are placed on the cellssurfaces during the HIV life cycle
Immune response (2)
2nd August 2011
• In naturally-occurring infection,these constant peptides wouldhave to compete with otherpeptides for space within thelimited number of HLAs on acells’ surfaces, resulting in fewerof the desired memory T cellsbeing produced
• In naturally-occurring infection,the constant peptides that areplaced on the cell surface duringthe HIV life-cycle are so few thatnot enough B cells (orantibodies) can form againstthem. Hence, they are never ableto out-number the virus,rendering them ineffective
Implication of SEEK’s vaccine
2nd August 2011
• SEEK’s vaccine would generatesufficient T cells and B cellsagainst conserved peptides andhence would be effective againstall clades of the HIV virus thatare known
• This should provide long-termprotection before exposure aswell as therapeutic benefit afterexposure to HIV
SEEK’s manufacturing approach
2nd August 2011
• A vaccine based on constantpeptides can be manufacturedin chemical plants
• This allows the vaccine to bemade in large quantities and ata low cost
• Such a vaccine can resolvethe problem of treating a largenumber of people in low-incomecountries, for whom the cost ofanti-retroviral treatments isprohibitive
SEEK’s antigen selection method
2nd August 2011
• The use of a proprietarycomputer algorithm has allowedthe identification of theseconstant peptides, making thedevelopment of the vaccinefeasible
• This technology can also beapplied to the identification ofvaccines for other highly-mutatingviruses
• SEEK has identified vaccinecandidates using this technologyagainst Flu, Hepatitis B & C,Rotavirus A, mosquito-bornediseases and others
