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HIV Vaccine
London
2nd 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.
2nd August 2011
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
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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
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Current vaccine approaches (2)
• Antibodies attach to the virus via
some of the surface proteins. Once
attached the virus is destroyed,
creating memory antibodies
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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
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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
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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
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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
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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 highlyvariable peptides, which mutate
regularly. This is how the virus
evades this arm of the immune
system
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T cell vaccine approaches
• 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
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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
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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 highlybinding and reactive of these
conserved regions to form the
basis of the antigen for its vaccine
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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
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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
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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
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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
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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
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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
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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