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Jerald C. Sadoff MD
AIDS Vaccine 2009 Journalist
Scholarship Training Overview
October 18th 2009 Paris, France
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D efresher: How Vaccines Work
D
asic principles in developing vaccines
D Vaccine esearch Today
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D The general answer
D The battle between the bugs and us
D Their Genes and our Genes
D Timing and location are everything
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D Vaccines work by fooling the body into
thinking it is infected with a bug so that
next time when it sees the real thing it will
be ready faster with a more powerful
response
D Sometimes it gets the body to do
something different and better then if it
were naturally infected
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D We recognize them as something different
not belonging inside the body
D Once recognized we try and kill them
D We have two systems of doing this:
± The Innate system
± The Cognate system
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D Ancient system found in almost all living
things in some form
D ecognizes patterns in pieces of the bugs
rather then specific pieces
D Immediate but no memory for next time
D Poisons released quickly that kill
everything around
D Massive numbers of all kinds of cells called
in rapidly that eat what they encounter
(called inflammation)
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D ewer more sophisticated system found in
higher animals which is dependent on the
innate system
D ecognizes very specific parts of the bug
called antigens or epitopes
D Comes up slower if hasn¶t seen it before
D It remembers from one time to the next
D Its weapons: antibodies and T cells
recognize and kill very precisely
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Vaccines induce the cognate

system to remember, recognize,
and kill viruses, bacteria, parasites
or cancer cells
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D Antibodies are proteins floating in our fluids
and organs everywhere they can get
D At one end they recognize and stick on the
surface of the bug
D When they bind bad things happen to the
bug
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D ecognize the back end of the antibody
stuck on the surface of the bug
D They use the antibodies like a zipper to
close around the bug and eat it
D Once the bug is inside the cell its held in a
bag and poisons are dumped in that kill it
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D ecognize our cells that have been
infected by bacteria, viruses or parasites
D They get very close to the infected cell
D They secrete signals to the cell in very high
concentrations that tell the cell to kill the
bug
D Some of these T cells are memory cells
that live a long time and some are effectors
that are out in the tissues ready to pounce
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D They protect themselves from innate White
cell engulfment and killing
±
acteria like Pneumococcus build thick walls
of sugar on their outsides that white cells cant
engulf without the zipper of antibody ± basis of
the new pneumococcal vaccine
± T
organisms poison the bag they are in
inside the cell so they cant be killed once
inside
± Viruses like varicella hide in the nerves where
white cells cant go
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D They move rapidly from one site to another
so they are gone by the time the cognate
system has responded
± The malaria parasite is only in the blood for
less then a minute before it gets to the liver
and then it changes so adaptive antibody isnt
made
± It only stays in the liver for 10-14 days so that
adaptive T cells are too slow
± The new malaria vaccine induces both
antibody and T cells that are ready for it
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D They avoid the cognate T cell response by
changing the ability of the cells they have
infected to show they are infected
± Measles, CMV and HIV all turn down the
ability of the infected cells to put pieces of the
virus on its surface so that a cognate response
is dampened
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D They can change their genes rapidly
because
± They reproduce so fast
± Sometimes like HIV they don¶t reproduce very
accurately
± They are a population attacking us not an
individual while we tend to be concerned
about protecting each individual in our
population
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D We cant change our genes rapidly
D We have a lot of genes
± We have genes to make antibodies that can
recognize just about everything including
plastic that doesn¶t exist in nature
± We have genes for T cells that can recognize
just about everything but each individual is
unique on what pieces of viruses can be
presented
D We can slowly change our antibody genes
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D They can change so rapidly that they can
out run the cognate responses
± HIV changes its surface variable regions so that
it avoids neutralizing antibody that develops
D About 25% of humans eventually develop broad
neutralizing antibodies
± HIV changes the epitopes that are recognized
by T cells within 10-20 days of first infecting
humans thus avoiding that cognate response
D HIV can eventually find something that it human host
cant respond to
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D They misdirect the cognate system to
immunodominant antigens that they can
change and away from antigens they cant
change
± Gonorrhea and E. coli pilus antigens highly
variable and immunodominant ± distract from tip
proteins that are required for attachment and
sex
± HIV gp120 variable regions are
cell dominant
and can vary rapidly
± HIV subdominant T cell antigens protect in the
few animals that recognize them (Watkins)
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D Timing - Vaccines work because the cognate
response after vaccination is much faster when
the bug is first seen then what occurs if it has to
develop from scratch
± Pneumococcal anti sera given within 3 days of
hospitalization 40% survival after 3 days no survival
± Most vaccines have very little effect after the infection
has progressed since the system is already mounting
a cognate response due to the infection
D abies is an exception - following a rabid animal bite the virus
travels slowly up the nerve to the brain ± immediate
immunization can save your life if the immunity develops
before the virus gets there, that¶s why a bite on the face is
worse then the arm
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D ocation is important because the cognate
immune response has to get to the
pathogen rapidly to be effective
± Only 4 of 8 sets of T cells directed exactly at
the same piece of malaria worked to protect
mice from malaria
± The 4 that worked are the one that got to the
liver
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D An example of where timing and location
are both thought to be critical is the
protection induced by CMV vaccine
against SIV infection to be further
presented at this meeting by ouis Picker
D The effector T cells induced by this vaccine
are not only ready to kill at the time of
infection but they are already located
where the virus goes.
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D se what the disease gives you
D Correlates and Surrogates make
everything easy
D When everything else fails ± Proof of
Principle studies and bootstrapping
D Manufacturing ± Vaccines are not iPods
D Assays rule
D Eternal triangle of risk vs time vs resources
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D Epidemiology ±
± Hemophilus type
± no disease till 4-6 month
± otavirus ± 2nd infection with different type
± Zoster ± more disease >65 years of age
D High Attack rate ±
± otavirus - efficacy in 400 children
± Malaria ± efficacy in 2000 children
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D Animal Model ±
± Hep
- on Human Primate
± Pnumococcus, Hemophilus,
± T
± (?) low dose HP challenge
± HIV- (?) SIV low challenge dose
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D Possibility of Human Challenge studies
± Shigella
± Cholera
± Malaria
± HIV (?)
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D se what the disease gives you
D Correlates and Surrogates make
everything easy
D When everything else fails ± Proof of
Principle studies and bootstrapping
D Manufacturing ± Vaccines are not iPods
D Assays rule
D Eternal triangle of risk vs time vs resources
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D se what the disease gives you
D Correlates and Surrogates make
everything easy
D When everything else fails ± Proof of
Principle studies and bootstrapping
D Manufacturing ± Vaccines are not iPods
D Assays rule
D Eternal triangle of risk vs time vs resources
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&+
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D Antigens
± everse Engineering
±
ioinformatics
± Epitopes
D Vaccine Delivery
± Adjuvants
± on-replicating vectors
± eplicating vectors
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D tilizing molecular modeling and immune
responses in protected volunteers to down
select from thousands of possible proteins
D imited number of proteins put in mouse or
other small animal studies
D ecent promising examples:
± Common Group
meningococcal protein
± Common Pneumococcal protein
± Common Staphylococcal protein
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D nderstanding the detailed molecular
structure of a target protein and its
interaction with antibody design an
immunogen to induce that antibody
D Influenza and HIV tremendous current
work
± Identified binding regions of monoclonals that
neutralize somewhat broadly including new
ones that bind V3 stem
± So far unsuccessful in designing immunogen
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D sing scoring systems with internal
validation combine all of the information
about antigen candidates to select
promising antigens for inclusion in vaccine
vector
D Example: T
antigens for inclusion in a
recombinant
CG for over-expression
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D Fundamental problem in
and T cell
based vaccines is epitope selection to
cover the variety of pathogens that might
be encountered
D Second problem is the virus changing its
epitopes
D Third problem is immunodominance of
some epitopes over others
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D The approach with Pneumococcal,
rotavirus and HPV vaccines is to make
multiple serotypes (up to 16 for Pneumo)
with the broadest epidemiologic coverage
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D Informatics approach to combine all known

variablility in the data base with natural
segments and maximize coverage
± Criticism of this is that the variability is escape
to variants that cant be responded to
± That this does represent incoming virus
D Search for epitopes that cant vary because
of their function
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D tilization of subdominant antigens in

absence of dominant antigens
D Sequential immunization
D Immunization with separate vaccines
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D Adjuvants stimulate the innate system ±
mainly through toll receptors
D Several new adjuvants in clinical trials
D AS04 with flu vaccines responses in 200-
800 range compared to 20-60 for most flu
vaccine
D AS01-E in malaria and T
vaccines
provide very high CD4 T cells in humans
D IC-31 in T
vaccines induce CD4 T cells
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D Vaccinia
ased: VAC, AVAC, MVA
± HIV- Alvac part of Thai trial
± T
± MVA AE AS-485 in a 2800 subject
Phase II
efficacy trial in Cape Town S, Africa
D Adeno based: Ad5, Ad35, Chimp Adeno
± HIV-
D Ad 5 ± Merck IH HIV trial,
D Ad 5 - Current V C trial
± Malaria -Chimp Adeno ± prime for MVA boost
± T
± Ad35 induced high CD8 T cells
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D Can¶t replicate in humans
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D eplicating vectors have the advantage of longer
antigen production and possibly more effector
cells
D ecombinant
CG:
± Persists for around 40 days
± Appears to be a good prime for protein or viral booster
D ellow Fever
±
eing used as a vector for dengue vaccine now in
phase II trials
±
eing explored for HIV with promising HP data
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D Persists throughout the life of the animal

D Down regulates the Class I so can re-infect
D Induces subdominant antigens
D Induces primarily effector memory T cells
D Prevents productive SIV infection in low
dose HP challenge
D Safety issues as a human vaccine
±
irth defects in new borns
± iver and potential heart disease
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D icensed (10)
± Hep A (VAQTA)
± Hemophilis type
(iquid Pedvax)
± Hemophilus type
± Hep
(Comvax)
± Varicella (4 degree Varivax)
± Measles-Mumps- ubella- Varicella (ProQuad)
± Hib-Hep
-DPT-IPV (Hexavac)
± Zoster (ZostaVax)
± otavirus ( ota Teq)
± Human Pappiloma Virus (Gardasil)
± Cholera (Dukoral)
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D Phase III
± Malaria ( TS,S) ongoing
± Cholera (Peru 15) beginning
D Phase II

± Shigella (John obbins - Polysaccharide conjugate) - successful
± Gonorrhea (Pili vaccine) ± failed
± Pseudomonas E. Coli Klebsiella (Passive Aby) failed
± HIV (Adeno Vectored Gag, Pol, ef) ± failed
± T
(MVA85A-AE AS-485) ± ongoing
± T
(AE AS-402) ± ongoing
D Phase II
± T
(GSK- M72) - ongoing
± T
(AE AS- 404 HyVac4 SSI/Sanofi) - Ongoing