how vaccines work (jerald sadoff)
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8/7/2019 How Vaccines Work (Jerald Sadoff)
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Refresher: How Vaccines Work;
Vaccine Research Today
Jerald C. Sadoff MDAIDS Vaccine 2009 Journalist
Scholarship Training Overview
October 18th
2009 Paris, France
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AERAS GLOBAL TB VACCINE FOUNDATION
Topics to be covered� Refresher: How Vaccines Work
� Basic principles in developing vaccines
� Vaccine Research Today
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Refresher: How Vaccines Work � The general answer
� The battle between the bugs and us
� Their Genes and our Genes
� Timing and location are everything
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The general answer how vaccines work � 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 willbe ready faster with a more powerful
response
�Sometimes it gets the body to dosomething different and better then if it
were naturally infected
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The Battle Between Us and the Bugs:
What we can do
� We recognize them as something different
not belonging inside the body
� Once recognized we try and kill them� We have two systems of doing this:
± The Innate system
± The Cognate system
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The Innate System
� Ancient system found in almost all livingthings in some form
� Recognizes patterns in pieces of the bugs
rather then specific pieces� Immediate but no memory for next time
� Poisons released quickly that kill
everything around� Massive numbers of all kinds of cells called
in rapidly that eat what they encounter (called inflammation)
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Vaccines induce the cognate
system to remember, recognize,
and kill viruses, bacteria, parasites
or cancer cells
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The cognate system has 3 weapons:
1. Antibodies
2. White cells: Macs and Polys
3. White cells: T cells
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Antibodies� Antibodies are proteins floating in our fluids
and organs everywhere they can get
� At one end they recognize and stick on thesurface of the bug
� When they bind bad things happen to the
bug
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White cells: Macs and Polys� Recognize the back end of the antibody
stuck on the surface of the bug
� They use the antibodies like a zipper toclose around the bug and eat it
� Once the bug is inside the cell its held in a
bag and poisons are dumped in that kill it
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White cells: T cells� Recognize our cells that have been
infected by bacteria, viruses or parasites
� They get very close to the infected cell� They secrete signals to the cell in very high
concentrations that tell the cell to kill the
bug
� 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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CD 4
T cell
CD 8
T cell
TH1 TH2 TH1 TH2
IFN-
IL-2
TNF-
IL-4
B - cell
antibodies
DTP, Hib, Pneumococcus,
Measles, Polio, Hep B,
Rotavirus, HPV, Malaria TB, Malaria, HIV
Central
or
Effector
Memory
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Battle with the Bugs: What they do� They protect themselves from innate White
cell engulfment and killing
±B
acteria like Pneumococcus build thick wallsof sugar on their outsides that white cells cantengulf without the zipper of antibody ± basis of the new pneumococcal vaccine
± TB organisms poison the bag they are ininside the cell so they cant be killed onceinside
± Viruses like varicella hide in the nerves wherewhite cells cant go
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Battle with the Bugs: What they do� They move rapidly from one site to another
so they are gone by the time the cognatesystem 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 isntmade
± It only stays in the liver for 10-14 days so thatadaptive T cells are too slow
± The new malaria vaccine induces bothantibody and T cells that are ready for it
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Battle with the Bugs: What they do� 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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Battle with the Bugs
Their Genes and Our Genes
� 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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Battle with the Bugs
Their Genes and Our Genes� We cant change our genes rapidly
� We have a lot of genes
± We have genes to make antibodies that canrecognize just about everything includingplastic that doesn¶t exist in nature
± We have genes for T cells that can recognize
just about everything but each individual isunique on what pieces of viruses can bepresented
� We can slowly change our antibody genes
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Battle with the Bugs: What they do� 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
� 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
� HIV can eventually find something that it human host
cant respond to
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Battle with the Bugs: What they do� They misdirect the cognate system to
immunodominant antigens that they canchange and away from antigens they cant
change± Gonorrhea and E. coli pilus antigens highly
variable and immunodominant ± distract from tipproteins that are required for attachment and
sex± HIV gp120 variable regions are B cell dominant
and can vary rapidly
± HIV subdominant T cell antigens protect in the
few animals that recognize them (Watkins)
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Timing and Location are Everything
� Timing - Vaccines work because the cognateresponse after vaccination is much faster whenthe 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 infectionhas progressed since the system is already mountinga cognate response due to the infection� Rabies is an exception - following a rabid animal bite the virus
travels slowly up the nerve to the brain ± immediateimmunization can save your life if the immunity developsbefore the virus gets there, that¶s why a bite on the face is
worse then the arm
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Timing and Location are Everything
� Location 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 theliver
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±
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Timing and Location are Everything
� An example of where timing and location
are both thought to be critical is the
protection induced by CMV vaccineagainst SIV infection to be further
presented at this meeting by Louis Picker
� 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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Basic Principles
� Use what the disease gives you
� Correlates and Surrogates make
everything easy� When everything else fails ± Proof of
Principle studies and bootstrapping
� Manufacturing ± Vaccines are not iPods� Assays rule
� Eternal triangle of risk vs time vs resources
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What the disease gives you
� Epidemiology ±
± Hemophilus type B ± no disease till 4-6 month
± Rotavirus ± 2nd infection with different type± Zoster ± more disease >65 years of age
� High Attack rate ±
± Rotavirus - efficacy in 400 children± Malaria ± efficacy in 2000 children
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What the disease gives you
� Animal Model ±
± Hep B - Non Human Primate± Pnumococcus, Hemophilus,
± TB ± (?) low dose NHP challenge
± HIV- (?) SIV low challenge dose
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What the disease gives you
� Possibility of Human Challenge studies
± Shigella
± Cholera± Malaria
± HIV (?)
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Basic Principles
� Use what the disease gives you
� Correlates and Surrogates make
everything easy� When everything else fails ± Proof of
Principle studies and bootstrapping
� Manufacturing ± Vaccines are not iPods� Assays rule
� Eternal triangle of risk vs time vs resources
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Basic Principles
� Use what the disease gives you
� Correlates and Surrogates make
everything easy� When everything else fails ± Proof of
Principle studies and bootstrapping
� Manufacturing ± Vaccines are not iPods� Assays rule
� Eternal triangle of risk vs time vs resources
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RISK RESOUR CES
TIME
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Vaccine Research Today
� Antigens
± Reverse Engineering
± Bioinformatics± Epitopes
� Vaccine Delivery
± Adjuvants± Non-replicating vectors
± Replicating vectors
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Reverse Engineering
� Utilizing molecular modeling and immune
responses in protected volunteers to down
select from thousands of possible proteins� Limited number of proteins put in mouse or
other small animal studies
� Recent promising examples:
± Common Group B meningococcal protein
± Common Pneumococcal protein
± Common Staphylococcal protein
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Reverse Engineering ± Structural studies
� Understanding the detailed molecular structure of a target protein and itsinteraction with antibody design animmunogen to induce that antibody
� Influenza and HIV tremendous currentwork
± Identified binding regions of monoclonals thatneutralize somewhat broadly including newones that bind V3 stem
± So far unsuccessful in designing immunogen
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Scoring of Antigens Over-expressed/Up-regulated in
AERAS-427 ± From List of Top 45
Rv3127
Rv2005c
Rv3873
Rv2626c
Rv2032
Rv0288
Rv1886c
Rv2031c
Rv0867cRv1009
Rv2623
Rv2450c
Rv1738
Rv2029cRv2006
Rv1813c
Rv1349
Rv1174c
Rv1908cRv0824c
Rv3131
Rv3130c
Rv0079
Rv3804c
Rv1980cRv2628
Rv0685
Rv2389c
Rv1996
Rv1733c
Rv2629
Rv1793
Rv1169c
Rv1130
Rv0467Rv3347c
Rv3132c
Rv2030c
Rv1926c
Rv3875
Rv2744cRv2620c
Rv1884c
Rv2780
Rv2627c
32/45 top scoring antigens by
bioinformatics analysis
directly over-expressed or
up-regulated in AERAS-427
Rv2029c
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Epitopes
� Fundamental problem in B and T cell
based vaccines is epitope selection to
cover the variety of pathogens that mightbe encountered
� Second problem is the virus changing its
epitopes
� Third problem is immunodominance of
some epitopes over others
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Epitope Diversity
� 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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Epitope Diversity- HIV
� 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
� Search for epitopes that cant vary because
of their function
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Epitope Immunodominance- HIV
� Utilization of subdominant antigens in
absence of dominant antigens
� Sequential immunization� Immunization with separate vaccines
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Vaccine Delivery - Adjuvants
� Adjuvants stimulate the innate system ±
mainly through toll receptors
� Several new adjuvants in clinical trials� AS04 with flu vaccines responses in 200-
800 range compared to 20-60 for most flu
vaccine� AS01-E in malaria and TB vaccines
provide very high CD4 T cells in humans
�IC-31 in T
Bvaccines induce CD4 T cells
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Vaccine Delivery ± Non-replicating vectors
� Vaccinia Based: NYVAC, ALVAC, MVA
± HIV- Alvac part of Thai trial
± TB ± MVA AERAS-485 in a 2800 subjectPhase IIB efficacy trial in Cape Town S, Africa
� Adeno based: Ad5, Ad35, Chimp Adeno
± HIV-
� Ad 5 ± Merck NIH HIV trial,� Ad 5 - Current VRC trial
± Malaria -Chimp Adeno ± prime for MVA boost
± TB ± Ad35 induced high CD8 T cells
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ITRITRE2B E2A E4
E1 L1-L3 E3L4 L5]
ITRITRE2B E2A E4
E1 L1-L3 E3L4 L5]
Genomic Structure
Ad35 Viral VectorTargets CD46 on
Human Dentritic CellsLow African seroprevalence
(<2% with neut >200)
E1 & Part of E3 deleted
�Makes room for T
Bantigens(85A, 85B, 10.4)
� Can¶t replicate in humans
Grows to high titer in
PerC6 cells
� Ad5 E1 in PerC6chromosome
� Ad5 E4 Orf6, 6/7
put in Ad35
� Ad35 pIX put back
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PRELIMINARY DATA ± 10 DEC 2008
A C 008 02D M O A 8 A/ C D8 R
CG/AERA 02 x10^10
0 8 1 8 112 11 12 1 0 182
0.0
0.1
0.2
0.
0.
0.
0.
0.
0.8
0.
1.0
CG 02 02
CD8 R
CG imm iz A l L i
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Replicating Vectors
� Replicating vectors have the advantage of longer
antigen production and possibly more effector
cells
� Recombinant BCG:
± Persists for around 40 days
± Appears to be a good prime for protein or viral booster
� Yellow Fever ± Being used as a vector for dengue vaccine now in
phase II trials
± Being explored for HIV with promising NHP data
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Replicating Vectors - CMV
� Persists throughout the life of the animal
� Down regulates the Class I so can re-infect
� Induces subdominant antigens� Induces primarily effector memory T cells
� Prevents productive SIV infection in lowdose NHP challenge
� Safety issues as a human vaccine
± Birth defects in new borns
± Liver and potential heart disease
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Vaccines I Have Helped Develop
� Licensed (10)± Hep A (VAQTA)
± Hemophilis type B (Liquid Pedvax)
± Hemophilus type B ± Hep B (Comvax)± Varicella (4 degree Varivax)
± Measles-Mumps-Rubella- Varicella (ProQuad)
± Hib-HepB-DPT-IPV (Hexavac)
± Zoster (ZostaVax)± Rotavirus (Rota Teq)
± Human Pappiloma Virus (Gardasil)
± Cholera (Dukoral)
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Vaccines I Have Helped Develop
� Phase III± Malaria (RTS,S) ongoing
± Cholera (Peru 15) beginning
� Phase IIB
± Shigella (John Robbins - Polysaccharide conjugate) - successful± Gonorrhea (Pili vaccine) ± failed
± Pseudomonas E. Coli Klebsiella (Passive Aby) failed
± HIV (Adeno Vectored Gag, Pol, Nef) ± failed
± TB (MVA85A-AERAS-485) ± ongoing
± TB
(AER
AS-402) ± ongoing� Phase II
± TB (GSK- M72) - ongoing
± TB (AERAS- 404 HyVac4 SSI/Sanofi) - Ongoing