How Vaccines Work (Jerald Sadoff)

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



AERAS GLOBAL TB VACCINE FOUNDATION

Topics to be covered� Refresher: How Vaccines Work

� Basic principles in developing vaccines

� Vaccine Research Today




Refresher: How Vaccines Work � The general answer

� The battle between the bugs and us

� Their Genes and our Genes

� Timing and location are everything




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




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




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)






Vaccines induce the cognate

system to remember, recognize,

and kill viruses, bacteria, parasites

or cancer cells




The cognate system has 3 weapons:

1. Antibodies

2. White cells: Macs and Polys

3. White cells: T cells




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




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




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




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




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




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




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




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




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




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




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)




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





� 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




±





� 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.




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




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





� Animal Model ±

± Hep B - Non Human Primate± Pnumococcus, Hemophilus,

± TB ± (?) low dose NHP challenge

± HIV- (?) SIV low challenge dose





� Possibility of Human Challenge studies

± Shigella

± Cholera± Malaria

± HIV (?)




Basic Principles




































Basic Principles










RISK RESOUR CES

TIME




Vaccine Research Today

� Antigens

± Reverse Engineering

± Bioinformatics± Epitopes

� Vaccine Delivery

± Adjuvants± Non-replicating vectors

± Replicating vectors




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




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






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




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




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




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




Epitope Immunodominance- HIV

� Utilization of subdominant antigens in

absence of dominant antigens

� Sequential immunization� Immunization with separate vaccines




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




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




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




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




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




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




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)




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

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How Vaccines Work (Jerald Sadoff)

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