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Refresher: How Vaccines Work; Vaccine Research Today Jerald C. Sadoff MD AIDS Vaccine 2009 Journalist Scholarship Training Overview October 18 th 2009.

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Presentation on theme: "Refresher: How Vaccines Work; Vaccine Research Today Jerald C. Sadoff MD AIDS Vaccine 2009 Journalist Scholarship Training Overview October 18 th 2009."— Presentation transcript:

1 Refresher: How Vaccines Work; Vaccine Research Today Jerald C. Sadoff MD AIDS Vaccine 2009 Journalist Scholarship Training Overview October 18 th 2009 Paris, France

2 AERAS GLOBAL TB VACCINE FOUNDATION Topics to be covered Refresher: How Vaccines Work Basic principles in developing vaccines Vaccine Research Today

3 AERAS GLOBAL TB VACCINE FOUNDATION Refresher: How Vaccines Work The general answer The battle between the bugs and us Their Genes and our Genes Timing and location are everything

4 AERAS GLOBAL TB VACCINE FOUNDATION 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 will be ready faster with a more powerful response Sometimes it gets the body to do something different and better then if it were naturally infected

5 AERAS GLOBAL TB VACCINE FOUNDATION 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

6 AERAS GLOBAL TB VACCINE FOUNDATION The Innate System Ancient system found in almost all living things 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)

7 AERAS GLOBAL TB VACCINE FOUNDATION Cognate System Newer more sophisticated system found in higher animals which is dependent on the innate system Recognizes very specific parts of the bug called antigens or epitopes Comes up slower if hasn’t seen it before It remembers from one time to the next Its weapons: antibodies and T cells recognize and kill very precisely

8 AERAS GLOBAL TB VACCINE FOUNDATION Vaccines induce the cognate system to remember, recognize, and kill viruses, bacteria, parasites or cancer cells

9 AERAS GLOBAL TB VACCINE FOUNDATION The cognate system has 3 weapons: 1.Antibodies 2.White cells: Macs and Polys 3.White cells: T cells

10 AERAS GLOBAL TB VACCINE FOUNDATION Antibodies Antibodies are proteins floating in our fluids and organs everywhere they can get At one end they recognize and stick on the surface of the bug When they bind bad things happen to the bug

11 AERAS GLOBAL TB VACCINE FOUNDATION 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 to close 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

12 AERAS GLOBAL TB VACCINE FOUNDATION 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

13 AERAS GLOBAL TB VACCINE FOUNDATION CD 4 T cell CD 8 T cell TH1 TH2 TH1 TH2 IFN-γ IL-2 TNF-α IL-4 B - cell antibodies DTP, Hib, Pneumococcus, Measles, Polio, Hep B, Rotavirus, HPV, Malaria TB, Malaria, HIV Central or Effector Memory

14 AERAS GLOBAL TB VACCINE FOUNDATION Battle with the Bugs: What they do They protect themselves from innate White cell engulfment and killing –Bacteria 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 –TB 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

15 AERAS GLOBAL TB VACCINE FOUNDATION Battle with the Bugs: What they do 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 days so that adaptive T cells are too slow –The new malaria vaccine induces both antibody and T cells that are ready for it

16 AERAS GLOBAL TB VACCINE FOUNDATION 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

17 AERAS GLOBAL TB VACCINE FOUNDATION 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

18 AERAS GLOBAL TB VACCINE FOUNDATION 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 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 We can slowly change our antibody genes

19 AERAS GLOBAL TB VACCINE FOUNDATION 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 days of first infecting humans thus avoiding that cognate response HIV can eventually find something that it human host cant respond to

20 AERAS GLOBAL TB VACCINE FOUNDATION Battle with the Bugs: What they do 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 B cell dominant and can vary rapidly –HIV subdominant T cell antigens protect in the few animals that recognize them (Watkins)

21 AERAS GLOBAL TB VACCINE FOUNDATION Timing and Location are Everything 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 Rabies 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

22 AERAS GLOBAL TB VACCINE FOUNDATION 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 the liver

23 AERAS GLOBAL TB VACCINE FOUNDATION Studies with NIH VRC – Bob Seder, Mario Roederer

24 AERAS GLOBAL TB VACCINE FOUNDATION Timing and Location are Everything 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 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.

25 AERAS GLOBAL TB VACCINE FOUNDATION 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

26 AERAS GLOBAL TB VACCINE FOUNDATION What the disease gives you Epidemiology – – Hemophilus type B – no disease till 4-6 month – Rotavirus – 2 nd infection with different type –Zoster – more disease >65 years of age High Attack rate – –Rotavirus - efficacy in 400 children –Malaria – efficacy in 2000 children

27 AERAS GLOBAL TB VACCINE FOUNDATION What the disease gives you Animal Model – –Hep B - Non Human Primate –Pnumococcus, Hemophilus, –TB – (?) low dose NHP challenge –HIV- (?) SIV low challenge dose

28 AERAS GLOBAL TB VACCINE FOUNDATION What the disease gives you Possibility of Human Challenge studies –Shigella –Cholera –Malaria –HIV (?)

29 AERAS GLOBAL TB VACCINE FOUNDATION 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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39 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

40 AERAS GLOBAL TB VACCINE FOUNDATION RISK RESOURCES TIME

41 AERAS GLOBAL TB VACCINE FOUNDATION Vaccine Research Today Antigens –Reverse Engineering –Bioinformatics –Epitopes Vaccine Delivery –Adjuvants –Non-replicating vectors –Replicating vectors

42 AERAS GLOBAL TB VACCINE FOUNDATION 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

43 AERAS GLOBAL TB VACCINE FOUNDATION Reverse Engineering – Structural studies Understanding the detailed molecular structure of a target protein and its interaction with antibody design an immunogen to induce that antibody 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

44 AERAS GLOBAL TB VACCINE FOUNDATION Bioinformatics Using scoring systems with internal validation combine all of the information about antigen candidates to select promising antigens for inclusion in vaccine vector Example: TB antigens for inclusion in a recombinant BCG for over-expression

45 AERAS GLOBAL TB VACCINE FOUNDATION Scoring of Antigens Over-expressed/Up-regulated in AERAS-427 – From List of Top 45 Rv3127 Rv2005c Rv3873 Rv2626c Rv2032 Rv0288 Rv1886c Rv2031c Rv0867c Rv1009 Rv2623 Rv2450c Rv1738 Rv2029c Rv2006 Rv1813c Rv1349 Rv1174c Rv1908c Rv0824c Rv3131 Rv3130c Rv0079 Rv3804c Rv1980c Rv2628 Rv0685 Rv2389c Rv1996 Rv1733c Rv2629 Rv1793 Rv1169c Rv1130 Rv0467 Rv3347c Rv3132c Rv2030c Rv1926c Rv3875 Rv2744c Rv2620c Rv1884c Rv2780 Rv2627c 32/45 top scoring antigens by bioinformatics analysis directly over-expressed or up-regulated in AERAS-427 Rv2029c

46 AERAS GLOBAL TB VACCINE FOUNDATION Epitopes Fundamental problem in B and T cell based vaccines is epitope selection to cover the variety of pathogens that might be encountered Second problem is the virus changing its epitopes Third problem is immunodominance of some epitopes over others

47 AERAS GLOBAL TB VACCINE FOUNDATION 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

48 AERAS GLOBAL TB VACCINE FOUNDATION 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

49 AERAS GLOBAL TB VACCINE FOUNDATION Epitope Immunodominance- HIV Utilization of subdominant antigens in absence of dominant antigens Sequential immunization Immunization with separate vaccines

50 AERAS GLOBAL TB VACCINE FOUNDATION Vaccine Delivery - Adjuvants Adjuvants stimulate the innate system – mainly through toll receptors Several new adjuvants in clinical trials AS04 with flu vaccines responses in range compared to for most flu vaccine AS01-E in malaria and TB vaccines provide very high CD4 T cells in humans IC-31 in TB vaccines induce CD4 T cells

51 AERAS GLOBAL TB VACCINE FOUNDATION Vaccine Delivery – Non-replicating vectors Vaccinia Based: NYVAC, ALVAC, MVA –HIV- Alvac part of Thai trial –TB – MVA AERAS-485 in a 2800 subject Phase 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

52 AERAS GLOBAL TB VACCINE FOUNDATION Genomic Structure Ad35 Viral Vector Targets CD46 on Human Dentritic Cells Low African seroprevalence ( 200) E1 & Part of E3 deleted Makes room for TB antigens (85A, 85B, 10.4) Can’t replicate in humans Grows to high titer in PerC6 cells Ad5 E1 in PerC6 chromosome Ad5 E4 Orf6, 6/7 put in Ad35 Ad35 pIX put back

53 AERAS GLOBAL TB VACCINE FOUNDATION PRELIMINARY DATA – 10 DEC 2008 BCG immunized Adults St Louis

54 AERAS GLOBAL TB VACCINE FOUNDATION 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

55 AERAS GLOBAL TB VACCINE FOUNDATION 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 low dose NHP challenge Safety issues as a human vaccine –Birth defects in new borns –Liver and potential heart disease

56 AERAS GLOBAL TB VACCINE FOUNDATION 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)

57 AERAS GLOBAL TB VACCINE FOUNDATION 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 (AERAS-402) – ongoing Phase II –TB (GSK- M72) - ongoing –TB (AERAS- 404 HyVac4 SSI/Sanofi) - Ongoing


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