Vaccine Design: A Statisticans Overview

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2 : A Statisticans Overview. Surajit Ray sray@samsi.info Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #1

3 The Chinese are credited with making the observation that deliberately infecting people with mild forms of smallpox could prevent infection with more deadly forms and provide life long protection. Introduction of first generation of vaccines for use in humans 1798 Smallpox 1926 Pertussis 1885 Rabies 1927 Tuberculosis (BCG) 1897 Plague 1923 Diphtheria 1927 Tetanus 1935 Yellow Fever Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #2

4 Live attenuated vaccines Inactivated or killed vaccines Recombinant sub-unit envelope vaccines Recombinant vectored vaccines DNA vaccines and replicons Involve HIV genetic sequences which, once injected, induce expression of HIV antigens by human cells. In the case of replicons, these sequences are wrapped in the outer coat of an unrelated virus. Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #3

5 Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #4

6 Major Histo Compatibility, also known as human leukocyte antigens or HLA Present on various human cells e.g. dendritic cells. Typically epitopes of length 9. MHC I animation MHC I movie 1 Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #5

7 Mechanism different from MHC I. More complicated as the binding length may be more than 9. MHC II animation MHC II movie 2 Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #6

8 Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #7

9 >A85A_MYCTU 48 GLPVEYLQV MQLVDRVRGAVTGMSRRLVVGAVGAALVSGLVGAVGGTATAGAFSRPGLPVEYLQVPSPS MGRDIKVQFQSGGANSPALYLLDGLRAQDDFSGWDINTPAFEWYDQSGLSVVMPVGGQSS FYSDWYQPACGKAGCQTYKWETFLTSELPGWLQANRHVKPTGSAVVGLSMAASSALTLAI YHPQQFVYAGAMSGLLDPSQAMGPTLIGLAMGDAGGYKASDMWGPKEDPAWQRNDPLLNV GKLIANNTRVWVYCGNGKPSDLGGNNLPAKFLEGFVRTSNIKFQDAYNAGGGHNGVFDFP DSGTHSWEYWGAQLNAMKPDLQRALGATPNTGPAPQGA >A85A_MYCTU 242 KLIANNTRV MQLVDRVRGAVTGMSRRLVVGAVGAALVSGLVGAVGGTATAGAFSRPGLPVEYLQVPSPS MGRDIKVQFQSGGANSPALYLLDGLRAQDDFSGWDINTPAFEWYDQSGLSVVMPVGGQSS FYSDWYQPACGKAGCQTYKWETFLTSELPGWLQANRHVKPTGSAVVGLSMAASSALTLAI YHPQQFVYAGAMSGLLDPSQAMGPTLIGLAMGDAGGYKASDMWGPKEDPAWQRNDPLLNV GKLIANNTRVWVYCGNGKPSDLGGNNLPAKFLEGFVRTSNIKFQDAYNAGGGHNGVFDFP DSGTHSWEYWGAQLNAMKPDLQRALGATPNTGPAPQGA >A85B_MYCTU 239 KLVANNTRL MTDVSRKIRAWGRRLMIGTAAAVVLPGLVGLAGGAATAGAFSRPGLPVEYLQVPSPSMGR DIKVQFQSGGNNSPAVYLLDGLRAQDDYNGWDINTPAFEWYYQSGLSIVMPVGGQSSFYS DWYSPACGKAGCQTYKWETFLTSELPQWLSANRAVKPTGSAAIGLSMAGSSAMILAAYHP QQFIYAGSLSALLDPSQGMGPSLIGLAMGDAGGYKAADMWGPSSDPAWERNDPTQQIPKL VANNTRLWVYCGNGTPNELGGANIPAEFLENFVRSSNLKFQDAYNAAGGHNAVFNFPPNG THSWEYWGAQLNAMKGDLQSSLGAG >ACTB_HUMAN 180 ALPHAILRL MDDDIAALVVDNGSGMCKAGFAGDDAPRAVFPSIVGRPRHQGVMVGMGQKDSYVGDEAQS KRGILTLKYPIEHGIVTNWDDMEKIWHHTFYNELRVAPEEHPVLLTEAPLNPKANREKMT QIMFETFNTPAMYVAIQAVLSLYASGRTTGIVMDSGDGVTHTVPIYEGYALPHAILRLDL AGRDLTDYLMKILTERGYSFTTTAEREIVRDIKEKLCYVALDFEQEMATAASSSSLEKSY ELPDGQVITIGNERFRCPEALFQPSFLGMESCGIHETTFNSIMKCDVDIRKDLYANTVLS GGTTMYPGIADRMQKEITALAPSTMKIKIIAPPERKYSVWIGGSILASLSTFQQMWISKQ EYDESGPSIVHRKCF Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #8

10 MHC class I genes (HLA-A, HLA-B and HLA-C) MHC class II genes (HLA-DP, HLA-DQ and HLA-DR) Database ALPHAILRL Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #9

11 We want to classify the peptides into Binders and non Binders. Binders of specific HLA-super types. Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #10

12 A supermotif is a motif which confers the ability to bind to several different HLA A supertype, the corresponding assembly of HLA As of October 2001, nine major HLA class I supertypes have been defined HLA-A1, A2, A3, A24 HLA-B7, B27, B44, B58, B62 e.g the 5 alleles belonging to HLA-A3 supertype: A*0301 A*1101 A*3101 A*3301 A*6801. Sette et al, Immunogenetics (1999) 50: Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #11

13 Mostly +ve examples. No good database of -ve examples. Include structural information of peptides in the classifier. In case of we do not know the position of binding. Supertypes are still being defined. Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #12

14 British: Tularaemia Pathogen: Francisella tularensis Infects small mammals ground squirrels, rabbits, hares, voles, muskrats, water rats and other rodents Arthropod vectors: ticks, biting flies, mosquitoes Uncommon zoonosis 125 cases/year in USA farmers, hunters, walkers, forest workers kills less than 50 people a year worldwide Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #13

15 Why is it important. Tested by Japan in WWII as potential bioweapon Weaponised and stockpiled by USA and USSR during Cold War Highly infectious: inhalation of 10 bacteria can cause disease Avenues: ingestion (water and food), inhalation, direct contact, arthropod intermediates, animal bites No person to person spread Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #14

16 Ulceroglandular Incubation period 3-6 days Sudden onset flu like symptoms Ulcer at site of infection Enlargement of draining nodes Typhoidal syndrome: septicemia without ulcer or lymphadenopathy Oropharyngeal: sore throat, enlarged tonsils, yellow-white pseudomembrane Gastrointestinal: persistent diarrhea, bowel ulceration - acute fatal disease Pneumonia Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #15

17 A World Health Organization model for a sizeable tularemia release over a metropolitan area with 5 million inhabitants predicted 250,000 people incapacitated and 19,000 deaths, Dennis cited. With antibiotic treatment, tularemia mortality rate is under 10treatment. Work in Progress... Slides produced with HA-prosper latex package Surajit Ray Samsi PostDoc Seminar: Nov 2: slide #16