Virology Antigenic Variation Vaccine Development. Microbial Pathogenicity March 12, 2019 Kevin Coombs

Size: px

Start display at page:

Download "Virology Antigenic Variation Vaccine Development. Microbial Pathogenicity March 12, 2019 Kevin Coombs"

Harry Davidson
5 years ago
Views:

1 Virology Antigenic Variation Vaccine Development Microbial Pathogenicity March 12, 2019 Kevin Coombs

2 Overview Host defense mechanisms General considerations of viral variation 4 Examples; Virus replication; Picornavirus Flavivirus Coronavirus Influenza virus Vaccine considerations (Sabin & Salk strategies) When things can go wrong

3 Whitton & Oldstone (2001) in Fields Virology, p.287

4 Kinetics of endogenous immune responses Biron & Sen (20017) Fields Virology, p. 332

5 Viral-induced Signaling pathways Biron & Sen (2007) In Fields Virology, p. 251

6 Summary of innate immune responses Biron & Sen (2007) In Fields Virology, p. 270

7 Class I Antigen Processing Yewdell & Hill (2002) Nature Immunol 3:1019 McMichael & Hanke (2002) Nature Rev. Immunol. 2:283

Class II Antigen Processing Nature Reviews Immunology 1; 126-134 (2001) CROSS-PRESENTATION IN VIRAL IMMUNITY AND SELF-TOLERANCE Youtube

8 Class II Antigen Processing Nature Reviews Immunology 1; (2001) CROSS-PRESENTATION IN VIRAL IMMUNITY AND SELF-TOLERANCE Youtube Class I: Class II:

9 Humoral Immunity Pazner (2004) Nature Rev. Immunol. 4:199

10 What is antigenic variation?

11 What is antigenic variation?

12 Implications of high mutation rate 10kb X X X X X X X Quasispecies X X X X X X X X X

13 Some viruses have segmented genomes: Allows assortment Orthomyxoviridae Reoviridae T1L T2J T3D Ritchey et al (1976) J. Virol. 20:307, in Krug (1989) The Influenza Viruses

14 Segmented Genomes Allow Assortment X

15 Viruses with Segmented Genomes 2 n Influenza (8 genes) = 256 possibilities Rotavirus (11 genes) = 2048 possibilities

16 RNA viruses with segmented genomes have capacity to generate altered genomes by both random mutation (where rates are high) and by assortment In Orthomyxoviridae random mutation leads to Genetic drift and assortment leads to Genetic shift Influenza pandemics generally* result from assortment of human and avian influenza viruses in a pig mixing vessel which results in new virus

17 SPECIFIC VIRUSES Basic Virology

18 + - The Baltimore Classification Scheme DNA Class VII ex. Hepatitis B virus +/- DNA Class II ex. parvoviruses bacteriophage fx RNA Class VI ex. HIV Rous sarcoma virus + - DNA Class I ex. herpesviruses polyomaviruses adenoviruses bacteriophage T4 - RNA Class V ex. rabies virus measles virus influenza virus Ebolaviruses mrna + - RNA Class III ex. reoviruses + RNA Class IV ex. poliovirus West nile virus rubella virus TMV Revised from: Baltimore (1971) Bacteriol. Rev. 35:235

19 mrna Protein synthesis Nucleus Nucleus

20 Antigenicity Type-specific (Neutralizing) Group-specific Modified from Stewart et al (1991) Cell 67:145

21 Virus Host Interactions Nucleus

22 Virus Host Interactions Nucleus

23 Virus Host Interactions Lytic Infection Latent Infection (Lysogeny) Persistent Infection Transformation

24 Tyler & Nathanson (2001) In Fields Virology, p. 201

25 SPECIFIC VIRUSES Basic Virology

[105](common cold) Hepatovirus [2](hepatitis A) Aphthovirus [8](Foot and mouth) Cardiovirus

26 Pico rnaviridae Very small ~30nm non-enveloped icosahedral particles 60 copies each of VP1, VP2, VP3, VP4 Genome ~ 7-8kb ss(+) RNA 5 genera: Enteroviruses [111 strains](poliovirus) Rhinoviruses [105](common cold) Hepatovirus [2](hepatitis A) Aphthovirus [8](Foot and mouth) Cardiovirus [7](Encephalomyocarditis)

27 Modified from Hollinger & Emerson (2007) In Fields Virology, p. 914

28 Overview of picornavirus life cycle Baltimore Class IV Cytoplasmic Polyprotein cleavage All proteins = amounts No glycosylation No splicing RNA replication through full-length (-) strand Racaniello (2001) In Fields Virology, p. 693

29 Translation and processing of picornavirus proteins Racaniello (2001) In Fields Virology, p. 691

30 Translation and processing of picornavirus proteins P1 2A P1 P1 P2 3C P1 P2 3CD L Racaniello (2001) In Fields Virology, p. 691

31 Genes and cleavage sites in various picornaviruses Rowlands (2001) Encyclop. Life Sci. - Picornaviruses

32 Alphaviridae Togaviridae Cloak: enveloped Flaviviridae Also considered Arboviruses (arthropod borne) Alphaviridae ~70nm virion with ~40nm icosahedral nucleocapsid 240 copies each of E1, E2, C Genome ~ kb ss(+) RNA Grouped by Antigenic complex : Eastern equine encephalitis Venezuelan equine encephalitis Western equine encephalitis Barmah forest Semliki forest

33 General Togaviridae Structure For Alphatogaviridae; the Flaviviridae envelope proteins are E and M E2 E1 C Membrane ssrna

34 Probable* life cycle Lindenbach & Rice (2001) In Fields Virology, p. 994

35 Hardy (1988) In The arboviruses: ecology and epidemiology

36 Flaviviridae Yellow Zika Fields Virology (1996)

37 Fields Virology (1996)

38 Yellow fever Dengue

39 YFV Fields Virology (1996)

40 Another prototypic Class IV ss(+) RNA virus (ex. Coronaviridae) Different Coronavirus transcripts are produced by differentially transcribed messages; The genome is copied into a fulllength (-) copy, from which various sub-genomic (+) are transcribed

Orthomyxoviridae http://www.google.ca/imgres?q=big+picture+book+of +viruses&um=1&hl=en&tbo=d&biw=1237&bih=557&t bm=isch&tbnid=rruhdhpzvl2gwm:&imgrefurl=http:/ /bakerinstitute.vet.cornell.

41 Orthomyxoviridae +viruses&um=1&hl=en&tbo=d&biw=1237&bih=557&t bm=isch&tbnid=rruhdhpzvl2gwm:&imgrefurl= /bakerinstitute.vet.cornell.edu/publicinfo/view.php%3f id%3d347&docid=fme5lmupehkdvm&imgurl= bakerinstitute.vet.cornell.edu/contentimages/ _ jpg&w=200&h=177&ei=umm1UIW HL6ftygGPhYCICQ&zoom=1&iact=hc&vpx=379&vpy =174&dur=3303&hovh=141&hovw=160&tx=81&ty=81 &sig= &page=1&tbnh=134& tbnw=152&start=0&ndsp=23&ved=1t:429,r:2,s:0,i:88 Current genera: Influenza A Influenza B Influenza C Thogotovirus Isavirus ~100nm virion Pleomorphic Segmented Genome (7-8 segments) ss(-) RNA Enveloped

42 History and Impact Epidemics documented since 1173 AD 1918 Pandemic Spanish Flu (HINI) - Killed Million 1957 Asian Influenza ( H2N2) 1968 Hong Kong Flu (H3N2) ( H5N1) 718 cases so far Avian Flu / 413 deaths (WHO, Jan, 2015) 2009 Swine origin H1N1; WHO reported 1225 deaths as of Aug2010; CDC re-estimates suggest up to 0.6M Influenza and Pneumonia Mortality Rates Yearly Epidemics lead to approx deaths in Canada, ~ 0.5 M deaths globally Figure 3. U- and W- shaped combined influenza and pneumonia mortality rates, by age at death, per 100,000 persons in each age group (United States, 1911 to 1918). Influenza- and pneumonia-specific death rates are plotted for the interpandemic years (1911 to 1917, dashed line) and for the pandemic year (1918, solid line). Reprinted from Grove RD, Hetzel AM. Vital Statistics Rates in the United States: Washington: U.S. Government Printing Office, 1968, and Linder FE, Grove RD. Vital Statistics Rates in the United States: Washington: U.S. Government Printing Office, 1943.

43 History of Influenza Outbreaks

44 History of Influenza Outbreaks

45 For Both Flu types - the virus came directly from birds - young and healthy make up most fatalities - The human immune system creates cytokine storm, filling the lungs with fluid newfluwiki2.com/

46 Unlike H5N1 and 1918: - ph1n1 is a quadruple reassortant; not directly from birds Like 1918 and H5N1: - young and healthy make up most fatalities - The human immune system creates cytokine storm, filling the lungs with fluid The 1918 flu had a Case Fatality Ratio of 2.5% H5N1 has a Case Fatality Ratio of 60% ph1n1 had a Case Fatality Ratio of ~ 1% newfluwiki2.com/

47 Wright, Neumann & Kawaoka (2007) In Fields Virology, Supplemental

B A Gene Protein Segment # Size (nt) Name MW (kd) Copy # per virion Function(s) 1 2 3 2341 2341 2233 PB2 PB1 PA 87 96 85 30-60 30-60 30-60 RNA polymerase; cap recognition RNA polymerase; elongation

48 B A Gene Protein Segment # Size (nt) Name MW (kd) Copy # per virion Function(s) PB2 PB1 PA RNA polymerase; cap recognition RNA polymerase; elongation RNA polymerase, protease HA Hemaglutinin, receptor binding, major antigen, fusion activity NP NA RNA binding & nucelar import Neuraminidase activity, surface glucoprotein Noda et al., (2006) Nature 439: M1 M Matrix, interacts with vrnps, nuclear export, budding Ion channel, assembly NS1 + NS NA Multi-functional; IFN antagonist Nuclear export of vrnps Nomenclature: A/PR/8/34 (H1N1) Figure 1. Influenza A/PR/8/34 genetic and structural organization. A. Gene protein coding assignments & characteristics. B. Virus structure; Top, electron micrograph; Bottom, Diagrammatic cartoon of virion, with proteins designated as in A, middle column. Type Isolate # Country of Origin Puerto Rico Year of Isolation Subtype

49 Phylogeny of Influenza A H and N Genes Palese & Shaw (2007) In Fields Virology, p New H17N10 and H18N11 viruses described from bats (Tong et al (2012) PNAS 109:4269)

50 Wright, Neumann & Kawaoka (2007) In Fields Virology, Supplemental

51 1 Amantadine a vrna mrna 8 mrna crna 11 Leptomycin B PB2 PB1 PA NP M1 NS1 NS2 9a 12 HA 13 NA M2 9b 15 10b Oseltamivir 14

52 Influenza Variation: From: Lamb & Krug (2001) In Fields Virology, Supplemental

53 Influenza virus transmission/assortment From: Wright & Webster (2001) In Fields Virology, Supplemental

54 Sites of maturation also influence antigenicity & presentation Hunter (2001) In Fields Virology, p. 184

55 Vaccine Development Considerations Which agents should be targeted? Who should be vaccinated? What constitutes a good vaccine? Live vs Dead

56 Vaccines & Preventable Diseases: List of Vaccine-Preventable Diseases The following links will lead you to the main page that describes both the disease and the vaccine(s). Anthrax Cervical Cancer (Human Papillomavirus) Diphtheria Hepatitis A Hepatitis B Haemophilus influenzae type b (Hib) Human Papillomavirus (HPV) Influenza (Flu) Japanese encephalitis (JE) Lyme disease Lyme disease vaccine no longer available in the United States. Measles Meningococcal Vaccines are available for all of the following vaccine-preventable diseases (unless otherwise noted): Monkeypox There is NO monkeypox vaccine. The smallpox vaccine is used for this disease. Mumps Pertussis Pneumococcal Polio Rabies Rotavirus Rubella Shingles (Herpes Zoster) Smallpox Tetanus Typhoid Tuberculosis (TB) Varicella (Chickenpox) Yellow Fever

58 Vaccine Considerations

60 Genetic Relatedness Between Vaccinia Virus and Variola major Brunham & Coombs (1998) CJIDMM

61 Salk Sabin Ogra & Karzon (1971) Prog. Med. Virol. 13:156 Pallansch & Roos (2001) In Fields Virology, p.764

62 Polio Eradication Program (WHO) Year WHO, 2004

63 Reliefweb.int

64 Reliefweb.int

66 Recent Successes Papillomavirus Vaccines Gardasil 9; Cervarix When should my child be vaccinated? All kids who are 11 or 12 years old should get two shots of HPV vaccine six to twelve months apart. Adolescents who receive their two shots less than five months apart will require a third dose of HPV vaccine. 3 Things Parents Need to Know about Preventing Cancers If your teen hasn't gotten the vaccine yet, talk to their doctor or nurse about getting it for them as soon as possible. If your child is older than 14 years, three shots will need to be given over 6 months. Also, three doses are still recommended for people with certain immunocompromising conditions aged 9 through 26 years. HPV Vaccines for Boys and Girls[2 pages] CDC Feature: Are your kids protected from HPV-related cancers? Frequently Asked Questions about HPV Vaccines Who else should get the HPV vaccine? Teen boys and girls who did not start or finish the HPV vaccine series when they were younger should get it now. HPV vaccine is recommended for young women through age 26, and young men through age 21. HPV vaccine is also recommended for the following people, if they did not get vaccinated when they were younger: young men who have sex with men, including young men who identify as gay or bisexual or who intend to have sex with men through age 26; young adults who are transgender through age 26; and young adults with certain immunocompromising conditions (including HIV) through age 26.

67 SOME Examples of when things can go wrong

68 Are all Antibody Responses Good? Hollinger & Liang (2001) In Fields Virology,

69 Are all Antibody Responses Good? Antibody-mediated enhancement of Dengue leads to worse disease if Ab mismatch Whitehead et al (2007) Nat. Rev. Microbiol. 5:518

Influenza viruses. Virion. Genome. Genes and proteins. Viruses and hosts. Diseases. Distinctive characteristics

Influenza viruses. Virion. Genome. Genes and proteins. Viruses and hosts. Diseases. Distinctive characteristics Influenza viruses Virion Genome Genes and proteins Viruses and hosts Diseases Distinctive characteristics Virion Enveloped particles, quasi-spherical or filamentous Diameter 80-120 nm Envelope is derived