Transcript chinese ass
Immunotherapy and Vaccination Immunotherapy: Chapter 14 Vaccination is most familiar Using Immune system to fight disease Also see on-line Influenza resource at http://www.influenzareport.com/ir/vacci nes.htm The Parents' Guide to Childhood Immunizations http://www.cdc.gov/nip/publications/Par ents-Guide/2005-parents-guide.pdf Self-Test Questions: Intro: both A: 1 – 5, 7, 8 B: 1 - 8 C - G: all Disease Virus Small pox Cow pox Chicken pox variola vaccinia varicella Immunotherapy 1 Edward Jenner and the origin of Immunotherapy (vaccination) Small pox caused by ‘variola virus’ Induced immunity dates to ancient Chinese -- practiced ‘Variolation’ -- brought to England in 1700s -- lead to the ‘Royal experiment’ Jenner discovered protective effect of cow pox -- ‘vaccinia virus’ -- ‘vacca’ Latin for cow - vaccination WHO irradicated small pox in 1970s Immunotherapy 2 What are different types of immunization? Passive Immunization -- direct transfer of protective antibodies -- no immunological memory Active Immunization -- activation of immune response -- immunological memory Therapeutic Immunization -- treat existing disease Immunotherapy 3 Passive Immunization to treat Fetal Erythroblastosis Conditions: mother Rh—; father, 1st and 2nd fetuses are Rh+ Rh Immune hemolysis Rhogam Given 24-48 hours after 1st pregnancy Immunotherapy 4 Active Vaccination: What are some important considerations in the design of vaccines? Characteristics of pathogen & disease Intra- vs extra-cellular short or long incubation acute or chronic disease Antigenic stability route of infection Characteristics of vaccine appropriate response booster safety stability, cost Characteristics of patient Infants (vs adults) have lower… -- GC activity -- Plasma cell production -- TH1 response Maternal Ab black responses Immunotherapy 5 What are the recommended childhood vaccines? Combined vaccines Why are boosters needed? Other vaccines for special needs TB, anthrax, plague, yellow fever, etc Immunotherapy 6 Vaccine efficacy vs Efficacy – under trial conditions incidence among those administered 1- ------------------------------------------- ------------------------------------------incidence among those not administered Example efficacies Diphtheria: 87%-96% Tetanus: >90% Oral polio: 90%-100% Mumps/Measles/Rubella: 90%-95% HIV vaccine trials 150 vaccines developed 6 have made it to efficacy testing 2009: 1st with efficacy (31%) [2007 had negative efficacy] Malaria vaccine trial 2011: 45 – 56% effectiveness Calculated under “field” conditions i.e., real world conditions -- religious/cultural opposition -- available medical facilities -- etc Is 100% efficacy necessary? -- “herd immunity” Diphtheria Hib (<5 yrs old) Measles Mumps Pertussis Polio (paralytic) Rubella Smallpox Tetanus Immunotherapy Cases per Year before in (average) 2003 175,885 1 20,000 (est.) 259 503,282 56 152,209 231 147,271 11,647 16,316 0 47,745 7 48,164 0 1,314 20 Decrease in Cases per Year 99.9% 98.8% 99.9% 99.9% 92.1% 100.0% 99.9% 100.0% 98.5% 7 How are vaccines made? Dead (inactivated) pathogens IPV – Inactivated polio vaccine – ‘Salk’ vaccine [old pertussis of DPT -- Bordetella pertussis] Live attenuated pathogens MMR – measles, mumps, rubella viruses OVP -- oral polio vaccine – ‘Sabin’ vaccine Cell cultured virus Subunit / Peptide components HBsAG -- Hepititis B surface antigen Flu – purified HA & NA antigens Conjugates (polysaccharides coupled to protein carrier) HiB – Haemophilus influenzae type B PCV – pneumococcal conjugate vaccine Remember Adjuvants? Toxoids DTaP -- diphtheria, tetanus toxoids [ + “acellular pertussis” molecular component] -- increase immune response e.g., aluminum hydroxide McGraw-Hill Vaccines Immunotherapy 8 What are pros and cons of different types of vaccines? Dead (inactivated) pathogens pros may be safer; more stable than attenuated cons weaker cell mediated response; boosters contaminants – pertussis endotoxin in old DPT Live attenuated pathogens pros better cell-mediated response cons reversion -- Sabin polio (Types 1 & 2) infection in immunodeficient patients less stable Molecular components pros No living pathogen present very stable cons fewer epitopes weaker cell mediated response Vaccine type Example reactions Vaccines from Chicken eggs and cell cultures Allergic reactions Contaminating pathogens Vaccines with Preservatives Allergic reactions Live attenuated Susceptibility during preganncy and among immunodepressed Dead whole cell Contamination with toxins Immunotherapy 9 Why do we not have vaccines for serious protozoal diseases -- malaria, African sleeping sickness Plasmodium causes Malaria -- Anopholes mosquito is vector Trypanosoma cause ASS -- tsetse fly is vector Complex life cycles Chronic diseases Undergo “Antigenic Shift” Trypanosoma carries ~1000 VSG genes (variant surface glycoprotein) ~1% of parasites shift AG Immunotherapy 10 Influenza: the disease Principal virus subtypes -- A & B Key surface antigens Hemaglutinin -- HA Neuraminidase – NA -- numbered 1,2,3, etc Causes of seasonality unclear: Δ antigenicity/ infectiousness social interactions environmental conditions Current circulating forms H3N2*, H1N1, H1N2, ~36K deaths ~200,000 hospitalizations Immunotherapy 11 Influenza con’t: Circulating stains vary annually -- “antigenic drift” -- vaccine must accommodate Recent vaccines contain A -- New Caledonia/20/99 (H1N1) A -- Wisconsin/67/2005 (H3N2) B -- Malaysia/2506/2004 Vaccines types Injection – inactivated whole virus or purified HA & NA antigens Nasal spray “FluMist” -- cold adapted attenuated Prepared in eggs Capacity only ~ 300 x 106 doses Immunotherapy 12 Pandemic Flu “Antigenic-Shift” can occur History 1918 Spanish Flu (H1N1; 40 mil dead) 1957 Asian Flu (H2N2; ~1 mil+ dead 1968 Hong Kong Flu (~0.75 mil dead) -- AG-shift from H2N2 to H3N2 Swine Flu 2009 H1N1 vaccine (influenza A/California/07/2009) 15 μg HA or 106.5-107.5 pfu of live attenuated virus Challenges to vaccination Development time Production capacity (use of eggs?) Distribution Economics Vaccination strategy Current spread of H5H1 Immunotherapy 13 Modern Immunotherapies Rituximab mechanisms Immunotherapies for Autoimmune disorders / transplant rejection 1) B-cell elimination -- e.g., Rituximab: -- mAb against CD-20 (Ca++ channel?) -- triggers B-cell destruction At advent of Cancer Immunotherapy -- Long history: “Coley’s Toxins” -- immune activation What are “Cancer Antigens”? Immunotherapy 14 Other Types of Cancer Immunotherapies Checkpoint inhibitors 2) Checkpoint inhibitors -- Why do many cancers evade immune destruction? 3) Cancer vaccines - target cancer-specific antigens 4) Cell coupling -- “Bispecific molecules” (mAb) -- e.g., Blinatumomab (“Blincyto”) B-cell leukemia -- mAb Fabs against CD3 & CD19 Immunotherapy 15 Types of Cancer Immunotherapy, con’t 5) Cell Therapy May involve Infusion of : A. Hematopoietic stem cells from either umbilical cord blood, peripheral blood, or bone marrow cells -- commonly used for leukemia, etc B. Dendritic cells C. T cells or NK cells treated in vitro to recognize and kill cancer cells directly. -- engineer to produce Anti- tAG TCR Immunotherapy 16