Immunotherapy1 Immunotherapy and Vaccination Chapter 14 Also see on-line Influenza resource at nes.htm The Parents' Guide to Childhood Immunizations ents-Guide/2005-parents-guide.pdf Self-Test Questions: Intro: both A: 1 – 5, 7, 8 B: C - G: all Immunotherapy: Using Immune system to fight disease Vaccination is most familiar DiseaseVirus Small poxvariola Cow poxvaccinia Chicken poxvaricella

Immunotherapy2 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

Immunotherapy3 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

Immunotherapy4 Passive Immunization to treat Fetal Erythroblastosis C onditions: mother Rh — ; father, 1st and 2nd fetuses are Rh+ Rh Immune hemolysis Rhogam Given hours after 1 st pregnancy

Immunotherapy5 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 -- T H 1 response Maternal Ab black responses

Immunotherapy6 What are the recommended childhood vaccines? Combined vaccines Why are boosters needed? Other vaccines for special needs TB, anthrax, plague, yellow fever, etc

Immunotherapy7 Is 100% efficacy necessary? -- “herd immunity” Cases per Year Decrease beforeinin Cases (average) 2003 per Year Diphtheria 175, % Hib (<5 yrs old) 20,000 (est.) % Measles 503, % Mumps 152, % Pertussis 147,271 11, % Polio (paralytic)16, % Rubella 47, % Smallpox 48, % Tetanus 1, % Vaccine efficacy vs Efficacy – under trial conditions incidence among those administered 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: 1 st 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

Immunotherapy8 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 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 Toxoids DTaP -- diphtheria, tetanus toxoids [ + “acellular pertussis” molecular component] Remember Adjuvants? -- increase immune response e.g., aluminum hydroxide Cell cultured virus McGraw-Hill Vaccines

Immunotherapy9 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 typeExample reactions Vaccines from Chicken eggs and cell cultures Allergic reactions Contaminating pathogens Vaccines with Preservatives Allergic reactions Live attenuatedSusceptibility during preganncy and among immunodepressed Dead whole cellContamination with toxins

Immunotherapy10 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

Immunotherapy11 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

Immunotherapy12 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 10 6 doses

Immunotherapy13 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 pfu of live attenuated virus Challenges to vaccination Development time Production capacity (use of eggs?) Distribution Economics Vaccination strategy Current spread of H5H1

Immunotherapy14 Modern Immunotherapies 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”? Rituximab mechanisms

Immunotherapy15 Other Types of Cancer Immunotherapies 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 Checkpoint inhibitors

Immunotherapy16 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