Vaccines and other immunological antimicrobial therapy 2

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1 Vaccines and other immunological antimicrobial therapy 2

2 The Development of New Vaccines Golden age of immunology: Introduction of antibiotics: decrease vaccine development Safety issue and fear of litigation: acceleration of this trend National Childhood Vaccine Injury Act in 1986: reverse this trend Interest of pharmaceutical company: not favorable to vaccine development

3 Vaccine Development Culture pathogen "Microbiology-An introduction" 11 th edition, p379, G. J. Tortora, B. R. Funke, and C. L. Case, Figure Pearson 18.1

4 The Development of New Vaccines Culture pathogen rdna techniques In plants Needle-free vaccines: Oral vaccine, patch type, inhalation, food-carrying vaccines Design to boost cellular immunity: against tuberculosis, cancer, HIV No useful vaccines against chlamydias, fungi, protozoa, and helminthic parasites Application to non-infectious diseases: cancers, cocaine addiction, Alzheimer disease, contraception, hypersensitivity, and etc. Adjuvants Deliver in combination

5 Adjuvants nonspecifically enhance the immune response The immune system 3 rd edition, p442, Peter Parham, Garland Science

6 Vaccines have yet to be found for many pathogens The immune system 3 rd edition, p448, Peter Parham, Garland Science

7 The immune system 3 rd edition, p448, Peter Parham, Garland Science

8 Genome sequences of human pathogens open up new avenues of vaccine design Many viral genomes are sequenced and genetic information is available now

9 A useful vaccine against HIV has yet to be found An effective and acceptable rotavirus vaccine has been developed Vaccine development faces greater public scrutiny than drug development Garland Science 2009

10 Safety of Vaccines Therapeutic index = Risk vs. benefit Several cases Savin polio vaccine Rotavirus vaccine for infant diarrhea MMR and autism

11 Some common side effects include: fever, pain around the injection site, and muscle aches. Some individuals may be allergic to ingredients in the vaccine. Unwanted effects of adaptive immunity cause autoimmune disease and transplant rejection Eg, Coxsackie viruses Garland Science 2009

12 Passive immunity the transfer of active humoral immunity in the form of ready-made antibodies, from one individual (human or animal) to another (mainly human). used when there is a high risk of infection and insufficient time to develop its own immune response, or to reduce the symptoms of ongoing or immunosuppressive diseases. Natural passive immunity: maternally supplied immunity. Breast milk provides IgA, which protects from bacterial infections until the newborn can synthesize its own antibodies. Artificial passive immunity: short-term immunization. provides immediate protection, but does not develop memory Intravenous or intramuscular administration of human or animal blood plasma or serum, pooled human immunoglobulin from immunized donors, and monoclonal antibodies. used prophylactically for immunodeficiency, such as hypogammaglobulinemia. Used for several types of acute infection and poisoning. potential risk for hypersensitivity reactions, and serum sickness, especially from foreign globulin

13 FDA approved products for passive immunization and immunotherapy Disease Product Source Use Botulism Specific equine IgG horse Treatment of wound and food borne forms of botulism, infant botulism is treated with human botulism immune globulin (BabyBIG). Cytomegalovirus (CMV) hyper-immune IVIG human Prophylaxis, used most often in kidney transplant patients. Diphtheria Specific equine IgG horse Treatment of diphtheria infection. Hepatitis A, measles Pooled human Ig human serum Prevention of Hepatitis A and measles infection, treatment of congenital or acquired immunodeficiency. Hepatitis B Hepatitis B Ig human Post-exposure prophylaxis, prevention in high-risk infants (administered with Hepatitis B vaccine). ITP, Kawasaki disease, IgG deficiency Pooled human IgG human serum Treatment of ITP and Kawasaki disease, prevention/treatment of opportunistic infection with IgG deficiency. Rabies Rabies Ig human Post-exposure prophylaxis (administered with rabies vaccine). Tetanus Tetanus Ig human Treatment of tetanus infection. Vaccinia Vaccinia Ig human Treatment of progressive vaccinia infection including eczema and occular forms (usually resulting from smallpox vaccination in immunocompromised individuals). Varicella (chicken-pox) Varicella-zoster Ig human Post-exposure prophylaxis in high risk individuals. Anti-venom (antivenin or antivenene): for venomous bites or stings. The venoms from the snake, spider or insect are injected into a horse, sheep or goat. The subject animal will produce antibodies against the venom which are harvested and used to treat envenomation. Internationally, anti-venoms must conform to the standards of pharmacopoeia and WHO.

14 Monoclonal Antibodies (Mabs) Hybridoma: Immortal cancerous B cell fused with an antibody-producing normal B cell, produces Monoclonal antibodies

15 Monoclonal Antibodies (Mabs) Muromonab-CD3: For kidney transplant Cf: sometimes, polyclonal anti T-cell antibody are made in sheep and goats that have been immunized with human thymocytes or lymphocytes. These antibody-containing fractions are called anti-thymocyte globulin (ATG) or anti-lymphocyte globulin (ALG) that are prepared from the animals blood. Alemtuzumab (Campath or MabCampath): For leukemia, binds to CD52 Infliximab (Remicade) and entanercept (Enbrel): For Crohn s disease and rheumatoid arthritis, block the action of TNFα (anti-tnfα) Ibritumonab (Zevalin) and Rituximab (Rituxan): For non-hodgkin s lymphoma Trastuzumab (Herceptin): for breast cancer, binds to a specific site called HER-2 receptor, limiting the spread of the breast cancer Basiliximab (Simulect) and daclizumab (Zenapax): Block IL 2 receptor (CD25) of T cell, immunosuppresives for transplants Palivizumab (Synagis): Treatment of RSV (respiratory syncytial virus), recommended for infants that are high-risk because of prematurity or other medical problems such as congenital heart disease.

16 Rituximab: Chimeric anti-cd20 antibody. deplete B cells in patients with rheumatoid arthritis Omalizumab: humanized antibody specific for human IgE for treating allergic asthma. Daclizumab: humanized monoclonal antibody specific for the alpha-chain of the high-affinity IL-2 receptor. Reduces the incidence of acute rejection in kidney transplantation by 40% Adalimumab is a widely used all-human monoclonal antibody specific for the inflammatory cytokine TNFα. This is used in the treatment of rheumatoid arthritis, a condition in which chronic inflammation of the joints is perpetuated by TNF-α.

17 Rheumatoid arthritis can be treated with monoclonal antibodies that target either TNF-α or B cells The immune system 3 rd edition, p414, Peter Parham, Garland Science

18 Improvement of Monoclonal Antibodies Immunotoxins: Mabs conjugated with a toxin to target cancer cells.

19 Improvement of Monoclonal Antibodies Chimeric Mabs: Genetically modified mice that produce Ab with a human constant region. Rituximab: Chimeric anti-cd20 antibody. deplete B cells in patients with rheumatoid arthritis Humanized Mabs: Mabs that are mostly human, except for mouse antigen binding Omalizumab: humanized antibody specific for human IgE for treating allergic asthma. Daclizumab: humanized monoclonal antibody specific for the alpha-chain of the high-affinity IL-2 receptor for reducing the acute rejection in organ transplantation. Fully human antibodies: Mabs produced from a human gene on a mouse Adalimumab: widely used human monoclonal antibody specific for TNF-α to use in the treatment of rheumatoid arthritis.

20 Diagnostic Immunology Sensitivity: Probability that the test is reactive if the specimen is a true positive Specificity: Probability that a positive test will not be reactive if a specimen is a true negative Koch s experiment Guinea pigs with TB injected with Mycobacterium tuberculosis: Site became red and slightly swollen

21 Serological Tests Direct tests detect antigens (from patient sample) Indirect tests detect antibodies (in patient s serum)

22 Serological Tests Precipitation: Soluble antigens Agglutination: Particulate antigens Hemagglutination: Agglutination of RBCs Neutralization: Inactivates toxin or virus Fluorescent-antibody technique: Antibodies linked to fluorescent dye Complement fixation: RBCs are indicator ELISA: Peroxidase enzyme is the indicator