Vaccines and other immunological antimicrobial therapy

2

The Development of New Vaccines Golden age of immunology: 1870-1910 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

Figure 18.1

Vaccine Development Culture pathogen

"Microbiology-An introduction" 11th edition, p379, G. J. Tortora, B. R. Funke, and C. L. Case, Pearson

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

Adjuvants nonspecifically enhance the immune response

“The immune system” 3rd edition, p442, Peter Parham, Garland Science

Vaccines have yet to be found for many pathogens

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

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

• Genome sequences of human pathogens open up new avenues of vaccine design

• Many viral genomes are sequenced and genetic information is available now

© Garland Science 2009

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

Safety of Vaccines

Therapeutic index = Risk vs. benefit

Several cases Savin polio vaccine Rotavirus vaccine for infant diarrhea MMR and autism

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

© Garland Science 2009

Eg, Coxsackie viruses

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

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.

Monoclonal Antibodies (Mabs)

Hybridoma: “Immortal” cancerous B cell fused with an antibody-producing normal B cell, produces

Monoclonal antibodies

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.

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 TNF-α. This is used in the treatment of rheumatoid arthritis, a condition in which chronic inflammation of the joints is perpetuated by TNF-α.

Rheumatoid arthritis can be treated with monoclonal antibodies that target either TNF-α or B cells

“The immune system” 3rd edition, p414, Peter Parham, Garland Science

Improvement of Monoclonal Antibodies

Immunotoxins: Mabs conjugated with a toxin to target cancer cells.

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.

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

Serological Tests

Direct tests detect antigens (from patient sample)

Indirect tests detect antibodies (in patient’s serum)

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