IMMUNITY &

PRINCIPLES OF VACCINATION

A Presentation byM. Isaac Umapathy,

Department of Microbiology & Parasitology,Faculty of Medicine,

International Medical & Technological University,

Dar-Es-Salaam, Tanzania.

Introduction

• The meaning of the term immunity (from the Latin immunitas – exemption from civic duties afforded to senators) as it is used today derives from its earlier usage referring exemption from military service or paying taxes.

• It has long been recognized that those who recovered from epidemic diseases such as smallpox and plague were exempt from further attacks and such immune individuals were often used in an epidemic to nurse those suffering from active disease.

• The immune system is a complex, highly regulated set of processes that require the host to detect changes in host cells or undesirable exogenous cells.

• The goals of the immune response are to protect an individual from challenge and to restore homeostasis.

Introduction

• These goals require the immune system to recognize offending challenges, to respond immediately or with some delay and then repair the site.

• Some mechanisms primarily rely on cell-cell interactions, whereas others are mediated by humoral substances (soluble chemicals secreted by cells).

• Two types of immunity , innate and adaptive work together to provide human defense to diverse challenges.

Edward Jenner

The Father of Immunization

The Immune System

• The immune system consists of a number of organs and several different cell types.

• All the cells of the immune system, tissue cells and white blood cells or leukocytes, develop from pluripotent stem cells in the bone marrow.

• These haemopoetic stem cells also give rise to the red blood cells or erythrocytes.

• The production of leukocytes is through two main pathways of differentiation. The two main lineages, lymphoid and myeloid, are derived from pleuripotent stem cells present in the bone marrow.

Blood cells are

produced in bone

marrowwhere

fighter cells are trained or sent to

the thymus gland.

HUMAN LYMPHOID SYSTEM

• A number of morphologically and functionally diverse organs and tissues have various function in the development of immune response.

• These lymphoid organs and tissues could be classified by function as

1. Primary Lymphoid Organ

2. Secondary Lymphoid Organ

3. Tertiary Lymphoid Organ

Lymphoid Organs

• Primary Lymphoid Organ (where immunocompetentl cells are developed i.e. where maturation of lymphcytes take place) Thymus. Bone marrow.

Lymphoid Organs

• Secondary Lymphoid Organ & Tissues (where immunocompetency is expressed i.e. which trap antigen and provide sites for mature lymphocytes to interact with that antigen). Spleen. Lymph nodes. Mucosa Associated Lymphoid Tissue (MALT).

Nasal Associated Lymphoid Tissue (NALT). Gut Associated Lymphoid Tissue (GALT). Bronchus Associated Lymphoid Tissue (BALT).

Lymphoid Organs

• Tertiary Lymphoid Tissue (which normally contain fewer lymphoid cells than secondary lymphoid organ, can import lymphoid cells during an inflammatory response. Cutaneous Associated Lymphoid Tissue (CALT)

• Once mature lymphocytes have been generated in primary lymphoid organs, they circulate in the blood and lymphatic system, a network of vessels that collect fluid that has escaped into the tissues from capillaries of the circulatory system and ultimately to return it to the blood.

Lymphoid Organs

( Non specific , Natural ) ( Specific, Aquired )

• General Barriers

• Physical barriers

• Chemical barriers

• Biological barriers

• Active

• Passive

• Adoptive

Innate Immunity

• Present from birth in all individuals.• Once activated the same mechanism occurs regardless

of which challenge is encountered or previous exposure.• Immediate response.

Innate Immunity - General Barriers

• Direct Factors Nutrition. Acute phase reactants. Fever. Age. Genetics. Race.

• Indirect Factors Personal hygiene. Socioeconomic status. Living conditions.

Innate Immunity - Physical Barriers

• Skin & Mucous Membrane• Respiratory System• Gastrointestinal Tract• Genitourinary Tract• Eye

Innate Immunity -Chemical Barriers• Gastric Juice• Salivary Glycoprotein• Lysozyme• Oleic Acid On The Skin• Urea• Blood, Lymph & Other Body Fluids

ComplementFibronectinHormonesBeta Lysin & Other Polypeptides InterferonsTumor Necrosis FactorsBacteriocins

Innate Immunity -Biological Barriers

• Normal Indigenous Microbiota.• Inflammation.• Phagocytosis.

Adaptive Immunity

• Immunity which is acquired or developed by an individual only after a specific challenge is encountered.

• The resulting adaptive immune products are effective only against the specific challenge.

• Immunologic memory in adaptive immunity provides greater efficiency should there be subsequent exposure to the same challenge.

• There is a time lag for development of adaptive immunity but secondary response is almost immediate.

Characteristics of Adaptive Immunity• In recent years, with increased knowledge of the molecular

processes underlying the function of cells, it has become possible to explain at a cellular and molecular level the features that are the hallmark of acquired immune responses. Specificity and diversity. Memory. Regulation. Self / non-self discrimination.

• The acquire immune processes that lead to the elimination of foreign material involve the concerted efforts of a number of different cells and molecules and can be divided into three stages. Recognition stage. Activation stage. Effector stage.

Classification of Adaptive Immunity• The two major arms of effective specific immunity are

humoral immunity and cell mediated immunity. While historically these are quite distinct, current knowledge suggests that each time adaptive immunity is activated, both arms are activated. It becomes a matter of the degree to which each arm is activated.

• Adaptive immunity may be classified based on the host’s role in developing the adaptive specific immunity. Active immunity is generated when an immunocompetent host is

exposed to the foreign challenge and the host’s native immune cells respond by generating specific immune products.

Passive immunity is bestowed to the host when preformed immune products are administered to the host.

In adoptive immunity, immunocompetent cells are transplanted to an immunoincompetent host to restore the immune system.

OVERVIEW OF IMMUNE RESPONSESEndogenous challenge

• Host tumor cells• Aged host cells

Exogenous challenge

• Microorganisms • Transplant cells• Toxins, Allergens, Chemicals

Host immune responsesAnergy

No

Innate immunity

Adaptive immunity

Cellular• NK cells• Macrophages• Neutrophils

Humoral

• Complement• Lysozyme• Fibronectin• Hormones• Beta lysin & other polypeptides• Interferons• Tumor necrosis factors• Bacteriocins

Cellular Humoral• T lymphocytes • Antibody

Immune dysfunction

• Central tolerance• Peripheral tolerance

• Infectious disease• Hypersensitivity• Graft rejection & graft vs host disease• Autoimmune disease• Immunodeficiency

Inadequate or misdirected

Yes

Yes

Antibody

• An antibody is a protein that is produced by lymphocytes (type of white blood cell) in response to the presence of a specific antigen.

• Specific antibodies bind to specific antigens and cause their destruction.

Antibody

OVERVIEW OF HUMORAL & CELL – MEDIATED IMMUNE RESPONSE

Vaccination

• You can become immune to a disease through vaccination. • Immunization programmes and the

development of new vaccines play an important role in protecting individuals against illness.

• Vaccination works by safely exposing individuals to a specific pathogenic microbe, artificially increasing their immunity to it.

Vaccination

Vaccination

Vaccines are made from:

• Live micro-organisms that have been ‘treated’ so that they are weakened (attenuated) and are unable to cause disease.

• Dead micro-organisms.

• Some part or product of the micro-organism that can produce an immune response.

Vaccine production.

Principles of Vaccination• The primary goal in vaccination is to provide protective

immunity by inducing a memory response to an infectious microorganism using a non-toxic antigen preparation. It is important to produce immunity of the appropriate kind: antibody / or cellular immunity.

• Antibodies produced as a result of immunization are effective primarily against extracellular organisms and their products e.g., toxins. Passively administered antibodies have the same effect as induced antibodies.

• Cell-mediated immunity (T cells, macrophages) induced by vaccination is important particulary in preventing intracellular bacterial and viral infections and fungal infections.

• The ultimate goal of any immunization program is the eradication of the disease.

• This requires that the infection is limited only to humans, with no animal or environmental reservoir, and the absence of any subclinical or carrier state in humans.

Principles of Vaccination

• Achieving elimination requires a high level of herd immunity to prevent person to person spread.

• This requires considerable infrastructure support to ensure that all at-risk populations are targeted for immunization.

• This has been achieved for small pox, although we are close to the elimination of polio.

POXVIRUSESVaccination

POXVIRUSESVaccination

POXVIRUSESVaccination

Characteristics of Effective Vaccines

• Safety No disease must be caused by the vaccine itself.

• Protection Protection must be at the population level and prevent disease when

the infectious agent is encountered.

• Long lasting effects Protection must be long-lasting i.e. induce T and B cell memory.

• Cost Inexpensive to produce and deliver.

• Administration Easy to deliver with no side-effects.

Passive Immunization

• Passive immunization is the administration of preformed antibodies either intravenously or intramuscularly.

• It is used to provide rapid protection in certain infections such as diptheria or tetanus or in the event of accidental exposure to certain pathogens such as hepatitis B.

• It is also used to provide protection in immune compromised individuals.

Passive Immunization

Infection Source of Antiserum Indications

Tetanus Immune human; horse Post exposure (plus vaccine)

Diptheria Horse Post-exposure

Gas gangrene Horse Post-exposure

Botulism Horse Post-exposure

Varicella-Zoster Immune human Post-exposure in immunodeficiency

Rabies Immune human Post exposure (plus vaccine)

Hepatitis B Immune human Post-exposure prophylaxis

Hepatitis A Pooled human Ig Prophylaxis

Measles Immune human Prophylaxis

Snakebite Horse Post-bite

Some autoimmune disease Pooled human ig Acute thrombocytopenia and neutropenia

Active Immunization

• Active immunization is the administration of vaccines containing microbial products with or without adjuvants in order to obtain long term immunological protection against the offending microbe.

• At present the normal route of vaccination in most instances is either intramuscularly or subcutaneously.

• Oral immunization is the method of choice for polio and Salmonella typhi vaccines. However, there is an increasing awareness that this route of immunization may be the best for most immunizations since nearly all infectious agents gain entrance through the mucosal surfaces.

Approaches to Vaccine Design

• Intact pathogen Heat-killed or chemically denatured. Attenuated by growth conditions or genetic manipulation.

• Subunit vaccines Recombinant proteins. Synthetic peptides.

• Vaccine vehicles Live vectors: viral (e.g. Adenovirus) and bacteria (Mycobacteria).

• Adjuvants Conjugated to lipid or protein carrier molecules. Microencapsulated in lipids.

• DNA immunisation Injection of plasmid DNA.

Antigen Preparations

• Protection against pathogenic microorganisms require the generation of effective immune mechanisms.

• Thus, vaccines must be capable of targeting the immune system appropriately i.e. cellular / or humoral mechanisms.

• Most vaccines consist of either attenuated organisms, killed organisms, inactivated toxins, or subcellular fragments and more recently genes for antigens in viral ‘vectors’, and DNA itself.

Antigen Preparations Used in VaccinesType of antigen Examples

Viruses Bacteria

Normal heterologous organism Vaccinia (Cowpox)

Living attenuated organism Measles BCG

Mumps Typhoid (New)

Rubella

Polio (Sabin)

Yellow fever

Varicella-Zoster

Whole killed oranism Rabies Pertussis

Poli (Salk) Typhoid

Influenza Cholera

Subcellular fragment

Inactivated toxin (toxoid) Diphtheria

Tetanus

Cholera (New)

Capsular polysaccharide Meningococcus

Pneumococcus

Haemophilus

Typhoid (New)

Surface antigen Hepatitis B

Adjuvants

• Nonliving vaccines, especially those consisting of small molecules require the inclusion of agents to enhance their effectiveness.

• These adjuvants include microbial, synthetic and endogenous preparations having adjuvant activity, but at present only aluminium or calcium salts are generally used in humans.

• Adjuvants should enable antigens to be slowly released, preserve antigen integrity, target antigen presenting cells and induce cytotoxic lymphocytes.

Experimental Adjuvants Currently Undergoing Assessment

Experimental, but likely to be approvedLiposomes (small synthetic lipid vesicles).

Muramyl dipeptide, an active component of Mycobacterial cell walls.

Immune stimulating complexes ( ISCOMS) (e.g. from cholesterol or phospholipids).

Bacterial toxins (E. coli, pertussis, cholera).

Experimental onlyCytokines: IL-1, IL-2, IFNγ.

Slow-release devices, Freunds adjuvant.

Immune complexes.

DNA Vaccines

• The use of DNA encoding antigens as vaccines as distinct from bacteria or bacteria proteins has shown potential.

• Intramuscular injection of circular DNA results in DNA uptake by muscle cells, expression of the encoded protein and induction of both humoral and cell-mediated immunity.

Recombinant Vaccines

• Using molecular genetics, selective recombinant proteins of defined epitopes can be prepared that protect the host.

• This approach overcomes the problem of disease complications which might occur with modified live vaccines.

Cytokines

• Cytokines can be added at the time of immunization to skew the immune response to a Th1 or Th2 type on which is associated with protection.

• The cytokines can be added either as purified protein made from recombinant technology, or they can be cloned into vectors (virus or bacterial vaccine) to be delivered at the time of vaccination.

• Cytokines that might be useful are IL-12 or IFNγ that favour a Th1 response, or IL-10 that favour a Th2 response.

Bacterial Vaccines

• Bacterial vaccines have been developed to many different types of bacteria: Escherichia, Haemoplilus, Pneumococcus, Vibrio, Helicobacter and Lyme’s disease spirochaete to name a few.

• Perhaps moe familiar is the diphthera, pertussis and tetanus (DPT) vaccine that many young children receive them from often childhood diseases.

Viral Vaccines

• Vaccines have been developed to viruses that infect the respiratory tract (flu, adenovirus), the gastrointestinal tract (polio, rotavirus, the skin (yellow fever, La Crosse fever) and some that infect the reproductive tract (herpes).

• As with bacteria, viral vaccine are either modified , live, killed or subunit.

Vaccines to Other Infectious Agents

• Protozoan parasites, such as that cause malaria (Plasmodium), Africal sleeping sicknes (Trypanosoma) and Schistosomiasis) are major diseases of the third world.

• The ability to vaccinate people and animals to protozoan diseases will allow people to live in areas that are endemic for the disease.

Tumor Vaccines

• Vaccination strategies against cancer are currently being investigated.

• Vaccines containing tumor antigens such as those associated with prostate cancer (prostate specific antigens) as well as those associated with the breast, colon, and ovarian cancers such as HER2 / neu offer hope for the future.

No cureNo cure No cureNo cure

Acquired Immuno Deficiency Acquired Immuno Deficiency SyndromeSyndrome

Acquired Immuno Deficiency Acquired Immuno Deficiency SyndromeSyndrome

No vaccineNo vaccine No vaccineNo vaccine

Obstacles to Development of HIV Vaccine

• Genomic diversity of HIV strains.• Progression of infection despite vigorous immune response.

Transmission of HIV in vivo by cell fusion as well as by cell-free virus.

• Lack of good animal model.• Potential enhancement of HIV replication by neutralizing

antibody.

Vaccine Strategies