Download IMMUNOPROPHYLAXIS: Vaccines and Immunotherapy 2014

IMMUNOPROPHYLAXIS:
Vaccines and Immunotherapy
2014
J.K. Actor, Ph.D.
with Special Thanks to: Semyon A. Risin MD, PhD
Department of Pathology and Laboratory Medicine Objectives
• Provide a perspective of active and passive immunization for vaccination against infectious agents • Emphasize important immunological principles as they relate to vaccination • Demonstrate how principles in immunology combine with biotechnology to advance the field of vaccinology
Discovery of Vaccination
Edward Jenner, 1796
• Edward Jenner (1749‐1823) was a country doctor in Gloucestershire county in the West of England. He observed that people who get cowpox often develop less severe disease and survive smallpox outbreaks.
• Jenner inoculated a young boy (James Phipps) with material from hand sores of a milkmaid Sarah Nelmes. Six weeks later, after the boy recovered from cowpox, he was re‐inoculated with the smallpox virus.
– The boy survived …
• The term "Vaccination" was introduced by Jenner (from the Latin Vacca, and Vaccinia virus) and later adopted for immunization against any disease (Pasteur).
Edward Jenner inoculating James Phipps with cow pox, May 14, 1796
Application of Antigenic Cross‐Reactivity
Immunization Basics
Objective of immunization is to provide long‐lasting immunologic protection against infectious agents.
• Types of Immunizations
1. Active – exposure to antigen with the host generating protective immunity. • Objective: provide long lasting immunity against future exposures
2. Passive – administration of humoral and/or cellular factors that provide immunity for the host. • Objective: provide temporary immediate protection against an imminent or ongoing exposure/threat
• “Herd” immunity in preventing spread of infection
• occurs when the vaccination of a significant portion of a population (or “herd”) provides a measure of protection for individuals who have not developed immunity
Active Immunization
• Natural Immunization
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acquired through infectious exposure
• Artificial immunization
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acquired via vaccination
Active Immunization
2 Historical active vaccine approaches:
• Attenuated pathogens
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ex. Rabies vaccine
• Killed pathogens –
ex. Anthrax vaccine
Attenuation
Coico and Sunshine, Chapter 20.
Basic Mechanisms of Protection
• Primary and Secondary Immune Response: – Rapidity of response critical as related to incubation period of infection (disease state).
– Long time to disease state results in extended incubation period; induction of strong immune response. – Secondary exposure results in protection to disease.
• Primary and Secondary Immune Response
– Rapidity of response (cont’d)
– Short time to disease state limits incubation period; limited induction of immune response. – Secondary exposure does not protect against disease.
• Induction of protection can be achieved with vaccine if able to sustain high long‐term antibody titer. • Achievable by giving several immunizations in a shorter time frame to raise sustained titer.
Age and Timing of Immunizations
• Children under 2 yr are limited in producing antibodies to bacterial capsular polysaccharides. – Limited response to T‐independent antigens
– Can be overcome partially by chemical link to carrier protein
– Can assist maturation of response using multiple vaccinations
• See previous point about high, sustained titers
Schedule of Vaccination
Adults
• Depends in part on Age of individual
– Elderly (>60 yr) have a reduce capacity to mount a primary response to some antigens. • However, they maintain strong response to bacterial polysaccharides
• Geographical location and prevalence of pathogen
• Usually one or two doses sufficient
– Think about “arm” of immune response desired
Adult Immunization Schedule
(CDC 2014)
no risk factors
risk factors
Vaccines in Selected Populations:
Medical Indications
Use of Vaccines in Selected Populations
(some additional examples)
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Military personnel
Animal handlers; veterinarians
Children/adults in high risk locations
Health care workers; physicians; blood product exposure
Travelers to high‐risk areas
College students
High HIV demographic; IV drug users
Odds and Ends
• Hazards
– Use in immunocompromised patient; those with severe immune disorders
– Patients undergoing concurrent immunosuppressive therapy
– Use of live organisms in pregnant women
• Side effects
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Local inflammation
Arthritis and arthralgia
Encephalopathy in infant
Local hypersensitivity
Further Advances in Vaccines Design
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Additional ways of obtaining non‐virulent antigenic substances for use as vaccines:
Toxoids
Recombinant DNA technology
Conjugation to achieve immunogenicity (polysaccharides and proteins)
Synthetic peptides
Live viral vectors to carry pathogen genes
Live bacterial agents to carry genes
DNA vaccines
Immunologic Adjuvants
• Components to potentiate the immune responses to an antigen and direct it towards the desired immune responses against the vaccine candidate.
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Excite innate immunity
Some mimic action of PAMPs
Some function to increase “depot” effect
Some function to stabilize antigenic components
• Examples:
– Aluminium salts (alum); mineral salts
• aluminium phosphate and aluminium hydroxide
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Oil‐based emulsions: AS04*, Squalene (MF59), thimerisol
Plant saponins: Quil A (detergent based delivery system); QS‐21
Cytokines
Bacterial cell wall products
• Complete Freund’s adjuvant (mycobacterial cell wall)
– Particulates: Virosomes (Viral Like Particles); ISCOMs
– CpG; nucleic acid motifs
*HPV; alum+lipid
Passive Immunization
• Natural Immunization
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transfer of antibody from mother to infant in placental circulation or colostrum
• Artificial immunization
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antibody therapy (serum therapy) via administration of immunoglobulins
Passive Immunization
Placental Antibody Transfer
Fetus protected with maternal IgG.
• Total Ig in newborn serum is at a level close to that of a normal adult
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almost all of it is IgG of maternal origin
• Normal half‐life of 2‐3 weeks
– 10% by 4 months; 3% by 6 months
• Colostrum
– At 2‐3 weeks post partum, antibodies (IgA, IgM, IgG) are found in high concentrations in breast milk.
– Of interest, B cells stimulated by maternal intestinal antigens migrate to breast, where they secrete Abs.
Passive Immunization
Passive Ab and Serum Therapy
Heterologous Abs raised in animals could be administered to humans to treat infections.
• Example: Horse serum against tetanus
– Problems: Type I and Type III hypersensitivities
• Normal half‐life of 23 days
• More recent: monoclonals allow homologous antibody made in the laboratory to limit cross‐
reactivity to heterologous epitopes.
– Invariant; lot‐lot stability.
FDA approved products for passive immunization and immunotherapy
• Botulism ‐ Specific equine IgG, 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
• Hepatitis A, measles, congenital or acquired immunodeficiency ‐ pooled human Ig
FDA approved products for passive immunization and immunotherapy (cont d)
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Hepatitis B ‐ Hep B Ig, post‐exposure prophylaxis, prevention in high‐risk infants
(administered with Hep B vaccine). ITP, Kawasaki disease, IgG deficiency ‐ Pooled human IgG
Rabies ‐ Ig (human) post‐exposure prophylaxis (administered with rabies vaccine). Tetanus ‐ Ig (human) treatment of tetanus infection. 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.
Other uses of Immunoglobulins
• RhoGam is an anti‐RhD antigen use for prophylaxis of HDN
– Given to Rh‐ mother after fetal Rh+ birth
• IVIG (agammaglobulinemia, ITP, GB etc.)
• Use of monoclonal antibodies to treat:
– examples from Autoimmune lecture (anti‐TNF)
– hematologic and solid tumors
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Bcr‐abl vaccine for CML
herceptin for breast cancer
rituximab for B cell malignancies
atemtuzumab for CLL
etc
Other ways of modifying immunity
• Removal of pathogenic antibodies and other humoral factors
• Enhancing antigen presentation and antigen processing • Targeting immunoregulatory pathways
Summary
• Vaccines have had tremendous impact on human life quality and longevity by eliminating devastating pathogens.
• New immunoregulatory approaches hold a tremendous promise for treating allergic, autoimmune, and chronic inflammatory conditions.