Active Immunity• Antibody mediated– B cells• Cell mediated– T cellsCytotoxic (destroy infected cells and viruses)Helper (stimulate and direct activity of B cells)
What is Antigen ?A live or inactivated substance (e.g. protein orpolysaccharide) capable of producing animmune response .
What are Antibodies ?Produced by B cells to help eliminate an antigen• Different types• IgM, IgG, IgA, IgD, IgE• Functions :Neutralize toxinsBlock adhesion/cell entry of the antigenNeutralize and prevent viral replication• Antigen specificity :Cannot cross-protect different types of micro-organism
Immune response following exposureto antigenPrimary response• rapid• mainly IgMSecondary response• faster and morepowerful• mainly IgG
-It aims to protect the host from disease upon exposure tonoxious microorganisms .-It can be achieved successfully if the host generatedavailable immune effector elements such as :Antibodies .- Antibodies are able to immediately recognize andneutralize this pathogen .Avian Immunology , Fred Davison P 374What is the Aim of Vaccination ?
How do vaccines mediate protection?• Long-term immunity is conferred by themaintenance of antigen-specific immuneeffectors and/or by the induction of immunememory cells that can rapidly reactivated intoimmune effectors in case of next pathogenexposure.
The main effectors of vaccineresponses• The nature of the vaccine exerts a directinfluence on the type of immune effectorsthat are predominantly elicited and mediateprotective efficacy .
Effector Mechanisms Triggered by VaccinesAntibodies prevent or reduce infections by extra-and intracellular agents and clear extracellularpathogens through : Binding to the enzymatic active sites of toxins orpreventing their diffusion Neutralizing viral replication, e.g. preventing viralbinding and entry into cells Promoting opsonophagocytosis of extracellularbacteria, i.e. enhancing clearance bymacrophages and neutrophils Activating the complement cascade
CD8+ T cells do not prevent but reduce, controland clear intracellular pathogens by:• Directly killing infected cells (release ofperforin, granzyme, etc.)• Indirectly killing infected cells throughantimicrobial cytokine releaseEffector Mechanisms Triggered by Vaccines
CD4+ T cells do not prevent but participate tothe reduction, control and clearance of extra-and intracellular pathogens by :• Producing IFN-γ, TNF-α/-β, IL-2 and IL-3 andsupporting activation and differentiation of Bcells, CD8+T cells and macrophages.(Th1 cells )• Producing IL-4, IL-5, IL-13, IL-6 and IL-10 andsupporting B cell activation and differentiation(Th2 cells)Effector Mechanisms Triggered by Vaccines
Initiation of Vaccine ResponseWorld Health Organization WHO , Vaccine Immunology ,http://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf
Recognition of Vaccine Determinants by PatternRecognition ReceptorsLigandsReceptorsCertain bacterial lipoproteinsTLR1Peptidoglycan, lipoproteins, glycolipids, lipopolysaccharideTLR2Viral double-stranded RNATLR3Bacterial lipopolysaccharidesTLR4TLR5Bacterial flagellinsTLR6Lipotechoic acid, lipopeptidesTLR7Single-stranded RNATLR8TLR9Single-stranded RNATLR10CpG olignucleotides Unknown PeptidoglycansNOD1 , NOD2World Health Organization WHO , Vaccine Immunology ,http://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf
Determinants of Primary Vaccine Antibody Responsesin Healthy IndividualsMechanismDeterminantHigher intensity of innate responses, higher antigencontent following replication and more prolonged antigenpersistence generally result into higher Ab responses tolive than inactivated vaccines.Vaccine typeLive vs inactivated.Recruitment of T cell help and induction of GCs resultsinto higher Ab responses to protein than to PS vaccines.Protein vs polysaccharideModulation of antigen delivery and persistence (depot orslow-release formulations) or enhancement of Thresponses (immunomodulator) may support or limit AbresponsesAdjuvantsWorld Health Organization WHO , Vaccine Immunology ,http://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf
Determinants of Primary Vaccine Antibody Responsesin Healthy IndividualsMechanismDeterminantFailure to induce GCs limit immunogenicity.Antigen naturePolysaccharide antigensInclusion of epitopes readily recognized by B cells,inclusion of epitopes readily recognizedby follicular helper T cells, elicitation of efficient follicularT cell help and the capacity of antigen to associate/persist in association to FDCs result into higher Abresponses.Protein antigenshigher Ag doses increase the availability of Ag for B / Tcell binding and activation, as well as forassociation with FDCsAntigen doseWorld Health Organization WHO , Vaccine Immunology ,http://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf
MechanismDeterminantA 3 week minimal interval between primary doses avoidscompetition between successive waves of primaryresponses.Vaccine scheduleInterval between doses..Gene polymorphisms in moleculescritical for B and T cell activation/differentiation arelikely to affect Ab responsesGenetic determinantsMostly yet identifiedEnvironmental factorsEarly life immune immaturity .Age at immunizationDeterminants of Primary Vaccine Antibody Responsesin Healthy IndividualsWorld Health Organization WHO , Vaccine Immunology ,http://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf
Types of viral Vaccines1- Live attenuated vaccine (MLV).2- Inactivated vaccines (Killed).3- Molecular-Based Vaccines
Live attenuated vaccine (MLV).A-Naturally occurring virus used as vaccines(e.g. Lentogenic strain of NDV).B- Immunologically related virus from differentspecies “Heterotypic vaccines” (e.g. Turkeyherpes virus against Marek’s disease virus,Sheep pox against LSD in cattle).C- Attenuated vaccines: Attenuation is usuallyachieved by passage of the virus in foreignhost such as ECE or tissue culture cells.Reference : Prof.Dr.M.Shalaby Lecture2005
Advantages of Live Vaccines1- Activates all phases of immune system can gethumoral IgG and local IgA.2- Raises immune response to all protective antigens,inactivation by formaldhyde may alter antigenicity.3- Induction of interferons.4- Low cost.5- Quick immunity in majority of vaccines.6- Easily administrated by all routes.7- Easy transport in field.8- Can lead to elimination of wild type virus from thecommunity.Reference : Prof.Dr.M.Shalaby Lecture2005
Disadvantaged of live vaccines1- Mutation, reversion to virulence (Major disadvantage).2- Spread to contacts of vaccines who have notvaccinated.3- Spread vaccine not standardized-may be mutated.4- Poor uptake in tropical areas.Reference : Prof.Dr.M.Shalaby Lecture 2005
Inactivated vaccines (Killed).• Made from virulent virus by eliminating its infectivityand retaining its immunogenicity.• Inactivating agents :most commonly used are :1- B-propiolactone2- Formaldehyde3- Ethylenimine and azuridineReference : Prof.Dr.M.Shalaby Lecture2005
Advantages of Killed Vaccines1- Gives sufficient humoral immunity if boostersgiven.2- No mutation of reversion ( A big advantage).3- Safe for pregnant animals.4- Better to be applied in tropical countries.Ref : Prof.Dr.M.Shalaby Lecture 2005
Disadvantages of killed vaccines1- Booster doses are needed (Short immunity).2- No local immunity.3- Administration only by injection.4- Adjuvants is essential to provoke cellmediated immunity.Reference : Prof.Dr.M.Shalaby Lecture2005
Live attenuated Vs Killed VaccineInactivated vaccinesLiving vaccines1-Stable on storage2-Unlikely to cause diseasethrough residualvirulence.3-Unlikely to contain livecontaminating organisms.1-Few inoculating dosesrequired.2-Adjuvants unnecessary3-Less chance ofhypersensitivity.4-Induction of interferon.5-Relatively cheap.Reference : Prof.Dr.M.Shalaby Lecture2005
Molecualr Based Vaccines• Acc .to USDA classification of Genetically EngineeredVeterinary Biologics:Category I: Vaccines that contain inactivatedrecombinant organisms or purified antigens derivedfrom recombinant organisms.Category II: Vaccines containing live organisms thatcontain gene deletion or heterologous marker genes.Category III: Vaccines that contain live expressionvectors containing heterologous genes for immunizingantigens or other immune stimulants.Reference : Prof.Dr.M.Shalaby Lecture2005
Novel Molecular Based Vaccines• Examples of Novel molecular based vaccinesin veterinary Field :1- VP1 Protective antigen of FMDV2- VP2 of IBDV4- H5 Gene of Avian influenza virus3- Thymidine Kinase TK Gene of Pseudorabiesvirus in swine .
Ideal Vaccine Characterstics1- Produce effective resistance to infection in vaccinatedanimal or bird.2- Have long lasting resistance (stabilizers and/or heatresistant mutants).3- Safe for vaccinated animals ( no reversion to virulence).4- Should be pure from other adventitious viruses (e.g.BVD).5- Sterile from bacteria, fungal and mycoplasmacontamination.6- Stable.7- Reasonably cheap to produce.Reference : Prof.Dr.M.Shalaby Lecture2005
Ideal Vaccine Characterstics• Give life-long immunity• Broadly protectiveagainst all variants oforganism• Prevent diseasetransmission• Rapidly induceimmunity• Effective in all subjects(the old & very young)
• Transmit maternalprotection to the foetus• Require fewimmunizations to induceprotection• Not need to beadministered byinjection (oral,intranasal,transcutaneous)• Stable, cheap & safeIdeal Vaccine Characterstics
Vaccine Assessment• Efficacy of a vaccine is called preventable fraction.% of controls dying - % of vaccinated dyingPF =% of controls dying• Good effective vaccines should have a PF of atleast 80%, Obviously less effective vaccines areacceptable if no better is available.Reference : Prof.Dr.M.Shalaby Lecture2005
Other Vaccine components• Conjugating agents :Carrier proteins which combine with antigens toimprove immunogenicity• Suspension fluid :Fluid (water, saline, tissue-culture mixture)• Preservatives, stabilizers, antimicrobial agents– Trace amounts used to stabilize vaccine– May cause allergic reaction
Other Vaccine components• Adjuvants :Aluminium salt used to increaseimmunogenicity of vaccines containinginactivated micro-organisms or their products.
Other Vaccine componentsThiomersal– Used in vaccine production since the 1930s– Mercury containing compound used in somevaccines to prevent bacterial and fungalgrowth.– Also used as inactivating agent in early stageof production of some killed vaccines– In 1999 EU and U.S. manufacturer’s decisionto decrease thiomersal levels in vaccines
Routes of Vaccination• S/C and I/M Routes• Intranasal ------ Mucosal immunity• Eye drops , drinking water ( Poultry )
Vaccination Timing1- Varies according to the species of animal and whethera live or inactivated vaccine is used. It is mostimportant to bypass the maternal immunity2- Activity of passive antibodies is determined by thelevel of Abs in the dam, how much is transferred viacolostrum and its capacity to neutralize the vaccine.Passive antibodies wanes because circulating IgG has ahalf life of 10-20 days in domestic animals and 2-4 daysin poultry.3- Action of passive immunity may be avoided by givenvaccines via the respiratory tract.4- Increasing passive immunity may be a deliberate partof the control program, thus neonatal diarrhea mightbe reduced by vaccinating the dams.Reference : Prof.Dr.M.Shalaby Lecture2005
Vaccination Failure• Disease induced by strains of organisms orantigens that differ from the strain in thevaccine you used• Faulty production of specific lot of vaccine(not enough antigen; accidental inactivationduring manufacture)• Unsatisfactory storage, exposure to heat(keeping it in the cab of a truck during theheight of summer), freezing (esp. modifiedlive vaccines)Reference : Prof.Dr.M.Shalaby Lecture 2005
Vaccination Failure• Administration by unconventional routes (e.g.,given intranasal vaccine intramuscularly, orvice versa)• Animals incubating disease at time ofvaccination• Disease due to an agent other than the one inthe vaccine• Blocking effects of maternal antibodies eg.,IBD Vaccination.Reference : Prof.Dr.M.Shalaby Lecture2005
Vaccination Failure• Administration of antibiotics in conjunctionwith live bacterial vaccines.• Chemical sterilization of syringes• Immune response is suppressed (heavilyparasitized or malnourished animals; stress ofpregnancy, extremes of cold and heat, andfatigue)Reference : Prof.Dr.M.Shalaby Lecture2005
Other Refernces• http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf• MERIAL , Internal scientific data , Vaxxitek