vaccine immunology m.fathy
TRANSCRIPT
Introduction
Active Immunity
• Antibody mediated – B cells• Cell mediated – T cells Cytotoxic (destroy infected cells and viruses)
Helper (stimulate and direct activity of B cells)
What is Antigen ?
A live or inactivated substance (e.g. protein or polysaccharide) capable of producing an immune response .
What are Antibodies ?
Produced by B cells to help eliminate an antigen• Different types • IgM, IgG, IgA, IgD, IgE• Functions : Neutralize toxins Block adhesion/cell entry of the antigen Neutralize and prevent viral replication• Antigen specificity : Cannot cross-protect different types of micro-organism
Immune response following exposureto antigen
Primary response• rapid• mainly IgM
Secondary response• faster and more powerful• mainly IgG
-It aims to protect the host from disease upon exposure to noxious microorganisms .
-It can be achieved successfully if the host generated available immune effector elements such as : Antibodies . - Antibodies are able to immediately recognize and neutralize this pathogen .
Avian Immunology , Fred Davison P 374
What is the Aim of Vaccination ?
How do vaccines mediate protection?
• Long-term immunity is conferred by the maintenance of antigen-specific immune effectors and/or by the induction of immune memory cells that can rapidly reactivated into immune effectors in case of next pathogen exposure.
The main effectors of vaccine responses
• The nature of the vaccine exerts a direct influence on the type of immune effectors that are predominantly elicited and mediate protective efficacy .
Effector Mechanisms Triggered by Vaccines
Antibodies prevent or reduce infections by extra- and intracellular agents and clear extracellular pathogens through :
Binding to the enzymatic active sites of toxins or preventing their diffusion
Neutralizing viral replication, e.g. preventing viral binding and entry into cells
Promoting opsonophagocytosis of extracellular bacteria, i.e. enhancing clearance by macrophages and neutrophils
Activating the complement cascade
CD8+ T cells do not prevent but reduce, control and clear intracellular pathogens by:
• Directly killing infected cells (release of perforin, granzyme, etc.)
• Indirectly killing infected cells through antimicrobial cytokine release
Effector Mechanisms Triggered by Vaccines
CD4+ T cells do not prevent but participate to the reduction, control and clearance of extra- and intracellular pathogens by :
• Producing IFN-γ, TNF-α/-β, IL-2 and IL-3 and supporting activation and differentiation of B cells, CD8+T cells and macrophages.(Th1 cells )
• Producing IL-4, IL-5, IL-13, IL-6 and IL-10 and supporting B cell activation and differentiation (Th2 cells)
Effector Mechanisms Triggered by Vaccines
Initiation of Vaccine Response
World Health Organization WHO , Vaccine Immunology , http://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf
Recognition of Vaccine Determinants by Pattern Recognition Receptors
Ligands Receptors
Certain bacterial lipoproteins TLR1
Peptidoglycan, lipoproteins, glycolipids, lipopolysaccharide TLR2
Viral double-stranded RNA TLR3
Bacterial lipopolysaccharides TLR4
TLR5
Bacterial flagellins TLR6
Lipotechoic acid, lipopeptides TLR7
Single-stranded RNA TLR8
TLR9
Single-stranded RNA TLR10
CpG olignucleotides Unknown Peptidoglycans NOD1 , NOD2
World Health Organization WHO , Vaccine Immunology , http://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf
Determinants of Primary Vaccine Antibody Responses in Healthy Individuals
Mechanism Determinant
Higher intensity of innate responses, higher antigen content following replication and more prolonged antigen persistence generally result into higher Ab responses to live than inactivated vaccines.
Vaccine typeLive vs inactivated.
Recruitment of T cell help and induction of GCs results into higher Ab responses to protein than to PS vaccines.
Protein vs polysaccharide
Modulation of antigen delivery and persistence (depot or slow-release formulations) or enhancement of Thresponses (immunomodulator) may support or limit Ab responses
Adjuvants
World Health Organization WHO , Vaccine Immunology , http://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf
Determinants of Primary Vaccine Antibody Responses in Healthy Individuals
Mechanism Determinant
Failure to induce GCs limit immunogenicity. Antigen naturePolysaccharide antigens
Inclusion of epitopes readily recognized by B cells, inclusion of epitopes readily recognizedby follicular helper T cells, elicitation of efficient follicular T cell help and the capacity of antigen to associate/persist in association to FDCs result into higher Ab responses.
Protein antigens
higher Ag doses increase the availability of Ag for B / T cell binding and activation, as well as forassociation with FDCs
Antigen dose
World Health Organization WHO , Vaccine Immunology , http://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf
Mechanism Determinant
A 3 week minimal interval between primary doses avoids competition between successive waves of primaryresponses.
Vaccine scheduleInterval between doses..
Gene polymorphisms in moleculescritical for B and T cell activation/differentiation are likely to affect Ab responses
Genetic determinants
Mostly yet identified Environmental factors
Early life immune immaturity . Age at immunization
Determinants of Primary Vaccine Antibody Responses in Healthy Individuals
World Health Organization WHO , Vaccine Immunology , http://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf
Types of viral Vaccines
1- 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 different species “Heterotypic vaccines” (e.g. Turkey herpes virus against Marek’s disease virus, Sheep pox against LSD in cattle).
C- Attenuated vaccines: Attenuation is usually achieved by passage of the virus in foreign host such as ECE or tissue culture cells.
Reference : Prof.Dr.M.Shalaby Lecture2005
Advantages of Live Vaccines
1- Activates all phases of immune system can get humoral 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 the
community.Reference : Prof.Dr.M.Shalaby Lecture2005
Disadvantaged of live vaccines
1- Mutation, reversion to virulence (Major disadvantage).2- Spread to contacts of vaccines who have not
vaccinated.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 infectivity and retaining its immunogenicity.
• Inactivating agents : most commonly used are : 1- B-propiolactone 2- Formaldehyde 3- Ethylenimine and azuridine
Reference : Prof.Dr.M.Shalaby Lecture2005
Advantages of Killed Vaccines
1- Gives sufficient humoral immunity if boosters given.
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 vaccines
1- Booster doses are needed (Short immunity).2- No local immunity.3- Administration only by injection.4- Adjuvants is essential to provoke cell
mediated immunity.
Reference : Prof.Dr.M.Shalaby Lecture2005
Live attenuated Vs Killed VaccineInactivated vaccines Living vaccines
1-Stable on storage2-Unlikely to cause disease
through residual virulence.
3-Unlikely to contain live contaminating organisms.
1-Few inoculating doses required.
2-Adjuvants unnecessary3-Less chance of
hypersensitivity.4-Induction of interferon.5-Relatively cheap.
Reference : Prof.Dr.M.Shalaby Lecture2005
Molecualr Based Vaccines• Acc .to USDA classification of Genetically Engineered
Veterinary Biologics:
Category I: Vaccines that contain inactivated recombinant organisms or purified antigens derived from recombinant organisms.
Category II: Vaccines containing live organisms that contain gene deletion or heterologous marker genes.
Category III: Vaccines that contain live expression vectors containing heterologous genes for immunizing antigens or other immune stimulants.
Reference : Prof.Dr.M.Shalaby Lecture2005
Novel Molecular Based Vaccines
• Examples of Novel molecular based vaccines in veterinary Field :
1- VP1 Protective antigen of FMDV 2- VP2 of IBDV 4- H5 Gene of Avian influenza virus 3- Thymidine Kinase TK Gene of Pseudorabies
virus in swine .
Vaccine Safety vs Efficacy
SafetyEfficacy
Recombinant HVT+ IBD Vaccine
MERIAL Scientific Data
MERIAL Scientific Data
Ideal Vaccine Characterstics
1- Produce effective resistance to infection in vaccinated animal or bird.
2- Have long lasting resistance (stabilizers and/or heat resistant 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 mycoplasma
contamination.6- Stable.7- Reasonably cheap to produce.
Reference : Prof.Dr.M.Shalaby Lecture2005
Ideal Vaccine Characterstics• Give life-long immunity• Broadly protective
against all variants of organism
• Prevent disease transmission
• Rapidly induce immunity
• Effective in all subjects (the old & very young)
• Transmit maternal protection to the foetus
• Require few immunizations to induce protection
• Not need to be administered by injection (oral, intranasal, transcutaneous)
• Stable, cheap & safe
Ideal 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 at least 80%, Obviously less effective vaccines are acceptable 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 increase immunogenicity of vaccines containing inactivated micro-organisms or their products.
Other Vaccine components
Thiomersal– 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 Timing
1- Varies according to the species of animal and whether a live or inactivated vaccine is used. It is most important to bypass the maternal immunity
2- Activity of passive antibodies is determined by the level of Abs in the dam, how much is transferred via colostrum and its capacity to neutralize the vaccine. Passive antibodies wanes because circulating IgG has a half life of 10-20 days in domestic animals and 2-4 days in poultry.
3- Action of passive immunity may be avoided by given vaccines via the respiratory tract.
4- Increasing passive immunity may be a deliberate part of the control program, thus neonatal diarrhea might be reduced by vaccinating the dams.
Reference : Prof.Dr.M.Shalaby Lecture2005
Vaccination Failure
• Disease induced by strains of organisms or antigens that differ from the strain in the vaccine you used
• Faulty production of specific lot of vaccine (not enough antigen; accidental inactivation during manufacture)
• Unsatisfactory storage, exposure to heat (keeping it in the cab of a truck during the height of summer), freezing (esp. modified live vaccines)
Reference : Prof.Dr.M.Shalaby Lecture 2005
Vaccination Failure
• Administration by unconventional routes (e.g., given intranasal vaccine intramuscularly, or vice versa)
• Animals incubating disease at time of vaccination
• Disease due to an agent other than the one in the vaccine
• Blocking effects of maternal antibodies eg., IBD Vaccination.
Reference : Prof.Dr.M.Shalaby Lecture2005
Vaccination Failure
• Administration of antibiotics in conjunction with live bacterial vaccines.
• Chemical sterilization of syringes• Immune response is suppressed (heavily
parasitized or malnourished animals; stress of pregnancy, extremes of cold and heat, and fatigue)
Reference : Prof.Dr.M.Shalaby Lecture2005
Other Refernces
• http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf
• MERIAL , Internal scientific data , Vaxxitek