vaccine immunology m.fathy

Vaccine Immunology

By Mohamed Fathy , B.V.Sc

Virology Pre-Master StudentE-mail : mohfathy.vet@hotmail.com

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