Vaccination Flashcards
Features of effective vaccines (x6)
1) Safe -must not itself cause illness or death
2) Protective -must protect against illness resulting from exposure to live pathogens
3) Gives sustained protection -protection against illness must last for several years
4) Induces neutralizing antibody -some pathogens (ie polio) infect cells that cannot be replaced (ie neurons). Neutralixing antibody is essential to prevent infection of such cells
5) Induces protective T-cells -some pathogens, particularly intracellular, are more effectively dealt with by cell-mediated responses
6) Practical considerations -low cost per dose, biological stability, ease of administration, few side-effects
Challenges to Vaccine Development (x3)
a) pathogens that provoke weak immune responses
b) pathogens that have large numbers of strains
c) pathogens that evade the immune response and elicit chronic illness
Precautions
- Age and timing of immunizations
- Hazards
Age and timing
-Newborn: immaturity of immune system
-Children
-Elderly
Hazards
-Immunocompromised patients:
-AIDS, immunosuppressive therapy
-pregnancy: live virus may cross placenta
-HypersensitivityTypes of Vaccines
1) Live attenuated organisms
2) Killed or non-viable organisms
a) Whole protein organisms
b) Part of organism
- toxoids
- subunit vaccines
- capsular polysaccharides
- conjugate vaccines
3) Recombinant ENA
4) DNA vaccines
Live-attenuated vaccines
live organisms that are no longer able to cause disease, can be used to stimulate immunity
Attenuated viruses
Yellow fever Chickenpox Polio (sabin) Measles, Mumps, Rubella -MMR given at 15 mo and 4-6 yr
Attenuated bacteria
Bacille Calmette-Guerin (BCG) -bovine strain of M.tuberculosis
Salmonella typhi
Attenuation
1) live organisms mutated to reduce pathogenicity
- can occur naturally as variants can arise that are less pathogenic (ie one of the oral sabin strains for polio -sabin 2)
2) attenuation can be done by growing viruses on non-human cell lines or animals
- selects for variant viruses that grow better in non-human cells and are less fit to grow in humans (ie cold adapted influenza virus -won’t grow at 37C)
3) attenuation can be done by genetic engineering
- (ie Salmonella typhi (typhoid fever) made mutagenesis of enzyme necessary for LPS synthesis)
Advantages of Attenuated vaccines
strong immune responses, can mimic the natural disease process and therefore immunity is generated to target the infectious process -this includes route of infection
Disadvantages of Attenuated vaccines
can cause problems in immunocompromised individuals, chance of reversion to pathogenic form
*Sabin oral polio vaccine contains 3 diff. live-attenuated viruses (trivalent). 3 people/million can develop polio from this, a result of strain 3 where reversion of one nucleotide results in virulence. Current solution, give killed vaccine first immunization with the live viruses subsequently
Killed or non-viable (inactivated) vaccines
-Whole organisms
Whole organisms:
1) Viruses (Salk polio virus, influenza, rabies)
- chemically treated or heated or irradiated so that they are no longer able to replicate
- trivalent influenza virus (grown in eggs) and inactivated using formalin
2) Bacteria (Bordetella pertussis or Vibrio cholera)
- killed organism extract
Disadvantage of inactivated whole organism
More side effects related to immune pathology or specific antigens that mediate the disease caused by the microbe
Killed or non-viable (inactivated) vaccines
-Part of Organism
Part of organism:
1) Target toxins using toxins inactivated with formalin (toxoids)
- e.g. diptheria toxin, tetanus toxin
- single vaccine is DTP with diptheria toxoid, tetanus toxoid, killed pertussis
Killed or non-viable (inactivated) vaccines
- Subunit vaccines
- >Capsular polysaccharides
- >Conjugate vaccines
Subunit Vaccines
- Hepatitis B virus (HbsAg) -purified from blood from patients or recombinant protein
- Encapsulated bacteria -antibody responses against CAPSULAR POLYSACCHARIDES are protective (ie S.pneumoniae, N. meningitis, H.influenza)
- > Capsular polysaccharides can provoke T-independent B cell responses, but not very immunogenic in infants or in elderly
- > Conjugate vaccines -conjugate toxoid (tetanus, diptheria) to polysaccharide converts to T dependent antigen
Conjugate Vaccines
-how do they work?
(slide 15)
1) B cell binds bacterial polysaccharide epitope linked to tetanus toxoid protein
2) Antigen is internalized and processed
3) Peptides from protein component are presented to the T cell
4) Activated B cell produces antibody against polysaccharide antigen on the surface of the bacterium
5) Activated B cell will proliferate and become either a polysaccharide specific memory or plasma cell
Recombinant DNA Vaccines
Insert genes for specific antigens into non-virulent viral or bacterial organisms
1) Salmonella vectors
- encoding antigenic genes for listeria, anthrax, plague
- administered orally
2) Vaccinia vectors
- no longer used to protect against smallpox
- avirulent carrier of heterologous antigens
3) Adenoviral vectors
- used for HIV vaccine development
- cancer immunotherapy
DNA Vaccines
Naked DNA plasmid injected into muscle induces flu-specific CD8, CD4, and Ab responses
-presumably the plasmid DNA is expressed by some of the muscle tissue
Adjuvants
- Killed/non-viable vaccines are not very immmunogenic themselves and requires an adjuvant to enhance immunity
- Vaccination can be enhanced by the addition of substances (adjuvants) that induce inflammation by antigen-independent mechanisms
1) Freund’s complete adjuvant: emulsion of killed mycobacteria and mineral oil
2) Alum (aluminum hydroxide): only approved adjuvant in US (MF59 in Europe)- tends to promote Th2 type responses, not Th1
A prerequisite to a good ____________________ is a state of _____________ due to _____________activation and recruitment of __________________.
adaptive immune response; inflammation; macrophage, inflammatory cells
Improvements in vaccine development and design
1) Understand disease pathogenesis better to identify targets
-using recombinant DNA tech. to produce purified vaccine proteins (HBV-HBsAg) or reduce virulence (Salmonella)
2) Need to understand how the immune system best protects from an infectious disease
-Th1 vs Th2 -addition of IL-12 can promote Th1
-route of immunization -site of infection
3) Improve adjuvants
-ISCOMS (Immune Stimulatory Complexes)
->lipid micelles, carrying class I restricted peptides or polypeptides, fuse with cell membrane and deliver them to cytoplasm
-Cytokines as molecular adjuvants
(eg GM-CSF, IL-2)
