An introduction to vaccines and immunotherapy Flashcards
Describe the history of vaccine development
The first vaccine was named after Vaccinia, the cowpox virus. Jenner pioneered its use 200 years ago. It was the first deliberate scientific attempt to prevent an infectious disease and was based on the notion that infection with a mild disease (cowpox) might protect against infection with a similar but much more serious one (smallpox), although it was done in complete ignorance of immunology.
It was not until the work of Pasteur 100 years later that the general principle governing vaccination emerged – altered preparations of microbes could be used to generate enhance immunity against the fully virulent organism. Thus Pasteur’s dried rabies-infected rabbit spinal cords and heated anthrax
bacilliwere. Even Pasteur did not have a proper understanding.
Finally, with Burnet’s clonal selection theory and the discovery of T and B lymphocytes, the key mechanism became clear.
In any immune response, the antigen(s) induces clonal expansion in specific T and/or B cells, leaving behind a population of memory cells. These enable the next encounter with the same antigen(s) to induce a secondary response, which is more rapid and effective than the normal primary response.
What are the principles of vaccination?
The principles of vaccination can be summarized as:
* priming of specific lymphocytes to expand the pool
of memory cells;
* use of harmless forms of immunogen – attenuated
organisms, subcellular fragments, toxoids or vectors;
* use of adjuvants to enhance immune responses; and
* production of safe, affordable vaccines to promote
herd immunity.
Q. Rabies is one of the few diseases in which active
immunization may be carried out after the individual
becomes infected. What particular feature of rabies infection makes this a reasonable treatment?
A. The time between infection and the development of
the disease is long, so an effective immune response has time to develop before virus reaches the CNS to produce symptoms.
Describe Live vaccines
These can either be natural (e.g. Vaccinia for smallpox and vole bacillus for TB) or attenuated (e.g. MMR, BCG for TB)
Apart from vaccinia, no other completely natural organism has ever come into standard use.
The natural vaccines are too risky, but now looking at knocking out genes to render live virus safe, eg new Rotavirus vaccine
Live vaccines better because they induce an appropriate immune response, and have many antigens to target.
Describe and give examples of attenuated vaccines
Attenuated microorganisms are less able to cause
disease in their natural host
Historically, the preferred strategy for vaccine development has been to attenuate a human pathogen, with the aim of diminishing its virulence while retaining the desired antigens.
Attenuation ‘changes’ microorganisms to make them less able to grow and cause disease in their natural host. In early attenuated organisms, ‘changed’ meant a purely random set of mutations induced by adverse conditions of growth.
Q. It is often found that attenuated viruses that are avirulent do not make good vaccines. Why should this be?
A. Inflammation induced by damage to the host has an adjuvant effect, leading to more effective presentation of the vaccine antigens.
Describe and give examples of dead vaccines
- some are very effective (rabies and the Salk polio
vaccine); - some are moderately effective (typhoid, cholera, and
influenza); - some are of debatable value (plague and typhus);
- some are controversial on the grounds of toxicity
(pertussis).
Killed vaccines don’t produce a prolonged antigenic
stimulus.
Describe and give examples of toxin-based vaccines
Inactivated toxins and toxoids are the most
successful bacterial vaccines
The most successful of all bacterial vaccines – tetanus and diphtheria – are based on inactivated exotoxins
Toxoid: Usually bacterial exotoxin which has been inactivated by heat or chemical action (eg by formalin). Active against toxin-induced
illness.
Describe and give examples of subunit vaccines
a number of other vaccines are in use which employ antigens either purified from microorganisms or produced by recombinant DNA technology. For example, a recombinant Hepatitis B surface antigen synthesized in baker’s yeast, has been in use since 1986.
Subunit vaccines may need adjuvants, small antigens may have issues with MHC restriction.
Describe Conjugate vaccines
Although protein antigens such as hepatitis B surface antigen are immunogenic when given with alum adjuvant for many types of bacteria, virulence is determined by the bacterial capsular polysaccharide, prime examples being Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae B. Such carbohydrate antigens, though they can be isolated and have been used for vaccination, are poorly immunogenic, particularly in infants under 2 years, and often do not induce IgGresponses or long-lasting protection. Attempts to boost immunity by repeat administration of these vaccines can actually compromise immunity by depleting the pool of antibody-producing B cells.
Polysaccharide antigens don’t stimulate T cells
Q. Why do polysaccharide antigens not induce IgG
responses or lasting immunity?
A.Polysaccharideantigens are not processedfor presentation to TH cells, so they do not induce class switching, affinity maturation, or generate memory T cells
Describe Pseudoviruses
Non-replicative
Virus-like particles
Can be used to deliver antigens/DNA/RNA
Choice of PsV determines delivery route, eg Papilloma virus PsV to mucosa.
Possible adjuvant effect
Give examples of vaccines with Prophylactic use and therapeutic use
Prophylactic use:
Most of the above:
Smallpox;
Polio;
Tetanus (but needs booster!)
Therapeutic use:
Rabies: rare case.
Louis Pasteur and Emil Roux and dried rabbit nerves,
Can be used prophylactically in high-risk groups.
But therapeutically in post-exposure.
Describe adjuvants and give examples
Boost the immunogenicity of poor antigens eg. some purified or recombinant proteins
Initiate an inflammatory response
Usually responsible for side-effects of vaccination (pain and swelling)
May concentrate Ag at site where lymphocytes are exposed to it (Depot effect)
Induction of cytokines
Q. Many bacterial carbohydrates and glycolipids are
good adjuvants, even though they are not good immunogens.
Why should this be so?
A.The discovery of Toll-like receptors and other pattern recognition receptors, such as lectin-like
receptors for carbohydrates has provided an
explanation for the long-known efficacy of many bacterial products as adjuvants. It is clear that they act mainly by binding to PRRs and stimulating the formation of appropriate cytokines by APCs.
Describe different issues surrounding vaccine safety
Usually mild side effects such as minor pain/swelling at injection site or mild fever.
But vaccines might get contaminated
Killed viruses might not be dead!
Attenuated virus may revert to wild type
Patient might be hypersensitive to trace contaminants
Patient might be immunocompromised
Some vaccines are reserved for special groups only
give examples for this
In some cases this is because of:
* geographical restrictions (e.g. yellow fever);
* the rarity of exposure (e.g. rabies);
* problems in producing sufficient vaccine in time to meet
the demand (e.g. each influenza epidemic is caused by a
different strain, requiring a new vaccine).
Describe how Passive immunization can be life-saving
Driven from use by the advent of antibiotics, the idea of injecting preformed antibody to treat infection is still valid for certain situationsIt can be life-saving when:
* toxins are already circulating (e.g. in tetanus, diphtheria, and snake-bite);
* high-titer specific antibody is required, generally made in horses, but occasionally obtained from recovered patients.
Non-specific immunotherapy can boost immune activity
Give examples of this
Finally cytokine inhibitors can be used for severe or
chronic inflammatory conditions. Various ways of inhibiting
TNFa and IL-1 have proved valuable:
* in rheumatoid arthritis, the use of monoclonal
antibodies targeting the inflammatory cytokine,
TNFa has become a front line therapy; and
* more controversially, in septic (Gram-negative)
shock and severe malaria.
Interleukin-2: T cell stimulus, NK, NKT
GM-CSF: APC stimulus
Type 1 Interferon: activates a number of immune cells and upregulates MHC
Give examples of Therapeutic antibodies
