Microbiology 9- Vaccination against bacterial infections Flashcards
Describe innate immunity
Innate immunity First line of defence Does not require exposure to the infectious agent Is immediate (almost) Mediated by monocytes and PMNs Initially an inflammatory reaction
Describe Acquired immunity
Acquired immunity
Requires exposure to infectious agents
Takes time to develop
Mediated mainly by lymphocytes (B and T cells)
Other cell types involved, e.g. monocytes and dendritic cells
What are vaccines aimed at
Vaccines stimulate both aspects of the immune response but are primarily aimed at eliciting acquired immunity which requires exposure to the infectious agent or its antigens.
Describe humoral immunity
Humoral Immunity
directly mediated by antibodies
antibodies are produced by B lymphocytes
Plasma cells (terminally differentiated B lymphocytes) are the primary source of secreted immunoglobulins
Describe cell-mediated immunity
Cell Mediated Immunity
not primarily mediated by antibody
mediated by T lymphocytes and NK cells
indirectly other cell types may play a role e.g. macrophages
What is important in clearing infections
A combination of humoral and cell-mediated immunity
Describe the importance of designing a vaccine that targets the appropriate immune response
Acquired immunity can be divided into two arms: humoral immunity which is mediated by antibodies and cell mediated immunity. It is important that a vaccine stimulates an appropriate immune response. For example, humoral immunity is usually important for preventing septicaemia whereas cell mediate immunity is often important for the prevention of intracellular infections. They are not mutually exclusive with both elements of the immune response playing a role in protection against may diseases.
Describe the role of the antibody in immunity to bacterial infections
Role of antibody
Toxin neutralisation, e.g. tetanus, diphtheria, botulism, anthrax etc.
As a focus for complement binding- Ab mediated bactericidal activity
As an opsonin promoting phagocytosis- Ab mediated bactericidal activity
Many bacteria produce exotoxins that have significant effects on the host, e.g. tetanus, botulism, cholera, anthrax, diphtheria, whooping cough etc. Their effects can be neutralised by antibodies binding to active sites or resulting in antibody antigen complexes.
Invasive bacteria and bacteria infecting mucosal surfaces do not always produce exotoxins. Protection against such infections is often mediated by antibodies that kill the bacteria through the classical complement pathway or opsonisation.
Describe the role of cell-mediated immunity in immunity to bacterial infections
Role of cell-mediated immunity
Particularly important for eliminating intracellular bacteria, e.g. tuberculosis, typhoid, legionella
interaction of the reactive T lymphocytes and the macrophage is key to clearance of infection
List the properties of a good vaccine
Ideally a vaccine:
Stimulates an effective immune response
Is safe and does not cause adverse reactions
Is inexpensive to manufacture and distribute
Is stable
Is easy to administer
Should be simple for both manufacturer and regulatory authorities to control
i.e. a good vaccine provides substantial benefit to health at low cost and low risk
What is meant by an effective immune response
It should elicit the correct balance of humoral and cell mediated responses
The immune response should be directed to the relevant site within the host (e.g. the gut in the case of enteric infections).
The immune response should be “functional”. For example, toxin-neutralising antibodies should be able to bind to toxin and neutralise its activity or if bactericidal antibodies are required the antibody should bind both the bacterium and complement.
An effective vaccine would be expected to elicits this response in all (or at least the majority of) vaccinees, give life-long protection without repeated doses, stimulate a boostable response and offer protection against antigenically diverse strains
Why is vaccine safety essential and how is this achieved
Vaccine safety is critical as they are given prophylactically to healthy individuals, who should remain healthy after vaccination.
A parenterally administered vaccine must be sterile (although an orally administered vaccine may only need only be free of enteric pathogens).
Vaccine manufacturers follow tightly regulated procedures (e.g. Good Manufacturing Practice; GMP) to ensure that vaccines are manufactured safely and consistently.
Wherever possible they avoid the use of materials of human or animal origin.
The acceptable safety of a vaccine may depend on the recipient. An adult choosing to receive a therapeutic anti-cancer vaccine may be prepared to accept a higher level of risk than a parent taking an infant for routine paediatric vaccination.
What is meant by a direct contact
Stopping colonisation leading to infection.
What is meant by indirect contact
Herd immunity- prevents pathogen from one organism to the next.
Describe herd immunity
Holding the infection in a small part of the population.The term herd immunity refers to the effect of immunity within a population to reduce transmission of the infectious agent, thereby protecting those who are susceptible (i.e. not immune) to the disease. The endemic state reflects a balance between the transmissibility of the infectious agent and the level of immunity in the population. Herd immunity can be modelled mathematically.
Do all vaccines result in herd immunity
No
Describe Phase 1 trials
Primarily for safety but are often also used to assess immunogenicity
Usually small numbers of adults
entail close clinical monitoring of vaccinees. Data collected might include information on the following: local and systemic reactions, fever, diarrhoea and vomiting and headache etc.
Describe phase 2 trials
Primarily for assessing immune response but also used to expand safety database
Typically includes all groups that are likely to use the vaccine
provide an opportunity to investigate the effect of different dose regimes and formulations, examine laboratory assays for correlates/surrogates of protection, and for regulatory laboratories to evaluate the prospective vaccine and validate QC tests. All groups that are likely to use the vaccine include both sexes, a range of ages and different ethnic groups.
Describe phase 3 trials
Protection studies, usually placebo controlled double blind trials
provide statistically conclusive data for licensure
Require good disease surveillance
case ascertainment
definition of endpoint
are designed to investigate directly the ability of a vaccine to offer protection against disease. This requires good disease surveillance. Efficacy is the measure of a vaccine to offer protection. Its assessment is scientifically rigorous (e.g. assessed by double blind, placebo controlled trial) and it is required for licensure. Effectiveness studies, sometimes termed phase 4 trials, measure the ability of the vaccine to achieve specific ends. They are scientifically less rigorous, study designs vary and they are not required for licensure. Effectiveness data can help to convince prospective users of the benefits of a vaccine.
What are effectiveness trials sometimes referred to as
Phase 4 trials
Why is phase 3 sometimes not carried out
Rarer diseases- not enough numbers to generate a high power.
Describe vaccine efficacy
Vaccine efficacy is determined in Phase III trials
blinded, placebo controlled
= 1- attack rate in vaccinated group/ attack rate in unvaccinated group
Usually expressed as a percentage.
What is Ro related to
There is a relationship between the basic reproduction number R0, vaccine effectiveness and coverage needed to reduce or eliminate disease
How can we calculate coverage needed to achieve herd effect
(1-1/R0)/Effectiveness
How can the herd effect be calculated
The herd effect is determined post vaccine introduction
= 1- Attack rate in unvaccinated post-introduction/ attack rate in unvaccinated pre-introduction
What are the constituents of vaccine formulations
Antigen
To stimulate the immune response to the target disease
Adjuvant
To enhance and modulate the immune response
Excipients
Buffer, salts, saccharides and proteins to maintain the pH, osmolarity and stability of the vaccine
Preservative, e.g. phenoxyethanol, thiomersal etc
Why do preservatives sometimes have to be added
Preservatives such as phenoxyethanol or the mercury containing Thiomersal may be added to multidose formulations to prevent growth of microbes once the vial has been punctured. Single dose vials or pre-filled syringes do not usually contain preservative.
List the different vaccine antigens
Live attenuated organisms (complex, ill-defined)
Killed whole organisms (complex, ill-defined)
Purified component vaccines
Toxoids
Polysaccharide conjugates
Describe live attenuated vaccines
These contain mutations that affect the ability of the organism to thrive and/or cause disease in the host. Historically, the mutants were isolated by chemical mutageneisis or multiple passaging of the organism; more recently attenuated isolates have been rationally mutated using targetted molecular methods.
Describe killed organisms
Probably the simplest sort of vaccine to produce. The organism is grown and then killed either chemically (e.g. with phenol or formaldehyde) or by heating.
Describe component vaccines
The emergence of purified component vaccines has depended upon technological advances since the latter part of the 20th century. These have included advances in physical and chemical methods of separation as well as the development of recombinant DNA techniques, genome sequencing and bioinformatics (for the identification of prospective antigen genes in the genome).
Describe DNA vaccines
The antigen gene is cloned in a vector so that it is expressed from a promoter sequence that is functional in the host. Once the DNA is injected, the host expresses the desired antigen and then mounts an immune response.
Describe the UK childhood vaccination programme
2, 3 and 4 months old
Diphtheria, tetanus, pertussis (whooping cough), polio and Hib
One injection
MenC
One injection
Around 13 months old
Measles, mumps and rubella (MMR)
One injection
3 years and 4 months to 5 years old
Diphtheria, tetanus, pertussis (whooping cough) and polio
One injection
MMR
One injection
10 to 14 years old (sometimes neonatal)
BCG
Skin test, one injection, if needed
13 to 18 years old
Diphtheria, tetanus, polio
One injection
From three years four months onward:-
Pre-primary school: DTaP-IPV booster, MMR booster
Live attenuated influenza vaccine
Girls 12-13 years old: HPV
During secondary education: dT-IPV booster, MenACYW
