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Case 9: Vaccines Case 9 – Vaccines Page 1 of 34 Case 9: Vaccines Case Introduction       Smallpox  Variola virus that is highly contagious and can spread through saliva droplets from breath  Causes symptoms of blistering rash, blindness and arthritis  Mortality of 30-50% from variola major ...

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Case 9: Vaccines

Case 9 – Vaccines

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Case 9: Vaccines

Case Introduction 

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Smallpox  Variola virus that is highly contagious and can spread through saliva droplets from breath  Causes symptoms of blistering rash, blindness and arthritis  Mortality of 30-50% from variola major strain  Thucydides noted that those who survived didn’t get re-infected Cowpox  Closely related to the vaccinia virus  Related to smallpox but causes milder infections  Dr Edward Jenner noted that dairy milkmaids contracted cowpox but not smallpox Why vaccinate?  Most countries have recommended routine vaccinations for their citizens  Vaccination’s primary purpose is to protect the individual from infectious diseases that cause significant harm  The recommended vaccines depend on lots of factors, such as which organism are prevalent in that area and who is most at risk  Vaccination can also benefit the wider population in the following ways:  Vaccinated individuals pose less of a threat to others as the disease doesn’t spread so much  If enough members of the population are vaccinated, you can eradicate the disease completely from that community  This is called herd/community immunity Benefits  Save lives  Eliminates the disease if enough people are vaccinated  Herd/community immunity benefits those who can’t be vaccinated or are more vulnerable including:  Infants  Elderly  Pregnant women  Immunosuppressed  Easier, safer and a lot more convenient than contracting the disease and having to treat it Risks  Mild illness, fever and rashes  Pain, redness, swelling and tenderness at injection site  Vaccines may fail due to insufficient immune response  Small anaphylaxis risk – MHRA data suggests incidence of 1 in a million doses approximately  Can be related to excipients or antigen e.g. ovalbumin (used as an antigen – can cause egg allergy)

Joint Committee on Vaccination and immunisation (JCVI) Page 2 of 33

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 Specialist branch of Public Health England  Responsible for monitoring and updating the vaccination schedule  Make recommendations to government about all matters relating to vaccination  Publish and update: The Green Book JCVI decisions to include a vaccine in the primary schedule can depend on many influencing factors: 1. Population  Age – babies lack immunity and elderly’s immunity declines over time  Risk category – some people are more at risk of serious illness than others e.g. flu in pregnant women  Social changes – children starting school or young people starting university  Public/media campaigns 2. Disease  Prevalence of organisms and environmental factors e.g. flu in the UK  Sudden outbreaks of a disease  Desire to increase herd immunity  Prevention of other risks related to the diseases e.g. more serious complications 3. Pharmaceutical  Cost of manufacturing vs effectiveness of vaccine programme  Antigenic shift meaning new strains becoming prevalent  If vaccine product is able to be produced – none so far for HIV, malaria  Sometimes, need to produce a vaccine quickly in response to sudden pandemics Global situation  WHO monitors vaccination use globally  Schedules vary and may include vaccines for diseases specific to the geographical area  Access to vaccination is a problem for some parts of the world

How Vaccines Work 

Immunity  The ability of the human body to protect itself from infectious disease  The defence mechanisms of the body are complex and include:  Innate mechanisms – non-specific and non-adaptive  Acquired systems – specific and adaptive

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Innate/non-specific immunity  Present from birth Page 3 of 33

Case 9: Vaccines Includes:  Physical barriers e.g. intact skin and mucous membranes  Chemical barriers e.g. gastric acid, digestive enzymes and bacteriostatic fatty acids of the skin  Phagocytic cells and the complement system  Enhances the body’s immune response to an antigen Adaptive/acquired immunity  Acquired immunity is usually specific to a single organism or to a group of closely related organisms – share common antigens  2 basic mechanisms for acquired immunity – active and passive  Active acquired immunity  Produced by an individual’s own immune system – usually long-lasting  Involves cellular responses (cell-mediated), humoral responses (antibodymediated) or a combination acting against one or more antigens on the infecting organism  Can be acquired by natural disease or by vaccination  Vaccines provide immunity similar to that provided by the natural infection, but without the risk from the disease or its complications 

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APCs see antigen They chop it up and present it as peptides with MHC class II to naïve CD4 T-helper cells They then become effector Tcells of 4 basic types

Intracellular pathogens

Extracellular pathogens Extracellular (including helminths) pathogens (including fungi)

Intracellular Cytotoxins pathogens FasL

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APCs (usually dendritic cells) see antigen (usually virus) They chop it up and present it (peptides) with MHC class I to naïve CD8 cells which then become cytotoxic T-cells (CTLs) They then produce cytotoxins or trigger apoptosis of the target cell To continue CTL production and create memory cells, APCs must interact with activated CD4 T-helper cell

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Antibody provides immunity against infection by: 1. Neutralising bacterial toxins, bacterial adhesins and viruses by blocking and binding to cell-surface receptors = neutralising antibodies 2. Targeting CTLs to infected cells – antibody-dependent cellular cytotoxicity (ADCC) 3. Coating/opsonising pathogens and targeting them for phagocytosis 4. Antibody-antigen complexes activate classical complement cascade which leads to destruction of pathogens by phagocytosis or bacterial membrane attack

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Roles of antibody subtypes in protection  IgM: major role in complement activation – limited role in neutralisation and induced by vaccination (primary response) – blood  IgG: systemic (blood, tissues, lymph) – all major roles (neutralisation, ADCC (antibody-dependant cellular cytotoxicity), opsonisation, complement activation) – induced by vaccination  IgA: principle isotype in secretions at mucosa (gut, respiratory tract, genital) – less potent at opsonising,

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a weak activator of complement but strong viral neutraliser – can be induced by vaccination (but needs adjuvants) IgE – Helminths IgD – no role

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Passive antibody immunisation  Passive immunity = protection provided by the transfer of antibodies from immune individuals, most commonly across the placenta (IgG) and from breast milk (secretory IgA)  Protection from cross-placental antibodies are more effective against some infections (tetanus and measles) than for others (polio and whooping cough)  This protection is temporary – last for a few weeks or months, as neonates are very vulnerable to disease  Mother should have an up-to-date vaccination profile, in particular MMR – to protect their child (rubella can damage the foetus irreversibly)  As healthy immune system is dependent on nutritional status, mothers should also eat well

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Cell-mediated immunity  Cell-mediated immunity is provided by effector lymphocytes (T-cells) of T-helper 1 type (includes CD8 CTLs)  2 principal classes – each has specific function 1. CD8 T-cells/cytotoxic/killer T-lymphocytes – recognise and destroy infected cells 2. CD4 T-helper cells – activate phagocytic macrophages to destroy engulfed bacteria and activate B-cells to produce IgG1 and IgG2 subtypes – strongly opsonising

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Vaccines produce their protective effect by inducing active immunity and providing immunological memory Immunological memory enables the immune system to recognise and respond rapidly to exposure to natural infection at a later date – prevents or modifies the disease The key to an effective vaccine is the ability for it to trigger proliferation of naïve T-cells Success depends on whether T-helper1 cells and CTL responses are induced against intracellular organisms –viruses T-helper2 antibody responses are induced against extracellular organisms – bacteria and parasites, or their toxins

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Role of adjuvants  Many soluble proteins are poorly immunogenic when used on their own as a vaccine  Adjuvants are compounds that enhance immunogenicity of the protein antigens  They do this in 2 ways 1. By converting soluble proteins into particles – can use alum (adsorbs proteins), mineral oils (emulsifies proteins) or Quil A detergent (forms colloids with proteins) 2. Effect is enhanced by including bacterial components – activates APCs and/or induces cytokine production and enhances inflammatory responses  Latter can be toxic – many not licensed for use in humans  Many APC receptors are now mapped and ligands are identified – provides costimulatory signals to activate T-cells, along with MHC + antigen peptide

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Principles of safe and effective vaccination  Search for attenuated organisms with reduced pathogenicity to stimulate protective immunity Page 7 of 33

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Develop inactivated (killed) organisms – won’t cause lethal systemic infection in the immunosuppressed Develop purified components of whole organisms containing key antigens that stimulate protective immunity

Requirements for an effective vaccine  Depends on the organism  Intracellular organisms usually need CTL and antibodies  Extracellular organisms usually need neutralising antibodies  It provides defence at point of entry  Stimulation of mucosal immunity may be required at specific mucosa (gut, respiratory epithelia, gut epithelia  Pre-existing antibody may be required  Pre-existing antibody protects against diphtheria/tetanus exotoxins – forms antigen-antibody complexes which are phagocytosed  Polio and HIV enter cells shortly after infection – antibodies must block ligand-cell receptor interaction  Protection optimised when specific epitopes are recognised  Immune responses directed at multiple epitopes  Not all of these generate protective antibodies or CTLs  Some may even generate suppressor T-cells  Correct epitopes must be targeted  It must be safe  Must have very low toxicity  Must protect most vaccines  Rapid generation of herd immunity  Reservoir of susceptibles falls – transmission drops  Must generate long-lived immunity  Repeated booster immunisations often impracticable  Cheaper and improves population health  It must be cheap  Will be administered to large populations  Very cost-effective healthcare  But benefit reduced if cost per dose rises

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Key points  Vaccines work by helping the body’s immune system to prevent infection from viruses, bacteria fungi and parasites  Effectively, the immune system responds to key antigens on the vaccine immunogen (entire organism or purified component) to develop an immune response  This includes components of both the non-specific innate and specific adapted immune response and involves the generation of memory T and B cells  On re-exposure of the pathogen, these memory cells rapidly expand to provide a potent and specific response to the infection  Key to the success of a vaccine immunogen is its ability to trigger the proliferation of T-cells – some epitopes may generate non-protective or even suppressive responses  These than mount to a Th-1 type response against intracellular pathogens, facilitated by macrophages and cytotoxic T-lymphocytes or a Th-2 type response against extracellular parasites, facilitated predominantly by antibodies  Many vaccine antigens (particularly purified components) are weakly immunogenic and can be potentiated by the addition of adjuvants to the formulation, which enhances the initial innate response  An ideal vaccine will be designed to provide protection against a specific organism at the point of entry – in most cases, this is the mucosa, where specialised regions regulate immunity  In addition, an ideal vaccine should be safe, effective, long-lasting and cheap  The immune system and a person’s exposure to pathogens changes throughout life  Vaccination schedules are arranged accordingly and offered to babies, infants, young adults and the elderly  Pregnant women and the immunosuppressed are special cases Page 9 of 33

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Specific vaccines may be given to those travelling to regions with a high prevalence of certain infections e.g. Yellow Fever, Cholera

Understanding Meningitis   

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Meningitis is defines being inflammation of the meninges The meninges are the 3 membranes which enclose the brain and spinal cord Meningism refers to the signs and symptoms that accompany the inflammation Causes – meningitis can be caused by a variety of microbial agents:  Bacteria  Viruses  Fungi  Protozoa People at risk  Babies and young children  Teenagers and young adults  Elderly people  People with a weak immune system – e.g. those with HIV and those having chemotherapy How is meningitis acquired and spread?  Often caused by organisms which colonise the back of the nose and throat  Sometimes acquired during birth e.g. Group B streptococci  Can be present in amniotic fluid – contaminated by organism and be passed through to the baby  Meningitis can be spread by close contact, coughing and sneezing

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Bacterial meningitis  Usually more severe than viral meningitis  High fatality rate unless treated immediately  Even with antibiotic therapy, many sufferers are left with disorders, most commonly hearing loss  Endotoxin release initiates organ dysfunction and blood disturbances  Blood leaks from capillaries causing a purple rash

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Meningitis and meningococcal septicaemia  N. meningitidis causes both meningococcal meningitis and meningococcal septicaemia (collectively meningococcal disease)  Gram negative diplococci, various virulence factors  Meningococci colonise the oropharynx in some healthy people – these are the carriers Page 10 of 33

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In these people, transition from carrier state to invasive disease occurs due to unknown factors Men A, B, C W and Y most commonly cause the disease (antigenic structure of the polysaccharide capsule – differentiated by the antigenic properties of the capsule) Bacteria can enter the bloodstream and cross the BBB to cause meningitis – bacteria can contain type 4 pili which attach to epithelial cells and pass through the brain side of the membrane May get meningitis – bacteria enters the bloodstream and reach the meninges and cause the meningitis Septicaemia results when bacteria enter the blood and multiply uncontrollably Patient may get one or the other or both Men W  Cases of Men W are rising  ST-11 is causing severe disease in healthy teenagers and young adults  The symptoms it presents are different to bacterial and viral meningitis  Severe respiratory problems and can cause GI problems

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Other causative bacteria  Largely depends on age group as to which organism can affect the patient  Streptococcus pneumoniae (gram positive and capsulated) can cause meningitic disease in any age group, but especially children and elderly – sometimes spread by an ear infection and can cause deafness  Group B streptococci meningitic disease occurs primarily in babies – organism can be acquired during birth which leads to symptoms developing within a few days  Type B Haemophilus influenza (Hib) causes meningitis in infants and toddlers  Meningitis caused by M. tuberculosis (can’t stain with gram stain, need to stain with acid-fast) is rare in the UK, but should be considered when assessing patients from high risk areas

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Viral meningitis  Most common form – more common than bacterial meningitis  Illness is less severe and can just sleep it off  Relatively benign illness and usually doesn’t need medical attention – may even go unrecognised  Usually presents as mild flu-like illness:  Headache Page 11 of 33

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 Fever  General malaise In more severe cases:  Neck stiffness  Muscular/joint pain  Nausea/vomiting  Diarrhoea  Photophobia  Severe symptoms require hospital admission Usually make a full recovery, but rarely can be left with residual effects similar to meningitic diseases

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Fungal meningitis  Causative fungi:  Cryptococcus neoformans (most common) – associated with HIV infection as patient is usually immunocompromised  Candida – in premature babies  Coccidioides immitis – found common and usually in immunosuppression  Histoplasma  Cryptococcus neoformans  Usually associated in patents with cell-mediated immune defects  Organism travels from initial site of infection to the lungs, then invades the blood stream  Symptoms appear more gradually, over days or weeks  Symptoms may include: o Headache o Fever o Nausea/vomiting o Stiff neck o Dislike of bright lights o Changes in mental state and hallucinations

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Early warning signs of meningitis  Fever  Headache  Vomiting  Muscle pain  Fever with cold hands and feet  Endotoxins produced can cause damage to the capillaries  Toxins can make the tight junctions leaky and allow the blood to leak  This will result in reduced blood volume and the heart in result will work harder to pump blood around  The body will restrict blood going to the skin and results in cold hands and feet  Don’t wait for a rash!!!!

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The tumbler test  Someone who becomes unwell rapidly should be examined particularly carefully for the meningococcal septicaemia rash  People with meningococcal septicaemia may develop a rash of tiny pink prick spots which can rapidly develop into purple bruising  To identify the rash, press a glass tumbler against it and if the rash does not fade, it be meningococcal septicaemia  On dark skin, check the rash on lighter parts of the body e.g. finger tips, soles of feet

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Diagnosing meningitis in the lab  Cerebrospinal fluid (CSF – a clear, colourless liquid that bathes the brain and spinal cord providing shock absorption and support) may be taken and:  Visually inspected – clear or turbid?  A cell count performed  Protein is analysed  Glucose levels are analysed  A centrifuged deposit is a) Gram stained and b) inoculated onto a range of media to support the main pathogens  Further specific tests performed  CSF is obtained by doing a lumbar puncture or spinal tap – a long, thin, hollow needle is inserted between two bones in the lower spine and into the space where the CSF circulates  Blood cultures

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NICE guidelines - prompt recognition of signs and symptoms of meningitis and meningococcal disease is key to saving lives

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Treatment  Fungal meningitis  Amphotericin B  Flucytosine  Fluconazole  Viral meningitis – no specific antiviral therapy, but Aciclovir for herpes simplex virus  Bacterial: initial empirical therapy  Transfer patient to hospital urgently  If meningococcal disease suspected, use benzylpenicillin (narrow spectrum but has activity against niceria) – cefotaxime or chloramphenicol  Consider adjunctive treatment with dexamethasone – see contraindications e.g...