vaccines case Flashcards
what is meant by individual protection?
- Most countries have recommended routine vaccinations for their citizens
- Vaccination’s primary purpose is to protect the individual from infectious diseases that can cause significant harm
what is meant by community protection?
- Vaccinated individuals are less threat to others, disease can’t spread so much, reduces outbreaks
- If enough members of the population are vaccinated, you can eradicate the disease completely from that community
- This is called ‘herd immunity’ (aka population or community immunity). Protects the wider populations and less outbreaks within communities
what is small pox?
- Variola virus, highly contagious, caused plagues for centuries
- Blistering rash, blindness, arthritis
- Mortality 30-50% from variola major strain
- Since 900s in Eastern Asia ‘variolation’ was practised using smallpox scabs. Try to inoculate them by trying to put the virus under the skin or up the nose
- Not introduced in the West until 1700s
what is cow pox?
- Vaccinia virus, related to smallpox but causes milder infections (orthopoxvirus family)
- Dr Edward Jenner - noted dairy milkmaids contracted cowpox but not smallpox
- Inoculated a boy with cowpox, once mild infection cleared, he later inoculated him with smallpox twice – no reaction
WHO small pox eradication programme
World Health Organization, 8 May 1980
• Eradicated worldwide
• Return of the virus is unlikely
what are the problems with vaccination programmes?
can’t vaccinate everyone against every infectious disease.
what are the Joint Committee on Vaccination and Immunisation (JCVI)
- 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’
what is the NHS schedule
- Groups are targeted according to susceptibility and risk
- Babies at 2,3 and 4 months old need a range including: diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b, hepatitis B pneumococcus, rotavirus, meningitis b
what are the factors in deciding who gets a vaccination?
• The JCVI take many things into account when deciding, they relate to:
– The susceptible populations
– The diseases themselves e.g. HIV vaccine
– Pharmaceutical issues and the vaccine products
the factors in a population in deciding if gets vaccine
- Age – babies lack immunity, older people’s immunity declines over time
- Risk category – some people more at risk of serious illness than others e.g flu in pregnant women, people with co-morbidities
- Social changes – children starting school, or young adults starting university
- Public/media campaigns/new research
how does disease determine who gets a vaccine
- 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
how does pharmaceutical determine who gets a vaccine • Costs of mass manufacturing versus effectiveness of vaccine programme
• Antigenic drift or shift meaning new strains become prevalent
• If vaccine product is able to be produced – none so far for HIV, malaria: world’s first 2018
• Sometimes need to produce a vaccine quickly due to sudden pandemics…like COVID-19
what are risk associated with vaccines
- Mild illness, fever and rashes
- Pain, redness, swelling, tenderness at injection site
- Vaccine failure, insufficient immune response
- Small anaphylaxis risk – MHRA data suggests incidence of 1 per million doses approx
- Can be related to excipients or antigen e.g. ovalbumin (relevant in those with egg allergy)
what are the benefits associated with vaccines
- Saves lives
- Herd immunity benefits for those who can’t be vaccinated or are more vulnerable e.g. infants, elderly, pregnant women, immunosuppressed
- Eliminates the disease in some cases
- Easier, safer, a lot more convenient than contracting the disease and having to treat it
what is the global situation on vaccines
- WHO monitors vaccination use globally
- Schedules vary, may include vaccines for diseases specific to the geographical area
- Access to vaccination is a health inequality problem in some parts of the world
what is meant by immunity?
• Immunity = ability of the human body to protect itself from infectious disease
• Two main groups of defence mechanisms in the body :-
1. INNATE (non-specific, non-adaptive) mechanisms
2. ACQUIRED (specific, adaptive) mechanisms
how does the innate mechanism of immune defence work?
blocks infection by utilising barriers of entry eg skin, tears, mucus, stomach acid
how does the adaptive immune defence system work?
if the innate defence fails to work, it destroys invaders such as cellular factors, natural killer cells, phagocytic cells and soluble mediators. if that fails this triggers the adaptive immune system (APCs with induce antigen specific fragments in MHC activate t-cells and b- cells to control infection and produce memory cells
give examples of passive and active naturally acquired immunity ?
active- infection contact with pathogen
passive- antibodies passed from the mother to the baby through breastfeeding
give examples of active and passive artificially acquired immunity
active - vaccine- dead or attenuated pathogens
passive -injections of immune serum (gamma globulin)
what is meany by acquired immunity
• Acquired immunity usually specific to a single organism or group of closely related organisms (share common ANTIGENS – ie Cowpox/Smallpox) because you have contact with the pathogen
what is meant by active acquired immunity?
- Produced by individual’s own immune system - usually long-lasting
- Involves CELLULAR RESPONSES (“cell-mediated”), HUMORAL RESPONSES (“antibody mediated”) or a combination of both acting 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
how does the adaptive immune system work CD4 lineage ?
antigen presenting cells sees antigen
which chops it up and present it as peptides with MHC11 to naive CD4+ t-helper cells
which becomes effectors t- cells of 4 basic types
how does the adaptive immune system work for CD8 lineage?
antigen presenting cells (usually dendritic cells) see antigen (usually virus)
chops it up and present it peptide with MHC1 to naive CD8 cells
which become cytotoxic t -cells
which produce cytotoxins or triggers apoptosis of the target cells
to continue cytotoxic t- cells production and create memory cells. antigen presenting cells must interact with activated CD4 t- cells
how does the body develop immunity?
the bodys adaptive immune system can learn new invading pathogens.
describe an immune response?
specialised antigen cells engulf the virus and display portions to it to activate t- helper cells
t-helper cells enable other immune responses
B cells make antibodies that can block the virus from infecting cells as well as mark the virus for destruction .
cytotoxic T cells identify and destroy virus infected cells
long lived memory b and T cells that can recognise the virus and produce antibodies against the virus quicker therefore providing immunity
what are the 4 ways that antibody mediated immunity - humeral response work?
blocking binding of pathogen to cell surface receptor= neutralising antibodies
targeting CLTs to infected cells
coating- pathogens and targeting them for phagocytosis
antibody- antigen complexes activate classical complement cascade which leads to destruction of pathogens by phagocytosis or bacterial membrane attack
what is meant by cell mediated immunity?
• CMI provided by EFFECTOR lymphocytes (“T cells”) of Th1 type (includes CD8+ CTLs)
• TWO principal classes – each has specific function:-
1. CD8+ T-cells (Cytotoxic (killer) T-lymphocytes = “CTLs”) - recognise and destroy infected cells
2. CD4+ Th1 T-cells (“Th1 cells”) – activate phagocytic macrophages to destroy and engulf bacteria
• Th1 cells activate macrophages by CYTOKINES, principally IFN-ϒ
name the different subtypes of antibody subtypes in protection?
IgM – major role in complement activation – limited role in neutralisation -INDUCED BY VACCINATION (primary response) - blood
IgG – SYSTEMIC (blood, tissues, lymph) - ALL major roles (neutralisation, ADCC, opsonisation, complement activation)- PRIMARILY INDUCED BY VACCINATION
IgA – principle isotype in SECRETIONS at MUCOSA (gut, respiratory tract, genital)
- Less potent opsonin, weak activator of complement – STRONG viral neutraliser
- CAN BE INDUCED BY VACCINATION (BUT NEEDS SPECIFIC ADJUVANTS/ROUTE
what is meant by passive acquired immunity
- Passive immunity = protection provided by transfer of ANTIBODIES from MOTHER, most commonly across the placenta (IgG) and (to some extent) from breast milk (secretory IgA) to CHILD
- Most infant deaths from PERTUSSIS at <3mo, so mother should be vaccinated to protect neonate; RUBELLA can severely damage foetus, so mothers can be offered MMR if not previously vaccinated ; pregnant women also have increased risk of death from INFLUENZA if not vaccinated [these three vaccines offered on NHS schedule]
- PROTECTION PROVIDED BY MTC TRANSFER IS TEMPORARY – FEW WEEKS OR MONTHS – neonate (1-28 days of life) very vulnerable to disease and protected by maternal antibodies. As healthy immune system dependent on nutritional status – mum should eat well too
how do vaccines protect us via acquired immunity?
- Vaccines produce their protective effect by inducing active acquired 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 and thus to prevent or modify the disease
- Thus, key to an effective vaccine is ability for it to TRIGGER PROLIFERATION OF NAÏVE T-CELLS
- Success depends on whether Th1 and CTL responses are induced (predominantly against INTRACELLULAR ORGANISMS)
- Or Th2 ANTIBODY responses are induced (predominantly against EXTRACELLAR ORGANISMS)
what are the two ways in which memory cells are made?
naive T- cells proliferates in response to antigen forms effector cells and memory cells which wait for future infections
naive B cells do the same with the help of t- cells from plasma cells to deal with current infection but also memory cells which also wait for future infections
what are the roles pf adjuvants?
• Soluble proteins often poorly immunogenic when used on their own as a vaccine
• Adjuvants = compounds that enhance IMMUNOGENICITY of protein antigens
• Two broad groups (base on mechanisms):-
1. Particulate vaccine-delivery systems target antigen to antigen presenting cells (APCs).
Convert soluble proteins into particles (APCs) – ie: alum (adsorbs proteins),
mineral oils (MF59 - emulsifies proteins), Quil A detergent (forms colloids with proteins) –
APCs preferably recognise and process particles (like viruses, bacteria etc)
2. Immunostimulatory adjuvants - directly activate APCs through specific receptors
(e.g. toll-like receptors (TLRs) - resulting in inflammatory responses that amplify the innate
immune response)
Active research field – many APC receptors now mapped and ligands identified – provides
Co-stimulatory signals to activate T-cells (along with MHC + antigen peptide)
New generation ligands can be used to “skew” adaptive immune response to Th1 or Th2 –
optimises immune attack on specific pathogens
what are the principles of safe and effective vaccinations?
- EITHER search for (or create) ATTENUATED ORGANISMS with reduced pathogenicity to stimulate protective immunity…
- OR INACTIVATE (KILL) organisms – will NOT cause lethal systemic infection in the immunosuppressed
- NOW use purified COMPONENTS of whole organisms containing only KEY ANTIGENS OR NUCLEIC ACIDS that simulate protective immunity
what are the requirements for an effective vaccine
- IT DEPENDS ON THE ORGANISM
• INTRACELLULAR organisms usually need CTL and Ab
• EXTRACELLULAR organisms usually Abs - IT PROVIDES DEFENSE AT POINT OF ENTRY
• Stimulation of MUCOSAL IMMUNITY may be required at specific mucosa (gut, respiratory epithelia, genital epithelia) - PRE-EXISTING ANTIBODY MAY BE REQUIRED
• Pre-existing antibody protects against diptheria/tetanus
exotoxins – forms antigen: antibody complexes which are phagocytosed
• Polio and HIV enter cells shortly after infection – antibodies
must be ready to BLOCK viral ligand:cell receptor interaction - PROTECTION OPTIMISED WHEN SPECIFIC EPITOPES RECOGNISED
• Immune responses directed at multiple epitopes
• Not all of these generate protective Abs or CTLs
• Some may even generate suppressor T-cells
• Thus, CORRECT EPITOPES must be targeted - IT MUST BE SAFE
• Millions immunised – very low toxicity
• “Cutter Incident” – IPV contained live
virus – hundreds paralysed, 10 deaths - MUST PROTECT MOST VACCINEES
• Rapid generation of herd immunity
• Reservoir of susceptible falls – transmission drops
• Confidence - MUST GENERATE LONG-LIVED IMMUNITY
• Repeated booster immunisations often impracticable
• Cheaper, improves population health - IT MUST BE CHEAP
• Will be administered to large populations
• Very cost-effective healthcare
• BUT benefit eroded if cost per dose rises
how do you optimise vaccinations strategies?
- Vaccination strategy greatly influences the immunogenicity, efficacy, and safety of a vaccine
- For any specific vaccine product, vaccine immunogenicity and efficacy can be dramatically affected by the vaccination strategy used, including number of and interval between immunizations, use of prime/boost regimens and vaccine modulators (adjuvants)
- Good vaccination schedule requires a minimal number of doses and an optimal interval between immunizations [think of COVID]
- Most currently licensed vaccines are administered either by intramuscular or subcutaneous needle injection, and require multiple doses to elicit an adequate antibody response with an interval variation between 4 weeks and 6 months
- Due to the complexity of different types of vaccines, there is no standard universal formula that can be used to determine an appropriate vaccination strategy
- However, it is important to understand the impact of vaccine administration parameters on immunogenicity and efficacy – not optimised for COVID
- See THE GREEN BOOK for optimised strategies for NHS Vaccines
what does life long vaccinations depend on immune status?
LIFE-LONG VACCINATION IS DEPENDENT ON IMMUNE STATUS
what are routes of administration in general
- Oral route: administered by mouth (per os)
- Subcutaneous route: injected into the area just beneath the skin into the fatty, connective tissue (sc)
- Intramuscular route: injected into muscle tissue (im)
- Intradermal route: injected into layers of the skin (id)
- Intranasal route: administered into the nose (in)
- NOT intravenous - generally leads to a relatively low immune response compared to other injection routes and can also cause anaphylaxis, including allergic reaction and toxicity
PARENTERAL VACCINATION
• Parenteral vaccine administration - three major routes: intramuscular (IM), subcutaneous (SC),
intradermal (ID) inoculation
• The relative immunogenicity of vaccines by these three routes (IM, SC, and ID) can vary,
depending on individual vaccines
• In general, ID immunization generates greater immune responses than IM injection
• Presumably, the reason for this may be that the dermis contains more dendritic cells (DCs)
which facilitate the capture of antigens, and local inflammation induces maturation of the DCs
and their migration into draining lymph nodes BUT may be difficult to administer (particularly
in children)
• Intradermal vaccination has been used for populations that do not respond well to an IM injection, such as the HBV vaccine in dialysis patents
• SC and IM immunizations induce very similar responses in clinical studies – less toxicity/anaphylaxis via IM (especially if using adjuvants) and easier to do then ID or SC
ROUTES OF ADMINISTRATION – MUCOSAL VACCINES
• Most vaccines given by i.m injection
• PRACTICAL aspects of this – painful, expensive (needles,
syringes, injector), unpopular (reduces uptake) , mass vaccination (laborious)
• IMMUNOLOGICALLY, may not stimulate optimal immune response - MOST pathogens enter via MUCOSA
• Ie: Gut (Vibrio cholerae, Shigella spp., Salmonella typhi, E.coli 0157): Respiratory mucosa (SARS-CoV-2, Flu, rhinovirus, Streptococcus pneumoniae, Mycobacterium tuberculosis); Genital/anal mucosa (HIV, bacterial STIs, Chlamydia)
• If given ORALLY or NASALLY, overcomes many issues
• Polio eradication campaign success due to simplicity of OPV – few drips into mouth or on a sugar lump
• Live paediatric flu vaccine given nasally
• ADJUVANTS can play key role in directing response to appropriate mucosa (ie: chitin in nasal vaccines)
what is meningitis
- Meningitis is defined as being ‘inflammation of the meninges’.
- The meninges are the three membranes which enclose the brain and spinal cord.
- Meningism refers to the signs and symptoms that accompany the inflammation.
What causes meningitis?
what causes meningitis?
Meningitis can be caused by a variety of agents: Microbial agents • Bacteria-Neisseria meningitis • Viruses • Fungi • Protozoa (very rarely) • What else?
who is at risk of meningitis?
Everyone! But particularly,
• babies and young children. Babies haven’t acquired a strong immune system.
• teenagers and young adults
• elderly people
• people with a weak immune system – for example, those with HIV and those having chemotherapy
How are the microbial agents of meningitis acquired?
- Usually caused by organisms which colonise the back of the nose and throat
- Sometimes acquired from the mother during birth e.g. Group B streptococci, E. coli
- Through food e.g. Listeria, E. coli
How are the microbial agents of meningitis spread?
- Kissing
- Coughing
- Sneezing
- COVID19 measures have influenced transmission
Viral Meningitis
- Most common form, more common than bacterial meningitis
- Relatively benign illness & usually does not need medical attention - may even go unrecognised
- Usually presents as a mild flu-like illness: Headache, 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 side effects similar to other meningitic diseases
Examples of viruses implicated in meningitis
- Enteroviruses such as Echovirus, Coxsackievirus
- Mumps (Paramyxovirus)
- Herpes viruses e.g. HSV, Varicella-Zoster
- HIV
Fungal Meningitis
- Causative fungi:
- Cryptococcus neoformans
- Candida
- Coccidioides immitis
- Histoplasma
Cryptococcus neoformans
- Usually associated with immune deficiency e.g. pre-existing HIV infection
- Symptoms appear more gradually, over days or weeks
- Symptoms may include headache, fever, nausea, vomiting, stiff neck, dislike of bright lights, changes in mental state and hallucinations
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
- Most commonly caused by Streptococcus pneumoniae and Neisseria meningitidis
Progression to bacterial meningitis
- Nasopharyngeal colonisation - carriage within the nose and the throat
- Invasion of the bloodstream
- Bacteraemia
- Meningeal invasion
- Multiplication in subarachnoid space
- Release of bacterial products & cytokines
Meningococcal disease
- Neisseria meningitidis can cause both meningococcal meningitis & meningococcal septicaemia (collectively meningococcal disease - Invasive Meningococcal Disease (IMD)
- Communicable
- Gram –ve diplococci (meningococci), various virulence factors. Gram -ve have liposaccharide layer.
- Meningococci colonise the oropharynx in some healthy people - these are carriers.
- In these people, transition from carrier state to invasive disease occurs due to unknown factors
- Numerous serotypes; 6 - Men A, B, C, W, X and Y - most commonly cause disease (antigenic structure of the polysaccharide capsule)
- Bacteria can enter the bloodstream and cross the blood-brain barrier to cause meningitis
- Can cause excessive clotting and the natural anticoagulation cycle is disrupted
Meningococcal septicaemia (meningococcemia)
- Septicaemia results when bacteria enter the blood & multiply uncontrollably
- Toxins damage lining of the blood vessels leading to leakage
- Lower blood volumes is insufficient to carry oxygen to all parts of the body – blood supply reduced to extremities
- Blood leakage presents as non-blanching rash
- Clots may form in skin/muscle tissue – may lead to amputation
name Some other bacterial causes of meningitis
- Streptococcus pneumoniae (pneumococci)
- Group A streptococci (GAS)
- Group B streptococci (GBS)
- Type B Haemophilus influenzae (Hib)
- E. coli
- Listeria
- M. tuberculosis
what are the Early Warning Signs of Meningitis
- Fever
- Headache
- Vomiting
- Muscle pain
- Fever with cold hands and feet
DO NOT WAIT FOR A RASH!
what are the specific symptoms of meningitis?
Specific symptoms: - Rash - Stiff neck - Dislike of bright light - Confused/delirious - Seizures Other symptoms may include: - Severe headache - Fever - Vomiting - Sleepy/vacant
Meningococcal septicaemia symptoms
Specific symptoms: • Aching limbs (particularly leg pain) • Cold hands and feet • A rash which starts like pin prick spots and develops rapidly into purple bruising • Confused/delirious Other symptoms may include: • Fever • Vomiting • Difficulty breathing • Change in skin colour – pale mottled skin • Breathing fast/breathlessness • Sleepy/vacant
what is 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 (non-blanching), it could be meningococcal septicaemia.
- On dark skin, check for the rash on lighter parts of the body, e.g. finger tips, soles of feet.
- Keep checking – rash may fade at first
How do we diagnose meningitis in the laboratory for meningitis?
Cerebrospinal fluid (CSF) may be taken and:
- Visually inspected – clear or turbid?
- A cell count performed (un-spun sample)
- 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. Unspun sample To know the concentration to get a cell count per ml. A spun sample to concentrate the organism sample.
- Further specific tests performed. The higher the protein level the higher the meningitis.
- Blood cultures
What is cerebrospinal fluid?
- Cerebrospinal fluid (CSF) is a clear, colourless liquid that
- bathes the brain and spinal cord providing shock absorption and support.
How do we obtain a CSF specimen?
CSF is obtained by doing a lumbar puncture. A long, thin, hollow needle is inserted between two
bones in the lower spine and into the space where the CSF circulates.
Management in a pre-hospital setting
“Primary healthcare professionals should transfer children and young people with suspected bacterial meningitis or suspected meningococcal septicaemia to secondary care as an emergency by telephoning 999”.
NICE Clinical Guideline 102
what does NICE guidelines say about meningitis
NICE meningitis press release on June 2010 says that “prompt recognition of signs and symptoms of meningitis and meningococcal disease is key to saving lives “
The NICE clinical guideline 102 Bacterial Meningitis and meningococcal septicaemia covers:
• Symptoms and signs of bacterial meningitis and meningococcal septicaemia
• Management in the pre-hospital setting
• Diagnosis in secondary care
• Management in secondary care
• Long-term management, including review of children and young people for morbidities
what is the treatment for meningitis
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, benzylpenicillin (cefotaxime or chloramphenicol) given prior to transfer (providing does not delay transfer)
• Consider adjunctive treatment with dexamethasone, see contraindications e.g. septic shock, meningococcal septicaemia (BNF). Doesn’t improve outcome
• Unknown aetiology 3 months – 50 years, cefotaxime (or ceftriaxone) (considering adding vancomycin)
• Unknown aetiology 50 years +, cefotaxime (or ceftriaxone) + amoxicillin, possibly with vancomycin
what is life like after meningitis?
Bacterial meningitis: many recover fully if treated early – can result in serious long-term issues
• Hearing or vision loss (partial or total)
• Issues with concentration or memory
• Epilepsy
• Co-ordination, movement, balance issues
• Loss of limbs
Vaccines: why are they so important?
• Meningitis and septicaemia can kill in under 4 hours
• The bacteria multiply in the body with alarming speed, overwhelming the immune system
• Early symptoms can be flu-like, making it extremely difficult to diagnose
• Prevention is better than cure!
• Not all causes of meningitis can be prevented by vaccines
Do meningitis vaccines already exist?
A number of vaccines exist that can prevent many cases of meningitis, both viral and bacterial, including:
• The measles, mumps and rubella (MMR) vaccine: 1 yr & 3 yrs 4 months
• The DTaP/IPV/Hib (Haemophilus influenzae b)/Hep B 6-in-1 vaccine : 8, 12 & 16 weeks
• The pneumococcal conjugate vaccine (PCV): 12 weeks, 1 yr/pneumococcal polysaccharide vaccine (PPV): 65 yrs
• The Hib/Men C vaccine: 1 yr
• The meningitis ACWY vaccine: 14 yrs & Uni students (19-25 yrs)
• The Men B vaccine: 8 & 16 weeks, 1 yr
what is meant by vaccine hesitancy
- Refers to a delay in acceptance or refusal of vaccines despite availability of vaccine services.
- Is complex and context specific varying across time, place and vaccines
- Is influenced by factors such as complacency, convenience and confidence.
what is the MMR vaccine and when is it administered?
• Measles, Mumps, Rubella Vaccine
• Recommended Infant Immunization since 1971
• Administration:
– Once at 12 months and again at 3 years 4 months
what does the Andrew Wakefield
- British gastroenterologist who believed he had discovered the cause of Autism in 1998.
- Published his findings in the medical journal, The Lancet
what does the Wakefield paper claim
- Children developed autism within 1 month of MMR and had GI symptoms
- Postulated MMR caused intestinal inflammation, led translocation of usually impermeable peptides to the bloodstream, then to the brain where they affected development
what are the flaws in the Wakefield paper
- Small, biased sample
- Conflicts of Interest
- No control
- Endoscopic /neuropsychological assessments were not blind
- GI symptoms did not predate autism in several children
- No encephalopathic peptides have ever been identified between GI and brain
what were the responses in the Wakefield paper to flawed study
- A flurry of studies refuting the original study
- Lancet retract original study
- Government drives to encourage vaccination
- Media runs research scandal story but not so enthusiastically
what role does the media cycle have
- media coverage
- public opinion
- govt responses
population vs individual risk
- Most scientists think about risk in terms of populations
- Most patients will think about risk to themselves/child
- To gain herd immunity people must think beyond the individual
why must you understand risk
• People are not computers – Use heuristics to make judgements • Many things influence our risk perception – The source of the information – How the data is presented
what is meant by Relative versus absolute risk
- The risk has doubled
* The chance has increased from 3% to 6%
what does the guidelines for communication of risk
• Department of Health (1997) issued guidelines on best practice
– Comparisons help provide a sense of perspective
– Relative risk can be seriously misleading, if used baseline rates must be included
what are the causes for covid -19 vaccination hesitancy
- Concerns about future unknown effects, with (42.7% of respondents)
- Worries about side effects (11.4%)
- Concern that others are in more urgent need of the vaccine (7.7%)
- Lack of trust in vaccines (7.6%)
what can pharmacists do to ensure efficiency of taking vaccines?
- The success of a vaccine program depends upon many factors including vaccine efficacy, supply, and individual uptake
- People will generally weigh up the perceived benefits against the perceived risks when deciding to vaccinate
- Vaccine hesitancy is complex and affected by many factors
what is the social determinant of health
Social determinants are often depicted in a rainbow diagram, proposed by Dahlgren and Whitehead in 1991. The innermost layer comprises age, sex, hereditary factors. The second layer comprises individual lifestyle factors, the third layer Social and community networks, then the fourth layer: living and working conditions: such as agriculture, education, work environment, unemployment, water and sanitation, health care services and housing. The outermost layer is general socio-economic, cultural and environmental conditions. These conditions will all impact child health globally.
These determinants will vary, between countries and within countries: it is possible to have regions within countries which have very differing life expectancies. For example, according to the ONS: male life expectancy in Glasgow city 73.4 years, versus Kensington and Chelsea 83.3 years. Life expectancy 10 years different.
how do we measure child health
- What measures do we use to compare how effective different countries are at improving child health?
- Mortality:
- Neonatal mortality rate
- number of deaths of babies under 28 days old who die, per 1000 live births in a given time period
- Infant mortality rate
- number of deaths in children under 1 year old per 1000 live births
- Under five mortality rate
- number of deaths in children under 5 years old per 1000 live births
- Why is it important to use rates rather than absolute numbers?
Rotavirus
- At least 28 strains
- Common in infants and under 5s
- Symptoms - severe watery diarrhoea, severe vomiting, fever and abdominal pain, loss of appetite, dehydration
- Duration 3-8 days
- Highly infectious: faecal-oral transmission
- Oral vaccines available Rotarix and Rotateq
- -live attenuated strain of human rotavirus
- Rotarix: 2 doses 4 weeks apart, before 24 weeks of age
- Rotateq: 3 doses 4 weeks apart before 26 weeks of age
Streptococcus pneumoniae (Pneumococcus)
- Gram +ve, encapsulated diplococcus
- > 90 known serotypes
- Droplet transmission
- carriage
- Causes pneumococcal pneumonia, meningitis, sepsis, otitis media & sinusitis
- Exacerbated by: crowding, indoor air pollution, tobacco smoke, immunosuppression , lack of exclusive breastfeeding
- Resistance to penicillins and other antibiotics common
- Vaccines recommended by WHO
Haemophilus influenzae
- Small gram-ve bacterium
- Carriage
- Several serotypes, based on capsular polysaccharides
- Type b (Hib) most virulent
- Transmission: respiratory droplets
- under5s: pneumonia, bacteraemia, cellulitis, meningitis, septic arthritis
- Vaccination adopted widely
- 1990 - 20% of LRTI deaths, due to Hib7
- 2013 -12% due to Hib7
Is vaccination effective
- Rotavirus vaccination introduced in 19 countries
- ⇊ very severe rotavirus infection by 74%
- Mexico: ⇊ diarrhoeal deaths in U5s by 46%
- Hib vaccination: reduces pneumonia by 18%
- 60% of children worldwide vaccinated with Hib
- Pneumococcal conjugate vaccine (PCV):30 countries have introduced PCV since 2010
- 23-35% reduction in pneumonia
- 31% of children worldwide vaccinated with PCV
- Drop in pneumonia mortality
what are the barriers to vaccination
Barriers to vaccination include Poor quality infrastructure: Weak health care system Poor governance Poor leadership Lack of domestic funding Lack of monitoring and surveillance
what are the solutions to over come vaccination barrier
- Health system strengthening:
- better leadership
- governance
- supply chain
- funding
- surveillance and monitoring
- Education?
- Ceasefires?
- Peace?
- Local manufacture of vaccines?
- Improved monitoring?
- Affordability?
- Collaboration
what are the biological sourced materials of vaccines
- Bioactives – toxins, fragments
- Bacterial polysaccharides, oligosaccharides, Zymosan fungal glycans
- Proteins, peptides, lipoproteins and glycoproteins, peptidoglycan, lectins
- Lipids, lipopolysaccharides e.g. Lipid A
- Chemically modified substances e.g. subunits, DNA/si-dsRNA
- Purity, virulence issues are paramount
- Unspecified trace contaminants?
what is meant by adjuvant?
is a formulation aid that modifies the effects of other agents. they are a variety of particles which enhances the immune response to an antigen. they are frequently included in a vaccine to enhance the recipient immune response
- Water soluble/dispersible adjuvants
q OM-174, soluble lipid derivative version of E. coli monophosphoryl lipid A (MPL) (OM Pharma)
q QS-21, acylated 3,28-o-bisdesmodic triterpene saponin (Antigenics/Cambridge Biotech)
q Synthetic analogues of double stranded RNA (dsRNA) e.g. Poly(I:C)
q E. coli heat labile enterotoxin (LT)
q Cholera toxin (CT)
q Tetanus toxoid (TT)
q Diptheria toxoid (DT)
- O/W or W/O emulsion adjuvants
q W/O Montanide ISA 720 (Seppic, France), vegetable oil
q W/O Montanide ISA 51, mineral oil/squalene
q W/O/W Montanide ISA 206D, mineral oil – snake venom peptide
q AS02 - O/W emulsion (Cambia) + MPL (Corixa Corp/GSK) + QS-21
q AF03 - O/W emulsion (Sanofi-Pasteur), squalene, Span 85 + inactive Influenza H1N1
q Fat dispersions: Specol, Titremax Gold, SPT, Arlacel (Al(OH)3 + arachis oil), etc.
q MF59 (Chiron/Novartis) squalene (4%)+emulsifiers e.g. AddaVax flu vaccine using MF59
q Freund’s complete adjuvant (CFA, FCA) [most common used]
• Mycobacterium tuberculosis (most commonly used) inactivated
• Monophosphoryl lipid A (MPL) - bacterial cell wall
• Unmethylated CpG oligodeoxynucleotide
q Freund’s incomplete adjuvant (IFA)
• As CFA but lacks mycobacterium component
Emulsions in vaccines
q “Fats” used: silicone oil, light paraffin, squalene, tristearin, vegetal (arachis, soya, olive, sesame, castor oils)
q Emulsifiers: fatty acids, PEGylated lecithins (Transcutol P, Kolliphor EL, Miranol C2M, Cremophor), sorbitan sesqui-oleate, polysorbates
q Dispersed phase 0.1-0.9 by volume
q Other ingredients: microcrystalline wax (emulsifier structuriser), E216 Na Benzoate (preservative), PEG (stabiliser, water binder), Vitamins E and C/BHT/BHA (antioxidant), tragacanth gum/cellulose (stabiliser)
- Entrapment or absorption agent adjuvants
q Alum, aluminum hydroxide anhydrous or hydrated q AS04 (Cambia) – MPL (monophosphoryl lipid A) plus alum q Silica q Latex q Calcium phosphate q Kaolin q Tannin q Starch q Sterilised tapioca q Gelatin
- Polymer particles and particulate adjuvants
q Virosomes (virus structured liposomes)
q Bacterial flagellin (Helicobacter pylori, E. coli, Salmonella typhimurium)
q Bacterial fimbriae and pili (e.g. E. coli)
q Liposomes e.g. AS01 (Cambia) liposomes + MPL + QS-21
q PLA/PLGA microbeads
q Haemophilus influenzae (Hib)
q Plasmodium falciparium and other protozoan components
Formulation “stabilisers”
- Freeze-drying cryoprotectants e.g. sugars such as, sucrose and lactose
- Buffers e.g. amino acids such as, glycine or Na glutamate
- Complexing and suspending agents e.g. proteins such as, human serum albumin or gelatin or EDTA
- Relics e.g. foetal bovine serum remnant from cell culture, deactivation substrates
- Delivery aids e.g. gums and viscosifiers e.g. gelatin
- Preservatives e.g. BHA
- Co-solvent e.g. 2-phenoxyethanol
- Emulsifiers e.g. Span, Tween, Brij
For example, Cambia’s adjuvant AS03 contains
q D,L-a-tocopherol
q Squalene
q Polysorbate 80 (oleate ether)
q Other additive components and aids e.g dextrose, NaCl
q Water
q Buffer salts
Antibiotic “stabilisers”
Multi-use vaccines need special formulation
- Contain antibiotics e.g. penicillin, sulpha drugs, cephalosporins and thiomersal/thimerosal fungicides used to prevent fungal and bacterial infection as consecutive aliquots are removed from the same bulk container
Process asepticity and hygiene
Examples of antibiotics used during vaccine manufacture include neomycin, polymyxin B, streptomycin and gentamicin.
q Antibiotics are used in some vaccine e.g. flu production methods to reduce bacterial growth in non-sterile eggs during “passaging” processing steps
q These antibiotics can be found in final products at VERY low concentrations
Chemical inactivation “agents”
q Chemical remnants e.g. cross-linkers are often found in vaccines.
q Cross-linkers remove pathogenicity and act as a disinfectant
q Formaldehyde (methanal) [converts to methanediol in water; aka formalin] remnant, used to inactivate viruses e.g. polio virus and bacterial diphtheria toxin, etc
q Formalin cross-links LYSINE, arginine, asparagine, glutamine, histidine, tryptophan, tyrosine amino acids in proteins and amine groups of nucleotides. Groups must be close to be linked < 0.4 nm apart (C-C bond ~ 0.1 nm)
q LD50 42mg/kg (mouse, oral); 30ml of 40% w/v formalin lethal in man, amount in vaccine dose <100 mg
q Glutaraldehyde (pentanedial)
q LD50 134mg/kg (rat, oral)
Toxin, virus, whole cell pathogen, subunit, conjugate inactivation for vaccines
q Application of heat, >60°C/10h e.g. heterotypic vaccines such as BCG
q low pH acid-denaturation,
Purification of antigens
Example HBsAg – Hep B surface antigen
A. Differential precipitation/solubilisation – ammonium sulphate, pH
B. Ultracentrifugation
C. Final purification by:
1. Ultrafiltration/nanofiltration (porous membrane molecular weight cut-off)
2. Gel permeation (or SEC) chromatography (GPC)
3. Hydrophobic interaction chromatography (HIC)
4. Affinity (ligand) chromatography?
D. Tested by Enzyme-Linked Immunosorbent Assay (ELISA), concentration in “EL U/mL” i.e. ELISA units per mL
give examples of different ways of purifying antigens
Example HBsAg – Hep B surface antigen
A. Differential precipitation/solubilisation – ammonium sulphate, pH
B. Ultracentrifugation
C. Final purification by:
1. Ultrafiltration/nanofiltration (porous membrane molecular weight cut-off)
2. Gel permeation (or SEC) chromatography (GPC)
3. Hydrophobic interaction chromatography (HIC)
4. Affinity (ligand) chromatography?
D. Tested by Enzyme-Linked Immunosorbent Assay (ELISA), concentration in “EL U/mL” i.e. ELISA units per mL
describe Enumeration - ELISA
q A colour indicating popular microtitre plate-type analytic assay of a solution, which uses a solid-phase immobilised enzyme in an immuno-assay to detect the presence of a vaccine antigen
q Used routinely for quality control
[Y] = k[X]
IY [X].
Antigens in vaccines
Homotypic vaccines
One type of component e.g. Hib, flu, rabies
Heterotypic vaccines
Many types of antigenic components e.g. in TB BCG jab (various strains of M. bovis bacille Calmette-Guérin)
Whole cell: live, killed, etc
Toxoid
pathogen components
Valency – refers to number of strains used and thus unversality e.g. influenza vaccines
Bivalent – 2 strains
Quadrivalent – 4 strains
MMR – 3 organisms or singles
what are the different Types of Vaccine Smartness
- Hepatitis B (Imx HBsAg, Abbott), tetanus (Infanrix, GSK), anthrax (Biotrax, Bioport Co)
- Swine flu H1N1 – TIV (trivalent inactive, 3 strains) or LAIV (live attenuated influenza) vaccines e.g. Pandemrix (GSK); Focetria (Novartis)
- Human Papilloma Virus - Gardasil (Merck, quadrivalent HPV), Cervarix (GSK, bivalent HPV)
what are GSK vaccine
• GSK is one of the world’s largest producers of vaccines now owning many of Novartis’ products. Some vaccines:
– Boostrix - Tetanus
– Cevarix - Human Papilloma Virus (HPV) (cervical cancer)
– Fluarix - Influenza
– Havrix – Hepatitis A
– Infanrix Hexa - Pertussis/Diptheria/Tetanus + Polio/Meningoccocal C/Haemophilus influenzae type B
– Kinrix - Diptheria/Tetanus/Pertussis/Polio
– Mosquirix – Malaria
how do you ensure Quality control for vaccines?
control
q Sterility: free of live micro-organisms
q Chemistry standpoint: correct adjuvant , preservative (if needed) and pH
q Content: uniformity of content and potency (PCQ)
q Safety: overdosing would carry no effective risk. Correct labelling
q Efficacy: each antigen present meets regulatory requirements and satisfies key tests. No component interference
q Virulence testing: via “passaging” in suitable model e.g. chick embreyo 10 day fertilised egg + cultivated for 3 days e.g. flu, Herpes simplex, Varicella pox
q Toxicity: no harm-causing constituents
q Environment: no risk or harm of spread or dissemination
q Stability test: shelf life, optimal storage determination
q Chemical QC: moisture content, headspace vacuum, pH
what are dosage issues with vaccines ?
- Variable: dose, dissipation, response, maturity of immune system (infants and neonates; elderly), temperature history, security
- Constancy: formulation injection properties e.g. viscosity, constant content (metered dose per vial), actives and excipients, stability profile
Delivery of vaccines
• The basic premise of effective vaccine delivery is based upon three notions:
– efficient encapsulation of the active
– successful ‘targeting’ of the active to a ‘specific’ region of the body and pathogen
– successful release of that active in situ
what are the different delivery forms of vaccines ?
- Liquids
– Parenteral (needle and syringe common) liquids
• Nanomulsions
• Liposomes
• Micelle solubilisation
• Adsorbates on colloidal solids e.g. alum
• Polymer PLGA/PLA micro-spheres
– Suspension (oral/IV)
– Solution oral syrups e.g. OPV-polio - Solids/semi-solids (oral, topical)
– Oral films, gels
– Solid dispersions and glasses (buccal sub-lingual, Flu)
– Tablets (e.g. TEVA Pharma febrile repiratory adenovirus type 4/7 enteric coated)?
– Capsules (e.g. VivoTif Typhoid – Salmonella Typhi)?
– Mucous membrane entry: aerosol inhalers: pulmonary, nasal e.g. FluMist, vaginal, oral
– Implants/TD patch, micro-needle technology
– Creams (e.g. current topical research – genital Herpes)? Microneedles favoured
– TD patch, flu , Sanofi in phase III
