Lec 6- Vaccine systems Flashcards

1
Q

Vaccines and public health

A
  • The two public health interventions that have had the greatest impact on the worlds health are clean water and vaccines
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2
Q

AIM of vaccines

A
  • To exploit the natural defence mechanism of a body immune system to promote long term immunological protection against the establishment of an infection
  • I.e.- an appropriate and effective immune response
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3
Q

Eradication of smallpox

A
  • 1796, Edward Jenner, an english doctor discovered the first successful smallpox vaccination
  • 1980, as a result of Jenner’s discovery, the world health assembly officially declared
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4
Q

1967: WHO global campaign to eradicate smallpox

A
  • The USSR first suggested a global effort and donated 80% of vaccines
  • A freeze-dried vaccine employed
    • Storable without refrigeration
    • 1-month stability
  • This was delivered with a bifurcated needle
    • Low dose and could be sterilized
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5
Q

Mechanism of vaccination: principle of specific immunity

A
  • Secondary response there shouldn’t be symptoms of the disease
  • Watch evolution of vaccines again
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6
Q

Vaccine Failures

A
  • Malaria
    • 225 million cases per year
    • Nearly 1 million deaths a year
  • HIV
    • 25 million deaths
    • 33 million people living with HIV
    • 2.6 cases every year
    • 1.8 million deaths per year
  • TB
    • 9.6 million new cases a year
    • 1.7 million deaths yearly
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7
Q

HIV, TB and malaria- ongoing challenges

A
  • Historically successful vaccines have been developed mostly against those pathogens that
    • Can be treated by antibodies
    • And have a stable antigen
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8
Q

Recent advance in malaria vaccine

A
  • RTS, S/AS01 malaria vaccine
  • Developed through a partnership between GSK and MVI (malaria vaccine initiative) with support from Bill & Melinda Gates Foundation and from a network of African research centres that performed the studies
  • RTS, S the first malaria vaccine to have completed pivotal Phase 3 testing and obtained a positive scientific opinion by a stringent medicines regulatory authority
  • RTS, S is a vaccine against P.falciparum, the most deadly malaria parasite globally, and the most prevalent in Africa (it offers no protection against P.vivax malaria)
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9
Q

Recent advance in malaria vaccine

A
  • There were two target age groups in the trial.
    • Infants who received the malaria vaccine together with other routine childhood vaccines at 6, 10 and 14 weeks of age.
    • Older children who received their first dose of the malaria vaccine between 5 and 17 months of age.
  • Over the full duration of the trial, efficacy against clinical malaria in infants was 27% in the group that received four doses of RTS,S (3 doses at 6, 10 and 14 weeks of age, and a fourth dose 18 months later); and 18% in the group that did not receive the fourth dose of the vaccine.
  • Among children aged 5-17 months who received four doses on a 0, 1, 2, 20-month schedule, vaccine efficacy against clinical malaria was 39% over the full duration of the trial. With a four-dose schedule, the overall efficacy against severe malaria among children in this age group was 31.5%. In children aged 5-17 months who did not receive a fourth dose of the vaccine, no protection was seen against severe malaria, These results highlight the importance of the fourth dose with this vaccine, as efficacy is short-lived
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10
Q

Herd immunity

A
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11
Q

Risk-benefit

A
  • The implementation of vaccines programmes depends on their perception in an environment of risk and benefit
    • I.e. adverse effects vs perception of the disease
  • In a climate of low risk of associated disease- concerns over vaccine safety intensify e.g. MMR
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12
Q

Examples of adverse responses

A
  • Live attenuated viral vaccines
    • Simple headache to encephalitis (MMR)
    • Intussception (Rotavirus)
    • Vaccine associated disease (Polio)
  • Inactivated vaccines
    • Nausea to anaphylactic reactions and neurological complications (extremely rare)
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13
Q

Highest MMR vaccine coverage in 25 years

A
  • The health and social care information centre (HSCIC) reported that from 2012 to 2013, 92.3% of children reaching their second birthday received MMR vaccination
  • This is the highest recorded level since the vaccine was first introduced in 1988
  • The latest MMR coverage figure also shows considerable improvement from the lowest recorded figure of 79.9% which occurred 03-04
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14
Q

Requirements of vaccines

A
  • Safe
  • Effective
  • Induce the right sort of immunity-
  • Affordable
  • Avoid needles
  • Avoid cold chain- refrigerated transport- makes transport harder due to stability
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15
Q

Classes of vaccine

A
  • Live attenuated
    • Bacille Calmette Guerin of a M.Bovis close to Mycobacterium TB
  • Inactivated
    • IPV- virus is killed via chemical treatment
  • Extracts
    • Hep B surface Ag. Grown in culture
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16
Q

1) Live, attenuated, vaccines

A
  • Attenuation: the process of elimination or greatly reducing the virulence
    • Using e.g. Heat, chemical treatment, enzymatic treatment, genetic modification
  • E.g. BCG is a strain of M.Bovis that fails to cause TB but retains much of the antigenicity of the pathogen
  • Can’t rule out microbe reverting back
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17
Q

1) Live, attenuated vaccines

Advantages v disadvantages

A
  • Advantages
    • Stimulate protective immune response as they replicate in the host
    • Generally, produce lifelong immunity
  • Disadvantages
    • Risk of reversion to more pathogenic form
    • Potential to induce disease in weak or immunocompromised patients
    • Vaccinated people can potentially pass on an infection
18
Q

2) dead or inactivated vaccines

A
  • Suspensions of intact bacteria or virus which has been treated physically or with chemical agents
  • These are now harmless pathogens but still able to induce an Ab response
19
Q
  1. Dead or Inactivated Vaccines
A
  • Advantages
    • No risk of reversion
    • Generally less toxicity issues
  • Disadvantages
    • Efficiency is variable
    • E.g. rabies is very effective yet plague has debatable value
20
Q

3) Pathogen-derived

A
  • Employs components located on the surface of the pathogen cell to promote immunity
  • Examples: Hep B; Pneumococcal vaccine- contains polysaccharides from 23 strains of Strep. Pneumoniae
  • Benefit- enough of the pathogen to bring about the immune response but no chance of causing infection
21
Q

Toxoids

A
  • E.g. Diphtheria and tetanus vaccines
  • The toxins of Corynebacterium Diphtheriae and Clostridium tetani are treated with dilute formalin (38% formaldehyde)
  • This converts intensely poisonous toxins into harmless toxoids
22
Q

Extracts and sub-unit vaccines

A
  • Advantages- good safety profile
  • Disadvantages- Low efficacy
23
Q

Challenges

A
  • Old challenges: TB, HIV, Malaria
  • New challenges: MDR bacteria + viruses, Pandemic influenza, Ebola, Non-communicable disease- Cancer/ Autoimmunity
24
Q

Changing standards

A
  • Regulatory issues
    • Live attenuated vaccines and can no longer be made
    • Killed whole cell vaccines are also difficult
    • Safety is more important than efficacy
  • New vaccines are sub-unit vaccines
    • Poorly immunogenic
    • Require adjuvants
25
Q

Human Papillomavirus (HPV)

A
  • 99.7% of cervical cancers are caused by HPV infections
  • 20 million people in the US are infected with HPV
  • HPV vaccines are proving to be effective vaccines against cervical cancer
  • HPV is so common that nearly all sexual active men and women will get the virus at some point in their lives
26
Q

HPV virus

A
  • 120 different types of HPV
  • HPV types 6 + 11 cause 90% of genital warts
  • HPV types 16+18 cause 70% of cerivical cancers
  • The subtypes that cause warts DONT cause cancer
27
Q

HPV vaccines

A
  • MERCK: Gardasil
    • Against diseases that are caused by HPV types 6,11,16 + 18
    • Protection against genital warts and cervical cancer
  • GSK: Cervarix (Launch in uk 2007)
    • Protects against types 16 and 18 thereby, protecting patients from 70% of cervical cancer
28
Q

Role of adjuvants

A
  • Definition: Any substance that, when incorporated into a vaccines formulation, generally acts to accelerate, prolong or enhance the quality of the specific immune response
  • Action
    1. Limit systemic distribution of Ag, i.e. Not soluble Ag
      • If we inject into blood, the concentration of Ag is lower, less likely to produce an immune response, IM injection= Ag stays in muscle= higher concentrations
    2. Ensure delivery of adjuvant and Ag to the same cell
    3. Modulate the desired immune response
29
Q

Adjuvants

A
  1. Adjuvants may express surface molecules which are PAMPs, therefore binding to host cell PRRs. This can promote uptake via receptor-mediated phagocytotic mechanisms. Typical PAMPS include bacterial molecules (LPS, Lipid A, MPL, TDM etc). This is a way to discriminate between Self/non-self.
  2. Cause local cellular damage – this is also known as ‘Signal 0’ and was proposed by Polly Matzinger, the idea relating to the release of DAMPs. Typical DAMPS include cytokines, IFN-g, uric acid.
  3. Localisation of antigen via simultaneous delivery of adjuvant and antigen to Immune system cells. This is in contrast to soluble antigen which is rapidly disseminated.
  4. The ‘Depot-effect’ in which the simultaneous administration of adjuvant and antigen results in a retention of antigen at the site of injection. There may also be adjuvant retention at the site of injection.
30
Q

Aluminium-based adjuvants

A
  • Proven safety profile
  • Still get associated local reactions
    • Erythema, subcutaneous nodules and contact hypersensitivity
  • AS04
    • A combination of aluminium and a bacterial lipid (already approved in Europe)
31
Q

Liposomes as adjuvants `

A
  • Spherical bilayer constructs built from phospholipids
  • Able to encapsulate both Ag and adjuvant together
  • Large and easy to see for macrophage = more likely to trigger immune response
  • Taking both Ag and Adjuvant together= better immune response
32
Q

Why liposomes

A
  • Avidly ingested by phagocytes, serving as APC
  • Soluble membrane Ag can be exposed in conformations similar to the original organism
  • Additional adjuvant, such as Lipid A can be added
33
Q

What about a vaccine for HIV

A
  • The first HIV vaccine to enter full-scale efficacy testing was AIDSVAX
  • It is baded on gp120 proteins
    • Grown in cell culture
  • Using alum as an adjuvant
    • Similar to 1st successful Hep B vac
  • No evidence of protection
34
Q

HIV case study

A
  • Briefly what was the rational for using the gp120 protein as a vaccine for HIV
    • Using a live-attenuated virus is deemed to dangerous
    • gp120 is a surface protein on the virus
    • Train immune system to recognise gp120 and it would then recognise the virus
  • Why was the vaccine developed unsuccessful
    • The virus can quickly evolve to change its surface protein
35
Q

Delivering oral vaccines

A
  • Adminstration orally= absorption in the small intestine
  • In intestine there are breaks in microvilli cells instead we get M cells with direct access to dendritic cells
  • controlled vaccine delivery straight to dendritic cells
    • Stimulation of B cells and CD4 cells => Immune protection
  • Challenges- GIT environment, Stability, Taste/palatibility
36
Q

Current oral vaccines include

A
  • Cholera- Dukoral (Novartis)
  • Rotavirus- Rotarix (GSK)
37
Q

DNA vaccines- a spin out of gene therapy

A
  • Aim of gene therapy: Insertion of genes into an individuals cell to treat disease
  • We delivery pDNA to produce a forgein antigen (Mimic viral infection)
    • MHC class I will present Ag and drive immune response
  • Problem = low efficiency
  • But- vaccination only requires low levels of expression due to applification cascade
38
Q

DNA vaccines

A
  • Benefit: Mimic viral infection
  • B cells will identify free Ag (killed by T cell and release of intracellular material) and detect MHC on T cells
  1. DNA taken up by myocytes
  2. Transfection
  3. Induction against the encoded Ag
  4. MHC-I present (CTL)
39
Q

Conditional approval- First therapeutic vaccine

A
  • Merial gained conditional approval for vaccine to treat oral canine melanoma
  • Delivered via a new canine transdermal device (Developed in conjugation with Bioject)
  • Uses a DNA plasmid containing the gene encoding for human tyrosinase
  • The tyrosinase protein is over-expressed in the melanoma cells
40
Q

Types of vaccines

A
  1. Live attenuated
    1. BCG
  2. Inactivated
    1. Polio
  3. DNA vaccines
  • Note as safety increases, efficacy decreases