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
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
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
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
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
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
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
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)
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
10
Q
Herd immunity
A
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
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)
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
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
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
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
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
- 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
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Human Papillomavirus (HPV)
* 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
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HPV virus
* 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
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HPV vaccines
* 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
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Role of adjuvants
* 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
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Adjuvants
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.
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Aluminium-based adjuvants
* 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
Liposomes as adjuvants `
* 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
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Why liposomes
* 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
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What about a vaccine for HIV
* 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
HIV case study
* 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
Delivering oral vaccines
* 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
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Current oral vaccines include
* Cholera- Dukoral (Novartis)
* Rotavirus- Rotarix (GSK)
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DNA vaccines- a spin out of gene therapy
* 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
DNA vaccines
* 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)
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Conditional approval- First therapeutic vaccine
* 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
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Types of vaccines
1. Live attenuated
1. BCG
2. Inactivated
1. Polio
3. DNA vaccines
* Note as safety increases, efficacy decreases
