9. Immunology of the gut mucosa 2 Flashcards
How are most traditional vaccines administered?
- Systemically
- They are delivered via a syringe.
- Intramuscular, subcutaneous and intradermal.
How are most vaccines given?
Intramuscularly
What are live attenuated virus vaccines?
- viruses that have been cultured or engineered to be infectious but at a reduced level.
- The virus isn’t fit and can’t replicate very well.
- It triggers a robust immune response but 1 that can be easily managed.
eg Mumps vaccine
What are killed pathogen or toxin vaccines?
- These are inactivated viruses or parts of a virus toxin.
- These can’t replicate and are not infectious.
- Antigen presentation and T cell activation still occurs.
eg Diptheria vaccine
What are some new vaccine platforms?
- RNA vaccins
- Viral vector vaccines
What are most traditional vaccines not good at doing?
- They are good at developing a systemic immune response like antibodies and T cells.
- However they are not good at protecting against some of the biggest pathogens that infect mucosal surfaces.
Are there any effective HIV vaccines?
- There have been countless clinical trials.
- Most showed no efficacy.
- The RV144 trial showed 31% efficacy to prevent HIV acquisition but it couldn’t be replicated.
- It can been 40 years of research and no vaccine have been found.
Do we have a vaccine for TB?
- Yes the BCG vaccine.
- But TB still causes lots of infections and deaths.
- It is debated whether the BCG vaccine is effective.
What is the BCG vaccine?
- A live attenuated vaccine.
- Based on M. bovis.
- It is good at protecting children but has efficacy issues.
- The efficacy reduces the older the vaccine is given.
- It protects against pulmonary TB but not other types.
- It does not protect against infection but reduces disease severity.
Is there a new TB vaccine in development?
- yes
- Trialled in about 3300 people
- Out of both the test and control group only 40 people developed TB.
- 26 of these were in the placebo group.
- This shows this vaccine has about 50% efficacy in preventing TB infection.
What immune responses developed following the use of the new TB vaccine?
- A strong antibody response developed rapidly after the vaccine was given.
- Over time the response reduces but it is still elevated at 36 months.
- Protection peaked at 2 months.
- Long term data is needed to understand this further.
- T cell responses were also generated and lasted for 36 months.
- These results allowed more studies into the vaccine.
Is there an effective RSV vaccine?
- Yes
- It was difficult to make this vaccine but is has been done
What is RSV?
- Respiratory syncytial virus
- It is a common cause of severe respiratory infections
- It can be very serious in children and old people.
How do most infections enter the body?
- Through mucosal surfaces
- This makes up around 70% of infections.
- these are mucosal pathogens
What needs to be considered when designing vaccine?
Do we want a systemic or mucosal immune response
What do you need to do to generate a mucosal immune response with a vaccine?
- You need to get T and B cells to the mucosal surfaces.
- This is done by priming and homing signals from mucosal dendritic cells.
- Antigens given through muscle are less likely to cause this response.
What does systemic immunisation cause?
- Only induces systemic immunity (serum IgG and systemic T cells).
- It resolves infection once the virus has spread from a mucosal site.
- It can allows shedding from replication in a mucosal site.
- It maybe sufficient to control both if mucosal inflammation recruits systemic effectors.
What does mucosal immunisation cause?
- Mucosal and systemic immunity (Local and serum IgA, IgG and mucosal and system T cells).
- Prevents uptake of virus into mucosal tissues.
- It reduces local replication.
- Shed virus may be complexed with IgA and be non infectious.
What is an example of a successful mucosal vaccine?
The polio vaccine
What is the Polio vaccine?
- A mucosal vaccine.
- It protects against different serotypes of polio.
- It consisted of a mixture of 3 live attenuated poliovirus strains.
- Induces antibodies to protect the mucosa and prevent spread to the CNS.
What is polio?
- A virus that attacks the CNS and causes paralysis.
- It used to be a very significant cause of infection and death.
- Paralysis can cause people to lose the ability to breathe and require iron lungs.
How do iron lungs work?
- They alternate between positive and negative pressure.
- This forces the lungs to expand and contract so the patients can breathe.
Are we close to eradicating polio?
- Very close
- It is 99.99% eradicated.
- More vaccination and maintenance of vaccination is important.
How does poliovirus infect people?
- Poliovirus binds to receptors in enterocytes in the gut.
- The virus copies itself and bursts out of cells.
- It infects more epithelial cells and continues to replicate and spread.
- The virus migrates around the body and to the CNS.
How did the oral polio vaccine work?
- It was a live attenuated vaccine.
- It has mutations so it cannot travel and infect the CNS.
- However it can replicate in the intestines.
- This pulls in the T and B cell response so they become resident in the gut.
- When it encounters wild type polio so it can prevent infection.
What is the down side of the oral polio vaccine?
Vaccine-associated paralytic polio
What is vaccine-associated paralytic polio (VAPP)?
- As the oral polio vaccine is live it can replicate.
- this means it can randomly mutate back into the virulent form of polio.
- This rarely happens. Around 1 in 2.7 million dose administered.
- This causes VAPP.
Why is VAPP no longer an acceptable risk of a polio vaccine?
- Because polio rates used to be very high so the risk was worth it.
- Now polio levels are lower, so the risk is not worth it.
Why was polio vaccination changed to the inactivated polio vaccine?
To eliminate the risk of VAPP
What is the inactivated polio vaccine?
- It is injectable so it doesn’t create mucosal immunity.
- It is very protective against disease.
- But vaccinated people can still be carriers of polio and infect other non-vaccinated people.
- This is because the virus still replicates in the gut.
Who was accredited with the invention of vaccine?
- Edward Jenner and the smallpox vaccine.
- However, a type of vaccination called variolation existed long before then.
What are the barriers to creating an effective vaccine for mucosal sites?
- The acidic pH in the gut.
- The mucus layer
- Physical barriers
- The commensal microbiome
- The gut does not want an immune response as inflammation reduce nutrient uptake.
What functions does IgA or soluble IgA have at the gut mucosal surfaces?
- Inhibition of adherence
- Mucus trapping
- Pathogen or toxin neutralisation
- Transport
IgA functions at mucosal surfaces: Inhibition of adherence
Soluble IgA binds to microbes to prevent them adhering to mucosal epithelia
IgA functions at mucosal surfaces: Mucus trapping
Soluble IgA antibodies can associate with mucins to trap sIgA bound microbes in the mucus layer and preventing adherence.
IgA functions at mucosal surfaces: Pathogen/toxin neutralisation
IgA binds to attachment receptors and toxins to prevent internalisation, infection and toxin entry.
IgA functions at mucosal surfaces: Transport
sIgA can bind pathogens and mediate their transport back out of the cell/mucosa via binding to pIgR.
What things are tolerated by the mucosal surfaces?
- food
- Pollen
- commensals
- Dust mites
but all can still cause a response
What does the mucosal immune system need to do?
Distinguish between harmless food and commensal antigens and those associated with pathogens and respond appropriately.
What is tolerance?
- A specific acquired mechanisms where prior feeding reduces an individuals ability to respond to subsequent presentation of that antigen.
- This is to protect the body from allergy induction.
Can tolerance become an issue for mucosal vaccination?
- Could we accidentally tolerise ourselves against the vaccinated antigen.
- Mucosal vaccines need to engineered to over come tolerance but not trigger immune responses to other things.
- In most adults the mucosal immune system is geared towards tolerance and to not respond to antigen unless necessary.
What do most animals that recover from mucosal infection develop?
homologous immunity
What is homologous immunity?
Immunity developed to a pathogen that results in protection against the same and similar pathogens.
What needs to be considered when designing mucosal vaccines?
- Do danger or activation signals need to be added?
- Does the vaccine need to be live?
- Do we need novel adjuvants and delivery vehicles?.
- Is the difference between tolerance and active immunity dependent on the site of antigen up take?
What is the advantage of a live vaccine?
- Live vaccines normally cause stronger immune responses.
- They induce more serum antibodies and a better T cell response.
- This is due to the viral replication that occurs in this vaccine.
- This amplifies the virus dose and causes cell death.
What are the 2 types of living vaccine vectors?
- Bacterial
- Viral
What are vaccine antigen vectors?
- Ways to deliver the antigen to the tissue.
- Either express the antigen on the surface or the production and release of the antigen.
What are some bacterial vaccine vectors?
- Mycobacteria
- Vibrio cholera
- Listeria
- Shigella
- Salmonella
What are some viral vaccine vectors?
- Adenoviruses
- Poxviruses.
- VSV
What is salmonella?
- A rod-shaped gram-negative facultative anaerobe.
- Part of the Enterobacteriaceae family
- Attenuated S. Typhi and S. Typhimurium have shown promise for mucosal immunisation.
- In the early stages of development as a vaccine vector
What are the advantages of salmonella as a vaccine vector?
- They are a pathogen so it mimics natural infection of mucosal pathogens.
- They are intracellular so they can hide in cells and constantly produce antigen and generate a good immune response.
- Bacteria are cheap so it’s good for mass production.
- They are irreversibly attenuated so they are very safe.
- It can be delivered orally which increases uptake of the vaccine.
- They can hold large amounts of DNA so you can deliver multiple foreign antigens
What is adenovirus?
- A non-enveloped icosahedral virion.
- a double stranded DNA virus.
- Easy to genetically manipulate
What are the advantages of adenovirus as vaccine vectors?
- They can infect a wide range of mammalian cells.
- Transgene expression is robust and can be enhanced by using heterologous promoters.
- The vaccine is delivered as a genetic sequence.
- The production of adenovirus is simple and can easily be grown at large scale.
- The vector genome doesn’t integrate into the host chromosome and mostly remain epichromosomal. This means there is no risk of mutagenesis.
- They induce strong immunity responses when given via parenteral or mucosal routes. both T cell and antibodies
What vaccines use attenuated viral vaccine vectors?
- Rabies
- Influenza virus
- Poliovirus
How does a rabies vaccine use attenuated virus?
- Used to vaccinate foxes.
- The attenuation is not stable.
- Newer vaccines are recombinant vaccines
How does the influenza vaccine use attenuated virus?
- The live attenuated influenza vaccine is a type of influenza vaccine in the form of a nasal spray.
- It doesn’t replicate at body temperature so it stays in the nose and generates a good immune response
How does a poliovirus vaccine use an attenuated virus?
- It has mutations of the capsid protein gene and non-coding regions.
- This prevents the translation of viral RNAs in the CNS.
What are some non-living antigen delivery systems?
- Micro and nano-particles.
- Liposomes
- DNA vaccines in gene guns
- Transgenic plants
How do liposome deliver antigens?
- by entrapping then releasing antigen from its aqueous core.
- The antigen can be expressed on the surface
How do gene guns deliver antigens?
- The DNA is fired into the arm.
- This is then taken up by cells.
- This is a kind of needless injection.
What happens if you vaccinate 1 mucosal surface?
- You can get an immune response at another mucosal surface
- This is called mucosal linkage.
- It is not reciprocal.
- This can help with vaccine delivery and compliance.
What does “mucosal linkage is not reciprocal” mean?
- If you immunise that nasal mucosa, you get an immune response also in the respiratory and genital tracts.
- But vaginal immunisation doesn’t provide protection elsewhere.
What is cholera?
- An acute diarrheal infection.
- It is caused by ingesting food or water contaminated with Vibrio cholerae.
- It leads to severe dehydration and can be fatal
What is the global burden of cholera?
- 2.86 million cases annually
- 95,000 deaths annually
- Many cases do not get reported.
What are the recent trends in cholera?
- Cholera outbreaks have surged in at least 30 countries due to climate change, political conflict, forced migration and economic and social factors.
- Out breaks in non-endemic regions and re-emergence in other places.
- Recently declared a global health crisis by WHO.
How does cholera infect the body?
- It enters the body through contaminated food or water.
- It infects cells using the cholera toxin.
- The CT B subunit binds to GM1 receptors on the small intestine cells.
- This allows the toxin to enter cells, and CT A subunits cause an increase in cAMP, which blocks sodium absorption and increases chloride and water secretion.
- This leads to huge amounts of diarrhoea.
What is the Infectious dose of cholera?
- It depends on the route of exposure, inoculum size and infecting strain.
- medium infectious dose is 100,000,000
3, Infectious dose can drop as low as 100-10,000
What are the clinical feature of cholera?
- Incubation period of 0.5-4.5 days.
- In severe cases stool output can be as high as 1000ml/h.
- Systemic manifestations are unusual
- If left untreated, cholera can lead to severe dehydration, hypovolaemic shock and death.
What role does innate immunity play in cholera infection?
- It plays a key role in controlling V. cholerae at the mucosal surface and initiating adaptive immunity.
- Infection induces a broad inflammatory response involving macrophages and neutrophils.
What role does adaptive immunity play in cholera infection?
- Directed against the LPS O-antigen and cholera toxin.
- Anti-O-antigen antibodies inhibit colonisation and motility.
- Anti-cholera toxin antibodies block receptor binding
- Vibriocidal antibodies are indirect markers for mucosal immunity and correlate to protection.
What type of vaccine are the cholera vaccines?
Mucosal vaccines
What are the 3 oral cholera vaccines available?
- Killed whole-cell vaccines.
- Killed whole cell vaccine with a recombinant B subunit.
- Live attenuated vaccine.
How do oral cholera vaccine work?
- They trigger B cells to secrete IgA.
- This provide protection if the B cells are in mucosal tissues.
- They neutralise the pathogen or toxin.
