13. Trends in vaccinology 2 Flashcards
What are the key challenges in vaccine development?
- Emerging pathogens like Ebola and SARS-CoV-2.
- Moving/evolving targets like HIV.
- Old pathogens with new problems.
- Aging populations.
- Antibiotics resistance.
- Non-communicable diseases
Why do evolving pathogens create challenges for vaccine development?
- These are older pathogens like HIV that we don’t have a vaccine for.
- These pathogens are rapidly evolving so the antigens are changing.
- This is hard to make a vaccine for.
Why does the aging population create challenges for vaccine development?
- Immune senescence happens in the elderly population.
- This means making a durable immune response is tricky.
- So more vaccines are made to target the older population.
What is the traditional way of developing vaccines?
- Identify, purify and grow the pathogen of interest.
- Use this to identify the pathogen that causes disease.
- From that you can identify that pathogen or part of pathogen that is triggering a protective immune response.
What can we now use to develop vaccines?
- We can now use just the sequence of the pathogen and computer programs to identify the target antigen important for that pathogen.
- Identify specific epitopes or proteins.
- Identify which proteins are presented on the surface of the cell.
- This can be used to select targets and undergo in vitro and in vivo studies to test their effectiveness in inducing a protective immune response.
- You also need to consider the epidemiology of the pathogen and trial the vaccine.
What technological advances in DNA analysis has allowed reverse vaccinology?
- Whole genome sequencing
- subtractive pathogenome analysis.
What is subtractive pathogenome analysis?
A method of analysis to see which sequences are specific to the pathogen of interest.
What technological advances in protein analysis has allowed reverse vaccinology?
- Mass spectrometry.
- Substractive pathoproteome analysis.
- Protein function
- Subcellular localisation
What are the challenges in developing a vaccine for N. meningitidis serogroup B?
- Most N. meningitidis serogroups have conjugate protein vaccines for them which work well.
- MenB has a number of challenges.
- There are >1000 strains with high antigenic diversity.
- The capsular polysaccharide is poorly immunogenic.
- The capsule is similar to host CNS proteins.
How was reverse vaccinology used to develop the 4CMenB vaccine?
- In silico techniques to find proteins that could be expressed on the surface using bioinformatics.
- It was then determined which of these 600 proteins were actually expressed on the surface by injecting them into mice. This narrowed it down to 350 proteins.
- Then antibodies were used to confirm surface antigen expression. This produced 91 proteins.
- Then they were tested to see if they produced a protective antibody response. This narrowed it to 28 proteins.
- Then 3 were put forward into a trial vaccine with an adjuvant.
- This became 4CMenB or Bexsero.
What is Bexsero (4CMenB)?
- The vaccine for meningitis B.
- It is given to infants and at-risk adults.
- The UK started giving Bexsero in 2015.
- It has around 62% efficacy against invasive disease and higher in some populations.
- However, it has little to no effect on transmission. (indirect effects)
What organism causes group A streptococcus?
Streptococcus pyogenes
What are examples of mild group A streptococcus (GAS)?
- Impetigo and pharyngitis
- Normally this is self resolving but can drive antibiotic use and AMR.
- It affects millions.
What is a more severe GAS infection?
- Scarlett fever
- Rheumatic fever
What is invasive GAS?
- Sepsis or necrotising fasciitis
- Rheumatic heart disease
- These can be fatal
What does repeated GAS infection cause?
- It leads to undesirable host mediated autoimmune responses.
- This can be rheumatic fever or post-streptococcal glomerular nephritis.
- This can lead to rheumatic heart disease which affects around 30 million people a year.
What are the challenges to developing a Group A strep vaccine?
- Variable immunodominant surface proteins.
- Possibility of driving bad immune responses.
- N knowing which immune responses are protective.
- Requires large and expensive vaccine trials.
Challenges to developing a Group A strep vaccine: variable immunodominant proteins
- The proteins that drive GAS immune responses are highly variable.
- We need to look for conserved antigens that are observed in all strains during natural infection.
- The conserved M region is being looked at as a vaccine target
Challenges to developing a Group A strep vaccine: Avoiding bad immune responses
- Need to make a precise clean vaccine.
- The immune response produced needs to be considered.
- Target antigens that lead to protective responses.
Challenges to developing a Group A strep vaccine: Clinical trials
- Very expensive due to low infection rates.
- can use human controlled infection models to help with cost.
How has reverse vaccinology been used to develop a GAS vaccine?
- Over 200 genomes were sequenced and 15 highly conserved, widely expressed were identified.
- These were tested bioinformatically to see which proteins should be expressed on the surface.
- Then tested to see which elicited a good immune response in mice.
- Found 3 well conserved, highly expressed, well exposed and highly immunogenic antigens to be targeted.
- SpyAD, SpyCEP, ALO.
- Developed by GSK
Why are good conserved vaccine targets hard to find?
Because conserved antigens tend to weakly immunogenic whereas variable proteins tend to be immunodominant
What is immunoinformatics and How can it help vaccine development?
- Screening T and B cell epitopes.
- Using in silico and in vitro methods to look at the human immune response.
- This can help identifying vaccine targets.
What GAS research is occurring in Bristol?
- The difference in T and B cell response to GAS in different age groups.
- Studying the mucosal responses in early infection which is important for vaccines.
- Looking at bacterial gene expression to identify target antigens.
- Use this as a rational approach to inform vaccine development.
What are the differences in GAS response in different age groups?
- Pharyngitis peaks around age 10
- Invasive disease peaks in the very young and very old.
- We are not sure why.
- It shows increasing immunity is acquired late in childhood but it is believed immunity wanes as you get older and develop immune senescence and other conditions.
- You can compare immune responses in young children and adults to see what immunity has been acquired by the older population.
What are adaptable vaccine platforms?
- Vaccine manufacturing approaches which can be rapidly adapted to insert new antigens.
- This is ideally suited to allow rapid responses to emerging pathogens with pandemic potential
What are some adaptable vaccine platforms?
- DNA vaccines
- RNA vaccines
- Viral vectors
- Virus-like particles.
What are the pros and cons of DNA vaccines?
Pros: cheap
Cons: poorly immunogenic in humans.
What are the pros and cons of RNA vaccines?
Pros: Rapid production
Cons: Expensive
What are the pros and cons of viral vector vaccines?
Pros: Cheap, storage at 4 degrees, rapid production,
Cons: Uncertain pre-existing immunity
What are the pros and cons of virus-like particle vaccines?
Pros: Safe, easy to produce, no adjuvant required
Cons: slower to manufacture
How has technology developed to provide fast vaccines for emerging pathogens?
- Before, vaccines like the typhoid vaccine took decades to develop.
- Now, very short time frames for developing vaccines is possible.
- The COVID-19 vaccine was developed within a month.
How was the SARS-CoV-2 vaccine developed so quickly?
- There were decades of pre-existing research into areas like sequencing, manufacturing and mRNA and vector biology technology.
- The virus was sequenced quickly after it was identified.
- The vaccine was developed without the need of the organism itself.
- This platform was developed for pathogens before covid then was adapted to suit it.
How do mRNA vaccines work?
- the mRNA is made in the lab to encode the target antigen
- This is the spike proteins for SARS-CoV-2.
- It is packaged into nanoparticles and injected into patients.
- The nanoparticles release the mRNA into immune cells to generate a strong neutralising antibody and T cell response.
What is an example of a viral vector vaccine?
the ChAdOx-S1 SARS-CoV-2 vaccine
What is ChAdOx-S1?
- A SARS-CoV-2 vaccine produce by the oxford vaccine group.
- This development pipeline was established for other infections like MERS.
- They rapidly adapted this for COVID-19 in early 2020.
- This was developed by an academic lab with mostly non-commercial funding which is unusual for a vaccine.
- They then partnered with AstraZeneca for the mass production and global distribution of the vaccine.
What are CHIMs?
Controlled human infection models.
What are controlled human infection models?
- A recently deployed way of using an old approach similar to Edward Jenner.
- They are carefully managed research study where volunteers are purposefully exposed to an infection in a safe way with healthcare support.
- They are challenged with the pathogen and sampled regularly to observe the infection.
- Important for understanding immunological responses to infection and accelerating and de-risking development of novel drugs and vaccines.
- You can control who is infected and who is not. This is different from a vaccine trial where you wait for natural infection.
- There are robust ethical review processes in place to protect the safety of volunteers.
Has the use of CHIMs increased?
- Yes
- Mostly for cold viruses like rhinovirus, influenza and RSV.
- Now being used for other things like malaria.
- It aids the understanding of what immune responses are important and protective for certain diseases.
What ethical considerations are there around CHIMs?
- They breach the do no harm principle.
- You Must weigh the risk of individual harm with global population health impact.
- The ethical principles are similar to phase 1 clinical trials.
- Informed consent is critical.
- Requires appropriate compensation for the volunteers
What did CHIMs for GAS show?
- Adults with no pre-existing immunity to GAS were challenge at the back of the throat.
- They were used to understand the infection model and the immune response.
- 2 doses were used.
- 75% developed pharyngitis
- It was very helpful in understanding what happens in early infection with both the pathogen and immune response.
- Now also used to test some early vaccines.
What is systems immunology?
- A way of looking more broadly at the immune response by using new techniques.
- It looks at everything available not just what is being targeted.
- It allows for better examination of the immune response during infection (immune profiling).
- Uses Flow cytometry, sequencing, systems serology, and proteomics.
- It is important when correlates of protection are unclear.
How can systems immunology be an addition to vaccine development?
- It can be used to look at initial response after vaccination to see which immune signatures lead to the generation of a broad and protective immune response.
- Trials are using these approches to find signatures of vaccine efficacy and protection.
What other developments in biology can inform vaccine development?
- Organoid models which used human or mouse cells.
- Challenge models
- Humanised mice to make mouse models more relevant to human disease.
- These are new ways to model infection that have broadened our understanding of infection and design new vaccines.
What are vaccine adjuvants?
- They are ingredients of vaccines that boost the immune response to the antigen.
- It was included in vaccines before we fully understood how they worked. (Immunology’s dirty little secret)
What vaccines are adjuvants critical for?
- Subunit or toxoid vaccines
- These don’t induce an immune response on their own.
- So adjuvants are required to trigger the response.
How do vaccine adjuvants work?
- They activate the immune system via innate signalling
- PRRs like TLRs
- They also contain the antigen at the site of infection.
What is an example of an adjuvant?
- MPL
- This is attenuated LPS.
- It triggers TLR4 and gives the danger signals without causing widespread harm.
What are the challenges in developing a HIV vaccine?
- HIV has a high mutation rate so there is lots of antigenic variability. (moving targets)
- It infects T cells.
- The infect can be latent and hide.
- There is no natural clearance of HIV so we don’t what immune response to aim for.
What are the challenges in developing an influenza vaccine?
- There are multiple type (A,B,C) and lots of strains of each.
- There is variability caused by antigenic shift and antigenic drift.
- The seasonal vaccines are developed to target circulating strains.
- These have variable efficacy and it’s hard to predict if the vaccine will work.
- Antigen sin effects subsequent infections.
- Trying to develop a universal influenza vaccine but the targets keep changing.
What are the challenges in improving the tuberculosis vaccine?
- Tuberculosis causes over 1.4 million deaths a year.
- The current BCG vaccine is safe and cheap but has variable efficacy.
- Around 25% of the world are latently infected with TB.
- An ideal new vaccine will prevent infection and disease progression.
- This is a challenge as the immunity is cell mediated not antibodies so a durable immune response is harder to induce.
What is the BCG vaccine?
- A safe and cheap vaccine for tuberculosis.
- It has beneficial off target effects.
- It has variable efficacy and doesn’t protect well against latent infection.
What are the 2 main ways we can improve vaccines for older diseases like tuberculosis?
- Revaccination with BCG
- A new subunit vaccine.
What are the benefits of revaccination with BCG?
- This has been used in South Africa.
- It protects against sustained infection.
- This is cheap and safe.
- However may not be the most effective
What is the new subunit vaccine for tuberculosis?
- It has been trialled in latently infected people.
- It protects against disease progression in infected adults after 3 years.
How can vaccine be made more equitable?
- This requires international collaboration to improve the development and manufacture to make them available to everyone.
- The main step is improving the production capacity of vaccines in low and middle income countries.
- India is now a major contributor to global vaccine supply which provides cheap large scale vaccine production.
- Efficacy studies are often done in the UK and US but these often don’t translate to the target population in low and middle income countries.
- It is often easier to perform efficacy studies in these countries.
What vaccines have been tailored for diseases in low and middle income countries?
- New Malaria vaccines.
- Meningitis A
How was a MenA vaccine tailored to the population?
- MenA causes a lot of disease in the meningitis belt of Africa.
- It causes lots of death, disease and disability.
- The MenAfriVac vaccine is specialised to focus on MenA.
- This is a cheap protein conjugate vaccine developed in India.
How else could vaccines be used?
As therapeutic treatments
What is the potential of therapeutic vaccines?
- These are vaccines that can help treat illness after it is acquired.
- Could be used for Cancer, HIV or alzheimer’s disease.
- They are only theoretical at the moment
How could vaccine be used as a possible cancer treatment?
- It is theoretically possible.
- There are new technologies to reprogram the immune response to target cancer neoantigens.
- These would be personalised vaccines.
- They are challenging to develop as tumours have multiple immune evasion mechanisms.
How could vaccines be used to treat Alzheimer’s disease?
You could create vaccines against the most toxic forms of amyloid beta.
What are the main advantages of vaccines compared to antibiotics?
- Resistance can develop to antibiotics whereas this rarely happens with vaccines.
- Vaccines can lead to the eradication of diseases.
What are the main advances in biology that have aided vaccine design?
- Systems immunology
- Synthetic biology
- Adjuvant design
What can the success of vaccines depend on?
- The vaccine itself
- The target population (age, genetics etc)
