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BMS2052 > Vaccines > Flashcards

Vaccines Flashcards

1
Q

History of vaccines

A

Smallpox was the first disease that vaccines were developed for - the vaccines facilitated the eradication of smallpox
Next came the rabies vaccine, the killed inactivated + live attenuated polio vaccine, the recombinant HPV vaccine, the mRNA/DNA COVID-19 vaccine. Eradication of polio through vaccines is in near sight
We are also now starting to develop vaccines for non-communicable diseases such as Cancer and Alzheimer’s- use it to prime our immune system to recognize what cancer cells look like

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2
Q

Smallpox vaccine - How was it invented

A

Edward Jenner noticed that milkmaids did not catch smallpox - they were often called pretty faces with ugly hands as they would have sores on their hands from milking cows but did not get any sores on their faces as they didn’t develop smallpox
Edward reasoned that there was something interesting about the disease that the milkmaids were catching from the cows that led to the sores on the hand - it was just similar enough to smallpox to end up providing them with immunity to smallpox - this is called cross protection - when exposure to a different virus provides protection to a human virus
To test his theory, he obtained fluid from a milkmaid’s sore, dipped a needle in it, and scratched a young boy with it - the inoculated boy was later exposed to small pox and was resistant

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3
Q

Outcomes of vaccination

A

Decreased symptoms/severity of disease
Decreased transmission of disease
Eradication of disease from community
Potential treatment of non-infectious diseases such as cancer

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4
Q

Smallpox eradication program

A

Was facilitated by smallpox vaccines
The smallpox vaccines contained a virus that causes cowpox, called vaccinia - the cowpox virus contained antigens similar to those present on the smallpox virus - thus exposure to cowpox virus through the vaccine resulted in the production of B memory cells that were able to produce antibodies specific for the antigens present on both the smallpox and cowpox disease, and thus be ready to bind and neutralize the virus.
Eradication was declared in 1980s

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5
Q

Why is smallpox the only human disease to be eradicated?

A

Disease is limited to humans - doesn’t infect animals and doesn’t utilize vectors, so there isn’t multiple reservoirs for the pathogen in nature - thus we just have to focus on stopping transmission in humans - as long as the we prevent every last human from getting the virus the disease dies out in humans and thus the virus can’t exist in nature - as the virus can’t remain in our waterways and soil and animals
No long-term carriers, only symptomatic acute infection or death - in diseases where you have long-term asymptomatic infection they continue shedding the pathogen, promoting transmission
The virus doesn’t have as many serotypes as influenza which changes seasonally - thus one vaccine can protect against all existing strains of smallpox
Stable, cheap, and effective vaccine present that can be distributed globally
Global Surveillance by WHO to monitor and prevent outbreaks

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6
Q

Polio

A

A highly infectious viral disease that can cause paralysis - virus infects CNS and lyses motor neurons as it multiplies
Spread through the faecal-oral route
If muscles of the diaphragm are affected then individuals cannot breathe and then they die
Iron chamber was used to help individuals breathe and stay alive so their body can fight off the infection
Some cases led to irreversible vaccine

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7
Q

Polio Vaccines

A

First vaccine was the Salk vaccine, which contained the killed/inactivated Polio virus
Second was the live attenuated Sabin vaccine which could be taken orally

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8
Q

Salk Vaccine

A

The polio virus was grown in monkey cells. Cell culture fluid containing viral particles release form the monkey kidney cells were treated with formalin to inactivate the virus so it was no longer-infectious - this killed inactivated virus was used in the vaccine - contributed greatly to reduction of polio cases

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9
Q

Sabin vaccine

A

The virus was passed through monkey cells until it accumulated enough mutations that the virus would not be able to cause disease in a healthy person - it was a weakened version of the virus but not killed/inactivated - this live attenuated version was used to develop the oral vaccine.
The oral vaccine contributed further to community immunity against polio - because the vaccine was oral and polio is spread through the fecal-oral route, the vaccinated individuals shed attenuated polio particles in their faeces - meant you could get incidental vaccination of family members of the person who got vaccinated with polio virus if there is not great hygiene

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10
Q

What strains of polio are eradicated?

A

Type 2 and Type 3
We have moved on to making a bivalent vaccine containing Type 1 and Type 3 (no need to include Type 2 as it has been eradicated for a while) so that there is no overvaccination - the virus in the vaccine is more stable and less prone to reversion of
virulence
Eradication requires surveillance to prevent outbreak

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11
Q

Which regions still have polio?

A

Afghanistan and Pakistan - lot of political unrest in these areas so it’s hard to roll out programs that ensure everyone gets vaccinated

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12
Q

Vaccine-derived polio cases

A

When a virus particle shed by a vaccinated person acquires gain-of function mutations that results it in it getting some of its virulence back - the vaccine can then infect and cause disease in unvaccinated contacts of the vaccinated individual who initially shed the virus

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13
Q

What does vaccination achieve

A

Protection for individual against disease
Protection for population against disease
If enough people are vaccinated, we can also protect vulnerable people that are unable to get vaccinated such as elderly, pregnant women, infants from disease through herd immunity

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14
Q

How does herd immunity work

A

Get a large number of population vaccinated
Reduces the chances of infected individuals existing in the population, and an infected person coming into a contact with a susceptible person who is not vaccinated
If we don’t have a large enough proportion of population vaccinated, then the disease is maintained population through unvaccinated individuals who give it to each other - the chain of transmission cannot be broken, and leads to outbreaks and disease persistence
R0 tells us what percentage of the population needs to be vaccinated in order for us to achieve herd immunity - the larger the R0, the more harder the disease spread is to control and thus the greater the portion of people in the community who needs to be vaccinated

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15
Q

Measles

A

Viral disease
Gets in via respiratory tract
Main outcome is skin cash
Can cause other complications -such as encephalitis and pneumonia - excessive inflammation of the brain and airway due to overactive inflammation - encephalitis can cause deafness/ retardation
We see really severe complications in children below 2 who contract measles - sub acute sclerosis pan encephalitis - degenerative condition of brain that is always fatal
Measles cases have been greatly reduced due to measles vaccine but disease remains persistent in population and there are occasional outbreaks due to vaccine hesitancy - more people need to be vaccinated for full protection of population

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16
Q

What is the impact of not being able to vaccinate for a disease?

A

Tuberculosis has no known effective vaccine
Means we cannot prevent individuals from catching TB, we can only treat it
Reliance on antibiotic cocktails for treatment has produced drug-resistant strains
Great time and expense required to treat individuals who have drug-resistant strains of TB such as XDR and MDR

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17
Q

What types of immunisation are there

A

Passive and Active

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18
Q

Passive immunization

A

Your body doesn’t produce the antibodies
You are given an external source of antibodies
Provides rapid onset of protection which is useful during outbreak when the individual is suspected to have been exposed - eg you were exposed to someone who has measles, can take an antibody cocktail to prevent measles infection
doesn’t provide long-lasting immunity that protects you from subsequent infections

Eg. mother passes antibodies she possesses to her child through breastmilk
Antibody cocktails present for snake bite

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19
Q

Active Immunization

A

Involves introducing the microorganism in a safe form to the host to induce the host’s immune system to make antibodies against the virus - you make the antibodies yourself, no antibodies are given to you
Thus when reexposed to the virus you get a secondary immune response that is greater in magnitude and earlier in so the body is able to clear the virus more quickly and effectively as you have B memory cells at the ready that quickly differentiate into neutralizing antibodies

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20
Q

Requirements for a vaccine

A

Is safe- no side effects besides things like sore arm, tiredness
Provides immunity against pathogen and this immunity is long-lasting
Vaccine is stable- so it is effective after shipping and transport
Only single dose required ideally
Vaccine is cheap
Potentially also oral or inhaled - other forms of administration are available

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21
Q

Advantages of Killed inactivated vaccines

A

Super safe and heat stable as pathogen is essentially killed, so is often the first vaccine to be created against a new virus - Sinovax
no risk of reversion to virulence despite whole pathogen being used, easy to make - just need to inactivate the virus using chemicals such as formaldehyde or heat

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22
Q

Disadvantages of Killed inactivated

A

Not very immunogenic so you may require multiple doses for immunity and adjuvants to stimulate an immune response against the killed virus
High cost
Only IgG antibodies are induced

23
Q

Advantage of live attenuated

A

Can be taken orally
Much more immunogenic, usually only need one single dose and no adjuvants are required as the presence of the virus alone is enough to stimulate the immune system
Is made by passaging virus into cells so it accumulates multiple mutations - these mutations weaken the virus - the weakened virus is able to go inside the host and replicate enough to trigger an immune response but not enough to cause disease
Low cost, and induces cell mediated immunity as well as mucosal immunity (igA and igG)

24
Q

Disadvantages of live attenuated

A

Harder to transport because the virus is live - need cold chain
Risk of reversion to virulence

25
Q

Examples of live attenuated

A

Measles, mumps, chicken pox, rubella

26
Q

Examples of killed inactivated

A

Influenza, typhoid, Cholera

27
Q

What needs to be in a vaccine

A

Vaccine needs atleast one component from the pathogen in order to induce an immune response
The more components the vaccine, the greater the immune response induced and the more specific the immune response is against the pathogen

28
Q

Summary of vaccine types

A 
Whole inactivated
Live attenuated
Recombinant subunit vaccines
Synthetic peptide vaccines
Recombinant viral/bacterial vectors
MRNA/DNA vaccine
29
Q

Classical vaccinology approach

A
  • Growing up numerous amounts of the pathogen, killing it or having it attenuated and giving it through needle
30
Q

Reverse vaccinology

A

Reverse:

- Using genomics and transcriptomics, we can discover which surface proteins are actually expressed during human infection - no point developing a vaccine using a surface protein that pathogen only expresses outside of host such as when it's in the soil) 
- Increased efficacy of vaccines developed in these ways - can specifically target the components 
- pathogen uses to cause disease within host 
- We can also take the plasma of someone who survived an infection and look at their antibodies and look at the shape of the antibody epitope to see if these antibodies can be manufactured in the lab
31
Q

Subunit vaccines - acellular

A

Very effective when all we need is an antibody response to provide immunity against pathogen

- e.g. for a toxin producing bacteria (like clostridium botulinum) - most of the damage is caused by toxins  
- can ensure production of neutralising antibodies against toxin by including an inactivated version of the toxin called toxoid inside the vaccine
- Sometimes we want to prevent the pathogen from binding to host cells in the first place using adhesins, so exposing host to these adhesion molecules (e.g. spike proteins) can produce an antibody response that is sufficient to confer immunity- eg for Hepatitis B we only need adhesin in vaccine
- Some pathogens can evade host immune system through polysaccharide capsules, so antibodies can be made against it too and these pathogens don't escape detection 
- VLPs - are like an empty virus (make the capsid and we can display what we like on that capsid and when this is presented to host, the host can develop an antibody response against it without developing disease as VLPs lack nucleic acid and therefore cannot replicate and  are non-infectious)
32
Q

Toxoid

A
  • Example of subunit vaccine ( used against pathogen secreting toxins)
    • We only need neutralising antibodies against the toxin, not for the bacterial cell
    • Safe version of toxin is used ( toxin is treated and inactivated with formaldehyde) - causes antibody response in host that neutralises it, so upon actual exposure to pathogen, these same neutralising antibodies would neutralise toxin and prevent disease
      Tetanus toxin causes rigid paralysis - consistent contraction of muscle, whereas botulinum toxin causes flaccid paralysis- all muscles are relaxed
33
Q

Conjugant vaccines

A
  • Another type of subunit vaccine
    • Used for bacteria with capsules - capsules if they are thick enough can protect bacteria from complement response and cell lysis
    • Capsular polysaccharides can be a good target for vaccines but aren’t very immunogenic (which is why bacteria use it to evade immune system). If our immune system fails to recognize capsules as foreign we won’t generate a good immune response against these bacteria
      However we can conjugate capsular polysaccharide with a protein carrier (toxoid) which is a good immunogen that attracts the immune response to work against itself and the capsular polysaccharide its bound to
34
Q

Recombinant Vaccines

A
  • Uses recombinant DNA technology to produce an antigen of interest - we don’t need to extract it from pathogen cell culture
    • If we find the antigen of interest, we can go back to the genome and clone it and express it in a safe system (like in yeast), instead of having to grow up hundreds of litres of a really dangerous pathogen
      Commonly used for the pathogens that are difficult to grow/ cannot e grown in vitro, such dangerous pathogens (PC3 and PC4 level) like rabies because we don’t want to be growing up large amounts of these pathogens
35
Q

Example of Recombinant Antigen Vaccine

A
  • We know that people who are immune to Hep B have high levels of antibody against Hep B surface antigen HBSAg in their serum
    • Because it’s a surface antigen, we can block it using an antibody, and that is sufficient to prevent virus binding and entering cell
    • Take HBSAg gene and clone it into a plasmid (mainly through a bacterial system) and move it into a eukaryotic cell (like yeast cell)
    • The yeast then pump out large amounts of HBSAg through efflux pumps that we can purify and add an adjuvant to
      Results in production of a super safe vaccine that is nowhere near any type of virus particle - there is just a protein in the vaccine
36
Q

Advantages of Recombinant Antigen

A

Very easy to scale up, Safe, no need to grow virus

37
Q

Disadvantages of Recombinant antigen

A

Requires adjuvant

38
Q

VLP

A
  • VLPS look just like the virus to the host but don’t have genetic material so are not infectious and cannot replicate. However you can express antigens on the surface of the VLP that are immunogenic and induce an immune response
    • Start with non-enveloped virus -
    • Take gene of antigen of interest, put it into our vector and clone it into a eukaryotic expression system (yeast) so we get lots of protein produced
    • Next to the gene that’s been cloned into the plasmid vector, the capsid protein genes are also incorporated. The products of these genes will then self-assemble into a virus like particle that displays our antigens of interest (no viral genome here, just an empty shell but to host it looks exactly like real virus)
      Eg includes HPV virus
39
Q

Recombinant Antigen Vaccine for TB

A
  • Researchers identified which TB proteins are expressed during human infection and out of these which ones were immunogenic (based on antibody and CTL response to those proteins in animal model)
    • They made an artificial long fusion protein from 6 highly immunogenic proteins - they combined the 6 proteins to form one whole protein - cloned it in such a way that when this is expressed in their protein expression model, they get a massive immunogenic looking 6 protein structure that has these little gaps between each individual protein so that all the proteins could fold properly into their structure
40
Q

Synthetic peptide vaccines

A

Synthetic Peptide vaccines:

- e.g. in case of Covid, instead of using the entire spike protein, we could work out what the important peptide or structure in the spike protein (epitope) is that we need to make a good neutralising antibody or T cell response to
- If we could identify this sequence, we could chemically synthesise the short peptide in the lab
- If we can work out the relevant sequence, we don’t need the dangerous pathogen, cell system or full protein, we just get the machine to synthesise the exact epitope we need 
- Because it's so tiny we need to add something to it to stimulate the immune system, so a lot of these go into liposomes and nanoparticles 
- Very safe
41
Q

How to make synthetic peptide vaccine

A
  • To find out what the peptide of interest is, we need to find convalescent patients (ones that have just survived infection and recovered) and take their plasma ( is an example of reverse vaccinology)
    • This allows us to look for what antibodies and T cells they had that allowed them to beat this pathogen
    • Within the plasma we look for the antibodies - we can clone out the B cells and find the particular antibody we want
    • Can then test this against the virus and see whether it’s a neutralising antibody and if it’s the right one
    • We can pick the right antibody and expand it up
    • We then ask what it is in that portion of the antibody’s antigen binding site that binds to the virus and inactivates it
    • In this example, the little bit in red on the antibody is the only peptide sequence (epitope) we need to consider as that is the peptide sequence of the antibody that the antigen actually binds to
      We mimic this particular shape and structure of this epitope when making the antigen and cover it with adjuvants, liposomes etc. and then inject them into our patient to get a great protective immune response
42
Q

Adjuvants

A
  • When we use a single protein or soluble antigens (not whole massive cells), it can be hard to get immune system to mount a sufficient immune response - This is where adjuvants come in
    • Adjuvants enhance immune response to antigens in vaccine in few ways:
      ○ Causes inflammation that alerts immune response to investigate what’s happening there at site of injection and sample antigens
      ○ Has a depot effect (slow release of the antigens) to make sure immune system doesn’t miss out on sampling these antigens
      Are immunogenic to push antibody response and cell mediated immunity
43
Q

Examples of adjuvants

A

Different types of adjuvants trigger different types of immunity
Eg aluminium based salts trigger humoral immunity, liposomes trigger both humoral and cell mediated immunity

44
Q

Recombinant Vector Vaccine

A

Recombinant Vector Vaccines:

- Foreign genes are inserted into a live viral vector which goes into host and express something we want to use as our vaccine antigen 
- Multivalent viral vector carries multiple genes (all genes can be from one species or from different species)
- A vaccine that carries multiple genes from different species can protect us from multiple pathogens
- Chimpanzee adenovirus is used as a viral vector in AstraZeneca Vaccine
- We can also use attenuated measles virus as a viral vector 
- Canary pox virus doesn't cause disease and replicate in humans but can serve as a vector for the 3 HIV proteins - when the virus is put into human, the infected host cell expresses these 3 proteins in their native forms, which is a nice way to get the correct shape and expression of these antigens instead of having to use an artificial yeast vector or  something  
- Safe because actual HIV genome is not used, only specific proteins
45
Q

Mode of action for AstraZeneca

A

We can clone the spike gene of coronavirus into the adenovirus
- The adenovirus will go inside host cells, and replicate
- The adenovirus genome will make the host cell produce spike proteins, which the immune system can mount a response to
Sometimes we can inactivate the viral vector before it goes into host, instead of using live vector

46
Q

Bacterial vectors

A
  • We could also use bacterial vectors
    • Take our pathogen of interest and identify the genes that code for the antigen we need in our vaccine
    • We take our gene of interest and put it on bacterial plasmid or chromosome
    • The bacteria are then used like the viral vectors mentioned above- we use live attenuated bacteria as vectors so that these bacteria don’t cause disease
    • Once the bacteria infects the host the bacteria produces the protein antigens
    • The immune system sees these antigens via different ways - antigens produced float in cytoplasm of bacteria and when this bacteria is chopped up and expressed on MHC, the vaccine antigens are displayed alongside it as well
    • Attach surface antigens to signal peptide which result in bacteria expressing the vaccine antigens on its surface
    • Make bacteria to secrete the antigen into the surrounding environment of host
47
Q

Nucleic acid vaccines

A
  • We’ve had DNA vaccines for a while (none in humans yet, but we’ve had some in the veterinary space and are very effective)
    • Clone out the gene we want to make the protein from and encourage host cell to take up this DNA via electroporation
    • Host cell gets tricked into making mRNA and the protein, leading to an immune response
      RNA Vaccines:
    • Take it to the next level
    • Completely cut out even needing to get to a nucleus because they’re encasing mRNA of the gene of interest into a lipid nanoparticle which fuses itself to our own lipid membrane
    • mRNA is then taken in to the cytoplasm where our translation machinery is
    • Straight away we get viral proteins that can then be shown to immune system
    • Examples include Pfizer and Moderna
48
Q

How to make DNA Vaccine

A
  • Traditional way to do DNA vaccines was through the gene gun
    • Take the gene of antigen
    • Insert gene into a plasmid that can replicate in both eukaryotes and prokaryotes, with the cloned gene of interest under the eukaryotic promoter and you coat a whole lot of tungsten or gold particles with it (makes it inert so it doesn’t hurt host)
    • This is loaded into a little chamber and blown out at high pressure against the skin
    • As the DNA is going through, it’s getting dragged through the dermis layers which are really rich in immune cells, and get through to the muscles
      The inert tungsten and gold particles fall away and we end up with the plasmid DNA getting into the cells
    • DNA vaccine goes to the nucleus to produce mRNA (whereas RNA vaccine would skip nucleus step and start at this point)
      Get free protein manufacture from the host - some of this produced protein is chopped up into fragments and displayed on MHC I so immune response can be launched
49
Q

New approaches for vaccines

A

Edible vaccines, nanopatches

50
Q

Edible vaccines

A

Feed people Hy.pylori, a gut colonising bacteria, which is used as a carrier for antigens
Express the antigens of interest in genetically engineered plants such as potato and bananas

51
Q

Nanopatches

A

Nano patches:
- Has tiny sharp protrusions at the nano level
- Can dry coat nano patch and stick it against the skin
- Don’t need adjuvants or refrigeration as it’s dry coated
Super cheap and 100 x reduction in dose is still effective in getting an immune response (animal trials)

52
Q

Why do vaccines fail sometimes

A
  • We get the wrong sort of immune response or an immune response towards the wrong target because the immune system gets distracted by other components in the vaccine
  • The response induced too low due to immature immune system/ non-responders in the population as a result of genetics
    Can’t be used for individuals that are immunosuppressed
    Some pathogens can evolve mechanisms to evade immune response - antigenic variation
53
Q

Vaccine side effects

A

Sore arm, headache, tiredness, due to local inflammation induced at injection site to trigger activation and recruitment of immune cells to the site
Fevers - caused by vaccine-induced innate immunity.
Seizers- due to fevers caused by vaccine-induced auto immunity.
Allergic responses because the vaccine antigens/cells are cultured in eggs/yeast which individuals are allergic to - this is why we have 15 min wait after vaccination
Guillan-Barre syndrome - when vaccine-induced innate immunity triggers auto immunity

We don’t really want to be getting seizures and allergic responses as side effects so in those cases we would stop the use of the vaccine

There are other harmful effects associated with use live attenuated pathogens in our vaccines - the live attenuated strain could cause disease in immunosuppressed individuals or cross the placenta in pregnant women and cause disease in foetus - the use of live attenuated vaccines is therefore not encouraged in such cases and we use killed inactivated vaccines instread

54
Q

Vaccines and Autism - are they linked?

A

The studies showing this used a very small sample sized, and mistook association for causation - people roughly get their childhood vaccines around the same time they are diagnosed with autism so people start thinking the vaccines caused autism

BMS2052 (8 decks)

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