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Immunology > Vaccines > Flashcards

Vaccines Flashcards

1
Q

what is the main goal of vaccination?

A

eradication of disease

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2
Q

how effective are vaccines?

A

Vaccination is one of the most effective weapons in medical armoury
- It is successful and cost-effective compared to pharmaceuticals
- Since the discovery and development of vaccination a number of formerly major afflictions have been controlled or the frequency hugely reduced
- Diphtheria, mumps, tetanus, pertussis (whooping cough) poliomyelitis, smallpox (last natural case in 1977, it is now eradicated)

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3
Q

what is poliomyelitis?

A

Causes lung paralysis due to diaphragm not being able to contract
- Patients have to be put in an iron lung
- This is why vaccine is so important

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4
Q

why is there a pressing need for vaccines?

A

There are a significant number of infections for which we still lack effective vaccines
- These diseases have a significant impact on mortality and quality of life

e.g. Malaria: Approximately 230 million cases (2020) Deaths: 760,000 (2014) - 400,000 (2017)
- Malaria has shifted our genetic background to cause sickle cell anaemia
- Even if we eradicate malaria, sickle cell will still exist in our genome

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5
Q

what is trypanosomiasis?

A

Several vertebrate diseases caused by parasitic protozoan trypanosomes of the genus Trypanosoma.
- In humans this includes African trypanosomiasis and Chagas disease (South America). A number of other diseases occur in other animals.
- African trypanosomiasis,: Approximately 65 million people in sub-Saharan Africa at risk.
- Chagas disease causes 21,000 deaths per year mainly in Latin America.
- There is no effective vaccine

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6
Q

what are the new pathogenic threats?

A

In recent history we have seen the emergence of a number of deadly threats in the form of zoonoses
- A zoonotic infection in which a pathogen jumps hosts from animal to humans
- The danger is that we have little or no natural immunity to these novel pathogens

Examples:
- HIV-1
- Ebola
- Covid-19

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7
Q

what is HIV?

A

RNA virus with reverse transcriptase to produce escape variants – many variants in circulation at any one time

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8
Q

how dangerous is HIV?

A

5 million people became newly infected with HIV in 2020.
- In 2020, around 690,000 people died from AIDS-related illnesses worldwide, compared to 1.2 million in 2010.
- Substantial economic impact of HIV/AIDS
- Now a pandemic
- Destruction of economies and human capital
- No really effective current vaccine
- Treatment – not cure, Antiretrovirals - AZT
- Treatments consume the majority of household budget

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9
Q

what is ebola?

A
  • Haemolytic virus
  • Resides in immune-privileged tissues even after clearance
  • Highly contagious
  • New strains can emerge at any time
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10
Q

how dangerous is ebola?

A
  • Death rates from 20-90%
  • Modern transport hubs mean that we are never more than 5 hours from an outbreak in a large population centre
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11
Q

what is variolation?

A
  • Observed in ancient times that infection with a particular disease renders the individual resistant to infection with the same disease
  • Ancient Greece Thucydides 429 BC, China 900AD
  • Purposely infecting someone with pus from disease
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12
Q

how was variolation used against smallpox?

A

Smallpox was a worldwide scourge:
- Fatality – 20%
- Survivors scarred
- Infection with a mild case protected the individual from subsequent serious infection
- Scratches on the arm inoculated with pus from a pustule - variolation

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13
Q

what did Edward Jenner do?

A

Based on the observation that milkmaids (who often suffered from cowpox) were resistant to infection by smallpox
- Infected people deliberately with pus from cowpox lesion
- The result was a resistance to smallpox
- Smallpox and cowpox share antigens
- Tested on a boy James Phipps 8 years old

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14
Q

what were the foundations of immunological theory? who laid these foundations?

A

The concept of microorganisms as source of disease
- The protective action of previous infection
- Robert Koch (1843-1910) – the association of particular diseases with a specific variety of microorganism
- Louis Pasteur (1822-1895) - The idea of generating weakened pathogens to infect subjects artificially – concepts still used today - Most famously developed a vaccine for rabies

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15
Q

what is active immunisation?

A
  • Manipulating the immune system to generate a persistent protective response against pathogens
  • Immunisation with a vaccine that can trigger an immune response and safely mimic natural infection
  • Mobilise the appropriate arms of the immune system and generate immunological memory
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16
Q

what is passive immunisation?

A
  • Transfer of preformed antibodies to the circulation
  • Can be natural or artificial
  • No memory, no T cell activation – no long-lasting change to immune system

Natural Passive Immunity occurs naturally by the transfer of maternal antibodies across the placenta to the developing foetus

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17
Q

what does natural passive immunity provide protection against?

A
  • Diptheria
  • Tetanus
  • Streptococcus
  • Rubella
  • Mumps
  • Poliovirus
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18
Q

what is artificial passive immunity used for?

A

Individuals with agammaglobulinemia – B cell defects so cannot make antibody– inborn or acquired
- Treated with pooled normal human IgG

Exposure to a disease that could cause complications –
- E.g. immune-compromised patient exposed to measles or other pathogens

Or - when there is no time for active immunization to give protection
- i.e. a pathogen with a short incubation time

Acute danger of infection

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19
Q

how was antisera and passive immunisation used to treat infectious disease?

A

Immunization was the major treatment for a range of infectious diseases
- Usually horse serum – despite the risks
- toxin put in horse and its preformed antibody serum is extracted
- These antisera were frequently used to neutralise toxins

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20
Q

how may some pathogens not be the primary source of infection?

A

With some pathogens the main hazard is not the primary infection itself, which can be eliminated by the immune system, rather it is the effects of very potent toxins released by the bacteria

Two common examples are:
- Tetanus: Clostridium tetani which releases tetanus toxin
- Botulinum: Clostridium botulinum which releases botulinum toxin

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21
Q

why is natural immunity to toxins difficult to achieve?

A
  • Given the lethal dose of botulinum toxin is approximately 1.5 ng/kg intravenous
  • Exposure to sufficient toxin to stimulate the immune system would be lethal
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22
Q

how can we become immune to toxins?

A
  • Deactivated toxin derivatives (toxoids) can be used as vaccines to produce immunity
  • Most commonly used is tetanus toxoid
  • Vaccine against the toxin, not the pathogen
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23
Q

what are the advantages of passive immunisation?

A
  • Use of pre-formed antibodies can quickly neutralise toxins and venoms - A conventional immune response may be too slow
  • In the case of highly virulent pathogens pre-formed antibodies can be used to prevent or limit infection
  • If no vaccine is available then pre-formed antibodies isolated or engineered from immunised animals may be the only means of treatment (Ebola as an example)
  • In some cases antibodies from surviving patients can be used (a certain level of risk here)
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24
Q

what are the limitations of passive immunisation?

A
  • Does not activate immunological memory
  • No long term protection
  • Possibility of reaction to anti-sera (if cross species)
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25
Q

what are humanised antibodies

A
  • Can change sequence of animal antibodies to be used in humans so that they are no longer seen as foreign
  • Biologics/genetic engineering
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26
Q

what are the main vaccine types?

A
  1. whole organism: live attenuated or killed/inactivated
  2. subunit
  3. peptides
  4. DNA vaccines
  5. engineered virus
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27
Q

what are live attenuated whole organism vaccines?

A

The pathogen is altered to reduce virulence
- for example by adaptation after prolonged cultivation in special medium
- The organism is used in a weakened form, still able to replicate but at a reduced rate
- Can produce a short-lived infection but can be cleared by the host without harmful outcome
- Most effective form of vaccine

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28
Q

what are inactivated whole organism vaccines?

A

The organism is rendered inactive and non-viable by heat, chemical, or other treatments
- Cannot replicate
- Less effective but safer

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29
Q

give some examples of whole organism vaccines:

A

live attenuated:
- tuberculosis (BCG)
- typhoid
- measles
- polio Sabin

Inactivated:
- cholera
- Influenza
- Polio Salk

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30
Q

how is the tuberculosis vaccine attenuated?

A

Bacillus Calmette-Guerin (BCG) vaccine
- Mycobacterium bovis – grown for 13 years on medium containing bile
- Became adapted and had reduced virulence

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31
Q

how is the polio sabin vaccine attenuated?

A

Polio virus grown on monkey kidney epithelial cells
- Prolonged culture leads to adaptation and a strain that has reduced virulence in humans

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32
Q

what are the advantages of live attenuated vaccines?

A
  • Attenuated pathogen sets up a transient infection
  • Activation of full natural immune response
  • Prolonged contact with the immune system
  • The stimulation of a memory response in the T and B cell compartments
  • Resulting in prolonged and comprehensive protection
  • As the vaccine is able to replicate, antigens are released over time, in contrast to a single vaccination with antigenic extracts or inactivated
  • Often only a single immunization is required – advantages in the Third World
33
Q

what are the disadvantages of live attenuated vaccines?

A
  1. Immunocompromised patients (or other rare individuals) may become infected as a result of immunization e.g. chemotherapy, genetic issue
    e.g. live measles vaccine = 1 per 1,000,000 - post-infectious encephalomyelitis
    - 0.5 – 1.0 per 1000 with natural disease will get this if they aren’t vaccinated
  2. Occasionally the attenuated organism can revert to a virulent form
    - e.g. – Polio Sabin, Approximately 1 case in 2,400,000 doses
    - In areas with poor sanitation this can lead to a serious outbreak – so Polio Salk is the preferred vaccine in undeveloped regions
  3. Refrigeration and Transport!
    - Typically live organisms need to be refrigerated for stable storage
    - This can be an issue in remote areas of the world
34
Q

what are the advantages of whole inactivated pathogen vaccines?

A
  • No risk of infection
  • Storage less critical
  • A wide range of different antigenic components are present so a good immune response is possible
35
Q

what are the disadvantages of whole inactivated pathogen vaccines?

A
  • Tend to just activate humoral responses
  • Lack of T cell involvement
  • Without transient infection the immune response can be quite weak
  • Repeated booster vaccinations required
  • Adjuvants can be used to increase the immune response
  • patient compliance for boosters can be an issue
36
Q

why is important that the inactivation procedure is correct?

A

-Salk Polio vaccine is prepared by inactivation of viral particles by formaldehyde treatment
- 1950s - A series of outbreaks were caused by improper chemical treatment
*- It is also important that the treatment does not reduce the immunogenicity of the pathogen – to ensure a correct response

37
Q

how can pathogens be inactivated nowadays for vaccine use?

A

– Modern approaches can exploit recombinant DNA technology to remove genes that control virulence but leave intact the genes for infection

38
Q

why are inactivated pathogen vaccines less effective than live attenuated vaccines?

A
  • Not as effective as live attenuated in producing cell-mediated immunity i.e. they are less effective at activating T cell immunity
  • Typically, repeated doses are necessary to provide protection
39
Q

what are subunit vaccines?

A
  • Simply using an isolated component of a pathogen rather than the whole organism
  • Theoretically safer than handling live or inactivated pathogens
  • No risk of infection
  • Purify molecular components as immunogenic agent
40
Q

what are the major types of subunit vaccines?

A
  1. Inactivated exotoxins (toxoids)
  2. Capsular polysaccharides
  3. Recombinant microbial antigens
  4. conjugate vaccines
  5. synthetic peptide vaccines
41
Q

why don’t we simply immunise with diptheria or tetanus microorganisms?

A
  • A number of important pathogens produce the symptoms of disease as a result of exotoxins
  • For example diptheria and tetanus

Diptheria toxin inactivates mammalian elongation factor EF2
- So it is an inhibitor of translation
- Lethal dose – approx 100 ng/kg -
- Necrosis of the heart and liver

Tetanus toxin – neurotoxin
- Uncontrolled contraction of voluntary muscles

42
Q

what is a bacterial exotoxin subunit vaccine?

A

Toxoid vaccine – heat treated or chemically modified to eliminate toxicity
- just inserts the modified toxin into the patient
- Cultivation of pathogen and subsequent processing to purify single component

43
Q

what are capsular polysaccharide subunit vaccines?

A

Capsular PSs are highly polar, hydrophilic cell surface polymers consisting of oligosaccharide repeating units.
- These molecules are the main antigens involved in the protective immunity to encapsulated bacteria.
- Capsular PSs may interfere with bacterial interactions with phagocytes by blocking opsonization.

Polysaccharide vaccines stimulate B-cell responses, thereby resulting in type-specific antibody production that enhances ingestion and killing of the pathogens by phagocytes.

44
Q

what are recombinant protein subunit vaccines?

A

Recombinant DNA technology has provided new ways of simply expressing and purifying subunits
- Cloning and expression of single gene in recombinant host
- Use vector (virus) to express pathogen antigen in host cells
- E.g. AstraZeneca SARS-CoV-2 vaccine: Chimp adenovirus with SARS-CoV-2 “spike” protein gene
- Use live attenuated virus/bacterium as a “vector” to express antigens from another pathogen e.g. vaccinia + Hep B. Latest HIV vaccines being developed also of this type

45
Q

what are examples of recombinant protein subunit vaccines?

A

Examples include subunit vaccine comprised of Hepatitis B surface proteins (expressed in yeast)
- Gardasil – a recombinant vaccine for human papilloma virus
- Virus coat proteins expressed in yeast
- Spontaneously assemble in virus like particles
- astrazeneca sars cov 2 vaccine with chimp adenovirus encapsulating the spike protein

46
Q

what are conjugate subunit vaccines?

A

some cases the target antigen - for example capsular polysaccharides - may only stimulate a weak T cell response
- As we know that would reduce the induction of immunological memory
- To overcome this the capsular polysaccharides can be chemically conjugated to a second antigen (frequently, but not necessarily, from the same organism)
- Immunisation with this conjugate vaccine can then stimulate both T and B cell responses

47
Q

what are synthetic peptide subunit vaccines?

A

Despite initial promise – the field has advanced slowly
- Aim – to produce a peptide that includes immunodominant B cell epitopes and can stimulate memory T cell development

Difficulties:
- It is now clear that knowledge of HLA presentation of peptides is essential
- Peptides can be stimulatory OR suppressive !
- Most B cell epitopes are conformational

48
Q

what are the advantages of subunit vaccines?

A
  • Safety
  • Only portions of pathogen are used
  • No risk of infection
  • May be easier to store and preserve
49
Q

what are the disadvantages of subunit vaccines?

A
  • Immune response is less powerful than to live attenuated vaccines
  • Repeat vaccinations needed and adjuvants
    -Subunits have to chosen that elicit a response in the widest range of subjects (HLA differences?)
50
Q

what are adjuvants?

A

Essentially any substance added to vaccine to stimulate the immune system

Can include:
- Whole killed organisms
- Toxoids
- Proteins (as in conjugate vaccines)
- Chemicals: Aluminium salts, Oil emulsions

51
Q

what are the mechanisms of adjuvants?

A

The mechanisms can vary:
- Aluminium salts may extend the half-life of immunogen in the site of injection (depot effect)
- Chemicals can cause irritation and inflammation
- Toxoids and killed organisms trigger the immune system and send out “danger signals”

52
Q

what are examples of adjuvants used in humans?

A
  • alum (dominant)
  • oil/water emulsions
  • detoxified bacterial lipopolysaccharide
  • Cytokines
  • More recently Toll-like receptor agonists
  • High efficiency can often be accompanied by safety hazards: Risk of autoimmunity, Chronic inflammation
53
Q

what are DNA vaccines?

A

Aim – to transiently express genes from pathogens in host cells. Generates immune response similar to natural infection
- Leading to T and B cell memory responses

54
Q

how do DNA vaccines work?

A
  • Expression vector is transfected into cells e.g. muscle
  • Expression from episomal plasmid
  • Other cell types may also take-up DNA – such as antigen-presenting cells (follicular dendritic cells)
  • Use DNA to transiently express pathogen antigen in host cells
  • DNA can be directly injected into muscle
55
Q

what evidence is there that DNA vaccines work?

A

proof of the principle of DNA vaccination, immune responses in animals have been obtained using genes from a variety of infectious agents
- Influenza virus, Hepatitis B virus, HIV, Rabies virus
- In some cases protective responses have resulted

Still too little is known about how DNA immunisation leads to immune response
- What adjuvants could be useful?
- Possible side effects?

56
Q

what are the advantages of DNA vaccines?

A
  • DNA vaccines do not require complex storage and transportation
  • Delivery can be simple and adaptable to widespread vaccination programs – “DNA gun”
57
Q

what are the disadvantages of DNA vaccines?

A
  • As with “killed” vaccines, and subunit vaccines, there is no transient infection
  • DNA vaccination is likely to produce a mild immune response and require subsequent boosting
  • Perhaps immune response to DNA
  • No examples of human DNA vaccines approved
  • Veterinary – West Nile Virus
58
Q

what are RNA vaccines?

A
  • Similar to DNA vaccines
  • Can be designed to encode specific antigens
  • Injection into cells leads to transient expression of antigen
  • As with DNA vaccines the RNA construct can be rendered stable by additives
  • Up to 18 months at room temperature
59
Q

what are recombinant vector vaccines?

A

Aim – to imitate the effects of transient infection with pathogen but using a non-pathogenic organism

Genes for major pathogen antigens are introduced into a non-pathogenic or attenuated microorganism and introduced into the host

60
Q

give examples of vaccines which use recombinant vectors:

A

Viral or Bacterial
- Vaccinia virus
- Canarypox
- Attenuated poliovirus
- Attenuated strains of Salmonella
- BCG strain of Mycobacterium bovis

61
Q

what vectors can be used in recombinant vector vaccines?

A

Adenovirus: Strains that can infect humans e.g. Oxford Covid Vaccine

Vesicular Stomatitis virus: Relative of rabies virus

62
Q

what are the advantages of recombinant vector vaccines?

A
  • Create ideal stimulus to immune system
  • Produce immunological memory
  • Flexible - different components can be engineered in
  • Safe - relative to live attenuated pathogen (how safe?)
63
Q

what are the disadvantages of recombinant vector vaccines?

A
  • Can we predict everyone’s response to engineered virus?
  • Require refrigeration for transport
  • Can cause illness in compromised individuals
  • Immune response to virus in subjects can negate effectiveness
64
Q

what properties make an ideal vaccine?

A
  • Safe: this could mean attenuated live if suitable or subunit if the pathogen is lethal for example
  • Should induce a suitable immune response, for example - mucosal (IgA) if pathogen uses this route
  • generates high antibody levels in the blood if antibody most useful protective agent
  • Generate T and B cell memory
  • Stable and easy to transport for use in remote areas
  • Should not require repeated boosting = patient compliance
65
Q

what is SARS-COV-2?

A
  • single-stranded RNA genome
  • Emerged around December 2019
  • Exact origin unknown
  • Sequencing shows closest similarity to a bat coronavirus (possible intermediate host)
66
Q

when else has a coronavirus been a public health threat?

A

SARS - Sudden Acute Respiratory Syndrome 2002-2004 outbreak
-SARS coronavirus (SARS-CoV) – virus identified in 2003.
- SARS-CoV is thought to be an animal virus from an as-yet-uncertain animal reservoir, perhaps bats, that spread to other animals (civet cats) and first infected humans in the Guangdong province of southern China in 2002.
- An epidemic of SARS affected 26 countries and resulted in more than 8000 cases in 2003. Since then, a small number of cases have occurred as a result of laboratory accidents or, possibly, through animal-to-human transmission (Guangdong, China).
*
MERS - Middle Eastern Respiratory Syndrome
- Coronavirus – bat -> ?? -> camel
- June 2012 Jeddah, SA

67
Q

how does the covid virus enter epithelial tissues?

A

s-spike protein mediates cell entry via the ACE-2 receptor:
- This makes the virus “tropic” for tissues expressing significant levels of ACE-2
- Respiratory Tract

68
Q

what is the s-spike protein of covid19? how does it facilitate entry into host cells?

A

Covid-19 makes use of a densely glycosylated spike (S) protein to gain entry into host cells:
- The S exists in a metastable pre-fusion conformation that undergoes a substantial structural rearrangement to fuse the viral membrane with the host cell membrane
- This process is triggered when the S1 subunit binds to a host ACE2 receptor.
- To engage a host cell receptor, the receptor-binding domain (RBD) of S1 undergoes hinge-like conformational movements that transiently hide or reveal the ACE2 binding residues.
- Receptor binding destabilizes the prefusion trimer, resulting in shedding of the S1 subunit and transition of the S2 subunit to a stable post fusion conformation.
- Conformational change triggered by ACE-2 binding S2 adopts a new conformation and draws virus to cell surface

69
Q

what vaccine strategy was used to target covid19?

A

Vaccine strategy:
- Induce neutralising antibodies that can block viral entry
- Relationship between antibody sequence and neutralisation activity

70
Q

what types of vaccines were used against covid?

A
  • RNA vaccines
  • adenovirus recombinant vector vaccine
71
Q

what RNA vaccines were used to target covid?

A

The mRNA vaccine developed by Moderna encodes the entire 1273 amino acid sequence of the viral S protein and is therefore named the mRNA-1273 vaccine.

Pfizer-BioNTech, however, developed two vaccines: - BNT162b1 (consisting of the RBD, a part of the S1 subunit of S protein)
- BNT162b2 (consisting full-length of S-protein amino acid sequence, similar to the Moderna vaccine)

mRNA vaccines feature modified 5′ and 3′ UTRs to optimize the mRNA sequence stability
- poly-A tail engineered to prolong stability
- Codons of the ORF are also optimized for translation activity
- Typical lipid nanoparticle structure for RNA vaccine delivery

72
Q

what adenovirus recombinant vector vaccine was used to target covid?

A

Oxford vaccine strategy:
- The ChAdOx1 vaccine is a chimpanzee adenovirus vaccine vector.
- This is a relatively harmless adenovirus that usually causes the common cold in chimpanzees.
- Engineered to express Covid spike protein

73
Q

why was a chimpanzee adenovirus used in the oxford covid vaccine?

A

There a number of human adenovirus strains that could be used as vectors
- The goal is to use the adenovirus to express the target antigen from within human cells

Advantages:
- Native conformation!
- Ease of production – the virus can replicate itself – so production can be rapidly scaled up
- It produces conditions that mimic a natural infection – thus engaging the immune system fully

74
Q

what is the structure of the adenovirus? how can it be made safe for use in vaccines?

A

Genome Double Stranded DNA – approx. 36 kb
- Regions E1, E3, E4 contain genes that modify the host and enable virus replication and release
- E1 proteins can immortalize host cells and place the cell into S phase which enables replication of viral DNA
- E3 proteins have evolved to neutralize the host immune response
- E4 genes modify the host cell cycle

When investigated as a possible gene therapy vehicle it was demonstrated that deletion of the E1 and E3 regions could allow for the insertion of up to 8 kb of DNA
- Deletion of region E1 prevents viral replication

75
Q

why are human adenovirus strains limited? how was this overcome?

A

The presence of neutralizing antibodies in the general population (due to previous exposure) limits the usefulness of human adenovirus strains
- Sarah Gilbert and her team identified a chimpanzee adenovirus strain for which the general population did not exhibit a high antibody titer strain Y25
- To carry out genetic engineering of Y25 the entire genome was cloned into a bacterial artificial chromosome

76
Q

how can we produce the adenovirus if its replication is defective?

A

A cell line is used which has been transfected with the missing viral components deleted in the engineered vector (E1 genes and others)
- HEK293 cells are used (embryonic kidney cells)
- This is a common immortal cell line used widely in research
- If the adenovirus DNA is transfected into the modified HEK293 cell then viral particles are produced in high yield
- These can be purified and used for immunization

77
Q

how did the oxford team produce the adenovirus covid vaccine?

A
  • The Oxford team were able to show that engineering regions of human adenovirus into the Y25 strain improved the yield of viral particles and expression levels of recombinant protein (Covid S protein)
  • The final adenovirus strain was patented and named ChadOX1
78
Q

where has the ChAdOX1 vaccine be used in experiments?

A
  • MERS: Experimental demonstration in mice
  • Tuberculosis: Vaccine in development
  • Malaria: Trials underway
  • December 30th 2020 – ChAdOX1-Covid S protein was approved by the UK government for use in the Covid-19 Vaccination Programme

Immunology (8 decks)

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