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MICR 270 > Module 5 > Flashcards

Module 5 Flashcards

1
Q

ELISA (enzyme-linked immunosorbent assay)

A

broadly applicable technique that can be modified to detect and quantify substances such as peptides, proteins, antibodies, hormones, and other molecules
- based on antigen-antibody interaction so its very specific

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2
Q

flow cytometry

A

method of detecting and quantifying different cell types in a mixed cell suspension

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3
Q

monoclonal antibodies

A

production of monoclonal antibodies is a technique that was developed by George kholer and cesar Milstein in 1975
- antibodies produced by a single clone of a B-cell that are specific for a single epitope

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4
Q

how does the ELISA work -step 1

A

the bottom of the wells are coated with an antigen that is specifically recognized by antibody you wish to measure (primary antibody)

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5
Q

how does the ELISA work -step 2

A

wells are washed to remove any excess antigen not attached to bottom of well

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6
Q

how does the ELISA work -step 3

A

sample containing the antibody to be measured is added to well – the primary antibodies if present, will bind to the antigen attached to bottom of well

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7
Q

how does the ELISA work -step 4

A

wells are washed again

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8
Q

how does the ELISA work -step 5

A

an enzyme-conjugated secondary antibody is added to the well, this will bind to Fc portion of primary antibodies
- the secondary antibody recognizes antibodies from a particular animal (anti-human, etc)

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9
Q

how does the ELISA work -step 6

A

wells are washed again

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10
Q

how does the ELISA work -step 7

A

substrate of the enzyme attached to secondary antibody is added to well
- the reaction of substrate (chromogen) and enzyme produces a coloured product which can be measured by absorbance

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11
Q

enzyme-conjugated secondary antibody

A

a secondary antibody specifically binds to primary antibody

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12
Q

chromogen

A

substance that can be readily converted into a dye or other coloured compound

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13
Q

what does the ELISA measure?

A
  1. measures a coloured reaction product by absorbance with the help of a machine called a spectrophotometric plate reader
  2. data measured correlates with presence of an antibody or antigen
  3. information can be used to detect the presence of a viral disease
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14
Q

indirect ELISA

A

detects or quantifies antibody (levels of antibodies that are present)

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15
Q

example of the indirect ELISA

A

used to determine the presence of serum antibodies against HIV

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16
Q

detection

A

only confirms the presence or absence of a substance

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17
Q

quantification

A

evaluates the concentration
- Requires a standard curve

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18
Q

standard curve

A

measurement of absorbance of known concentrations of the substance

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19
Q

sample concentration

A

can be determined by comparing the measured absorbance of the sample against the absorbance of the standard curve

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20
Q

sandwich ELISA

A

detects or quantifies an antigen

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21
Q

how does the flow cytometry work - step 1

A
  1. narrow stream of cells in a single file is passed through a laser light source
  2. the way laser light is scattered is unique to each cell type
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22
Q

what does measuring FCS do?

A

allows for discrimination of cells by size

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23
Q

FCS intensity

A

proportional to diameter of the cell

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24
Q

SSC (sample stained cells)

A

provides information about internal complexity of a cell

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25
Q

other way flow cytometry can be used

A

used to determine the proportion of cells expressing a particular antigen

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26
Q

how can FC be used to determine the proportion of cells expressing a particular antigen?

A
  1. cells are labelled with a specific antibody
  2. the antibody is coupled with a fluorescent marker (or “stained”)
  3. this fluorescent marker can be excited by a light of a specific wavelength
  4. the fluorescent marker emits a light with a characteristic different wavelength
  5. only cells expressing the antibody in question will emit light of this specific wavelength
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27
Q

what does flow cytometry measure?

A

measures physical properties of a cell + used to determine complete blood counts (CBC)
- also used to detect specific antigens on or inside a cell
- measures size, shape, and granularity to identify distinct cell types in a mixed cell suspension

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28
Q

What can be readily determined due to each cell in a mixed suspension being assessed?

A
  1. total number of cells in the suspension
  2. number of cells of a particular type in the suspension
  3. overall composition of the suspension
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29
Q

Clinical Application of Flow Cytometry

A
  1. can be used to diagnose cancer in a variety of ways
  2. main diagnostic tests focus on detecting DNA aneuploidy, analyzing cell cycles and the immunophenotypical characterization
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30
Q

example of flow cytometry measure?

A

diagnosis of AIDS is made based upon the number of CD4+ T-cells found a patients serum (below 200 cells/mm2)
- FC used to identify and count these specific T-cells in a blood sample

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31
Q

how do monoclonal antibodies work?

A

produced in labs by hybridomas, immortal cells that produce unlimited quantities of one identical antibody

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32
Q

hybridomas

A

result of fusion between a plasma cell and a cancerous cell
(myeloma)
- share properties of both plasma cells and myeloma cells

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33
Q

myeloma cells

A

immortal growth = divides indefinitely

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34
Q

plasma cell

A

produce specific antibodies against on antigen

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35
Q

hybridoma cell

A

a perpetual source of antibodies against one antigen

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36
Q

what do monoclonal antibodies measure?

A

not a specific technique of measurement, rather is a tool useful in many applications

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37
Q

clinical applications

A
  1. immunotoxins and radiolabelled antibodies
  2. can be produced for defence against specific diseases and even cancer
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38
Q

immunotoxins

A

consists of a tumour-specific monoclonal antibody attached to a deadly toxin
- used to target and eliminate tumour cells and treat cancer

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39
Q

radiolabelled antibodies

A

monoclonal antibodies tagged with a radioactive isotope can be used to diagnose tumours earlier than other methods
- can bind to antigens on a tumour thereby allowing the precise location of a tumour within the body to be visualized

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40
Q

why are monoclonal antibodies better than polyclonal antibodies?

A

they are a homogenous population of antibodies with exquisite specifically for a single antigen whereas polyclonals could recognize multiple antigens

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41
Q

what are vaccines made up of?

A

fragments of the pathogen or the entire pathogen that is modified (killed or attenuated), allowing the IR to develop without counteracting the disease

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42
Q

what does vaccination allow?

A

IS the opportunity for “target practice”

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43
Q

vaccine

A

type of biological preparation which provides active artificial immunity to a particular disease-causing agent

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44
Q

what is the type of vaccine largely dependent on?

A

nature of disease-causing agent and how the IS recognizes and responds to infection

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45
Q

4 types of vaccine

A
  1. Live-attenuated vaccine
  2. Killed-inactivated vaccine
  3. Toxoid vaccine
  4. Subunit vaccine
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46
Q

live attentuated vaccine characteristics

A

contains a modified strain of the disease-causing agent which has lost its pathogenic ability, but retains its capacity to replicate within the host

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47
Q

advantages of live attentuated vaccine

A
  1. provides prolonged exposure to disease-causing agent
  2. is suitable to generate cell-mediated immunity
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48
Q

disadvantages to live attentuated vaccine

A
  1. potential to revert to a virulent form
  2. requires a specific storage and transport conditions (ex. Refrigeration)
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49
Q

examples of live attentuated vaccine

A
  1. smallpox vaccine
  2. oral poliovirus vaccine (sabin)
  3. measles vaccine
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50
Q

killed-inactivated vaccine characteristics

A
  1. contains a strain to the disease-causing agent that has been inactivated by heat, chemicals or radiation
  2. has the ability to generate IR, but is unable to replicate
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51
Q

advantages to killed-inactivated vaccine

A
  1. safer option as it cannot mutate back to virulent form
  2. easy to store and transport
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52
Q

disadvantages to killed-inactivated vaccine

A
  1. generally requires multiple booster doses to maintain immunity
  2. generally must be administered by injection
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53
Q

examples of killed-inactivated vaccine

A
  1. Rabies vaccine
  2. Flu (influenza) vaccine
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54
Q

booster doses

A

extra administration of a vaccine after a primary dose has been given

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55
Q

toxoid vaccine characteristics

A

contains an inactivated toxin which is a product from the pathogen that is causing the disease

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56
Q

advantages of the toxoid vaccine

A
  1. safe as it is not a living organism that can divide, spread and/or revert
  2. stable as they are less susceptible to changes in temperature, humidity and light
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57
Q

disadvantages of the toxoid vaccine

A

may require several doses and usually need an adjuvant

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58
Q

examples of the toxoid vaccine

A
  1. tetanus vaccine
  2. diphtheria vaccine
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59
Q

adjuvant

A

a substance that enhances the body’s IR to an antigen

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60
Q

subunit vaccine characteristics

A

contains only a small part or fragment of the disease-causing agent

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61
Q

advantages of the subunit vaccine

A

safest type of vaccine – can be used on everyone, including immunocompromised pregnant and elderly populations

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62
Q

disadvantages of the subunit vaccine

A

rarely successful at inducing long-lasting immunity, which means it will require multiple booster doses to maintain immunity and might even need to be conjugated to a carrier

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63
Q

example of the subunit vaccine

A

hepatitis B vaccine

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64
Q

carrier

A

a stronger antigen than the desired target antigen
- by covalently attaching a strong antigen to a poor antigen, the overall immunological response is strengthened and hopefully the immunological response to the poor antigen is also improved

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65
Q

what are mRNA vaccines used for?

A

known for their use against SARS-CoV-2

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66
Q

what is mRNA used for?

A

used in several formulations to fight the virus (ex. Bivalent vaccine, boosters, etc.)

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67
Q

what are formulations of mRNA vaccine being used to investigate?

A
  1. other infectious diseases (HIV, influenza)
  2. non-infectious clinical conditions (pancreatic cancer, heart tissue regeneration)
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68
Q

what does the principle of assay rely on?

A
  1. relies on use of mRNA to produce viral proteins and recruit immune cells to respond to antigenic target
  2. these proteins are then displayed on cell surface of an APC to induce B-cells (antibodes) and T-cell immunity
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69
Q

SARS-CoV-2

A

virus that caused COVID-19

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70
Q

mRNA vaccine for COVID-19

A

uses lab-made SARS-CoV-2 messenger RNA 9mRNA) to trigger an IR

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71
Q

RNA and DNA-based vaccines

A

involve making genetic material only they do not require the use of a whole virus

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72
Q

mechanism for mRNA virus steps

A
  1. vaccine production
  2. host cell
  3. APC
  4. IR
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73
Q

vaccine production

A
  1. mRNA is made in lab from a DNA template of the virus
  2. mRNA encodes an antigen of the virus
  3. for COVID-19 the mRNA encodes the spike proteins on surface of the virus
  4. mRNA is incorporated into a formulation that can administered as a vaccine
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74
Q

host cell

A

once inside the body, the mRNA entered the host cell and uses host cell machinery to produce the spike protein

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75
Q

APC

A
  1. newly formed spike proteins exits the cell and is recognized by an APC
  2. APC internalizes the spike protein and processes it into a peptide (or antigen)
  3. APC then displays the antigen on the surface of cell via MHC
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76
Q

immune response

A
  1. antigen is recognized by a T-helper cell which initiated an IR
  2. B-cells produce antibodies that stop the virus from infecting cells
  3. T-cells destroys cells infected with the virus
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77
Q

antivirals medication against COVID-19

A
  1. antiviral medication can treat COVID-19 once being infected
  2. does not prevent COVID-19 - only treats
  3. taken orally
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78
Q

2 main antiviral medications

A
  1. polymerase inhibitor
  2. protease inhibitor
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79
Q

polymerase

A

enzyme that plays a central role in viral replication and transcription

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80
Q

polymerase inhibitor used to treat COVID-10

A

Molnupiravir

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81
Q

polymerase inhibitor function

A

increases frequency of viral RNA mutations and impairs replication of virus

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82
Q

proteases

A
  1. cut proteins into smaller, more workable pieces
  2. often administered in combination
  3. since these drugs disrupt the assembly of the virus, they cant replicate and infect other cells
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83
Q

types of protease inhibitor

A
  1. Nirmatrelvir
  2. Ritonavir
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84
Q

Nirmatrelvir

A

stops protease from cutting viral proteins into functional pieces

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85
Q

Ritonavir

A

protects nirmatrelvir from destruction by the body and allows it to keep working

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86
Q

evolution of vaccines

A
  1. recognized by the British Medical Journal as one of the greatest medical advances in history
  2. Dr. Edward Jenner’s use of extracts prepared from cowpox lesions as a means of protecting his patients against smallpox infection
  3. jenner’s discovery of using vaccination for protection against a viral disease came nearly 100 years prior to the discovery of viruses by Dmitry Ivanovsky in 1982
87
Q

HPV

A

causes cervical cancer and genital warts
- in 2002 a clinical trial demonstrated that a virus like particle (VLP) vaccine could protect against infection by a type of HPV often associated with cervical cancer
- efficacy was 100%

88
Q

VLP

A

composed of the structural proteins of HPV, which can self-assemble into particles that resemble the natural virus both structurally and immunologically

89
Q

are VLP infectious

A

do not contain viral DNA

90
Q

3 HPV vaccines

A
  1. Cervarix
  2. Gardasil
  3. Gardasil 9 (protects against 9 types)
91
Q

ebola virus (EBOV) and marburg virus (MARV)

A

part of the filoviridae family of viruses that case hemorrhagic fever with high mortality rates in humans and nonhuman primates

92
Q

what do EBOV and MARV produce?

A

transmembrane glycoproteins (GPs) though to play a role in the virulence of these viruses

93
Q

mice with EBOV and MARV GPs

A

the mice became protected against infection from the live virus

94
Q

vaccine using GPs from EBOV

A

put GPs from EBOV into a live attenuated recombinant vesicular stomatitis virus (VSV) that expresses the transmembrane GPs of EBOV and MARV
- vaccine prevented spread of EBOV in 2018

95
Q

genital herpes

A
  1. caused by infection with herpes simplex virus (HSV) types 1 or 2
  2. infections are permanent, requiring lifelong management
  3. pose a serious health threat to newborns through vertical transfer
  4. cause significant emotional distress in infected individuals
  5. increase susceptibility to and spread of HIV infection
96
Q

genital herpes vaccine

A

subunit vaccine
- composed of a prominent structural protein of HSV-2 (type most associated with genital infections)

97
Q

genital herpes vaccine efficacy

A
  1. vaccine showed promise in early clinical trials
    - effiacy of >70% in women who were seronegative for noth HSV-1 and HSV-2 at beginning of trial
  2. larger trial involving 8323 seronegative women showed much lower efficacy (20%) and no protection from HSV-2
98
Q

what does failure of genital herpes vaccine cause?

A

considering developing a live attenuated vaccine

99
Q

vertical transfer

A

passage of a disease-causing agent from mother to baby during the period immediately before and after birth

100
Q

seronegative

A

giving a negative result for a test of blood serum for presence of host antibody response against a foreign particle/pathogen

101
Q

what 3 things does seronegative inform you of?

A
  1. IgG vs. IgM levels – indicate when host was exposed to pathogen
  2. If the host has even been exposed to a pathogen
  3. If the host has been vaccinated
102
Q

phases of vaccine development

A
  1. lab studies
  2. preclinical studies
  3. clinical trial phase I
  4. clinical trial phase II
  5. clinical trial phase II
  6. health canada approval
103
Q

step 1 - lab studies - vaccine development

A
  1. identify the infectious agent causing disease and select a strain (or subtype) relevant to the target population used to produce the vaccine
  2. largely depends on research from lab via assays
  3. involves developing and testing manufacturing process of vaccine according to good manufacturing practice standards
104
Q

step 2 - preclinical studies - vaccine development

A
  1. involve research carried out in animal models
    2 occurs before clinical trials begin
  2. researchers carry out challenge studies to demonstrate the immunogenicity of the vaccine in animal models
  3. carries out safety studies to evaluate possible toxicity of vaccine which would prevent its use on humans
105
Q

which stage evaluates possible toxicity?

A

preclinical studies

106
Q

what does clinical development involve for vaccines?

A

3 phases

107
Q

3 phases of clinical vaccine development?

A
  1. clinical trial phase I
  2. clinical trial phase II
  3. clinical trial phase III
108
Q

clinical trial phase I

A
  1. involve small trials (10-<100 people) to assess vaccine safety by evaluating local and systemic reactions after administration
  2. provides data on immunogenicity of vaccine and IR it evokes
109
Q

clinical trial phase II

A
  1. occurs at a bigger scale (50-500 people) to collect data on safety, side-effects and efficacy of vaccine
  2. evaluates dosage requirement and vaccination schedule (ex. need for booster) in target populations
110
Q

clinical trial phase III

A
  1. involve multiple geographic sites with many hundreds of subjects (300 - 30,000 people) to evaluate efficacy under natural disease conditions
  2. must complete safety assessment
  3. if successful in retaining safety and efficacy, requires license to market for human use
111
Q

heath canada

A

regulatory authority in Canada responsible for ensuring the quality, safety and efficacy of all biologic drugs, including vaccines for human use

112
Q

health canada and vaccine

A

vaccine candidates must be submitted to HC to be considered for approval with sufficient scientific and clinical evidence to show its safe, efficacious and of suitable quality
- vaccines cannot be used clinically without approval from HC

113
Q

why is vaccine regulation necessary?

A

they are usually given to very large numbers of healthy individuals

114
Q

vaccination in canada

A
  1. routine in canada
  2. responsible for a dramatic decline in vaccine-preventable disease incidence over the years
  3. free of charge for eligible individuals through respective provincial immunization program
  4. confer protection against a wide range of diseases
115
Q

vaccine trends in canada

A

number of cases has significantly dropped for multiple diseases when vaccine is induced

116
Q

challenges with the vaccine development

A
  1. cost
  2. the cold chain
  3. continuous monitoring
  4. the gold standard
117
Q

cost of vaccine development

A

high cost of development of vaccines sometime leads to premature abandonment of clinical research, especially if the disease threat is restricted to developing countries

118
Q

solving challenge of cost of vaccine development

A

reducing cost of vaccine is one measure of ensuring that a larger population can afford the vaccine and that the vaccine can be used by developing countries

119
Q

the cold chain and vaccine development

A
  1. live-attenuated vaccine (most effective for long-term immunological memory) need to be stored and transported in specific conditions (refrigeration
  2. if cold chain is broken, the vaccine risks losing potency or becoming unusable
120
Q

solving the challenge of the cold chain and vaccine development

A

a vaccine that doesn’t require refrigeration reduces cost associated with storage and distribution and ensures it can be used in developing countries where refrigeration often exists

121
Q

continuous monitoring of vaccine development

A
  1. if disease-causing agents evolve by changing or losing their major antigenic determinants the vaccine could lose its efficacy
  2. if the vaccine is based on a variable antigen, the genetic variation of the pathogen must be continuously monitored
122
Q

example of continuous monitoring of vaccine development

A

high mutation rate of influenza virus means its antigenic determinants can change every year, thus the influenza vaccine must change in response

123
Q

antigenic determinants

A

antigen molecule which can be recognized and bound by an antibody

124
Q

the gold standard of vaccine development

A
  1. even if a vaccine is approved it doesn’t mean the work is done
  2. new strategies are developed to create better vaccines by using recombinant vector or by improving vaccine adjuvant
  3. when a new version of an existing vaccine is developed, it must be as good or better than the existing version = gold standard conundrum
125
Q

vaccine development challenges of the influenza virus

A
  1. flu vaccine to combat the influenza virus
  2. structural nature of the virus impacts production of a one-for-all flu vaccine
126
Q

structural components of the influenza virus

A
  1. neuraminidase antigen (NA)
  2. hemagglutinin antigen (HA)
127
Q

Neuraminidase Antigen (NA)

A

surface protein that removes sialic acid from cell surfaces and enables new viral copies to infect and spread to other cells

128
Q

how many NA subtypes is there?

A

11 NA subtypes, each with sequence variabilities in their receptor

129
Q

hemagglutinin antigen (HA)

A
  1. surface protein that recognizes and bind sialic acid on cell surface of glycoproteins
  2. HA-cell surface interactions lead to endocytosis of the virus and the Has are activated to fuse the endosome and viral membrane
130
Q

how many hemagglutinin antigen subtypes are there?

A

18 HA subtypes, each with sequence variabilities in their receptor binding sites

131
Q

how many potential strains of influenza virus is there ?

A

18x11 = 198 potential strains of influenza virus

132
Q

what does having 198 strains of influenza mean?

A

explains why we can be vaccinated against the flu virus one year, but still get sick the next

133
Q

herd immunity

A

form of indirect protection from an infectious disease that occurs when a large proportion of the population is immune to an infectious agent

134
Q

what type of population is herd immunity for?

A

provides a measure of protection for individuals who are not immunized, as it slows or completely stops spread of disease
- the greater proportion of individuals within a community who are immunized, the smaller the probability those who aren’t immunized will come in contact with the infectious agent

135
Q

who is herd immunity important for?

A

immunocompromised individuals who cannot be vaccinated

136
Q

how is herd immunity measured?

A

by calculating the basic reproduction number, R nought (R0)

137
Q

R0 (R nought)

A

the average number of secondary cases in a totally susceptible population

138
Q

function of R0

A
  1. determines the herd immunity threshold and therefore the immunisation coverage required to achieve elimination of an infectious disease
  2. as R0 increases, higher immunisation coverage is requires to achieve herd immunity
139
Q

what is herd immunity important for?

A

fighting measles

140
Q

prevalence of cancer

A

1 in 2 Canadians will develop cancer in their lifetime

141
Q

cancer

A

an error in either cell growth or cell death, which can result in out-of-control growth of cells
(body has mechanisms in place to control the balance between these two things)

142
Q

cancer cells vs normal cells

A
  1. do not need specific growth factors to divide, normal cells do
  2. don’t respond to signals that cause normal cells to stop dividing
143
Q

cancer cells

A

self cells that have been altered to escape the normal growth-regulating mechanisms

144
Q

what causes the changes of normal cells into cancer cells?

A

result of alterations in DNA, which induces cell transformation

145
Q

cell transformation

A

the change that a normal cell undergoes as it becomes malignant (cancerous)

146
Q

what is cancer transformation a result of?

A

carcinogenic chemicals or radiation

147
Q

tumour

A

an abnormal mass of tissue

148
Q

what causes a tumour?

A

cancer cells continue to divide and grow, ultimately forming a tumour

149
Q

immunotherapies

A

either based on secreted or cellular components of the IS

150
Q

purpose of immunotherapies

A

primarily aimed at enhancing host anti-tumour immune responses

151
Q

two types of tumours

A
  1. benign
  2. malignant
152
Q

benign tumour

A

not cancerous; unable to grow indefinitely or invade surrounding tissues

153
Q

malignant tumour

A

cancerous and has ability to metastasize
- continue to grow and become progressively invasive

154
Q

metastasis

A

colonization by tumour cells of sites different from their primary site of origin
- small clustered of cancerous cells will break off from the tumour and invade the surrounding blood or lymphatic vessels, travelling to different areas of the body where they can proliferate

155
Q

the resilience of cancer cells

A

cancer cells show resilience when in environments that a normal cell might not survive

156
Q

resilience

A

a cells ability to cope with environmental disturbances, and possibly even adapt for future exposure

157
Q

stress

A

an umbrella term for the harsh environmental exposures on tumour cells

158
Q

HeLa cell line origination

A
  1. Henrietta lacks, donor of cells known as the HeLa cell line
  2. Henrietta was diagnosed with carcinoma
  3. sampled her ovarian cells without consent, and these cells were the first line of human cell culture to ever survive outside of the human body – immortality
159
Q

breakthroughs involving the HeLa cells

A
  1. recombinant protein production
  2. HPV vaccine
  3. understanding virology
  4. toxicity testing
  5. monoclonal antibody (mAB) production
  6. polio vaccine
  7. genome sequencing
  8. telomerase activity
160
Q

recombinant protein production

A

although bacterial cells can be utilized for protein production, they lack the required mechanics to produce more complex proteins
- HeLa cells line allowed researchers to overcome this challenge

161
Q

HPV vaccine

A

researchers found that HeLa cells were infected with HPV-18 virus, which led to HPV vaccines

162
Q

understanding virology

A

experimental viral infection on HeLa cells allowed researchers to characterize how specific viruses can evade the IS, such as CD4 T-cell receptor utilization by HIV

163
Q

toxicity testing

A

HeLa cells are now used to test cytotoxicity of drugs because hepatocytes were too unstable for a sustained use

164
Q

monoclonal antibody (mAB) production

A

monoclonal antibodies, which can be produces using hybridoma crosses of HeLa and other animal cells, have many applications such as medical diagnoses and cancer therapy

165
Q

polio vaccine

A

HeLa cells were the only human cells that could be used to test the polio vaccine

166
Q

genome sequencing

A

HeLa cells fused with mouse cells because the first hybrid cells, the fusion of two cell types
- aided the emergence of the human genome project

167
Q

telomerase activity

A

Gregg morin isolated telomerase from HeLa cells, which were previously found in animal embryos

168
Q

what hypothesis did telomerase activity support?

A

supported hypothesis that both embryos and cancer cells utilize telomerase to rapidly divide, giving researchers insight on the importance of telomerase in human embryology

169
Q

the cancer-immunity cycle

A

series of events that must occur in order for an effective IR to be initiated against cancer cells

170
Q

what does the cancer-immunity cycle decribe?

A

how the IS balances the recognition of an defense against, non-self molecules and prevention of autoimmunity

171
Q

step 1 of the cancer-immunity cycle

A

release of cancer cell antigens (cancer cell death)
- antigens are released by mutated cancer cells, indicating that they are not healthy cells
- IS can recognize these antigens

172
Q

step 2 of the cancer-immunity cycle

A

cancer antigen presentation (dendritic cells/APCs)
- cells of IS capture the released antigens and travel to lymph nodes where they find T-cells

173
Q

step 3 of the cancer-immunity cycle

A

priming and activation (APCs and T-cells)
- T-cells are activated by antigens and IR against the cancer cells is initiated

174
Q

step 4 of the cancer-immunity cycle

A

trafficking of T-cells to tumours (CTLs)
- the activated T-cells move through the blood vessel to site of tumour

175
Q

step 5 of the cancer-immunity cycle

A

infiltrations of T-cells into tumours (CTLs, endothelial cells)
- once the T-cells reach the cancerous cells, they invade the tumour and attack it

176
Q

step 6 of the cancer-immunity cycle

A

recognition of cancer cells by T-cells (CTLs, cancer cells)
- T-cells recognize cancer cells because of the antigens they had previously released

177
Q

step 7 of the cancer-immunity cycle

A

killing of cancer cells (immune and cancer cells)
- T-cells initiate a pathway that results in cancer cell death

178
Q

theory of tumour immunosurveillance

A

states that tumour cells are identified and kept under control by the IS of healthy individuals

179
Q

tumour and cancer cell progression

A
  1. cancer cells sometimes evade the recognition by the IS, or magnitude of the anti-tumour IR is not sufficient to kill all of the cancer cells
  2. often the immune environment around the cancer cells can promote tumour progression
180
Q

immunoediting

A

dynamic process which describes the connection between the tumour cells and the IS in context of immunosurveillance and tumour progression

181
Q

3 phases the cancer immunoediting process is constituted by?

A
  1. elimination
  2. equilibrium
  3. escape
182
Q

phase 1 of cancer immunoediting

A

elimination
- when a tumour cell arises in a tissue, the IS can quickly act to remove it
- a variety of immune cells, including NK cells, cytotoxic cells and helper T-cells can recognize the altered cell and work to eliminate it

183
Q

phase 2 of cancer immunoediting

A

equilibrium
- if the tumour cells are not eliminated, they can enter a state of equilibrium wher the cell proliferation is matched by cell killing by the IS
- equilibrium phase can last for a short time or many years

184
Q

phase 3 of cancer immunoediting

A

escape
- tumour cells are no longer recognized by the IS and so avoid elimination
- these cells are able to grow uncontrolled and eventually proliferate to form a tumour

185
Q

what do the 3 phases of cancer immunoediting allow?

A

allow cancer cells to overcome the IR, proliferate and form tumours

186
Q

two mechanisms tumour cells use to avoid detection by the immune system

A
  1. reduced MHC expression
  2. poor co-stimulatory molecules
187
Q

reduced MHC expression

A
  1. tumour cells display low levels of MHC class I molecules on their cell surface
  2. as cytotoxic T lymphocytes (CTLs) recognize antigens in context of MHC class I molecules, an absence of these molecules will inhibit recognition of tumour cells
188
Q

poor co-stimulatory molecules

A
  1. T-cells requires both expression of MHC and co-stimulatory molecules to become activated
  2. tumour cells lack these co-stimulatory molecules, which contribute to poor immunogenicity
  3. T-cells will only be partially activated
189
Q

new cancer therapies

A

should seek to improve the recognition of abnormal/potentially cancerous cells or strengthen the IR to abnormal/potentially cancerous cells

190
Q

cancer immunotherapy

A
  1. immune cells don’t see the cancer cells as foreign and leaves them alone
  2. new drugs affect interaction between IS and cancer cells – allows IS to see what the cancer cell is
  3. focusing more on flagging cancer cell for immune system to attack not giving a drug to attack
191
Q

cancer drugs

A

drugs don’t activate ones immune system to attack cancer cells

192
Q

4 reasons immunotherapy has the potential to be highly effective to treat cancer?

A
  1. able to attack cancerous cells throughout all organs in the body
  2. allows IS to specifically target and eliminate cells without damaging healthy cells, resulting in fewer side effects, than traditional cancer treatments (traditional and chemotherapy)
  3. takes advantage of immunological memory, allowing for possibility of long-term protection
  4. can be applied to almost all types of cancers
193
Q

how would using immunotherapy as a cancer treatment affect the cancer-immunity cycle?

A

immunotherapy can be used to enhance the body’s immune system in steps 2 and 7 of the cancer-immunity cycle
- presentation and destruction of antigens on cancerous cells

194
Q

most effect lymphocyte population in killing cancer cells

A

T-cells
- B-cell lymphocytes are also important

195
Q

B-cell lymphocytes

A

tumour infiltrating lymphocytes (TILs)

196
Q

what parts of TILs are suggested as a prognostic biomarker in some cancers?

A

type, density and location of TILs have been suggested as a prognostic biomarker in some cancers

197
Q

TILs as prognostic biomarkers

A

these TILs leave the bloodstream and migrate to infiltrate the tumour under influence of various chemotactic gradients of specific types of chemokines

198
Q

what can TILs be a mix of?

A

T- and B-cells

199
Q

number of TILs

A

not always reflective of their activity and prognostic significance

200
Q

dynamic phenotypic markers expressed on TILs

A

some reflect their activation status and therefore must accompany any interpretations on their roles as biomarkers for diagnosis, such as in the case of breast cancer

201
Q

prognostic biomarker

A

biological characteristics that are objectively measured and evaluated to predict the course of a disease or a response to a therapeutic intervention among patients with the same characteristic

202
Q

biomarkers

A

a measurable substance in an organism, the presence of which is indicative of some phenomenon such as disease, infection or environmental exposure

203
Q

T-cell inflamed (“Hot”) tumours

A

show higher immune activity compared to cold tumours

203
Q

solid tumours

A

immunologically classified as either T-cell inflamed (“hot”) or T-cell non-inflamed (“cold”) tumours

204
Q

characteristics of the hot tumours

A
  1. high numbers of CD8+ TILs
  2. high levels of interferon (IFN) genes
  3. usually respond well to treatment (chemotherapy and immunotherapy)
205
Q

T-cell non-inflamed (“Cold”) tumours

A

show lower immune activity compared to hot tumours

206
Q

characteristics of the cold tumours

A
  1. low numbers of CD8+ TILs
  2. low levels of interferon (IFN) genes
  3. usually inferior response to treatment (chemotherapy and immunotherapy)
207
Q

treatment of hot and cold treatments

A
  1. one could convert cold tumours to hot by stimulating the tumour interferon activity
  2. knowledge has led to the exploitation of anti-tumour immunity towards development of newer treatments
208
Q

a new immunotherapy tool

A

the immunoscore

209
Q

an immunoscore

A

measures the density/numbers of T-cells in the center (CT) and at the periphery (IM) of the tumour by immunochemistry

210
Q

what is the purpose of an immunoscore?

A

helps stratify patients as having high risk or low risk cancers, and aid in developing treatment plans

211
Q

workflow for determining an immunoscore

A
  1. separating tumour in central (CT) and peripheral (IM) regions
  2. staining for T-cells and conducting digital pathology
  3. assigning a score to tumour to relate it with an associated diagnosis or risk attribution
212
Q

approaches used to unleash anti-tumour immunity

A
  1. target immune inhibitory pathways in tumour microenvironment
  2. promote immune activation in tumour microenvironment

MICR 270 (5 decks)

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