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BIOL321 Clinical Immunology > Lecture 7: Infectious Diseases and Vaccines > Flashcards

Lecture 7: Infectious Diseases and Vaccines Flashcards

1
Q

Around what percentage of all mortality globally is due to communicable disease?

A

around 25%

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2
Q

Which virus can cause cervical cancer?

A

Human papillomavirus

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3
Q

Why can many communicable diseases that used to be fatal now be treated or prevented?

A

Due to improvements in:
- Sanitation (clean water, safe sewage disposal)
- Vaccination
- Treatments (antibiotics, anti-virals, anti-fungals, anti-protozoals)

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4
Q

What challenges to combatting infectious disease still remain?

A
  • large variation in healthcare and sanitation globally
  • emerging resistance to current to current treatments (E.g. MRSA)
  • emerging diseases due to new forms of pathogens
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5
Q

Define pathogen

A

a microbe or parasite that can cause disease

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6
Q

Define pathogenicity

A

the ability of a pathogen to cause disease in a host. It is a qualitative trait in that an organism is either pathogenic to a particular host or not, but not all hosts are the same

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7
Q

Define virulence

A

used to quantify the effect of a pathogen on its host. It is a quantitative trait in that a highly virulent organism will cause lot of damage to its host

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8
Q

Which components of the innate and adaptive immune system are involved in a response against a viral infection?

A

Innate:
Interferons, Macrophages, NK cells

Adaptive:
CTLs

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9
Q

Which components of the innate and adaptive immune system are involved in a response against an extracellular bacterial infection?

A

Innate:
Complement

Adaptive:
B-cells, antibodies

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10
Q

Which components of the innate and adaptive immune system are involved in a response against an intracellular bacterial infection?

A

Innate:
macrophages, NK cells

Adaptive:
CTLs

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11
Q

Which components of the innate and adaptive immune system are involved in a response against extracellular stages of a protozoa infection?

A

Innate:
Complement

Adaptive:
B-cells, Antibodies

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12
Q

Which components of the innate and adaptive immune system are involved in a response against intracellular stages of a protozoa infection?

A

Innate:
macrophages, NK cells

Adaptive:
CTLs

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13
Q

Which components of the innate and adaptive immune system are involved in a response against a helminth infection?

A

Innate:
Mast cells, eosinophils

Adaptive:
B-cells, IgE antibodies (important in cross-linking mast cells to degranulate)

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14
Q

Which components of the innate immune system are involved in a response against a fungal infection?

A

Innate:
Complement, macrophages

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15
Q

Describe a virus

A

They are all obligate intracellular pathogens
- consist of RNA or DNA genome
- surrounded by a protein coat and sometimes a membrane envelope as well

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16
Q

How does the immune system detect and respond to a viral infection? list the cells involved in this response?

A

Detection: DNA and/or RNA from viral genomes or replication intermediates are detected as PAMPS by intracellular PRRs.

Responses:
- Type 1 interferons (INF-α and -β) are produced by the infected cell or APC that have taken up virus by phagocytosis
–> these signal in an autocrine and paracrine manner to establish an anti-viral state in the infected cell and neighbouring cells (increase antigen presentation by upregulating MHCI and activating DCs and macrophages to increase chance of activating adaptive immune response involving CTLs, also induce Mx5, PKR and 2’-5’ linked adenosine oligomers gene to induce resistance to viral replication)
- activation of NK cells to kills virally infected cells
- induce chemokines to recruit lymphocytes to activate adaptive immune response and CTLs

Cells involved:
NK cells, macrophages, CTLs (all kills virally infected cells)

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17
Q

Describe the changes to a cell in response to INF-α and -β induction of an anti-viral state

A
  • induce resistance to viral replication by inducing Mx proteins, 2’-5’ linked adenosine oligomers, and kinase PKR
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18
Q

Where are antibiotic resistance genes often located in bacteria and what is the consequence of this?

A

Often located on plasmids

Since plasmids can be shared/transferred between bacteria, theses antibiotic resistance genes can be passed through a population

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19
Q

Give two examples of bacteria that have acquired antibiotic resistance

A
  1. Staphylococcus aureus (extracellular) - resistance to MRSA (on plasmid)
  2. Mycobacterium tuberculosis (intracellular pathogen in macrophages) - multidrug-resistant TB (MDR-TB) can occur
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20
Q

Describe the antibody-mediated mechanisms against extracellular bacteria

A
  1. Antibodies can bind to and neutralise toxins
  2. Complement activation and lysis
  3. Antibodies and C3b opsonise bacteria for phagocytosis
  4. C3a and C5a anaphylatoxins stimulate mast cell degranulation, and the released mediators cause vasodilation (more movement of cells into tissue by extravasation) and attract neutrophils and macrophages
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21
Q

What are parasites?

A

Eukaryotic pathogens (excluding fungi) and include:
- protozoa = single celled eukaryotes (Plasmodium - malaria, Trypanosoma brucei - sleeping sickness)
- Helminth = multicellular worms (Schistosoma - swimmer’s itch, Ascaris, Tapeworm)

22
Q

Due to the various lifecycle stages, species, and strains, what does this mean for the immune response (and vaccine development)?

A

immune response needs to be specific to the species, lifecycle stage and strain
- the antibodies generated against one stage or strain are not effective against others

23
Q

What type of immune response is raised against helminths?

A

Th2 response with IgE antibodies and activation of granulocytes (mast cells and eosinophils) - release histamine and leukotreines from granulocytes, which causes smooth muscle contraction and mucus production (flush out pathogen)

24
Q

True or false: fungal infections can often be controlled by the innate immune system only?

A

True (in immunocompetent individuals)

25
Q

Describe the immune response to fungal infections in immunocompetent individuals

A
  • macrophages detect fungal cell wall components (chitin, beta-glucans) using TLRs and Dectin-1 receptors
  • antibodies and complement enhance phagocytosis of fungal cells by neutrophils and macrophages
26
Q

When can fungal infections cause problems?

A

Immunocompromised individuals (E.g. HIV)
or
if normal microbiota are disrupted (E.g. following antibiotics)

27
Q

What are 4 immune evasion mechanisms evolved by pathogens to evade or block the hosts immune responses to establish an infection?

A
  1. living intracellularly (avoid antibodies and complement)
  2. Virulence factors that block immune signals (e.g. by sequestering cytokines with decoy receptors or by blocking immune signalling cascades)
  3. Subversion of immune responses (E.g. mimicking immune molecules that regulate immune response so that they ultimately benefit the pathogen)
  4. Antigenic variation (escape adaptive immunity in subsequent infections)
28
Q

Describe the Influenza A virus?

A

Influenza A Virus (IAV) is a -ssRNA virus with a segmented genome which encodes 11 proteins (including the highly variable haemagglutinin (H) an neuraminidase (N) proteins as well as the non-structural protein NS1)

29
Q

What is the function of NS1 non-structural protein in an IAV infection?

A

It is a multifunctional immune evasion protein:
- binds viral RNA to prevent recognition by PRRs
- it inhibits the RNA receptor RIG-1 (an cytosolic PRR)
- inhibits gene expression by the cell (host cell shut-off)
- promotes transcription of viral genes

30
Q

What is antigenic drift?

A

point mutations due to error-prone RNA dependent RNA polymerase gradually result in a protein no longer recognised by the original antibodies

31
Q

What is antigenic shift?

A

When an individual becomes infected with multiple different strains of the influenza virus, due to the segmented genome, new viruses with different combinations of haemagglutinin and neuraminidase proteins

32
Q

What are two ways in which the IAV can evade the adaptive immune system?

A

Antigenic drift (point mutations due to error prone RNA dependent RNA polymerase)

Antigenic shift (infection with multiple strains causes complete change in surface HA and N due to reassortment of viral genome)

33
Q

What is the first example of a live vaccine?

A

using the less virulent cowpox to vaccinate against the more virulent smallpox by Edward Jenner

34
Q

Define immunisation

A

process of generating long-lived immune protection against a pathogen, either by recovering from the disease (natural immunity) or through vaccination (artificial immunity)

35
Q

Define vaccination

A

the intentional exposure to forms of pathogens that do not cause disease in order to elicit an effective immune response that results in the formation of memory B and T cells that recognise antigens on a pathogen

36
Q

Define herd immunity

A

if many individuals in a population are immune, there will less disease transmission to unvaccinated and vulnerable people

37
Q

What is the only disease that has ever been eradicated (by vaccination)?

A

Smallpox

38
Q

What response occurs upon first exposure via a vaccine?

A

development of an adaptive immune response, formation of effector cells and memory cells and removal of infectious agent

39
Q

What responses occurs upon subsequent exposures to the infectious agent following vaccination?

A

Protective immune responses - recognition of pathogen by preformed antibody and effector T-cells (E.g. long-lived plasma cells residing in tissue)

Immunological memory responses - recognition of pathogen by memory cells, rapid expansion and differentiation into effector cells

40
Q

What components of vaccines are required to stimulate an effective adaptive immune response involving immune memory?

A
  1. antigens (usually proteins) from the pathogen that can be recognised by T-cells, B-cells and antibodies
  2. adjuvants (E.g. isolated PAMPs, alum salts, pathogen components) - molecules that help to activate the innate immune system (need to turn on the innate immune system to fully activate the adaptive immune response)
41
Q

True or false: all vaccines require the addition of adjuvants?

A

False: live or inactivated vaccines already contain PAMPs but subunit vaccines need additional adjuvants

42
Q

Briefly explain how vaccination has changed over time

A
  • started with live virus vaccination (variolation and the cowpox vaccine)
  • development of live vaccines attenuated in animals (passaged through animals so over time infectious agent no longer as pathogenic)
  • development of killed/inactivated pathogen vaccines (antigen and PAMPs still present)
  • development of live vaccines attenuated in cell culture (passaged through many cell lines so over time infectious agent no longer as pathogenic and reduces virulence)
  • development of subunit vaccines:
    –> polysaccharide (E.g. typhoid)
    –> inactivated toxins (E.g. Pertussis toxin used as an antigen for subunit vaccine to stop whooping cough)
43
Q

Describe the traditional development of a vaccine

A

Pre-clinical development in laboratory (design, in vivo (animals) toxicology studies)

Clinical trials:
Phase I = <100 people for safety and immunogenicity data
Phase II = several hundred people to establish dose and vaccine regimen (frequency of booster doses to maintain the antibody concentration)
Phase III = several thousand people to test safety and efficacy

Regulatory review and approval (FDA, EMA)

Large scale production and distribution

–> whole process can take around 15 years

44
Q

How was the development of a SARS-CoV-2 vaccination sped up?

A
  • already had some prior knowledge from previous infections from SARS-CoV-1 in birds and from MERS coronavirus - already knew that the spike protein was the target for vaccine development
  • clinical trials phases were run concurrently
  • investment - started producing the vaccine in large quantities before knowing if it was going to be useful, functional or safe - vaccine was ready to go after clinical trials passed

–> whole process took around 1.5 years

45
Q

What are the different types of COVID-19 vaccines?

A

Chemically inactivated whole virus vaccines = CoronaVac

Viral vector vaccines = Oxford/Astra Zeneca uses modified chimpanzee adenovirus vector expressing S protein

Subunit vaccines = Novovax uses recombinant S protein with adjuvant

mRNA vaccines = Moderna, Pfizer vaccines uses a LNP to deliver mRNA encoding the spike protein

46
Q

Describe how viral vectors are used in vaccines

A

the virus is genetically edited to include an open reading frame for the expression of the antigen from another pathogen (the antigen is normally a surface protein of the pathogen and should cause the production of neutralising antibodies)
The recombinant viruses can be grown in cell cultures

47
Q

Why does the choice of viral vector matter when creating a vaccine?

A

the viral vector needs to be safe (not cause pathology in humans) and needs to have the capacity to be gene edited (E.g. large DNA viruses)

48
Q

Describe the Oxford/Astra Zeneca COVID-19 vaccine

A

uses chimpanzee adenovirus lacking replication factors but encoding the S protein from SARS-CoV-2 as an antigen

49
Q

What is the difference between the Moderna and Pfizer COVID-19 vaccines?

A

Moderna = uses mRNA for full length S protein with stabilising mutations

Pfizer = uses mRNA for the trimeric receptor-binding domain of the S protein

50
Q

Describe how mRNA vaccines are developed?

A
  • mRNA is synthesised chemically with a 5’ cap analogue and using modified bases (pseudouridine) to prevent recognition by PRR RIG-1
  • the mRNA encodes the antigen based on the receptor binding domain of the SARS-CoV-2 spike protein
  • mutations are introduced to stabilise the trimeric RBD structure to make it most like the native protein on the virus and ensure the production of effective antibodies
  • the mRNA is encapsulated in a lipid nanoparticle (LNP) which optimises uptake and stimulation of innate immunity
51
Q

What are 4 challenges to vaccine design?

A
  1. changing surface antigens (antigenic drift (E.g. HIV and IAV) and antigenic shift)
  2. Multiple pathogen strains in circulation (E.g. malaria)
  3. Multiple life cycle stages (E.g. helminths)
  4. Emerging diseases (E.g. due to new pathogens in host - zoonoses)

BIOL321 Clinical Immunology (10 decks)

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