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Molecular Immunology Y3 > Watson L11-13 > Flashcards

Watson L11-13 Flashcards

1
Q

What is a zoonotic infection?

A

Pathogen jumps hosts from animal to humans. Dangers are that we have little or no natural immunity to these novel pathogens.

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2
Q

What are examples of zoonotic pathogens?

A

HIV. Ebola. Covid-19

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3
Q

What are the characteristics of HIV?

A

1.5 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 and is now a pandemic. Causes destruction of economies and human capital with no really effective current vaccine. Treatment – not cure but includes Anti-retro-virals like AZT. Treatments consume the majority of household budget.

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4
Q

What are characteristics of Ebola?

A

Highly contagious with new strains being able to emerge at any time. Death rates can be 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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5
Q

What are characteristics of Covdi-19?

A

Worldwide infections – approximately 243 million. Approximately 5 million deaths. The virus is believed to have originated in bats.

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6
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. 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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7
Q

How did individuals play a role in vaccination origins?

A

Observed variolation in Turkey 1718 – had her son treated by “engrafting.” Edward Jenner – 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.

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8
Q

Who developed immunological theory?

A

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 artificially infect subjects – concepts still used today. Most famously developed a vaccine for rabies.

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9
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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10
Q

What is passive immunisation?

A

Includes the transfer of preformed antibodies to the circulation can be natural or artificial. Natural Passive Immunity occurs naturally by the transfer of maternal antibodies across the placenta to the developing foetus

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11
Q

What can artificial passive immunity be used for?

A
  • Individuals with agammaglobulinaemias – B cell defects – inborn or acquired. Treated with pooled normal human IgG
  • Exposure to a disease that could cause complications eg. immune compromised patient exposed to measles or other pathogen
  • When there is no time for active immunization to give protection ie. a pathogen with a short incubation time
  • Acute danger of infection
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12
Q

What are advantages of passive immunity?

A
  1. Use of pre-formed antibodies can quickly neutralise toxins and venoms. A conventional immune response may be too slow
  2. In the case of highly virulent pathogens pre-formed antibodies can be used to prevent or limit infection
  3. 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)
  4. In some cases antibodies from surviving patients can be used (a certain level of risk here)
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13
Q

What are drawbacks to passive immunity?

A
  1. Does not activate immunological memory
  2. No long term protection
  3. Possibility of reaction to anti-sera (if cross species)
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14
Q

What is active immunisation?

A

This is where the immune system is manipulated 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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15
Q

What are the types of vaccine used during active immunisation?

A
  1. Whole organism – either live attenuated or killed, inactivated pathogen
  2. Subunit – toxoid, antigenic extracts, recombinant proteins, conjugate vaccines
  3. Peptides
  4. DNA vaccines
  5. Engineered virus
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16
Q

What occurs in 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.

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17
Q

What occurs in inactivated whole organism vaccines?

A

The organism is rendered inactive and non-viable by heat, chemical or other treatments meaning it cannot replicate.

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18
Q

What are 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
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19
Q

What are disadvantages to live attenuated vaccines?

A
  • Immunocompromised patients (or other rare individuals) may become infected as a result of immunization.
  • Occasionally the attenuated organism can revert to a virulent form, in areas with poor sanitation this can lead to a serious outbreak – so Polio Salk is the preferred vaccine in undeveloped regions
  • Typically live organisms need to be refrigerated for stable storage, this can be an issue in remote areas of the world.
20
Q

What are advantages of whole inactivated vaccines?

A
  • No risk of infection
  • Storage less critical
  • Wide range of different antigenic components are present so a good immune response is possible
21
Q

What are disadvantages of whole inactivated 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 are required
  • Adjuvants can be used to increase the immune response by holding and releasing vaccine over time. Made of things that can stimulate immune response,=.
  • Patient compliance can be an issue
22
Q

What occurs in subunit vaccines?

A

Simply using an isolated component of a pathogen rather than the whole organism. Theoretically safer than handling live or inactivated pathogens with no risk of infection Purify molecular components as immunogenic agent.

23
Q

What are the three types of subunit vaccines?

A
  1. Inactivated exotoxins
  2. Capsular polysaccharides
  3. Recombinant microbial antigens
24
Q

What are toxoid subunit vaccines?

A

A number of important pathogens produce the symptoms of disease as a result of exotoxins. Diphtheria toxin inactivates mammalian elongation factor EF2 so it is an inhibitor of translation. Tetanus toxin is a neurotoxin causing uncontrolled contraction of voluntary muscles. A toxoid is heat treated or chemically modified to eliminate toxicity.

25
Q

What are capsular polysaccharide vaccines?

A

Highly polar, hydrophilic cell surface polymers consisting of oligosaccharide repeating units. These molecules are main antigens involved in protective immunity to encapsulated bacteria. May interfere with bacterial interactions with phagocytes by blocking opsonisation. Opsonisation is the coating of organisms by specific antibodies and complement which enables host phagocytes to ingest and destroy invading bacteria.

26
Q

What are recombinant antigens subunit vaccines?

A

Recombinant DNA technology has provided new ways of simply expressing and purifying subunits. Recombinant Proteins (since 1970s) - Cloning and expression of single gene in recombinant host. 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.

27
Q

What are conjugate subunit vaccines?

A

In 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.

28
Q

What is the aim with synthetic peptides as vaccines?

A

To produce a peptide that includes immune dominant B cell epitopes and can stimulate memory T cell development

29
Q

What are the difficulties with synthetic peptides as vaccines?

A
  • 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
30
Q

What are advantages of subunit vaccines?

A
  • Safety
  • Only portion of pathogen are used
  • No risk of infection
  • May be easier to store and preserve
31
Q

What are disadvantages with subunit vaccines?

A
  • Immune response is less powerful than to live attenuated vaccines
  • Repeat vaccinations needed and adjuvants
  • Have to choose subunits that elicit a response in the widest range of subjects.
32
Q

What are adjuvants?

A

Essentially any substance added to vaccine to stimulate the immune system. Includes whole killed organisms, toxoids, proteins as in conjugate vaccines or chemicals like aluminium salts and oil emulsions.

33
Q

What is the mechanism of adjuvants?

A

Can vary: Aluminium salts may extend the half-life of immunogen in the site of injection (depot effect) while chemicals can cause irritation and inflammation. Toxoids and killed organisms trigger immune system and send out danger signals.

34
Q

What is the aim of DNA vaccines?

A

To transiently express genes from pathogens in host cells. Generates immune response similar to natural infection. Leads to T and B cell memory responses.

35
Q

What are advantages of DNA vaccines?

A
  • Do not require complex storage and transportation
  • Delivery can be simple and adaptable to widespread vaccination programs – “DNA gun”
36
Q

What are 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
    o Veterinary – West Nile Virus
37
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. Stable up to 18 months at room temperature.

38
Q

What is the aim of recombinant vector vaccines?

A

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. Can be viral or bacterial.

39
Q

What are 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?)
40
Q

What are disadvantages of recombinant vector vaccines?

A
  • Can’t 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
41
Q

How does Covid enter the cell?

A

S - spike protein mediates cell entry via the ACE-2 receptor makes the virus “tropic” for tissues expressing significant levels of ACE-2. Causes it to affect the respiratory tract.

42
Q

What is the mechanism for Covid entry into a cell?

A

2019-nCoV 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. 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. 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. Conformational change triggered by ACE2 binding S2 adopts new conformation and draws virus to cell surface.

43
Q

What were the RNA Covid vaccines?

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) and 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.

44
Q

What was the Oxford vaccine strategy for Covid?

A

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.
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. Chimpanzee were used due to native conformation and 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.

45
Q

What is the genomic structure of adenoviruses?

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.

46
Q

How do we produce the adenovirus if it is replication 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. 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).

Molecular Immunology Y3 (3 decks)

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