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3s2: Infection and Immunity > Week 12 > Flashcards

Week 12 Flashcards

1
Q

What is active immuntiy?

A

Long-term immunity that is generated from exposure to immunogen (e.g. infection or via vaccination) that results in the induction of an immune response

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1
Q

What is an immunogen?

A

Molecule that induces a humoral or cellular immune response

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2
Q

What is vaccination?

A

The word “vaccine” was initially derived from the vaccinia virus (member of poxvirus family), which was used to generate immunity against smallpox.
Vaccines are formulations that aim to induce active immunisation against a particular infectious agent

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3
Q

What are examples that demonstrate why vaccination are important with examples from England?

A

Diphtheria - Around 50-60,000 cases a tear then vaccine introduced 1940 caes by 1950 where 0
Polio - Pre-1945 were 1000 but after spiked to around 4000 1956 vaccine introduced 0 cases by 1962

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4
Q

How many lives can a vaccine save?

A

~4 million deaths prevented by childhood vaccination every year
By 2030, it is estimated that over 50 million deaths could be prevented through vaccination programs between 2021-2030
“COVID-19 vaccinations have saved more than 1.4 million lives in the WHO European Region

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5
Q

What are examples of vaccine preventable diseases?

A

Cholera
COVID-19
Tetanus
Meningococcal disease
MMR

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6
Q

What is an overview of eradicating a disease?

A

Prior to 1980, outbreaks of smallpox were common across the globe approx. 300 million deaths in 20th century
Caused by infection with variola virus
Mortality rate as high as 30%
Vaccination was key to eradicate- Edward Jenner
WHO ‘Smallpox Eradication Programme’ in 1966-1980

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7
Q

What is precursor of vaccination and its UK history?

A

16th Century- Variolation used to inoculate against smallpox
Introduction of material from smallpox lesions into breaks in the skin of uninfected people- caused a mild, but not fatal, case of smallpox to provide future protection
1721- Lady Mary Montagu campaigns for the use of variolation in England

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8
Q

What is an overview of Edward Jenner’s work?

A

Inspired by the practice of variolation, Jenner observed that milkmaids and people who were previously infected with cowpox did not contract smallpox.
This is the origin of the word vaccine- “vacca” means cow in Latin (for cowpox)

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9
Q

What is an overview of 1870’s- 1880’s Louis Pasteur’s work on vaccines?

A

Experiments conducted on chicken cholera (Pasteurella multocida)- coining of the term “attenuation”
In 1885, Emile Roux and Pasteur tested their rabies vaccine on 9-year old Joseph Meister who had been bitten by a rabid dog. The vaccine contained attenuated rabies virus (achieved via serial passage in rabbits). Meister was inoculated 13 times
over 11 days- he survived!

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10
Q

What are key vaccine developments over time?

A

1921- BCG (Bacille Calmette-Guérin) vaccine for tuberculosis trialed in human
1924- Tetanus vaccine- inactivated tetanus toxin (toxoid)
1945- Influenza vaccine
1955- Polio vaccine

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11
Q

What is herd immunity?

A

Aims to disrupt the chains of transmission
So if there is a fall in vaccination rates, there is less herd immunity and outbreaks can occur!

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12
Q

What is an overview of the pre adaptive immunity response to vaccination?

A
  1. Protein antigen injected into muscle
  2. Antigen is taken up by dendritic cells
  3. Peptide fragments of antigen are presented by MHC on dendritic cells
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13
Q

What is an overview of the adaptive immunity response to vaccination?

A
  1. Interaction between TCR of T cell and MHC/antigen activates T cells, which in turn drive B cell development
  2. B cells proliferate and produce antibodiesdifferentiate into memory B cell or plasma cells
  3. CD8+ memory T cells proliferate rapidly upon another infection, and CD8+ effector T cells assist in clearing of infected cells
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14
Q

What are the 3 outcomes of vaccination?

A

Decrease in antibodies below protection level this can be split in two for long incubation pathogens such as hepatitis B the threshold can be achieved. Howeever, for short incubation patheogens such as Heamophilus influenzae type B, threshold isnt reached in time

Antibodies hit and stay above threshold for protection such with yelloe fever vaccination

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15
Q

What are side effects of vaccination?

A

Side effects of vaccination (e.g. localised swelling,
pain, redness)
Depends on reactogenicity of vaccine – e.g. local
inflammatory response at site of injection
Generally lower reactogenicity for oral vaccines
Higher reactogenicity typically in live and whole cell vaccines vs. subunit vaccines

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16
Q

What is in a vaccine?

A

Water - main ingredient
Preservatieves - eg Sorbitol - found in larger quanities in fruit
Residual traces of manufacuture - Formaldehyde, naturally found in human body, usually ppm or ppb
Adjuvants - Aluminium, naturally found in drinking water at higher levels
Acitve ingredient - Small amount of what you are protecting from

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17
Q

What are types of vaccines in use?

A

Live attenuated
Killed whole organism
Toxoids
Subunit
Nucleic acid
Viral vector

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18
Q

What is an overview of live attenuated vaccines?

A

Contain live pathogens that have been weakened (or attenuated) so that they still induce an immune response but do not cause disease
The smallpox vaccine in 1798 was the fist example of a live
attenuated vaccine
Examples: measles, mumps and rubella (MMR) vaccine, varicella zoster, yellow fever, BCG, oral polio vaccine, anthrax vaccine

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19
Q

What is the efficacy of live attenuated vaccines?

A

Typically, they only require a single dose for long term immunity (humoral and cellular)

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20
Q

What is an overview of live attenuated vaccines generation?

A

Can be attenuated via serial-passage of the pathogen through a foreign host species either in vitro or in vivo or via genetic manipulation.

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21
Q

What are the advantages of a live attenuated vaccine?

A

Induces a strong immune response that is long-lasting
Typically only requires one dose
Replication is limited, but the vaccine pathogen can travel to typical sites of infection, mimicking natural infection

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22
Q

What are the disadvantages of a live attenuated vaccine?

A

There is some possibility that the pathogen could revert back to a virulent form
Several live attenuated vaccines not recommended for use or are not effective in immunocompromised individuals
Tend to have a limited shelf life (1-3 months)
May require cold storage conditions (extra storage requirements needed)

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23
Q

How is attenuation achieved?

A

In vitro culture of pathogen under sub-optimal conditions (e.g. in a different species or at a different temperature)
Serial passage through other species- e.g. mice, non-human primates
Genetic manipulation- e.g. deletion of virulence genes (More reliable and precise, but requires a good understanding of the pathogen and host biology to identify virulence genes)

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24
Q

Why is attenutation a balancing act?

A

Over-attenuation= limited immune response
Under-attenuation= increased chance of developing disease symptoms

25
Q

What is an overview of Killed whole organism vaccines?

A

The pathogen is killed, but antigens remain intact so that they can be recognised by the immune system
There is no chance of infection as the pathogen is inactivated/ “killed”, hence it cannot replicate within host cells
Examples: Salk polio vaccine, whole cell pertussis, rabies, hepatitis A

26
Q

How are killed whole organism vaccines made?

A

Inactivation achieved using heat, chemicals (e.g. formaldehyde) or radiation

27
Q

What is the main advantage of attenuated vaccines?

A

Improved safety profile over live attenuated vaccines

28
Q

What are the advantages of a killed whole organism vaccine?

A

Improved safety profile compared to live vaccines
Can be used in immunocompromised individuals

29
Q

What are the disadvantages of a killed whole organism vaccine?

A

Weaker immune response generated (e.g. mostly humoral)
Costly as it requires large scale culture of the pathogen
Strict regulations- have to make sure that the pathogen is adequately inactivated
Have to ensure that the inactivation process doesn’t disrupt the antigen required for the immune response!
Often requires the use of adjuvants!

30
Q

What are adjuvants?

A

Substance added to enhance immunogenicity of an antigen-typically used in ‘killed’ vaccines
Immunostimulants or delivery systems
Common adjuvants - aluminium salts (alum), oil-in-water
emulsions (MF59 or AS03) and toll-like receptor agonists (AS04- conjugated to alum) (Mechanisms of action not fully elucidated- e.g. Alum)

31
Q

What is an overview of Toxoids vaccines?

A

In use since the 1920’s (for tetanus)
Act by priming the immune system against exotoxins secreted by pathogens
Induce mostly humoral responses with several booster shots required
Examples include diphtheria, tetanus – often combined

32
Q

What is an overview of toxoid vaccine production?

A

Pathogen is cultured on a large scale and the toxin is isolated followed by inactivation using formalin

33
Q

What is an overview of subunit vaccines?

A

Only contain a fragment of the pathogen- e.g. the antigen, which may be a purified or recombinant
protein, polysaccharide, peptide

34
Q

What are exmaples of subunit vaccines?

A

Protein subunit- recombinant HBsAg Hepatitis B vaccine (hepatitis B virus)
Polysaccharide-, Pneumococcal polysaccharide (Streptococcal pneumoniae)
Conjugate- haemophilus influenzae type B (Hib) conjugate vaccine

35
Q

What is an overview of emerging subinit technology?

A

Emerging technologies: virus-like particles and nanoparticles
Virus-like particles= virus-derived structures

36
Q

What is an overview of nucleic acid vaccines?

A

Vaccine containing either DNA or mRNA that encodes the antigen required
Delivery into host cells can be enhanced using drug delivery methods (e.g. nanoparticles, lipid encapsulation)
Easy and cheap to manufacture, no chance of replication BUT challenges with stability and delivery

37
Q

What is an overview of DNA vaccines?

A

Insertion of a gene that encodes a specific antigen into a bacterial plasmid (under control of a promoter), possibility to
also deliver genes that encode proteins to stimulate a gene response (e.g. TNF, GM-CSF)
None currently licensed, but are being investigated for bacterial, viral and protozoan pathogens

38
Q

What is an overview of mRNA vaccines?

A

mRNA that encodes for antigen- delivered directly into APCs to be translated into antigenic protein
2 mRNA vaccines currently in use for SARS-CoV-2- Pfizer/BioNTech, Moderna vaccines

39
Q

What is an overview of Viral vector vaccines?

A

Use of a viral vector to deliver DNA that encodes a specific antigen
Offer both humoral and cellular immunity (without need for adjuvants)
More stable than mRNA vaccines
Examples: COVID-19 (4 vaccines in use) and Ebola (2 vaccines in use)

40
Q

What are used as viral vectors in viral vector vaccines?

A

Commonly used viral vectors include adenovirus, vaccinia, vesicular stomatitis virus, measles, influenza

41
Q

What is an overview of Mucosal vaccines?

A

Mucosal surfaces are the predominant site of infection for a
majority of pathogens
Respiratory tract, intestine, oral cavity, urogenital tract
With many pathogens gaining entry into the body via the mucosa, there is an unmet need to produce better vaccines
Either live attenuated or whole, inactivated vaccines

42
Q

What is an oveview of mucosal barriers and immunity?

A

Mucosal barriers act to prevent infection via both innate and
adaptive immunity
Innate- mucus, epithelial lining, pH, antimicrobial peptides
Microbiome
MALT- mucosal-associated lymphoid tissue

43
Q

What are the problems for mucosal vaccines?

A

Issues with current intravenous/ intramuscular vaccinesà how effective are they at inducing an immune response at mucosal sites?

44
Q

What are the pathogens investigated for mucosal vaccines?

A

Several mucosal vaccines are currently in use including for cholera, influenza A and B, polio, rotavirus and Salmonella

45
Q

What are the outcomes of current mucosal vaccines?

A

Increased induction of mucosal IgA and IgG, tissue-resident memory T cells and B cells

46
Q

What are the advanatges fo mucosal vaccines?

A

Immunise locally as well as systemically
Quicker to administer
No use for needles- may be seen as less daunting to some, cheaper, requires less training for those administering the vaccine
Typically less reactongenic

47
Q

What are the challenges for mucosal vaccines?

A

Antigen needs to be resistant to degradation- e.g. mucus, pH of stomach acid, enzymes
Only a small dose will reach the MALT

48
Q

What makes a good vaccine?

A

Adequate immune response generated
Life-long immunity- ideally only one dose required
Few side effects
Easy to manufacture
Easy storage
Cost effective

49
Q

What is an overview of vaccine development process?

A

Discovery and pretrials - 2-3 years
3 phases of trials - 7-11 years
Approval - 1-2 years
Manufactoring and post-marketing survalience - 1-2 years

50
Q

What is an overview of Zaire Ebolavirus?

A

Zaire Ebolavirus (ZEBOV) is a strain of Ebolavirus with a mortality rate of 50-90%, which largely affects central Africa

51
Q

What is an overview of virus–Zaire Ebola virus (rVSV-ZEBOV) vaccine?

A

Recombinant vesicular stomatitis virus–Zaire Ebola
virus (rVSV-ZEBOV) developed to prevent Ebola disease
A viral vector vaccine utilising live, replication competent VSV, which expresses the EBOV GP gene
Approved for use in 2019, single dose- prevents transmission of ZEBOV with 97.5% efficacy (WHO)

52
Q

When was the virus–Zaire Ebola virus (rVSV-ZEBOV) first developed?

A

First trialed in non-human primates in 2005- demonstrated protective effects and reduction in mortality rate following exposure to ZEBOV, compared to unvaccinated animals
2013 Oubtreak begins in Guinea, WHO permits use of the rVSV-ZEBOV vaccine for emergency use (first time being used in humans)

53
Q

What was the overview of virus–Zaire Ebola virus (rVSV-ZEBOV) first developed?

A

Phase I trials began in 2014 in several countries in Africa, Europe and North America- healthy subjects
Several side effects observed (e.g. arthritis and skin reactions)à found replicating virus in synovial fluid of joints
Phase II and III trials began in 2015 in Guinea with a lower dose- results were largely inconclusive due to issues with the trial design

54
Q

What is an downside of virus–Zaire Ebola virus (rVSV-ZEBOV) efficacy

A

Storage at below -60oC, low stability in fridge and room temp and is only protective against Zaire strain of Ebolaviruses

55
Q

What is the economics of vaccine development?

A

Very high cost for developing and manufacturing a vaccine
£30,000,000
Reason for AstraZeneca withdrawing covid vaccine

56
Q

Why is vaccine development low?

A

Very low success rate (6%)!
Many of the pathogens we need vaccines for predominantly affect low-income countries- this is not very profitable for companies
Potential for a vaccine to be ‘outcompeted’ by other vaccines as pathogens adapt in different populations

57
Q

What are challenges in vaccine production?

A

Emerging pathogens/ infections- identification of virulence mechanisms
Some pathogens exhibit high sequence variability among different strains- e.g. influenza
Demand for a single-dose vaccine- how feasible is a multi-dose vaccine in some communities?
Vaccines for pandemics can only be tested during active outbreak

58
Q

What is an overview of the vaccine debate and controversy?

A

Andrew Wakefield lied and used false data to show measles part of MMR vaccine caused autism however, poor data and opposite proof showed otherwise

59
Q

What is a concequence of the vaccine debate and controversy?

A

Whooping cough cases at highest in more than a decade
2024 Q1 - 2750 cases
2016 Q1 - 1300 cases
2012 Q3 - 3500 cases

60
Q
A

3s2: Infection and Immunity (12 decks)

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