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Tuberculosis Vaccines Flashcards

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1
Q

How many people fell ill with TB in 2015?

A

10.4 million

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2
Q

How many people died of TB infection in 2015?

A

1.8 million

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3
Q

95% of TB deaths occur in?

A

Low and middle income countries

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4
Q

Risk of reactivation in latently infected individuals is?

A

5-10%

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5
Q

Countries in which TB infection is most common?

A

Nigeria, India, Pakistan, China, Indonesia, South Africa

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6
Q

How many people are latently infected with TB?

A

1/3 of the world’s population, ~2 billion

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7
Q

How many people died of MDR TB in 2016?

A

240,000

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8
Q

XDR TB has been detected in how many countries?

A

117 countries

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9
Q

What is the WHO End TB Strategy?

A

Aims to reduce the number of TB associated deaths by 95% and the number of people infected by 90% worldwide between 2015 and 2035

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10
Q

When is goal for the WHO End TB Strategy?

A

2035

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11
Q

What does BCG stand for?

A

Bacille Calmette Guérin

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12
Q

In order to reach the WHO End TB Strategy by 2035 what is needed?

A

A new vaccine that is more efficacious than BCG

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13
Q

When were the first human trials of BCG?

A

1921

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14
Q

What is BCG made out of?

A

Live attenuated mycobacterium bovis

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15
Q

How was the BCG made?

A

Through subculturing on different types of media

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16
Q

How many subcultures did it take to make the original BCG vaccine?

A

230

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17
Q

Why are there different strains of the BCG vaccine?

A

Original BCG developed in 1921, sent out to different laboratories worldwide which had different growth protocols. Led to slight genetic differences and the development of strains.

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18
Q

When was TB first identified?

A

1882

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19
Q

When was BCG first tested on humans?

A

1921

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20
Q

When was streptomycin seen to be effective against TB?

A

1943

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21
Q

When was the genome of TB sequenced?

A

1998

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22
Q

What caused BCG to be attenuated?

A

RD1 deletion

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23
Q

RD1 encodes how many ORFs?

A

9 ORFs

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24
Q

Which specific genes encoding which proteins were the most important deletion as part of the RD1 deletions?

A

Genes encoding the virulence factors ESAT-6 and CFP-10

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25
ESAT-6 virulence?
Can block TLR2 to prevent signalling and macrophage activation
26
CFP-10/ESAT-6 complex virulence?
As a complex they can down regulate ROS- reactive oxygen species production
27
Benefits of BCG?
- Safe - Very effective in children in preventing extra-pulmonary TB and TB associated meningitis - Protects against other infections such as leprosy and also can be used to treat bladder cancer
28
Disadvantages of BCG?
- Safety concerns in immunocompromised/HIV+ - Variable efficacy in adult pulmonary TB - Injectable - Scar formation - Not very effective in 16-35 year olds - Limited antigenic repertoire - Can interfere with TB diagnosis
29
Why does TB have variable efficacy against adult pulmonary TB?
- Different BCG strains - Different TB lineages - Previous mycobacterium infection: masking/blocking hypotheses - Infection with parasites e.g. helminths - Nutrition e.g. vitamin D deficiency
30
Growing BCG in Sauton media rather than Middlebrook 7H9 media?
BCG grown in Sauton media was shown to be more persistent inside macrophages, more effective at inhibiting apoptosis of infected cells and induced stronger inflammatory responses
31
Why have different BCG strains arisen?
BCG sent to different laboratories worldwide and the growth protocols differ within laboratories which is why there are slight genetic differences between strains
32
What is the masking hypothesis of previous mycobacterium infection?
Masking hypothesis suggests that the protective effect of sensitizing mycobacteria is nearly as good as that of BCG, so improvement by adding BCG is minimal.
33
What is the blocking hypothesis of previous mycobacterium infection?
Blocking hypothesis suggests that pre-existing immune responses to antigens common for the Mycobacterium block the replication of BCG and thereby the vaccine “take” 
34
PPD in the tuberculin skin test stands for?
Purified Protein Derivative
35
PPD in the TST causes what?
A type IV hypersensitive response also known as a delayed hypersensitivity reaction
36
TST alternative name?
Mantoux test
37
How long does it take to obtain results from the TST?
48-72 hours
38
Best alternative to the TST test which is not impacted by BCG vaccination?
Interferon Gamma Releas Assay: IGRA
39
What can occur in some immunocompromised individuals who receive BCG?
Very rare but disseminated BCG disease can occur
40
What are three new TB vaccines you need to know about?
MVA85A MTBVAC VPM1002
41
MVA85A was developed by?
Oxford University
42
MTBVAC was first tested on humans where and when?
Switzerland | 2015
43
MVA85A is made up of?
Attenuated vaccinia virus Ankara | Ag85A
44
What is Ag85A?
Mycolyltransferase
45
MVA is what?
A type of attenuated vaccinia ankara virus
46
The MVA85A is what type of vaccine?
A booster of pre-existing immune responses to antigen 85A, which are present in most people either as a result of BCG vaccination or natural exposure to TB.
47
Was MVA85A successful?
No more successful than BCG
48
Most promising new vaccine?
MTBVAC
49
MTBVAC is?
First live attenuated mycobacterium tuberculosis vaccine
50
Why is it thought MTBVAC will be more effective than BCG?
Contains more T cell epitopes than BCG | Retains ESAT-6 and CFP-10 as it does not have the RD1 deletions
51
How is MTBVAC attenuated?
Mutations in fadD26 and phoP genes
52
What is PhoP?
A transcription factor which is responsible for controlling around 2% of the coding capacity, including expression of cell wall lipids and antigen secretion systems
53
Mutations in phop gene result in what?
ESAT-6 can be produced but cannot be secreted
54
fadD26 deletion causes what?
Complete abolishment of PDIM synthesis which is a major virulence factor and membrane constituent
55
What is VPM1002?
Recombinant BCG
56
What changes have been made in VPM1002?
Lacks Urease C gene | Addition of LLO: Listeriolysin encoding gene from Listeria monocytogenes
57
What does Urease C do?
Drives neutralisation of the phagosome | Leads to the release of ammonia which neutralises the acidity in the phagosome which inhibits phagosome maturation
58
What does LLO stand for?
Listeriolysin
59
What does Listeriolysin (LLO) do?
It creates pores in the phagosomal membrane
60
When is Listeriolysin (LLO) active?
pH 5.5
61
How does VPM1002 work?
Deletion of Urease C causes phagosome acidification Allows the perfect pH for the action of Listeriolysin (LLO) The antigens and bacterial DNA are released into the cytosol where the endogenous antigen can be expressed on MHC-I
62
LLO (listeriolysin) is usually found in which bacteria?
Listeria monocytogenes

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