Tuberculosis Vaccines Flashcards

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
Q

ESAT-6 virulence?

A

Can block TLR2 to prevent signalling and macrophage activation

26
Q

CFP-10/ESAT-6 complex virulence?

A

As a complex they can down regulate ROS- reactive oxygen species production

27
Q

Benefits of BCG?

A
  • 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
Q

Disadvantages of BCG?

A
  • 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
Q

Why does TB have variable efficacy against adult pulmonary TB?

A
  • 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
Q

Growing BCG in Sauton media rather than Middlebrook 7H9 media?

A

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
Q

Why have different BCG strains arisen?

A

BCG sent to different laboratories worldwide and the growth protocols differ within laboratories which is why there are slight genetic differences between strains

32
Q

What is the masking hypothesis of previous mycobacterium infection?

A

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
Q

What is the blocking hypothesis of previous mycobacterium infection?

A

Blocking hypothesis suggests that pre-existing immune responses to antigens common for theMycobacteriumblock the replication of BCG and thereby the vaccine “take”

34
Q

PPD in the tuberculin skin test stands for?

A

Purified Protein Derivative

35
Q

PPD in the TST causes what?

A

A type IV hypersensitive response also known as a delayed hypersensitivity reaction

36
Q

TST alternative name?

A

Mantoux test

37
Q

How long does it take to obtain results from the TST?

A

48-72 hours

38
Q

Best alternative to the TST test which is not impacted by BCG vaccination?

A

Interferon Gamma Releas Assay: IGRA

39
Q

What can occur in some immunocompromised individuals who receive BCG?

A

Very rare but disseminated BCG disease can occur

40
Q

What are three new TB vaccines you need to know about?

A

MVA85A
MTBVAC
VPM1002

41
Q

MVA85A was developed by?

A

Oxford University

42
Q

MTBVAC was first tested on humans where and when?

A

Switzerland

2015

43
Q

MVA85A is made up of?

A

Attenuated vaccinia virus Ankara

Ag85A

44
Q

What is Ag85A?

A

Mycolyltransferase

45
Q

MVA is what?

A

A type of attenuated vaccinia ankara virus

46
Q

The MVA85A is what type of vaccine?

A

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
Q

Was MVA85A successful?

A

No more successful than BCG

48
Q

Most promising new vaccine?

A

MTBVAC

49
Q

MTBVAC is?

A

First live attenuated mycobacterium tuberculosis vaccine

50
Q

Why is it thought MTBVAC will be more effective than BCG?

A

Contains more T cell epitopes than BCG

Retains ESAT-6 and CFP-10 as it does not have the RD1 deletions

51
Q

How is MTBVAC attenuated?

A

Mutations in fadD26 and phoP genes

52
Q

What is PhoP?

A

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
Q

Mutations in phop gene result in what?

A

ESAT-6 can be produced but cannot be secreted

54
Q

fadD26 deletion causes what?

A

Complete abolishment of PDIM synthesis which is a major virulence factor and membrane constituent

55
Q

What is VPM1002?

A

Recombinant BCG

56
Q

What changes have been made in VPM1002?

A

Lacks Urease C gene

Addition of LLO: Listeriolysin encoding gene from Listeria monocytogenes

57
Q

What does Urease C do?

A

Drives neutralisation of the phagosome

Leads to the release of ammonia which neutralises the acidity in the phagosome which inhibits phagosome maturation

58
Q

What does LLO stand for?

A

Listeriolysin

59
Q

What does Listeriolysin (LLO) do?

A

It creates pores in the phagosomal membrane

60
Q

When is Listeriolysin (LLO) active?

A

pH 5.5

61
Q

How does VPM1002 work?

A

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
Q

LLO (listeriolysin) is usually found in which bacteria?

A

Listeria monocytogenes