Problem pathogens and vaccine strategies

Question 1

Why are there so many diseases for which vaccines do not exist?

Answer 1

Escape - development of mutations to avoid the immune system e.g. influenza and HIV
Evolution of protective mechanisms e.g. S.pneumoniae and HIV
Integration into the host genome e.g. herpes simplex
Dormancy in immune privileged sites e.g. M.tuberculosis and Ebola
Strain variation extending beyond immunological memory e.g. dengue

Question 2

What causes seasonal flu?

Answer 2

Antigenic drift - small changes in the surface proteins

Question 3

What causes new flu viruses and pandemic outbreaks?

Answer 3

Antigenic shift - recombination of proteins from different viruses

Question 4

Why is HIV difficult to develop a vaccine for?

Answer 4

HIV attacks the WBCs of the immune system, causing the patient to become immunodeficient
There are a limited number of targets on the HIV surface to attack and they are well hidden
HIV uses glycan shielding to hide the envelope protein
HIV releases envelope as a decoy
HIV has a very high mutation rate
The aim of a HIV vaccine has to be to prevent infection not to respond to infection

Question 5

What does a HIV vaccine need to do?

Answer 5

Needs to stop the virus penetrating the outer layer (epithelium) of the skin - vagina or rectum

Question 6

What are the mechanisms of transmission of HIV?

Answer 6

Physical breach in epithelium - e.g. herpes simplex infection causing ulcer will allow HIV to get across vaginal epithelium
Infection can also occur without physical breach - Langerhans cells squeeze between epithelial cells and grow up to the surface and HIV can attach to the Langerhans cells via DC-SIGN protein, then when Langerhans cell withdraws, it pulls the virus along with it

Question 7

What is the exposure time of HIV after ejaculation?

Answer 7

30-60mins - this is how long the virus will survive in the vaginal cavity

Question 8

If the virus infects via the Langerhans cells, how long does transfer take?

Answer 8

1-4 hours

Question 9

What is virus latency?

Answer 9

The ability of a virus to remain dormant within a cell
Latency is related to but not the same as chronic viral infection

Question 10

What happens in latency?

Answer 10

The viral genome is not fully eradicated but proliferation of virus particles ceases and the infection is subclinical
The virus may be reactivated and begin producing large amounts of new virus, causing acute infection

Question 11

How does a virus become latent?

Answer 11

Infection of mucosal epithelial cells in HSV causes replication and virions are produced that spread to infect additional epithelial cells
Virus then enters innervating sensory neurons and nucleocapsids are transported to the neuronal cell body
Viral DNA is released into neuronal nucleus and circularises
Circular viral DNA persists in the neuronal cell nucleus and latency-associated transcript is expressed

Question 12

What factors can reactivate a latent virus?

Answer 12

UV exposure
Drugs

Question 13

What happens when a virus become reactivated?

Answer 13

Upon reactivation, viral lytic gene expression is initiated and newly formed capsids are transported to axonal termini
Infectious virus released from the axon and infects the mucosal epithelial cells, resulting in recurrent infection and virus shedding

Question 14

What is an example of a bacterium that causes latency?

Answer 14

Mycobacterium tuberculosis

Question 15

How does M.tuberculosis become latent?

Answer 15

By residing in macrophages

Question 16

What is the classic way of M.tb becoming reactivated?

Answer 16

HIV infection

Question 17

What are commercial reasons for many diseases not having vaccines?

Answer 17

All new medicines are extremely expensive
Vaccines are made and sold by pharmaceutical companies
Infectious disease is primarily a developing country problem

Question 18

On average, how long do new pharmaceuticals take to develop?

Answer 18

10-15 years

Question 19

How much does it cost to bring a new medicine into the market?

Answer 19

Approx. $1billion

Question 20

What are disincentives of vaccine investments?

Answer 20

High costs of development
Demand for new vaccines at lowest prices - this means that there is a low chance of making profit on vaccines as people will only pay so much for them

Question 21

What are logistic reasons for many diseases not having vaccines?

Answer 21

Developing countries have limited infrastructure
The cold chain - must keep the vaccine cold otherwise will go off; this is difficult and expensive
Political/religious interventions