Problem pathogens and vaccine strategies Flashcards
name some viral vaccines that are available in the uk now
Hepatitis A Hepatitis B Human papillomavirus Influenza Japanese encephalitis Measles Mumps Rubella Yellow fever Polio Rabies
name some bacterial vaccines that are available in the uk now
Anthrax Cholera Diphtheria Meningococcal C Neisseria meningitidis Tetanus Typhoid Tuberculosis
Global diseases for which vaccines do not exist
Hepatitis C Herpes simplex HIV Influenza (universal) Leishmaniasis Malaria Melioidosis Respiratory syncytial virus Rhinovirus Schistosomiasis Shigella Cytomegalovirus Dengue Epstein-Barr Ebola
These are diseases that you are unlikely to come across -> these diseases often happen in areas that are not particularly developed
Why are there so many diseases
for which vaccines do not exist?
technical issues, commercial issues and logistics issues
Technical:
- “Escape” – development of mutations to avoid the immune system (eg influenza and HIV)
- Evolution of protective mechanisms (eg S. pneumoniae and HIV)
Integration into the host genome (eg herpes simplex)
- Dormancy in “immune privileged” sites (eg M. tuberculosis and Ebola)
- Strain variation extending beyond immunological memory(eg dengue)
Commercial issues – would not invest in vaccines that are only going to be used in one country
- All new medicines are extremely expensive
- Vaccines are made and sold by pharmaceutical companies
- Infectious disease is primarily a developing country problem
Logistics
Developing countries have limited infrastructure
The cold chain
Political / religious intervention
Flu virus – the shape shifter
-why do you need a flu jab every year?
Antigenic shift – recombination of proteins from different viruses, resulting in a new flu virus and pandemic outbreaks
e.g. human H2N2 and avian H3N8 becoming human H3N2
Antigenic drift – small changes (mutations) in the surface proteins.
Results in seasonal flu.
why is it so difficult to make vaccines against HIV?
- HIV attacks white blood cells of the immune system
In HIV infection, the number of white blood cells goes down and the patient becomes immunodeficient
Envelope protein – ligand for CD4 allowing virus to be internalisd into cell - There are only a limited number of targets on the HIV surface to attack and they are well hidden.
Gp120 is the only thing that our immune system can recognise of HIV, and its very sparse anyway
Also, it’s heavily coated in sugars, protecting it from recognition by antibody and allowing evasion - HIV releases envelope as a decoy - soluble form of gp120
Antibodies have to avoid binding to soluble antigen then bind to surface gp120 - acts as another layer of evasion - HIV has a very high mutation rate. It is a moving target.
-reproduces sloppily, accumulating lots of mutations when it copies its genetic material. RNA polymerases have no proof reading ability and create many errors
- reproduces at lightning-fast rate — a single virus can spawn billions of copies in just one day.
HIV has the highest mutation rate reported for any biological entity. - The aim of an HIV vaccine has to be to prevent infection, not to respond to infection.
An HIV vaccine needs to stop the virus penetrating the outer layer (epithelium) of the skin – vagina or rectum.
Multiple mechanisms of HIV transmission
columnar epithelium and stratified epithelium
e.g. in menstruation, epithelium thins, also there is a weak point where you have a single line of cells
Virus can enter by infecting the epithelial cells
Also langerhans cells – survey the contents of epithelial layer, sometimes they go to the surface
HIV can attach to langerhans cells, as the projection is retracted, HIV can be presented to the T cell leading to infection
Virus latency - what does this mean?
the ability of a virus to remain dormant (latent) within a cell.
In latency, the viral genome is not fully eradicated, but proliferation of virus particles ceases and the infection is sub-clinical. Can go to an immnuoprivaleged site to hide.
The virus may be reactivated and begin producing large amounts of new virus, causing acute infection.
e. g herpes simplex
e. g. TB
is latency the same as a chronic viral infection?
no, but it is related
The cost of new pharmaceuticals:
New pharmaceuticals take on average 10-15 years to develop
Increasing regulatory burden - safety
High failure rate – only 1:10,000 compounds currently under development, will be marketed
Approx. $1bn to bring a new medicine to the market
Vaccine Investment Decisions - Disincentives:
High costs of development
Demand for new vaccines at lowest prices
Result: Large pharma companies are reluctant to make a significant investment in new vaccines for developing country infectious diseases.
