27. Viral Vaccines Flashcards
who do infectious diseases mostly effect?
the poor and those living in poverty
what are the current diseases growing in burden?
CVD and other diseases associated with affluent and sedentary lifestyles
why are vaccines not the magic bullet they could be?
not everybody can access the vaccines they need
people in poverty and lower income countries have less access to healthcare and healthcare education
what is the only thing that had a bigger impact on disease burden then vaccines?
Access to clean drinking water
why have most infectious diseases decreased over the last 100 years?
because of vaccines
why does measles still have a high disease burden?
- it is not really perceived as dangerous
- Chances of dying even when not vaccinated are still very low
- low word of mouth worry encouraging vaccine uptake
- spreads easily so masses of cases
- 100,000s still die every year
what are vaccine preventable deaths?
people dying from diseases that could be prevented but they are not getting the vaccines they need to prevent the deaths
how much have measles death decreases in since 1999?
1 million deaths in 1999
100,000 deaths in ~2020
why do we not have vaccines for massive viral diseases?
- the virus changes too much that the vaccine won’t be effective for very long
- we don’t know what the next big viral threat will be so we don’t know where to invest the money and which vaccines to develop
what are some viruses that don’t have vaccines?
HIV
Dengue
Herpes viruses
Hepatitis C
SARS
what are other factors that reduce the infectious disease burden?
- access to clean drinking water
- adequate nutrition
- proper sewage disposal (links to clean water)
- insect/rodent control
- medical services (can be as simple as having 1 nurse)
- uncontaminated blood supplies
what is a major determinant of health and public health?
availability of medical professionals
this also helps with effective vaccine role out
why is there no HIV vaccine?
no one’s immune system has figured out how to defeat HIV so we don’t know what kind of immune response to mimic for it to be an effective vaccine
diversity and plasticity of the virus
what are the unknowns that means we cannot make vaccines?
- what immune response is protective
- what immune response needs to be induced by vaccines
- what induces long term protection
- differences in natural and induced immune responses
what will happen when you give 100 people the same vaccine?
they will all have different immune responses to the vaccines and someone’s will figure out a way to defeat the virus
what is the problem with early childhood immunisations?
- maternal IgG antibodies until 2 months which suppress the child’s natural immune response and clear the vaccine without leaving protection
- new born immune response is very different to adults and we don’t really understand how it works due to problems with studying sick babies
what is the problem with vaccination and mucosal immunity?
IgA is secreted across the epithelial barrier and is harder to induce through a vaccine
but is important for a lot of infections
what is the problem with vaccination and animal models?
Animal models are used to evaluate toxicity and efficacy of experimental vaccines on the disease and infection in question
however the models are rarely accurate to the equivalent human infection and disease
how do viruses have lots of antigenic variation?
- high error rates
- lack of proof reading
- the ability of the viral particle to tolerate changes in the structure
what is an example of a virus with low plasticity?
measles
the particle cannot tolerate changes so vaccine protection can last for life
what is an example of a virus with high plasticity?
HIV
so plastic the immunity system cannot effectively target it
what needs to be considered in viral vaccine design relating to the virus?
- how is the disease caused?
- where does the virus gain entry?
- what is the structure of the virus?
- does the virus display lots of antigenic variation?
- does the virus have a persistent or latent form?
- is there cell-to-cell transmission?
what needs to be considered in viral vaccine design relating to the host’s immune response?
- do we need to induce mucosal or systemic immunity or both?
- what immune response is protective from disease?
- do we want neutralising antibodies?
- do we want a Th1 or Th2 response?
- is the immune response subverted in some way?
- does the immune response enhance infection?
- will maternal antibodies reduce efficacy?
- do we need sterilising immunity?
- is there a suitable animal model?
what is sterilising immunity?
the virus is completely cleared with no viral particles remaining
what are possible routes of vaccination?
- intranasal
- aerosolised
- oral
- Intramuscular or intradermal
Rarer methods: intraperitoneal or intravenous
what are the 7 types of vaccine?
- live attenuated virus
- inactivated virus
- subunit vaccine
- DNA vaccine
- Nanoparticles
- RNA vaccines
- Viral vector vaccines
what are inactivated viral vaccines?
viruses that have been grown and then kill them
what is the most famous live attenuated viral vaccine?
the polio vaccine
how was the live attenuated polio vaccine made?
- passage the polio through a monkey and then through monkey kidney cells
- the obtain a neurotropic version of polio
- put through more kidney cells
- plaque purification
- extract virus and make a vaccine
what is plaque purification?
- put 1/2 viral particles on a cell sheet and add jelly
- let the virus grow
- only 1/2 cell will be infected and release new virions
- the jelly prevents the viruses spreading
- a hole of dead cells form that is full of virus particles that are clones of the 1st
- extract these viruses
what was the principle behind this random method of polio vaccine development?
adapting the virus to another animal and then putting it back into humans.
less dangerous virus but wouldn’t be allowed to be done now
they didn’t know what they were doing they were just trying to find a virus that wasn’t neurovirulent
why was the random method of polio vaccine development allowed when it wouldn’t be today?
it’s risky as the virus can revert back to the human virus
the diseases it was used for were so terrible that the risk was worth it
they needed a less dangerous virus but didn’t know how to do it
why are live attenuated vaccines good?
- oral administration
- induce mucosal immunity in the gut
- cheap to produce
- 1/2 doses for near 100% protection
- life long immunity
how was the inactivated polio vaccine derived?
3 serotypes of the virus grown on monkey kidney cells then inactivated formaldehyde
what is good about the inactivated polio vaccine?
- Intramuscular administration
- systemic immunity
- protect from paralysis
- 1/2 doses for 90% protection
- long shelf life
what are the problems with live attenuated vaccines?
- Possibility of the presence of other viruses in the vaccine
- Reversion to virulence in a host and then excretion into the sewage system and spreading
- low temperature storage needed
what are the problems with inactivated vaccines?
- Possibility of not all viruses being dead
- cellular material can cause side effects
- more than 1 injection will be required
- expensive to make
- contamination with viruses
what happened due to the cutter labs incident?
massive changes to vaccine development and approval to ensure safety and proper inactivation of the virus
what happened when PCV-1 got into vaccines?
pig trypsin was used to cut up cells and pig PCV-1 got into the vaccine
didn’t hurt humans so took a while to be detected
showed that it could happen with a more dangerous virus
how can live attenuated viruses be made safely now?
using recombinant DNA technology to remove virulence genes that don’t play a role in triggering the immune response
how are subunit vaccines made?
take the viral proteins and grow them in a yeast system and make a fake viral particle with no genetic material.
what are the advantages of subunit vaccines?
- single antigens or mixture of antigens
- safer as it is not infectious
- induces good immunity
what are the disadvantages of subunit vaccines?
- less effective than whole agent vaccines
- expensive research and production costs
- often requires boosters
what are VLP vaccines?
Virus-like particles
look indistinguishable from the real thing
HPV vaccine
what is the HPV vaccine?
Human papilloma virus vaccine
one of the most effective vaccines ever made
how do DNA vaccines work?
- make a recombinant plasmid encoding a specific antigen
- OR engineer sequence
- inject into the arm
- some cells take up the plasmid and produce and display the antigens
- trigger an immune response
what are advantages of DNA vaccines?
- antigen is expressed in its native form with post-modifications
- antigen is expressed in MHC1/2 as well
- antigen can be modified
- no carrier required
- can display multiple antigens as well as cytokines
- gene gun delivery for mass vaccination
- easy and cheap to produce
why are DNA vaccines no longer that relevant?
because RNA vaccines are more effective
what are nanoparticle vaccines?
add a viral surface protein to something that gives it structure
- making a fake viral particle that presents the protein to trigger an immune response
- triggers a very good immune response
when were mRNA vaccines were first used?
1990s in pre clinical trials
2013 in humans
why weren’t RNA vaccines developed before covid?
we already have an effective vaccine for the viruses that would be good targets for RNA vaccines
it’s hard to prove RNA vaccines are better and more effective than current vaccines
- lots of time and money
how do RNA vaccines work?
- synthetic mRNA with 1 ORF encoding the spike protein of SARS-CoV-2
- lipid nanoparticle helps mRNA enters the cell
- ribosome find the mRNA
- spike protein made and displayed on the cell
- T and B cells kill the cells presenting the spike protein
- normal cells regrow
- the vaccine has created an immune memory for the virus
how much of a case reduction did the mRNA vaccine trials show?
95% reduction
what is mostly used for viral vector vaccines?
genetically modified chimpanzee adenovirus with the E1 region of the genome removed
why is adenovirus chosen for viral vector vaccines?
adenoviruses are very species specific so the chimpanzee virus won’t infect humans
how are adenoviruses vector vaccines made?
- remove the E1 region of the virus
- replace E1 with the SARS-CoV-2 spike protein
- grow up the adenovirus in E1 complementing cell lines
- virus infects cells and presents antigen triggering an immune response
- immune memory is created
what are vaccine adjuvants?
they are added to vaccines to boost the immune response by provoking inflammation and the innate response
what do adjuvants do?
they help present the antigens in a way that is obvious to the immune system
what are example of vaccine adjuvants?
- freund’s complete adjuvant
- aluminium salts
- Muranyl dipeptides in synthetic oils
- Iscoms- immune stimulating complex
- lipsomes
how can adjuvants work?
- depot effects
- presentation array
- immunomodulation
- antigen processing effects
- targetting
- innate immune responses
OR an combo of all the above
