vaccines Flashcards
History
Ancient Egyptians, Indians and Chinese 1100BC discovered
1796 Jenner develops small pox vaccine
- Observed milkmaids who contracted cow pox did not get small pox
- Scratched a boy with needle with fluid of cow pox infection
- The boy was later exposed to small pox but was resistant
1885 Pasteur rabies vaccine
1979 smallpox eradicated
- Cowpox and small pox shared similar antigens
- Immunisation with cow pox induced antibodies against cow pox
Cow pox antibodies neutralised the smallpox virus
Outcomes of vaccines
- prevention of disease and transmission
- Eradication
- Potentially treating non-infectious disease
○ Cancer, Alzheimers etc.
Eradication successful for smallpox
- Disease limited to humans (cant exist in any other animal or soil etc.)
- No long term carriers (no asymptomatic)
- Always recognisable
- Few variants/serotypes
- Stable, cheap, effective vaccine
- Eradication is cost effective
Global surveillance
Polio eradication program
- Highly infectious Faecal oral route disease
- Mostly under 5yr old children
- Invades intestine and nervous system
- Paralysis in limbs or in some cases breathing muscles (death)
- Inactivated (salk) vaccine 1955 (IPV)
○ Took 3 strains grown in monkey kidney cells –> formalin treated to inactivated virus - Attenuated (oral, Sabin) vaccine 1962 (OPV)
○ 3 polio strains passaged to accumulate mutations
§ Strain 1 - 57 mutations
§ Strain 2 - 2 mutations
Strain 3 - 10 mutations
cVDPV
- Circulating vaccine-derived polio virus
If OPV vaccinated children shed virus in an under immunized population there is a chance for infection of immunocompromised and reversion to virulence
Measles
- R0 =18
- Many deaths from pneumonia
- If contracted before age 2 - increase risk of rare complications, SSPE
- 1980 –> 2016 - 2.6m/yr deaths –> 90,000/yr
- In USA example
○ 1963-1983 - 400,000 cases –> 1479 cases with vaccine
○ 1990 - only 70% coverage –> cases rise to 27,786
○ 1993 - public health effort cause immunisation to 90% range - 312 cases
○ 2000 - USA declared effectively eradicated with case load of <60 cases/yr
2014 - measles cases increase due to lack of vaccination
TB
- Incredibly difficult to treat, many antibiotics
- No sufficient treatment yet
- Anyone with TB needs to be treated
○ Cost high - Focus on prevention
Drastically lower cost
Types of immunisation - passive
- Transfer of immunity to patient by using specific antibodies = immune prophylaxis
- You get given it (antibodies) not make it yourself
- Best given before infection
- Rapid onset of protection
- Maternal immunity - antibodies from mother to infant via placenta or breast milk
- Limited duration 3-6 months
○ Antitoxins, tetanus
Gas gangrene, Hep A, measles
Types of immunisation - active
- Induction of a specific, protective immune response by exposure to antigen = vaccination
- Introduce immune system to a safe form of a micro-organism that will induce immune response
When infection occurs, a secondary response will occur- more rapidly and greater magnitude
- Introduce immune system to a safe form of a micro-organism that will induce immune response
Ideal vaccine
- Safe (minimal side-effects)
- Produce a protective immune response
- Long lasting response (memory)
- Stable (effective after storage and shipping, cold chain
- Single dose
- Oral/inhaled administration
Low cost (measles vaccination = 1 USD)
Vaccine types
- Live attenuated
- Killed/inactivated
- Vaccine must contain at least 1 component of the organism
The more components, the more the immune response will resemble that against the target organism
Live attenuated
oral
Single dose
No adjuvant
Possible reversion to virulence
Requires cold chain
Low cost
Long duration of immunity
IgG, IgA, cell mediated
Killed/inactivated
Parenteral (inject)
Multiple dose
Adjuvant required
safe
Heat stable
High cost
Short/ long duration of immunity
Mainly IgG
Live attenuate - BCG
○ Bovine TB strain passaged in vitro
○ No reversion
Administer intradermally
Live attenuated - Oral polio virus
○ Passaged in monkey kidney cells
○ Rare reversion
○ Good mucosal immunity
Potential to cause vaccine derived polio in immunocompromised
Live attenuated - bacterial vaccine
○ Typhoid
§ Oral for travellers to areas where typhoid is prevalent
○ TB
BCG used for people at special risk of contraction
Live attenuated- viral vaccine
○ Chicken pox ○ Measles ○ Mumps ○ Rubella ○ Poliomyelitis ○ Yellow fever ○ Rotavirus
Killed/inactivated vaccines -
- derived treatment with chemicals
- Non-infectious, safe
- Less immunogenic and require adjuvants
- Polio
○ Inactivated with formaldehyde (adjuvant) - Influenza
○ Same as polio but cultured in eggs - Hep A
○ Same as polio - Typhoid
○ Killed whole cells - Cholera
○ Killed whole cells - Covid 19
○ Grown in Vero cells
○ Inactivated with BPL
Adjuvant added
Classical vaccinology
Growing pathogens
Reverse vaccinology
- Design from information
E.g. Finding particular antigens and direct antibodies to those
Subunit vaccines - “acellular”
- Used when immunity depends on antibody to a particular microbial component that can be purified
- Can be a protein e.g. toxoid (inactivate)
- Or polysaccharide e.g. capsules (e.g. Neisseria meningitidis)
Non-infectious viral-like particles such as HPV
Toxoids
- When a disease is caused by a toxin, immunity may depend not on Ab to the microbe, but on Ab to the toxin (anti-toxin)
- Inactivated bacterial toxin (formaldehyde)
○ DTaP (triple antigen) vaccine
Tdap (booster)
- Inactivated bacterial toxin (formaldehyde)
Conjugant vaccines
- Purified capsular material can be a good target
- But often not very immunogenic
- Conjugating linking a less immunogenic Ag to a strong protein Ag(toxoid) increases recognition of the vaccine antigen
Whooping cough - Pertussis toxoid
Influenza - Capsule
Strep - Capsule
Neisseria meningitidis - Capsule
Typhoid
Capsule
Recombinant antigen vaccine
- Where protective antigen is known, can be produced by recombinant DNA tech
- Useful in cases where the causative agent cannot be grown in vitro
○ Rabies - G antigen
○ Influenza - recombinant hemagglutinin
○ Hep B - surface antigen
Covid 19 - recombinant spike protein
- Useful in cases where the causative agent cannot be grown in vitro
Recombinant antigen vaccine - Hep B example
○ Gene encoding hep b surface antigen (HBSAg) cloned in yeast plasmid
○ The yeast produce surface hep b surface antigen to be purified
○ Move to
Block binding to cell
Protein subunits
○ Identify protein required for protective immunity ○ Clone gene encoding protein ○ Express and purify ○ Add adjuvant ○ No need to grow virus Very safe to scale up
VLPs
○ Virus like particle
○ Look like virus to host no genetic material
○ No infection
○ Display antigen
○ insert gene and surface protein into vector in eukaryotic, yeast of insect cell
Self-assembly with similar surface proteins
H65 for TB
○ Looked at proteins transcribed during infection
○ Looked at immune response
Found 6 immunogenic proteins put into a single fusion protein named H65
Single peptide vaccines
- Only use epitope needed to stimulate immune response
○ Identify sequence and chemically synthesize the short peptide- Get epitope required for protective immunity from immune host
○ Take b cells and clone to find the antibody
○ Take the neutralising antibody
○ Look at the shape of the binding site for the antibody
Mimic the molecule at the binding site
- Get epitope required for protective immunity from immune host
Adjuvants
- Soluble antigens are less immunogenic than particulate antigens
○ So, most single proteins or toxoids require an adjuvant- Adjuvants enhance immune response
○ Local inflammation
○ Depot slow release of antigen
Modern adjuvants to enhance and direct the desired type of immune response
- Adjuvants enhance immune response
Recombinant vector vaccines
Insertion of foreign genes into a live viral vector
Multivalent attenuated viral vectors
○ Adenovirus
○ Attenuated measles virus
Canary pox virus
Bacterial vector e.g. AstraZeneca covid 19
○ If we know the antigen that needs to be expressed
○ We can clone that gene
○ Transform that into a bacterial vector
○ Once in a bacteria the antigen is expressed
§ Floating in cytoplasm
§ On surface
○ Multivalent attenuated bacterial vectors
§ Attenuated salmonella typhi
□ Oral
□ Antigens for enteric pathogens
§ Attenuated s. enterica serovar typhimurium
□ Oral
Express recombinant PSA antigen of prostate cancer
Nucleic acid vaccine
- Just DNA or just RNA as vaccine
- Cheap, easy
- Pfizer covid 19 vaccine
- DNA
○ DNA that contains gene of interest
§ Creates pores in membrane that increase uptake of DNA into cell that allows gene to be expressed in the cell - RNA
○ mRNA encased in lipid coat so it can enter cell and express the gene
§ Lipid fuses with cell membrane and allows mRNA to enter cytoplasm to make viral protein to be taken up by immune system
○ Not as stable as DNA
§ Storage at -70 degrees
Self adjuvating (induce inflammation)
DNA nucleid acid vaccine
- put into a plasmid that has a promotor that switches on only in human cells
○ Either a syringe or gene gun
○ Once in nucleus will transcribe mRNA and trick cell to make antigen
§ Either send out of cell as free antigen
§ Or get broken up as a peptide and get presented on MHC class 1- Injection of naked DNA comprising of foreign gene and a plasmid
- Plasmid must be able to replicate in bacteria and eukaryotic cells
Foreign gene under control of eukaryotic promotor (e.g. cytomegalovirus)
Edible vaccine
- Potential to feed people helicobacter pylori a gut bacteria that express vaccine antigens
- Expression of vaccine antigens in genetically engineered plants
- Nanopatches
○ Needle free
○ Dry coat stamp
○ No adjuvants
○ No refrigeration
○ Cheap
No reduction in dose
Sometimes vaccine fails
- Wrong immune response
- Response too low
- Wrong target
- Immature immune system
- Non-responders
- Immunosuppression
- Immune evasion
Antigenic variation
Side effects
- Swelling
- Allergic response (grown in eggs and yeast)
- Seizures
- Guillian-barre syndrome
○ Triggers auto-immunity - Harmful effects on foetus and immunocompromised
