vaccines

history

• in 1500ssome part of smallpox pustules ground up and blown up the nose to provide protection

• 1970s edward jenner innoculates an 8 year old

• 1880s Louis Pateur first uses a weakened form of microbe - first attenuated vaccine

• help prevent spread of disease but also helps prevent the disease itself

herd immunity

• when 95% of more of the population is immunised

• protects the whole community

• there are impediments to achieving this by:

  • concerns regarding side effects

  • vaccines are expensive

active vs passive immunity

ACTIVE

• exposed to weakened microbe or infected

• memory response

• activation of T/B cells

• primary role is the creation of memory response

PASSIVE

• when delivery of antibodies is not provided by the host

• can be against the following infectious agents:

  • toxins

  • botulism

  • measles

  • hepatitis

  • diptheria

  • tetanus

  • snake/spider bites

• babies with congenital immune deficieny can recieve these

• no memory response

• used when unvaccinated individuals are infected

• host can produce AB response against theraputic agents (systemic anaphylaxis)

• can cause an immune reaction forming complement immune complex

how do vaccines work

• activate 2 arms of the immune system

• can either be an element of a pathogen or a whole weakened pathogen

• phagocytosis by langerhans cells and activation of DCs which present the antigen to T cells in lymphnodes

• there is a risk that the microbe may not be recognised well as not all antigens are immunogenic

• adjuvants are used to help activate the immune response

adjuvants

• modulate the immunogenicity of a vaccie without causing adverse side effects

• they boost the primary immune response

• effects:

  • more immunogenic

  • increased levels of antibody

  • increased cytotoxic cellular response

  • makes antigen more potent - less dose of vaccine required and so cheaper vaccines

mechanism of action for adjuvants

1. A DEPOT EFFECT

• the antigen maintains in the skin for longer

• oil adjuvants/aluminium compounds are used

• the adjuvent itself doesnt activate the immune system

2. ATTRACTION AND STIMULTION OF APCs

• can activate TLRs

• TLRs recognise pathogen more too

• activated APCs due to activated TLRs

3. INFLAMMASOME ACTIVATION

• cytosolic intracellular pathogen recognition detection

• able to recognise patterns in phagocytosed antigen

• activation of inflammasome results in signalling pathways which produce cytokines

4. IMPROVED DELIVERY OF ANTIGEN

• recognised by phagosome better, presentation of Ag better which provides a better memory response

aluminium salts

• common adjuvents

• help with the depot effect

• initially used for bacterial infections

• aluninium hydroxide, aluminium potassium sulphate, aluminium phosphate

• side effects

  • redness

  • swelling

  • fever

  • chills

  • pain

• somewhat outdated, newer adjuvants:

  • MF59

  • monophosphoryl lipid A (similar to LPS on gram negative bacteria

  • virosomes

vaccine evasion: influenza

• heamagluttanin proteins on the surface fuse with the cell membrane so the virus is taken up

• neurmidase and heamagluttanin are essential for the virus to survive (viruses proteins found on the surface which help them enter cells)

  • neuramidase is needed for budding of new particles

nomenclature

• virus type/origin/strain no/year of isolation/virus subtype

  • E.g: A/Fujian/411/2002/H2N2

• its important to know the strain so we know if its mutated

• Influenza A more virulent

• named based off proteins onn the surface as the immune system reacts based of the proteins on the surface

• Note; influenza is a negative stranded virus which means that its genome cant directly be translated into protein by the host cell and the genome is complementary to mRNA —> must be translated into positive sense first

antigenic drift and antigenic shift

ANTIGENIC DRIFT

• accumulation of point mutations eventually yeilds a variant protein no longer recognised by the AB to the original antigen

• cause of seasonal flu

• E.g: avian flu

ANTIGENIC SHIFT

• assortment of entire ssRNA between humans and animal variants effecting same cell

• the proteins on the surface on the new influenza subtype are so different that human ABs no longer recognise them and therefore have no immunity

• cause of pandemics

• E.g: swine flu

designing a vaccine

• has to be safe, effective and achievable in the target population

• primary immune response is not enough to produce a memory response

• branch of immune system activated crucial for success

• different approaches:

  • live attenuated

  • whole inactivated

  • split inactivated

  • recombinant virus vector —> where the virus is packaged into a vector and it allows the immune response of the pathogen but its not pathogenic

  • recombinant subunits —> proteins similar to pathogen like the toxins inserted)

  • DNA/RNA

  • synthetic peptides

Live attenuated vaccines

• the whole microbe is used, its attenuated so that its still intact but it has a reduced ability to grow

• doesnt replicate or cause disease

• can attenuate naturally by using a similar less virulent pathogen

• more common method: grow the micro-organism in sub optimal conditions which causes it to mutate (not expressing full virulence factors) and is a lot less virulent

HOW DO THEY WORK

• innoculation via mouth (linked to mucosal immune response)

• injected into host and used host replication to create more copies of the attenuated virus

• APC takes up and presents to IS —> generates B and T cell response

• this generates a strong immune response due to

  • same as pathogen just weaker

  • allowed to grow due to prolonged exposure

EXAMPLE

• BCG

• prevents TB

• uses attenuated version of bacteria

live attenuated - disadvantages and advantages

ADVANTAGES

• can replicate so provides a long exposure time so generates a strong immune response

• larger, more sustained antigen dosage

• no booster needed

• longer lasting immunity

• more efficient production of memory cells

DISADVANTAGES

• live vaccines, require refrigeration

• may develop symptoms of natural disease

• innumisation of immune deficient individual may lead to serious complications

• reversion to virulent form

inactivated vaccine

• microorganisms killed by external source like chemical agent: formaldehydde, gluteraldehyde

• E.g: pertussis, cholera, typhoid, polio, influenza, zika

• pathogen not able to replicate but still recognised so can produce danger signal

HOW DO THEY WORK?

• same way as other vaccines except immune response predominantly promotes an AB response as it cant replicate

• over time AB conc waynes → booster is required to produce memory response

inactivated vaccine - advantages and disadvantages

ADVANTAGES

• safer for immuno compromised individuals

• less chance of converting to pathogenic form

• more stable - no refrigeration

• suitable for less developed world - can be freeze dried

• viral and bacterial

DISADVANTAGES

• failiure to inactivate pathogen

• weaker immune response

• requires booster

• multiple doses

• dont induce T cell mediated response

subunit vaccine

• collection of vaccines classed together as subunit vaccines

• mostly consist of purified molecules from vaccine

• can e purified molecules from microorganism or generated through recombinant expression

• macromolecules recognised by immune system —> present similar to live organism, generate immune response

• toxoids used —> non toxic but looks like toxin

• can also be capsid polysaccarides —> protect microorganism from being taken up by APC —> can be used as an immunogen

• can generate recombinant proteins

• Examples: Hep B, strep pneumonia, meningitis, diptheria, tetanus

• good for immunocompromised individuals

bacterial capsular polysaccharides

• proteins and sugars associated with capsule prevent bacteria from being taken up

• antibodies to these molecules help to opsonise bacteria ad activate the innate immune system

• strep pneumonia have 13 antigenically distinct polysaccharides in vaccine which are also found on the surface of bacteria

• neiserria meningitis vaccine also has polysaccharides

HOW DOES IT WORK?

• polysaccharides on surface of bacteria avoid phagocytosis

• surface polysaccharides cultured and put into vaccine —> ABs made against bacteria if present

toxoid vaccine

• some bacteria produce toxins responsible for symptoms

• E.g: tetanus and diptheria

• toxin is purified and inactivated chemically with formaldehyde to eliminate toxicity

• when coupled to adjuvent toxin cant bind to cells

• promote antibody mediated IS but cant generate T cell mediated immune response

• polysaccharides generate B cell response without T cell help but no class switching

  • mostly IgM

  • although this can be improved with a protein carrier which can generate a T cell response

toxoid vaccine - advantages and disadvantages

ADVANTAGES

• dont expose host to whole pathogen - safer for immunocompromised individuals

• stable

• easy to produce

• generally well tolerated

DISADVANTAGES

• requires strong adjuvent

• can lead to pain/swelling

• dont always generate t cell help response - shorter lived

• booster required

• little cell mediated immunity

future of vaccines

2 potential methods:

1. viral vector carrier

2. DNA/mRNA vaccine

recombinant viral vector

• the viral genome is packaged inside less harmful vector

• maintain advantages of live attenuated vaccines

• doesnt ahve the mahor disadvantages of adverse effects

• can be used for virus, bacteria

HOW IT WORKS

• vaccinia vector used - plasmid containing vaccinia promoter

• gene from pathogn inserted into plasmid

• plasmid cultured with virus

• vaccinia virus then injected into patient

• use all the prooerties of adenovirus

• not restricted to one gene - multiple Ags

• the vector is easily exposed to host and the vector is taken up by host cell

• gene of interest translated into protein

• protein produced and presented to the immune system

• Ag present but not whole pathogen

• generted B and T cell response and also strong memory response

• E.g: astrozenica/oxford university vaccine

  • adenoviral vector used to contain gene to produce spike protein on sars cov 2

DNA Vaccines - advantages and disadvantages

ADVANTAGES

• actual DNA low immunogenicity

• induce long term immune response

• easy to generate

• can be produced large scale

DISADVANTAGES

• effects of long term expression unknown

• formation of anti nucleic acid AB possible

• poor delivery

• Ag must be known

• restricted to peptide and protein Ag

cancer vaccine

• doesnt need a viral vector

• can directly transduce cells with DNA via electrooperation

• muscle cells produce protein and present it to DCs

• generates cytotoxic t cell response against cancer cell

• kills tumor cell as if its pathogenic

COMPLICATIONS

• tumor lives in suppressor environment

• macrophages and Tregs killing t cells

• antigen not sufficient for immune response

• more antibodies required to supress immune environment —> CTLA4, PD1

mRNA vaccines

• mRNA against spike protein packaged in lipid nanoparticle

• 5’ cap which helps to have better translation by stabilising mRNA

• 5’ UTR and 3’ UTR which conatin regulatory genes - can be recognised by ribosomes

• coding domain: trimerised receptor binding domain of Sars Cov2 spike protein

• Poly A tail for translation

• important mRNA protected

• fuses with host cell and protein produced —> proteosome

• antigen presented on MHC —> t helper cell and B cell activation

mRNA vaccines - advantages and disadvantages

ADVANTAGES

• may appear to perform better

• doesnt need to enetr the nucleus

• safer - no possibility of host integration

DISADVANTAGES

• stable at -80 degrees