MII2 vaccination and immunotherapy

what is passive immunisation

immediate, temporary transfer of antibodies to an individual to provide rapid protection against infection

what are the two forms of passive immunisation

natural - infants acquire antibodies from their mother

artificial - transfer of antibodies from the blood of immune people

what is active immunity

the immunity that results from the production of antibodies by the immune system in response to the presence of an antigen.

what are anti-sera

a blood serum (often non human) containing polyclonal antibodies used to provide rapid, passive immunity against specific diseases, toxins, or venoms

how is the animal immunised

given non-lethal doses of an antigen, then the blood is collected and antigen purified

what are the applications of antibody transfer and give examples

rapid treatment during acute illness

- try to prevent full infection after exposure to a pathogen

- snake venom or toxins

- Ebola, measles, rabies etc

as a preventive measure

- cytomegalovirus after transplantation

what are two advantages of antibody transfers

fast acting (important for snake venom or rabies)

support for immunodeficiencies

what are 4 disadvantages of antibody transfers

antibody levels fall quickly

given intravenously

serum sickness

expensive and complex to produce and store

what is serum sickness

immune system reacting to the foreign antibodies from the transfer

how are monoclonal antibodies made

Monoclonal antibodies are made by combining mouse B cells and a tumour cell to form a hybridoma

what are the advantages of monoclinal antibodies (2)

near unlimited supply

even rare antibodies can be isolated

can be manipulated

have a single specificity

why can't humans have mice antibodies

serum sickness

how are mice antibodies converted to human antibodies

Raise a monoclonal antibody with the right specificity from an immunised mouse.

Replace the CDR (hypervariable region) of a human monoclonal antibody with the CDR derived from the mouse monoclonal antibody.

what are the three modern ways of making monoclonal antibodies

1. phage display

2. EBV transformation

3. single cell expansion & selection

what is phage display

a bacteriophage is engineered to display a particular antigen on its surface

what is the principle of vaccination

• introduce the immune system to a pathogen in a "controlled" environment

• cause the immune system to remember the pathogen and respond to it

• enable the immune system to effectively clear the pathogen to prevent disease

what is the most common type of vaccine

live attenuated -- weakened/inactivated pathogen

how might a pathogen be weakened

virulent genes are deleted or modified

what chemical is often used for attenuating pathogens

formalin

give examples of diseases prevented with a live-attenuated vaccine

MMR, flu, yellow fever, polio

what is the mechanism of the live-attenuated polio vaccine

passage through non-human cells causes spontaneous mutation which cannot replicate in the nervous system

what are subunit vaccines

use components of pathogenic organisms, not the whole organism

what is the advantage of subunit vaccines

no extraneous pathogenic particles such as DNA

what is the principle of vector vaccines

Antigen genes are inserted into the vaccinia virus genome with virulence factors removed

which type of vaccine covered so far might require multiple doses

killed whole organism

how are chicken eggs used in vaccine production

Primarily for influenza—acts as a sterile environment to replicate large quantities of the virus.

- Virus strains are injected into fertilised chicken eggs to incubate and harvest for purification.

- These are used for the vaccine

what are some limitations to traditional vaccines

- not all organisms grow in culture

- expense

- insufficient attenuation?

- reversion to infectious state

what are virus-like particle vaccines

self-assembled homogenous nanoparticles derived from the coat proteins of viral capsids

give an example of a non enveloped virus like particle vaccine

HPV

do virus like particles contain genetic material

no

what are outer-membrane vesicle vaccines

Non-replicating, nano-sized particles secreted by gram-negative bacteria. These are highly immunogenic.

what uses outer membrane vesicle vaccines

N. meningitis

what is the principle of protein-polysaccharide conjugate vaccines

Combines a bacterial capsular polysaccharide with a carrier protein to induce strong T cell immunity.

what type of vaccine was the covid-19 vaccine originally

viral vector

why was a chimpanzee adenovirus used for the covid vaccine (2)

1. unlikely to be pre-immune to the vector

2. encoded the spike protein of covid

what type is the modern covid vaccine

mRNA vaccine

what is the mRNA for the covid vaccine enclosed in

lipid nanoparticles

do the covid vaccines require adjuvant?

no

how does the intranasal 'FluMist' flu vaccine work

it is live-attenuated and replicates in the nose (cold adapted), causing a small immune response. this modified virus strain cannot replicate in the temperature of the lungs

what is the necessity of adjuvants

enhance and direct the adaptive immune response to the vaccine antigens.

what might happen without adjuvants

immune tolerance/ignoring the antigen

how do adjuvants direct adaptive response

activate DCs by mimicking components of microbes that bind to PRRs

what is the most widely used adjuvant

alum or aluminium salts

what do adjuvants increase release of at injection site

chemokines and cytokines

what are two risks of vaccine adjuvants

1. increases reactogenicity locally or systemically

2. nonspecific immune activation (rare)

- immune mediated disease

- inflammatory disease

when can vaccine derived infection occur

in areas where sanitation is poor, pathogens (from the vaccine) can replicate and be passed on to non vaccinated people through faecal/oral routes

what can cause live-attenuated pathogens to become dangerous

mutations can revert them to their pathogenic state

also lowkey not good for immunocompromised people

what are 3 advantages of live-attenuated

activates all phases of the immune system

provides more durable immunity, less boosters needed

fast acting

what is original antigenic sin, and what it is also known as

Also known as immunological imprinting, it is the tendency of the immune system to preferentially utilise immunological memory based on the first strain of a pathogen it encountered when subsequently encountering a slightly different strain.

which process makes flu vaccines change each year

antigenic drift

what is a phase I human trial for

testing safety and dose response - 6-20 people

how many participants in a phase II human trail

200-300 people

what is a phase III human trial for

efficacy (reduces cases), identifying rare side effects (1000s of participants)

what is an experimental way of testing vaccine efficacy

check for the antibodies using radioimmunoassay or ELISA protocol

what is the synovium

The Synovium is a thin layer of tissue inside the synovial capsule that secretes synovial fluid.

what causes rheumatoid arthritis

autoimmune disorder

what causes immune cells to attack mucosal sites in RA and what does this result in

post translational modifications to joint cells leading immune cells to not recognise them as self, cyto/chemokine build-up and autoantibody formation.

hyperplasia of the lining layer, bone and cartilage destruction

what are the two types of antirheumatic drugs (DMARDs)

Synthetic DMARDs and Biological DMARDs

what does DMARD stand for

disease modifying anti-rheumatic drugs

what is the most common target of biological DMARDs

Tumor necrosis factor alpha - TNFa (TNFa inhibitors)

how is TNFa involved in rheumatoid arthritis

it is a cytokine involved in inflammation. When it is overproduced it causes inflammation and cell death which leads to arthritis

what are the two methods of blocking cytokine action

1. neutralise the cytokines before they reach the receptor

2. block the receptor with an antagonist or monoclonal antibody

which method of blocking cytokine action is used for TNFa

neutralise the cytokine

what are the three methods of preventing cytokine binding to tis receptor

soluble receptor, natural antagonist, monoclonal antibody

describe the immune systems control of cancer (4 steps)

1. dead cancer cells release antigens that activate the immune system

2. T cells are trafficked to the tumour

3. T cells infiltrate the tumour and kill the cells

4. T cells die and release more antigens

what is the 3 step process by which tumour cells can evade the immune system

1. immunoediting

2. immunosuppression

3. escape

describe the stages of tumour cells evading the immune system

1. immunoediting - The cancer cells change from highly immunogenic to poorly immunogenic

2.  Immunosuppression - Use of immunosuppressive molecules such as PDL1

3.  Escape - Large tumours induce stromal cells to surround the tumour and act as a physical barrier to the immune cells

how can monoclonal antibodies contribute to tumour therapy (2)

1. target specific protein overexpressed on specific tumour cells

2. target proteins normal expressed on certain cell types and also on tumour cells

give an example of a protein that is overexpressed on tumour cells (protein and what tumour)

HER2 on breast cancer cells

give an example of a normally expressed cell found on tumour cells (protein and what tumour)

CD20 on B cell lymphomas

what is the HER group of receptors

human receptor for EGF

how is HER2 involved in tumorigenesis

activation of HER1,3,4 activates HER2.       Amplification of the HER2 gene leads to overexpression of HER2 proteins, increasing cell division and growth.

what type of therapy is used to target HER2

monoclonal antibodies

how can targeting CD20 on B cell lymphomas prevent tumorigenesis

Using a monoclonal antibody that targets and binds the CD20 antigen on B lymphocytes.

The binding marks the B cell for destruction via CDC (complement dependant cytotoxicity) and ADCC (antibody dependant cellular cytotoxicity), depleting CD20 cells.

what are tumour antigens

any antigen expressed by the cancer cells that elicits an immune response

what is a neoantigen

mutations in normal human proteins that are recognised as foreign by the immune system

what will display the neoantigens to T cells

type I MHC

will a T cell be activated once shown a neoantigen?

no, they need the second co-stimulatory signal

what can a tumour do to prevent T cell activation once bound

up regulate CTLA4 and PD1

why does upregulating CTLA4 and PD1 prevent T cell activation

they are inhibitory surface co-stimulatory receptors that will prevent T cell activation when binding.

what therapy can be used to inhibit PD1 and CTLA4

monoclonal antibodies

what is CAR T-cell therapy

personalised immunotherapy that modifies a patients T lymphocytes to recognise and destroy cancer cells

what does CAR T stand for

chimeric antigen receptor T cell

what feature of CAR T cell cytoplasm enhances tumour killing

it contains extra co-stimulatory domains

what is the benefit of personalised anti cancer therapy as opposed to universal

less likely to be rejected by the body