Lecture 3: Drug repurposing and vaccine development Flashcards
Vaccine definition
A preparation that is used to stimulate the body’s immune response against diseases.
Vaccines are usually administered through injections, but some can be administered by mouth or sprayed into the nose.
Vaccination
The act of introducing a vaccine into the body to produce protection to a specific disease.
Prophylactic Vaccines
Induce an immune response that protects against subsequent infection or disease.
Therapeutic Vaccines
Induce or augment immune responses involved in the control of virus replication. Prevent disease recurrence.
Treat existing cancers by stimulating the body’s natural immune defences.
BENEFITS OF VACCINATION
Disease Control
Mitigation of disease severity
Prevention in unvaccinated populations
Protection against related diseases and cancer
Societal and other benefits
Immunology 101
- First line of defence – Innate Immunity
- Second line of defence – Acquired Immunity
- Two different types of immunity important for acquired immunity.
- antibody-mediated immunity (humoral immunity)
- cell-mediated immunity
- Vaccines stimulate the body’s own immune system to protect the person against subsequent infection or disease.
Main Vaccine Technologies
Inactivated vaccines
* Live Attenuated vaccine
* Subunit vaccines
* Toxoid vaccines
* Viral vectored vaccines
* mRNA vaccines
Inactivated Vaccines
- Killed virus particles (e.g. heat, formaldehyde, radiation)
- Inactivated vaccines generally induce the weakest immune responses and recipients often require a “booster” vaccination.
- Generally, the immune response dominated by neutralising antibodies.
- Killed vaccines are considered safe - cannot replicate and cause disease.
- Typhoid vaccine, Salk poliomyelitis vaccine.
Live Attenuated Vaccines
a type of vaccine that uses a weakened (or “attenuated”) form of the germ that causes a disease (e.g. cold adapted)
The vaccine contains live germs, but these germs have been weakened so they can’t cause serious illness.
Because the germs are alive but weakened, they mimic a natural infection very closely. This helps the immune system learn to fight the actual disease effectively.
These vaccines tend to create a strong and long-lasting immune response, often with just one or two doses.
- Often the most successful vaccines
- Organism can still multiply and appear like a genuine infection.
- Both antibody-mediated and cell-mediated immunity.
- Immunity produced is often lifelong
- Carry the greatest risk – reversion to virulence, not for the immunocompromised.
- Measles, mumps, and rubella.
Subunit Vaccines
- Use parts of an organism (antigens) that are known to stimulate the immune system.
- Protein antigen can be produced in large quantities in cell culture.
- Antibody-mediated immune response
- Subunit vaccines cannot revert to a virulent form – good for oncogenic or persistent viruses
- Example: Hepatitis B vaccine, COVID-19 vaccine (Nuvaxovid, Novavax), RSV (Arexvy, GSK)
- Can self-assembled in ‘virus-like particles’ which have the structure and antigenic characteristics of virions, but with no genome (HPV vaccine; Gardasil)
Toxoid Vaccines
- A toxin from certain bacteria that has been made harmless but that elicits an immune response against the toxin.
- Generally induce a weaker immune response requiring a booster and adjuvants
- Cannot cause disease.
- Example: tetanus or diphtheria.
Viral Vectored Vaccines
a type of vaccine that uses a different, harmless virus to deliver important instructions to your cells.
This harmless virus carries genetic material from the germ that causes the disease. This genetic material gives your cells the instructions to make a part of the germ called an “antigen.”
Your immune system recognizes this antigen and learns how to fight the actual germ.
E.g. Ervebo Ebola vaccine, AstraZeneca COVID-19 vaccine
- In-vivo production of antigen = correct folding, posttranslational modifications etc
- Can be grown to high titres in many mammalian and insect cell lines.
- Induce neutralizing antibody responses.
- Induce cell mediated immunity
- Ideally…
- Low risk of pre-existing immunity
- Low anti-vector response
- Lack of a DNA intermediate during viral replication (doesn’t risk insertional mutagenesis)
COVID-19 Vaccine (AstraZeneca)
- Chimpanzee adenoviral vector (ChAdOx1) – avoids pre-existing immunity to human Adv vectors (common cold)
- Replication deficient viral vector
- Delivering codon‐optimised DNA sequence of SARSCoV-2 spike protein.
- Spike proteins is properly produced, folded and presented to the immune system via cell surface MHC
- Stimulated neutralising antibody and cellular immune responses
Ervebo Ebola vaccine (Merck Sharp & Dohme Corp.)
- Replication-competent, live attenuated (weakened) recombinant vesicular stomatitis virus (rVSV) vaccine.
- Non-segmented, negative-stranded RNA vector with VSV glycoprotein (GP) gene replaced by Ebola GP gene.
- Vector delivers the antigen gene of interest inside the target host cell for protein production and presentation
(on MHC) by the cell.
mRNA Vaccines
A type of vaccine that uses a small piece of the messenger RNA (mRNA) from the germ that causes the disease. This mRNA gives your cells the instructions to make a protein that triggers an immune response.
- mRNA vaccines are relatively easy and quick to design
- mRNA vaccines cannot revert to a virulent form.
- mRNA is processed in the cytosol not the nucleus and cannot be integrated into the host genome (no risk of insertional mutagenesis)
- Produces properly folded spike protein for presentation to the immune system on cell surface MHC proteins.
- Storage and transportation issues at various levels of complexity
- Pfizer vaccine: -70 degree storage, once thawed can be kept refrigerated for 5 days
- Moderna vaccine: -20 degree storage, once thawed can be kept refrigerated for 60 days.
