L14: COVID Virus: Vaccines and Drug Development

Question 1

what are the three parts of a simplified schematic of a virus?

these are in most viruses, but specifically the SARS-CoV-2 virus

Answer 1

1. viral nucleic acid on the inside = recipe for viral infection
2. proteins and lipids on the outer coat
3. spike proteins on the outside

Question 2

what is the human gene/protein that accepts the SARS-CoV-2 virus

Answer 2

ACE2 protein

• binds tightly to the spike proteins on the covid virus

Question 3

what happens when the virus is inside the cell? (3 steps)

Answer 3

• it releases its own genetic material, so its viral RNA
• the infected human cell reads the genetic material and begins to make parts of the virus (could be the s-spike protein – we are the bioactive part)
• the new copies of the virus are assembled and carried to the outside of the cell to infect nearby healthy cells

Question 4

what are coronaviruses? what does corona mean? how common is it?

Answer 4

• a large family of viruses that can infect humans or animals

-“Corona” = the spike proteins look like the corona (crown) of the sun

• Cause illnesses that range from the common cold to the 2003 SARS and 2012 MERS outbreaks

Question 5

what is the transmissibility of covid-19? how do we measure it?

Answer 5

• it is a highly transmissible virus like other known viral infections
• R0 tells us how contagious a disease is
• Average # of individuals that get infected from one infectious person
• Ideally, we want R0 ≤1

R0s for common viruses:
COVID = 2-2.5
SARS= 2-4
Ebola = 1.6-2

Question 6

what is the fatality of COVID

Answer 6

• it has a low fatality rate compared to other diseases like SARS, tuberculosis, Ebola, MERS etc.

Question 7

what are the several approches that have been used to develop covid-19 vaccines?

(4)

Answer 7

Traditional approaches:
1. Killed or attenuated virus
- viruses that are very weak or have been killed entirely
- used to stimulate our immune system to recognize surface proteins on the virus and mount and immune response
- doesnt cause disease, but allows the immune system to recognize the foreign virus

2. Protein
   - use pieces of proteins from the pathogen to do the same as above
   - used commonly in the SARS-CoV-2 spike protein

Novel approaches:
1. viral vectors
- using viruses to actually carry material for us into the host cells so our body can recognize it and fight against it
- using adenovirus to carry the SARS-CoV-2 DNA into the host cells
- ex. oxford/astra zeneca, and johnson&johnson

2. DNA / RNA
   - DNA -> RNA -> Protein
   - protein has been traditionally used to mount an immune response
   - can create the protein in different ways: through mRNA or DNA
   - ex. Moderna, Pfizer

Question 8

what are the three approaches to trigger an immune response

Answer 8

1. using a whole virus or bacterium
2. parts that trigger the immune system (ex. spike proteins)
3. just the genetic material in the nucleic acid

all make effective vaccines

Question 9

what are viral vectors – type of vaccine

Answer 9

• Modified viruses that deliver the target antigens genetic code so the body can recognize and fight against it
• When the modified virus is administered as a vaccine, it enters cells and instructs them to produce the antigen proteins, triggering an immune response
• Vectors do not contain disease-causing genes
• Can be broken down into 2 types:
  –> Replicating
  –> Non-replicating

Question 10

what are DNA/RNA types of vaccines

Answer 10

• DNA or RNA (nucleic acids) that codes for a single antigen protein so that the body can recognize this bad protein and fight against it
• RNA especially are charged and dont sit stabley in the environment… thus:
• Can be encapsulated in a vessicle/ fatty coat (or bubble) to fuse with the cell membrane and deliver the genetic material for the protein code inside the person to create the vaccine

Question 11

what are protein based vaccines

Answer 11

• A protein is extracted from the virus, purified, and injected as a vaccine
• these are different kinds of biologics
• acts as a bioreactor
• Mimic the coronavirus to trigger an immune response

Question 12

how are killed or weakened viruses made?

Answer 12

• Killed virus – virus is inactivated using chemicals or heat
• Weakened virus – virus has mutations in its genome (genetically engineered), so it doesn’t express its viral proteins as well

Question 13

Why did we not find a treatment for SARS given that another viral disease is likely to reoccur?

OG virus was in 2003 called SARS-CoV

COVID was in 2019 and was SARS-CoV-2

Answer 13

• After the SARS outbreak in 2003, vaccines against SARS-CoV were developed
• However, development was halted as virus was eradicated and diminished
  –> the Rnot and lethality of the virus was low and thus eventually stopped
• No commercial reason to revive development at the time, took time and money

Question 14

how is the clinical trial process during the pandemic different to what it is like typically?

Answer 14

It was accelerated tremendously!

• typically takes 15 years to develop vaccine but for covid they developed it in 10 months to 1.5 years
• they had pre-exisiting data from SARS-CoV and MERS-CoV and toxicology reports which limited the testing from 4+ years to months
• they overlapped the phase 1, 2, 3 trials instead of waiting till completion for one to start the other
• they really riskly started mass producing the vaccines even before getting approval so they could distribute it asap if approved.

Question 15

what was diversity like in early clinical trials for a covid vaccine

Answer 15

very high diversity rates because we didnt know which type of vaccine would work (mRNA, viral vector etc..)

Question 16

Describe the comirnaty vaccine of COVID made by BioNTech & Pfizer. what is it, how was it tested in each phase

Answer 16

what was it:
- mRNA that encodes the spike protein enclosed in a lipid nanoparticle (person converts mRNA to protein and mounts immune response)

• Two doses administered intramuscularly 3 weeks apart
• Health Canada authorized this vaccine with conditions on December 9, 2020

Phase 1:
- Placebo-controlled, observer-blind, dose-escalation trial (n=195)
- Evaluated the safety of different vaccine doses of 2 vaccine candidates – has some differences in the formulation. tested in elderly also (BNT162b1 and BNT162b2)

Phase 2/3:
- 360 adults
- Evaluated the efficacy of 30 μg BNT162B2 vaccine dose against placebo
- Data pooled with Phase 3 trial

Phase 3:
- ~44,000 adolescents and adults
- Evaluated the efficacy of 30 μg
against placebo (let both groups roam and tested if they would be effected)
- Vaccine was 95% effective in preventing COVID-19

Question 17

how is the efficacy rate calculated for pfizer vaccine?

Answer 17

• Had a 20,000 large group for both placebo and vaccine
• after they roamed, 162 placebo participants were infected, and 8 vaccine participants were infected.
• the infection risk was calculated bt dividing infected by initial group size
• relative risk was calculated by subtracting infection risk percents
• efficacy rate = relative infection risk/ placebo infection risk

= 95%

Question 18

Describe the Spikevax vaccine of COVID made by Moderna. what is it, how was it tested in each phase

Answer 18

what is it:
- mRNA that encodes the spike protein enclosed in a lipid nanoparticle
- Two doses administered intramuscularly 4 weeks apart
- Health Canada authorized this vaccine with conditions on December 23, 2020

Phase 1:
- 120 healthy adults
- Evaluated the safety of 25-250
μg vaccine doses
- Vaccine was generally safe and well tolerated – what we are testing in phase 1

Phase 2:
- 600 healthy adults
- Evaluated the efficacy of 50 and 100 μg vaccine doses against placebo

Phase 3:
- ~30,000 adults
- Evaluated the efficacy of 100 μg vaccine against placebo
- Vaccine was 94.1% effective in preventing COVID-19

Question 19

how long did it take for the Pfizer vaccine to be made

Answer 19

11 months to a year.
- SARS-CoV-2 genome was released late feb
- preclinical started right after
- Phase 1, 2 started late april
- phase 2, 3 started late july
- rolling submission of data started in october
- EUA use started december

Question 20

why did we get COVID vaccines so quickly? ten reasons

Answer 20

1. pandemic plans were already in place
2. China identified the novel coronavirus early on
3. Tremendous funding was provided immediately
4. Speedy clinical trials process
5. Quick commencement of vaccine trials
6. Availability of research data
7. Studies garnered many volunteers
8. Rapid results from trials
9. Early vaccines worked well
10. Regulation took place while the studies were continuing

Question 21

what won the nobel prize in 2023

Answer 21

mRNA vaccines for COVID-19:
Katalin Karikó and Drew Weissman

for physiology or medicine

Question 22

why were infographics so important in covid posters — NYC’s approach

Answer 22

helped everyone understand what was in and what was not in the vaccines so people know correct information about the vaccine

these infographics were shown in NYC and steered people to be vaccinated

Question 23

explain canada’s novel approach to a covid vaccine and why it was discontinued

Medicago’s plant based COVID-19 vaccine

Answer 23

Medicago’s plant based COVID-19 vaccine
- Virus-like particles are made in plants, which are then harvested and purified
- 71% efficacy against COVID-19
- Approved in Feb 2022 by Health Canada
- However, financial and production difficulties, did not bring vaccine to market

Question 24

what was Nuvaxovid (Novovax), another canada-approved vaccine for covid, and what did it contain

Answer 24

Nuvaxovid (Novovax)

• protein-based vaccine
  –> This kind of vaccine has been used for >30 years (e.g. hepatitis B vaccine)
• given as primary (first vaccine) or Omicron XBB.1.5 subvariant vaccine
• Contains:
  –> Spike protein, produced by insect cells (bio-reactor)
  –> Immune system stimulant, derived from the soapbark tree (so that it will react against the protein)
  –> Health Canada approval December 2023

Question 25

what is drug repurposing

-what type of molecule
- what are the two types of new purposes

Answer 25

• its a small molecule drug treatment (not a vaccine approach)
• the initial response is to repurpose old drugs
• Uses existing drug or preclinical chemical compound for a new purpose, either:
  –> New target and/or
  –> New disease (“indication”)

new target: the same drug can act on another target to inhibit another disease
same drug –> different target than previously targetted –> prevention of different diseases

new disease indication: the same drug and target is used to prevent another disease
same drug –> same target as previous target –> prevention of another disease

Question 26

what are some pros to drug repurposing– both scientific and financial?

Answer 26

• it is time and cost effective

Scientific
- New knowledge gained about role of protein target in a new disease
- New knowledge gained about role of protein target in an old disease

Financial
- May not have to re-test its safety in phase I trials
- Existing pharmaceutical supply chains could facilitate the manufacturing and distribution of the drug

Question 27

what is Remdesivir – failed to benefit drug #1

Answer 27

• small molecule drug
• Originally produced to treat Ebola virus infections
• Antiviral agent that needs to be metabolized to become active
• helps grow nucleic acid chains (Adenosine mimic “analog”) but does not build the chain any further
• However, in the clinic there was no significant effect on mortality, length of hospital stay even though it was a good idea

Question 28

what is Lopinavir-ritonavir – failed to benefit drug #2

Answer 28

• Used for the treatment and prevention of HIV/AIDS
• Protease inhibitor
• However had no added benefit beyond standard care

Question 29

what is Chloroquine/ hydroxychloroquine – failed to benefit drug #3

Answer 29

• Anti-malarial drug
• Increases pH of lysosomes and endosomes to neutralize virus
• No added benefit beyond standard care

these drugs are great in theory and scientifically but do not benefit in clinical trial testing - should be used to repurpose

Question 30

What is Paxlovid and what was special about the guy that led the clinical trials – how long did it take him

Answer 30

• Paxlovid is used as a treatment for COVID-19
• Paxlovid: each dose is comprised of 3 tablets
• 2× 150 mg nirmatrelvir + 1× 100 mg ritonavir
• From idea to clinical trials in 2 years
• Rookie drug development leader
  –> “having never led a drug discovery project before, Owen didn’t feel bound by any preconceived notions of how such a program should be run”
• Chemical similarity to peptide, blocks viral protease (target)
• Had a lead chemical (hit + improvements) from 2003 drug dev project for SARS

Question 31

What are pharmacokinetic boosters (PK boosters)

Answer 31

• Compounds used in combination with a primary therapeutic agent that do not directly affect the disease but rather enhance/restore the activity of the primary agent
• essentially, used in conjunction with main active drug to help prolong the initial drugs effects (naturally when the body takes a drug it destroys it but this booster helps maintain it)
• ex. Ritonavir: is the component of paxlovid that affects the PK of nirmatrelvir

Question 32

what are three advantages of PK boosters

Answer 32

◦ Allows for lower dosage of primary agent while maintaining therapeutic levels
◦ Reduces pill burden and dosing frequency, thereby improving adherence
◦ Reduces extent of toxic side effects due to lower daily dose of primary drug

Question 33

what was the paxlovid clinical trials like? comment on efficacy

Answer 33

EPIC (Evaluation of Protease Inhibition for COVID-19) Phase 2/3
◦ N = 2,246 at final analysis; trial stopped early due to demonstrated benefit!!!!
◦ 88-89% reduction in hospitalization/death compared to placebo
◦ 0 deaths in Paxlovid arm vs. 12 deaths in placebo arm

Efficacy: reduction in risk of COVID-19-related hospitalization or death from any cause in patients who took PAXLOVID within five days of symptom onset

Question 34

what is long covid?

how many symptoms are recorded?

what percent of adults experience longer-term symptoms 3 or more months after infection?

Answer 34

• symptoms of COVID-19 persist for more than 12 weeks after the infection
• > 100 symptoms recorded
• 15% of adults who got COVID-19 experienced, or still experience, longer-term symptoms 3 or more months following their initial COVID-19 infection.

Question 35

give stats about the adults with longer-term symptoms of covid:

percent who have symptoms for 1 year or longer

percent who reported their symptoms to limit daily activities

percent who missed work or school because of long covid

Answer 35

*47% had symptoms for 1 year or longer
*21% reported their symptoms often or always limited their daily activities
*74.1% of those who were employed or attending school missed work or school due to their symptoms
–> on average, these adults missed an estimated 20 days each

Question 36

Long covid symptoms and pathology:

heart
lungs
immune system
pancreas
Gastrointestinal tract
neurological system
kidneys, spleen, liver
blood vessels
reproductive system

Answer 36

heart
- chest pain
- palpitations

lungs
- prolonged cough
- dyspnoea – shortness of breath

immune system
- irregularities

pancreas
- diabetes

Gastrointestinal tract
- stomach pain
- nausea

neurological system
- cognitive impairment
- fatigue
- memory loss
- disordered sleep

kidneys, spleen, liver
- organ injury

blood vessels
- fatigue

reproductive system
- reduced sperm count
- irregular periods
- erectile dysfunction

Question 37

why did long covid happen (5 proposed mechanisms)

Answer 37

some people thing that covid is prolonged because …

1. immune dysregulation
   - infection itself is persistent
2. microbiome dysbiosis
   - 90% of cells in us are bacteria
   - this is present in our microbiome which can change (in our gut)
   - people believe our microbiome has shifted to prolong covid
   - fix would bring it back in balance
3. autoimmunity and immune priming
   - helped prolong covid
4. blood clotting
   - endothelial dysfunction
5. nerve disorder
   - dysfunctional signaling in brain stem

Question 38

describe the study that stated that vaccination is best for prevention against long COVID

why is this against what some people think?

Answer 38

most people believe that when you get covid and recover, you are immune from it now. people argue this immunity is equal to the immunity you get from a vaccine.

this study used 20 million people (10 million vaccinated +
10 million unvaccinated people) showed that there is much more protection against long covid if you are vaccinated
- used all age groups
- showed strong evidence
- mainly stresses the protection for young adults

Question 39

describe the NIHs long covid clinical trial that just opened up (march 12, 2024)

what are the Interventions being tested?

Answer 39

NIH opens long COVID trials to evaluate treatments for autonomic nervous system dysfunction.

the Interventions being tested to see if they actually benefit long covid:
1. Intravenous antibodies
2. Oral pill to treat heart rate (Ivabradine)
3. High-salt diet

the clinical trial prioritizes diversity!