3. COVID Mortality
• Current infected worldwide- 65, 067, 153
• India- 9, 556, 881
• Current death toll worldwide-1, 503, 445
• India- 138, 946
• 2nd most affected country in the world
5. Introduction
• Previous work to develop a vaccine against the coronavirus
diseases SARS (2002-2004) and MERS established knowledge about
the structure and function of coronaviruses, which accelerated
development
• Development of the world's COVID-19 vaccine research involves
organizations in North America (40%), Asia and Australia (30%), Europe
(26%), and South America and Africa (4%)
• As of October 2020, there were 321 vaccine candidates in development
worldwide
• In November, 56 vaccine candidates were in clinical research: namely
41 in Phase 1–2 trials and 15 in Phase 2–3 trials
6. Outline
• Global Regulatory Bodies for COVID-19 Vaccine Development
• Phases of Clinical Drug Trials
• mRNA vs. Viral Vector Vaccines
• Current Vaccine Pipeline
• Pfizer- BioNTech (USA)
• Moderna (USA)
• Oxford- AstraZeneca (UK)
• Sputnik- V (Russia)
• Covaxin (India)
• ZyCov-D (India)
7. International Leaders
• WHO- World Health Organization
• CEPI- Coalition for Epidemic Preparedness Innovations
• GAVI- Global Alliance for Vaccines and Immunization
• ACT- A- Access to COVID-19 Tools Accelerator
• COVAX (COVID-19 Vaccines Global Access)
• Bill and Melinda Gates Foundation
• OWS- Operation Warp Speed
8. OWS: body responsible for strategic
approach, coordination and resource
allocation
ACTIV: NIH established public-private
partnership for coordinating COVID-19
response
COVPN: NIH funded networks being
utilized for COVID-19 Phase 3 trial
design and execution
ACT-A: Global collaboration to
accelerate development, production
and equitable access to new
diagnostics, therapeutics and vaccines
• Vaccines: COVAX Facility (GAVI, CEPI,
WHO)
• Diagnostics: FIND, Global Fund
• Treatment: Unitaid, Wellcome Trust
• Health Systems Strengthening: World
Bank, Global FundCEPI: Global partnership to accelerate
development of vaccines against
emerging infectious diseases and enable
equitable access
GAVI: Global vaccine alliance with goal of
creating equal access to new and
underused vaccines
Who’s Who?
US Effort
Global Effort
9. COVAX
• Vaccines pillar of the ACT-A, led by
CEPI, GAVI, and WHO
• Aims accelerate the development and
manufacture of COVID-19 vaccines
• Provide doses for at least 20% of
countries' populations
• Diverse and actively manage portfolio
of vaccines
• Vaccines delivered as soon as they
are available
• End the acute phase of the pandemic
• Rebuild economies
10. What is a Clinical Drug Trial?
• Clinical trials are studies to test new drugs, drug combinations, new
uses for existing drugs, and medical devices
• They are a way to test new methods of diagnosing, treating, or
preventing health conditions. The goal is to determine whether
something is both safe and effective, and performed only if deemed
appropriate for care of patients.
• Many trials look at new ways to detect, diagnose, measure the
extent, or even look at ways to prevent diseases from happening.
• All new treatments must go through clinical trials before being
approved by the Food and Drug Administration (FDA)
11.
12. Preclinical Research
• It assesses the features of a test or treatment- if research suggests that the new
drug or treatment is likely to be safe and effective in people, they move forward with
a clinical trial
• Includes:
• Cell studies: These are often the first tests done on a new treatment. To see if it
might work, researchers look for effects of the new treatment on human/ animal
cells that are grown in a lab dish or a test tube
• Animal studies: Treatments that look promising in cell studies are tested next on
in live animals. This gives researchers an idea of how safe the new treatment is
in a living creature.
• The US Food and Drug Administration (FDA) must give permission before the
treatment can be tested on people
13. Phase 0 Clinical Trial
• First clinical trial done among people
• Aim to learn how a drug is processed in the body and how it affects
the body
• A very small dose is given to about 10 to 15 people for a short period
of time
• The purpose is to help speed up and streamline the drug approval
process. If the medication acts differently than expected, the
investigators will likely to do some additional preclinical research
before deciding whether to continue the trial.
• They aren’t widely used; not a required part of testing a new drug
14. Phase 1 Clinical Trial
• Aims to find the highest dose that can be taken with the fewest side
effects, as well as the best way to administer the drug
• About 20 to 80 people participate (healthy individuals)
• Safety is the main concern- investigators monitor participants very
closely to see how their bodies react to the medication and vice versa
• Doctors start by giving very low doses of the drug to a few patients.
Higher doses are given to other patients until side effects become too
severe or the desired effect is seen.
• Most often include people with different types of disease or variants
of the disease
• Placebos are not used
• According to the FDA, approximately 70% of medications move on to
phase 2
15. Phase 2 Clinical Trial
• Assess safety and drug efficacy
• Often new combinations of drugs are tested
• Treated using the dose and method found to be the safest and most effective in
phase 1 studies
• The drug is often tested among 100 to 300 patients with a specific type of
disease that the new drug is meant to treat
• Investigators monitor participants for several months or years to see how
effective the medication is and to gather more information about any side
effects it might cause.
• The new drug is rarely compared to the current (standard-of-care) drug that is
used
• Placebos are not used in most cases
• The FDA estimates that about 33% of medications move on to phase 3
16. Phase 3 Clinical Trial
• Compares the safety and effectiveness of a new drug to the
standard-of-care drug- assessment of side effects and which drug
works better
• Because doctors do not yet know which treatment is better, study
participants are often randomized to get either the standard treatment
or the new treatment. When possible, a double-blind study is used. A
computer program is often used to randomly assign people.
• Placebos may be used in some phase 3 studies, but they’re never
used alone if there’s a treatment available that works. Sometimes, a
patient who is randomly assigned to the placebo for part of the study
will at some point be offered the standard treatment as well.
17. Phase 3 Clinical Trial
• Usually involves up to 3,000 participants who have the condition
that the new medication is meant to treat and can last for
several years
• Due to the larger number of participants and longer duration or
phase 3, rare and long-term side effects are more likely to show
up
• Phase 3 clinical trials are often needed before the FDA will
approve the use of a new drug for the general public-
roughly 25 to 30% of medications move on to phase 4
18. Phase 4 Clinical Trial
• Tests new drugs approved by the FDA
• Tested in several hundreds or thousands of patients and can last
many years- this allows for better research on short-lived and long-
lasting side effects and safety
• Investigators get more information about the medication’s long term
safety, quality of life, cost effectiveness, etc.
• Drugs are available for doctors to prescribe for patients
• Safest type of clinical trial
19.
20. Novel Approaches in COVID-19 Vaccine Trials
• WHO initiatives
• Harnessing a broad global coalition to develop and evaluate candidate
vaccines as quickly and safely as possible by convening and coordinating
multiple public and private meetings
• Mapping candidate vaccines and their progress across the world and
fostering regular open dialogue between researchers and vaccine
developers to expedite the exchange of scientific results, debate concerns
and propose rapid and robust methods for vaccine evaluation
• Defining the desired characteristics of safe and effective vaccines
• Coordinating clinical trials across the world
21. Novel Approaches in COVID-19 Vaccine Trials
• Skipping over some animal testing
• Although virologists at the National Institute of Allergy and Infectious Diseases did
give the experimental vaccine to lab mice on the same day that the human trial
began recruiting participants
• The head of the U.S. FDA says they may consider allowing a COVID-19
vaccine to be put on the market before finishing all phases of clinical
trials
25. Basic Requirement
The World Health Organization had said that a “clear
demonstration of efficacy ideally with ∼50% point estimate”
should be a minimum criterion for any coronavirus vaccine
candidate. It had also said that the efficacy can be assessed
against disease, severe disease, and/or shedding.
26. mRNA Vaccines
• Works by introducing an mRNA sequence which is coded for a disease
specific antigen- once produced within the body, the antigen is
recognized by the immune system (triggers innate immune response),
preparing it to fight the real thing
• Types
• Non-replicating mRNA
• In vivo self-replicating mRNA
• In vitro dendritic cell non-replicating mRNA vaccine
• Have been studied before for flu, Zika, rabies, and CMV, cancer
27. Viral Vector- based Vaccines
• Once inside a cell, viral vectors hack into the same molecular system
as SARS-CoV-2 and faithfully produce the spike protein
• This resembles a natural infection- provokes a robust innate
immune response
• Have been extensively studied in animal models- low pathogenic
viruses are often selected
• The vaccinia virus and adenovirus are the most widely used vectors
because they can induce a strong immune response against the
expressed foreign antigens
• Promising tool for gene therapy and vaccines
30. mRNA Vaccines
Advantages
• Synthetic production- egg
and cell free
• Rapid and scalable
production
• Non-infectious, non-
integrating, and naturally
degrading
• Expression in situ to produce
antigens with structure
unaltered by in vitro
manufacturing process
Disadvantages
• Concerns with instability
• Limited immunogenicity data
in humans
• Potential toxic effect of free
extracellular mRNA
• Inflammation due to
enhanced type 1 IFN
activation
31. Viral Vector- based Vaccines
Advantages
• High efficiency gene transduction
• Highly specific delivery of genes to
target cells
• Induction of both humoral and cell-
mediated immune responses
• Improved efficacy and safety
• Reduced administration dose
• Enable large-scale manufacturing
• Potential targets ranging from
cancers to a vast number of
infectious diseases
Disadvantages
• Risk of integrate into the host
genome and lead to other
diseases
• The presence of pre-existing
immunity against the vector
caused by previous exposure to
the virus and the production of
neutralizing antibodies can reduce
vaccine efficacy
32. Pfizer- BioNTech
• Vaccine name- BNT162
• Clinical phase- 3
• Type- mRNA vaccine
• Storage- (-70˚C) for weeks to months in special packaging
• Doses- 2 doses 3 weeks apart
• Trial- 170 confirmed cases, 162 placebo group and 8 vaccine group
• Estimated efficacy- 95%
• Adults > 65 years- over 94%
33. Pfizer- BioNTech
• Adverse effects- well-tolerated; mild to moderate
• Severe > 2% - fatigue (in 3.7% after the second dose) and headache
• Estimated price- $20 per dose
• Estimated roll out time- 100 million doses pre-ordered by the U.S.
government, promising by the end of the year, with the possibility an
additional 500 million doses in 2021
• The company estimates that about 15 million to 20 million people will be
vaccinated in the first six months once delivery begins
• Pfizer and BioNTech believe that they have enough data to apply for an
Emergency Use Authorization (EUA) from the Food and Drug
Administration for the same
34. Moderna
• Vaccine name- mRNA- 1273
• Clinical phase- 3
• Type- mRNA vaccine
• Storage- (-20˚C) for 30 days
• Doses- 2 doses 4 weeks apart
• Trial- 30,000 people, 15,000 placebo group and 15,000 vaccine
group
• 185 placebo group, 11 vaccine group showed symptoms
• 30 severe disease, but not the vaccine group
35. Moderna
• Estimated efficacy- 94.5%
• Severe cases- approx100%
• Adverse effects- severe- fatigue 9.7%, muscle pain 8.9%, joint pain
5.2%, headache 4.5%
• Estimated price- $37 per dose ($15 US, $25 EU)
• Estimated roll out time- 20 million doses ready to ship to the U.S. by the
end of the year
• Moderna believe that they have enough data to apply for an Emergency
Use Authorization (EUA) from the Food and Drug Administration for the
same
36. Oxford- AstraZeneca
• Vaccine name- AZD1222
• Clinical phase- 3
• Type- Chimpanzee adenovirus (viral vector)
• Storage- 2- 8˚C
• Doses- 2 doses 4 weeks apart
• Trial- 23000 (total), 9000 (two full), 3000 (half then full)
• 101 placebo group (either a saline injection or a meningitis vaccine)
• 30 vaccine group- 3 (half then full) and 27 (two full)
• Estimated overall efficacy- 70%
• half dose then full dose- 90%
• two full doses- 62%
37. Oxford- AstraZeneca
• Adverse effects- injection-site pain and tenderness, fatigue, headache, fever,
muscle pain
• Estimated price- $3-4 per dose (due to COVAX)
• Estimated roll out time- Health Ministry has announced a target of 300-400
million doses by July 2021- currently producing 50-60 million doses a month
which by January-February will be scaled up to 100 million doses a month
• COVISHIELD- produced and marketed by Serum Institute of India
• will be ready and available for healthcare workers and elderly people by
February 2021
• general public will receive 300- 400 million doses by July 2021
38. Theoretical Differences in Efficacy of First Half
Dose and Full Dose
• A full initial dose generated antibodies to the adenovirus vector itself, which might have
limited the immune response to the coronavirus spike protein- the team measured the
antibodies to the adenovirus in earlier studies and found only a small effect.
• Inducing a high-quality immune response by giving just the right amount of vaccine
antigen at the first dose and then expanding it with the second dose
• The lower initial dose does a better job of getting through the body’s defences, allowing
the vaccine to infect cells and create the immune response
• The immune system may become inured by the initial high dose of vaccine and then
ignore the subsequent dose (tolerance or immune desensitization)
• It was found that the half-dose group only included people younger than 55
39. Oxford- AstraZeneca
In the Oxford- AstraZeneca trial in Britain, researchers counted infections
by swabbing participants weekly. That detection method was likely to have
turned up more infections than the trials run by Moderna and Pfizer, which
tested people who developed symptoms and may have failed to find any
asymptomatic cases. The different approaches to counting infections could
make it harder to compare how well the different vaccines work.
40. Sputnik- V
• AKA- Gam-COVID-Vac
• Manufacturer- Gamaleya Research Institute of Epidemiology and
Microbiology
• Clinical phase- 3
• Type- Two different Human adenovirus (viral vector)
• Storage- 2- 8˚C
• Doses- 2 doses 4 weeks apart
• Trial- 40,000 people post registration
• Estimated efficacy- 91.4%
41. Sputnik- V
• Adverse effects- to be taken cautiously
• 14%- weakness, muscle pain, and fever
• Estimated price- $10 per dose
• Estimated roll out time- RDIF and Hetero have agreed to produce over
100 million doses per year, intending to start the production at the
beginning of 2021
• will be produced by RDIF’s international partners in India, Brazil,
China, South Korea
• EpiVacCorona- granted approval without entering phase 3
42. Covaxin
• Manufacturer- Bharat Biotech
• With Indian Council of Medical Research (ICMR)- National Institute of
Virology (NIV)
• Clinical phase- 3
• Type- Inactivated
• Storage- 2- 8˚C
• Doses- 2 doses 4 weeks apart
43. Covaxin
• Trial- 26000 people in 25 centers
• 800 people in 12 centers in phases 1 and 2
• Begin enrolling healthy volunteers between 18 and 55 years of age from
December 2 and commence the third phase trial tentatively from
December 5 or 6
• Estimated efficacy- at least 60%
• Adverse effects- safe thus far
• Estimated roll out time- if successful, Q2 of 2021
44. Zydus Cadila
• Vaccine name- ZyCov- D
• Clinical phase- 2
• Type- two types
• DNA vaccine (plasmid)
• Live attenuated recombinant measles (viral vector)
• Trial- 1,048 people, data unavailable
• Phase 3 tentatively to begin by December- 30,000 people
• Estimated roll out- March 2021 with 100 million doses
45.
46. Candidate Mechanism Sponsor Trial Phase Institution
AZD1222
Replication-deficient viral
vector vaccine (adenovirus
from chimpanzees)
The University of
Oxford; AstraZeneca; IQVIA;
Serum Institute of India
Phase 3
The University of Oxford, the
Jenner Institute
BNT162 mRNA-based vaccine Pfizer, BioNTech Phase 3
Multiple study sites in Europe
and North America
mRNA-1273 mRNA-based vaccine Moderna Phase 3
Kaiser Permanente
Washington Health Research
Institute
Ad5-nCoV
Recombinant vaccine
(adenovirus type 5 vector)
CanSino Biologics Phase 3 Tongji Hospital; Wuhan, China
CoronaVac
Inactivated vaccine (formalin
with alum adjuvant)
Sinovac Phase 3
Sinovac Research and
Development Co., Ltd.
Covaxin Inactivated vaccine
Bharat Biotech; National
Institute of Virology
Phase 3
JNJ-78436735 (formerly
Ad26.COV2.S)
Non-replicating viral vector Johnson & Johnson Phase 3 Johnson & Johnson
No name announced Inactivated vaccine
Wuhan Institute of Biological
Products; China National
Pharmaceutical Group
(Sinophar)
Phase 3
Henan Provincial Center for
Disease Control and
Prevention
NVX-CoV2373 Nanoparticle vaccine Novavax Phase 3 Novavax
Sputnik V Non-replicating viral vector
Gamaleya Research Institute,
Acellena Contract Drug
Research and Development
Phase 3 Various
ZyCoV-D DNA vaccine (plasmid) Zydus Cadila Phase 2 Zydus Cadila
47.
48.
49. Human Challenge Studies?
• A type of clinical trial for a vaccine or other drug involving the intentional exposure
of the test subject to the condition tested
• Under consideration to hasten the development of a vaccine- as an alternative,
regulatory agencies could allow early emergency use of the vaccine, while the
challenge study continues collecting data for eventual licensure
• May be ethically controversial because they involve exposing test subjects to
dangers beyond those posed by potential side effects of the substance being
tested.
• Beginning in January 2021, dozens of young adult volunteers will be deliberately
infected with COVID-19 in a challenge trial conducted in a London hospital Once
an infection dose of COVID-19 is identified, two or more of the candidate COVID-19
vaccines will be tested for effectiveness in preventing infection.
• Volunteering for a vaccine challenge study during the COVID-19 pandemic is
likened to the emergency service of healthcare personnel for COVID-19-infected
people, firefighters, or organ donors.
50. Summary Messages
• The WHO and CEPI play huge roles in manufacture and equal distribution of
vaccines- mainly through COVAX
• Clinical trials can take many years to approve one drug or vaccine, but COVID
vaccine development is being expedited to meet the global demands
• mRNA and vector viral vaccines may be the way to go for the future of COVID-
19 vaccines (published safety and efficacy data unavailable)
• Pfizer, Moderna, and Oxford- AstraZeneca have all made a plea to apply for an
Emergency Use Authorization (EUA) from the Food and Drug Administration- of
which Pfizer has been approved for use in the UK
• First round of vaccines may be available as early as the end of December 2020
• Vaccination for children may still be “months away”- testing could start as early
as January 2021
