A brief overview of the process of vaccine production, clinical trials, and licensing, along with a summary of the different vaccines platforms and vaccine candidates.

1. COVID
VACCINES
HUSSEIN MHANNA, MD, DO

2. INTRODUCTION

3. Timeline to the pandemic
mysterious cases of
pneumonia in Wuhan.
31 Dec. 2019
The outbreak was
identified as a new
coronavirus.
7 Jan. 2020
China reported its first
known death from
COVID.
11 Jan.
First US case
21 Jan.
WHO announced the
name COVID-19.
11 Feb.
The first recorded
coronavirus death in the
U.S.
29 Feb.
WHO declares COVID-
19 as a pandemic.
118,319 cases globally.
11 Mar.
As of December 14:
72 million cases globally!

4. COVID in New Jersey
First NJ case
4 Mar.
First COVID-19 Case
Reported in Montclair –
Admitted to MMC
12 Mar.
NJ surpasses a 1000 cases.
20 Mar.
NJ issued a stay-at-home
order.
21 Mar.
NJ surpasses a 100,000
cases.
22 Apr.
415,075 confirmed
18,003 Deaths
16 Dec.

5. As of today,
In the US…
17,005,697
confirmed
310,253
Deaths

6. Hope…
 Vaccines are the most promising
approach.
 March 16: 1st experimental shot in the US.
 As of December 10, 2020:
 52 candidate vaccines in human trials.
 162 were in preclinical trials.
 December 11, 2020: FDA granted EUA for
Pfizer and BioNTech’s coronavirus
vaccine candidate

7. GENERAL
PRINCIPLES

8. Back to the
Basics

9. Overview of vaccine development
 Preclinical evaluation and 3 distinct clinical stages,
phases I, II, and III.
 Traditionally, these steps occur sequentially, and each
usually takes several years for completion.
 SARS-CoV-2 vaccine: unprecedented pace, with each
step occurring over several months. Nevertheless, safety
criteria remain stringent.
 In the US, the FDA must approve progression to each
next step.

10. Preclinical studies
 Vaccine candidates administered to small animals
(mice) and the resulting immune responses are
measured.
 Must generate an immune response to undergo
further testing.
 Toxicity studies also conducted.
 With SARS-CoV-2, nonhuman primate models of
infection have been employed;
 vaccinated then challenged with wild-type
SARS-CoV-2.
 Vaccines that stimulate an immune response
without toxicity concerns progress to phase I human
trials.

11. Phase I clinical trials
 Healthy subjects.
 <100 individuals, ages of 18 - 55 years.
 Primary objective: safety
 (although immunogenicity is also measured).
 Dose-ranging studies.
 Subjects screened for their ability to be
closely monitored and comply with
rigorous safety assessments.
Coronavirus disease 2019 (COVID-19): Vaccines to prevent SARS-CoV-2 infection - UpToDate

12. Phase II
clinical trials
 Larger numbers of
subjects (several
hundred).
 Expand the safety
profile and immune
response assessment
 DSMC assessments.
Coronavirus disease 2019 (COVID-19): Vaccines to prevent SARS-CoV-2 infection - UpToDate

13. Phase III clinical trials
 Determine whether the vaccines prevent a
predefined endpoint related to infection,
usually laboratory-confirmed disease.
 Subjects randomly assigned and blinded
(vaccine or placebo).
 Vaccine efficacy: ((attack rate in the
unvaccinated – attack rate in the
vaccinated)/attack rate in the
unvaccinated) x 100.
Coronavirus disease 2019 (COVID-19): Vaccines to prevent SARS-CoV-2 infection - UpToDate

14. Lessons from SARS-CoV-1 and
MERS-CoV vaccines
 Paved the way for rapid development of SARS-CoV-2 vaccines.
 Major antigenic target was the spike protein.
 An analogous protein is also present in SARS-CoV-2
 Binding to the receptor-binding domain (RBD) of the SARS-CoV-2
spike protein can prevent attachment to the host cell and neutralize
the virus

15. Immunologic basis for SARS-CoV-2
vaccination
 In nonhuman primate studies, experimental infection with wild-type
SARS-CoV-2 virus protected against subsequent reinfection
 Vaccination of primates also protected against viral challenge
 Epidemiologic studies in humans have also suggested that
neutralizing antibodies are associated with protection from infection
 Thus, vaccines that elicit a sufficient neutralizing response should be
able to offer protection against COVID-19.

16. Platforms for SARS-CoV-2 vaccines
in development


21. mRNA Vaccines:
An innovative
approach

22. How does an mRNA vaccine work?

23. Overview of
the main
candidates

24. BioNTech and Pfizer
BNT162B2

25. BNT162b2
(BioNTech and
Pfizer)
 mRNA vaccine delivered
in a lipid nanoparticle to
express a full-length spike
protein.
 IM in 2 doses 21 days
apart.
 Has been authorized for
use in the United States,
United Kingdom (UK),
and Canada.

26. Phase I/II trials results
 Randomized, placebo-controlled, observer-blind dose
escalation study
 in healthy adults 18 to 85 years of age,
 binding and neutralizing antibody responses comparable
to those in convalescent plasma from patients who had
asymptomatic or moderate SARS-CoV-2 infection [37].
 Responses in participants ≥65 years old were generally
lower than in younger subjects, but still comparable to titers
in convalescent plasma.

27. Phase III trial results
 95% efficacy (95% CI 90.3-97.6) in preventing symptomatic COVID-19 at or
after day 7 following the second dose.
 170 confirmed COVID-19 cases (8 in the vaccine group and 162 in the
placebo group) among over 35,000 participants.
 9 of the 10 severe cases that occurred during the study were in the placebo
group.
 Among adults ≥65 years who had other medical comorbidities or obesity,
vaccine efficacy was 91.7 percent (95% CI 44.2-99.8).
 Estimated vaccine efficacy of 52%, 95% CI, 29.5-68.4 between the two doses.
However, the actual magnitude and duration of protection from a single
dose is unknown because most participants received the second dose three
weeks after the first.

28. Adverse Effects
 Local and systemic
 dose dependent and relatively common
 after the second dose
 < 55 years:
 fever 16%
 moderate to severe fatigue 38%
 headache 28%
 chills 18%
 Rates among older participants were slightly lower.
 Anaphylactoid reactions in the UK outside a
clinical trial.
 Further analysis of these reactions are needed.
 Individuals with histories of severe allergies to
other vaccines or the BNT162b2 components
had been excluded.

31. Moderna
MRNA 1273

32. mRNA 1273 (Moderna)
 developed and administered to humans
within two months of publication of the SARS-
CoV-2 genomic sequence.
 mRNA delivered in a lipid nanoparticle to
express a full-length spike protein.
 IM in 2 doses 28 days apart.
Jennifer Haller receives the first shot in
the first-stage safety study clinical trial of
a potential vaccine for COVID-19 on
March 16 at the Kaiser Permanente
Washington Health Research Institute in
Seattle.

33. Phase I Trial results
 Healthy individuals 18 to 55 years of age.
 binding and neutralizing antibody responses
comparable to those seen in convalescent plasma.
 >55 y/o elicited comparable immune responses.
 antibody responses declined slightly over 3 months but
remained elevated compared with levels seen in
convalescent plasma.

34. Phase III Trial Results
 94.1% efficacy in preventing symptomatic COVID-19 at
or after two weeks following the second dose.
 196 confirmed COVID-19 cases
 11 in the vaccine group and 185 in the placebo group among
approximately 30,000 study participants.
 Thirty cases were severe, and all of these occurred in the
placebo group.
 No major safety concerns were reported.

35. Novavax
NVX-COV2373

36.  Recombinant protein nanoparticle vaccine composed of
trimeric spike glycoproteins and a potent Matrix-M1
adjuvant.
 IM in 2 doses 21 days apart.
 In a phase I/II randomized, placebo-controlled trial of
healthy individuals <60 years old, it induced high binding and
neutralizing responses.
 CD4 cell responses with a Th1 bias were also detected.
 6% experienced systemic effects (mainly fatigue, headache,
myalgias, and/or malaise) following the second dose.

37. Oxford, AstraZeneca, Serum Institute of India
CHADOX1 NCOV-19/AZD1222

38.  replication-incompetent chimpanzee adenovirus vector ->
spike protein.
 IM, being evaluated as a single dose or two doses 28 days
apart.
 Phase III: 70.4% efficacy (95% CI 54.8-80.6) at or after 14 days
following the second dose.
 SE: fatigue, headache, and fever - 8% in earlier phases.
 In the phase III trial, 2 cases of transverse myelitis.
 One was thought to be possibly related to vaccination
 the other was thought to be possibly related to a previously
unrecognized multiple sclerosis.

39. Jansen
AD26.COV2.S

40.  Replication-incompetent adenovirus 26 vector -> spike protein.
 IM, being evaluated as a single dose.
 Phase I/II randomized, 18 to 85 years old; antibody responses
were slightly lower than those in convalescent plasma.
 >1% severe systemic reactions.
 CD4 cell responses with a Th1 bias were also detected.
 Adenovirus 26 vectors used in an Ebola vaccine (licensed in EU),
RSV, HIV, and Zika vaccine candidates.
 Baseline seroprevalence to adenovirus 26.
 Nonhuman primate studies suggest that these low titers do not
suppress responses to adenovirus 26 vector vaccines.

41. CanSino Biologics
AD5-BASED COVID-19 VACCINE

42.  Replication-incompetent adenovirus 5 vector -> spike protein.
 IM, Single dose.
 In early clinical trials: immunogenic in healthy adults at 28
days.
 Both pre-existing immunity to adenovirus 5 and older age
were associated with lower titers of antibodies following
vaccination.
 Licensed in China for limited use by the military.

43. Gamaleya Institute, Russia
SPUTNIK V

44.  2 replication-incompetent adenovirus vectors -> spike
glycoprotein.
 IM, initial adenovirus 26 vector dose followed by an
adenovirus 5 vector boosting dose 28 days later.
 Phase I/II trial: humoral and cellular immune responses.
 Mild to moderate local and systemic reactions.
 Licensed in Russia prior to completion of any efficacy trials.
 Phase III trial: 91.4% efficacy rate
 questionable validity
 based on only 39 cases

45. Sinopharm
BBIBP-CORV

46.  Inactivated vaccine based on a SARS-CoV-2 isolate
from a patient in China
 Aluminum hydroxide adjuvant.
 IM, 2 doses 28 days apart.
 Phase I/II placebo-controlled randomized trials:
 18 to 80 years old,
 developed neutralizing and binding antibodies.
 No severe reactions were reported.
 Licensed in UAE based on interim data from a phase III
efficacy data from trial in that country.

47. Sinovac, China
CORONAVAC

48.  Inactivated SARS-CoV-2 vaccine
 Aluminum hydroxide adjuvant.
 IM, 2 doses 28 days apart.
 Phase I/II randomized, placebo-controlled trial:
 18 to 59 years
 safe and immunogenic

49. Final Steps

50. Establishing efficacy
 FDA and WHO minimal efficacy criteria for
licensure: vaccine efficacy at least 50 percent,
with a lower bound of a 95% confidence
interval of 30 percent.
 30,000 study subjects (divided equally between
vaccine and control)
 estimated number necessary to determine
efficacy over a follow-up of 6 months.
 This time frame depends on the infection
rate in the control group;
 the higher the infection rate, the less time is
needed to determine vaccine efficacy.
 Each trial targets a defined number of
detected cases, and when that number of
cases has been reported, efficacy will be
assessed.

51. “Correlate of protection”
 It is hoped that results from vaccine efficacy trials can
be used to establish standardized functional antibody
responses that correlate with protection from disease,
called a correlate of protection.
 This usually entails measuring antibody titers before
and after vaccination and identifying an association
between responses below a certain threshold and
vaccine failure.
 If such correlates are established, it may be possible to
license vaccines based on the achievement of these
serologic benchmarks and not require each vaccine
to be tested in large clinical efficacy trials.
 This is especially relevant for candidate vaccines that
will not have already entered efficacy trials by the
time a SARS-CoV-2 vaccine is available and in use, as
it will then be logistically and ethically challenging to
conduct large placebo-controlled efficacy trials for
new vaccines.

52. Licensing a vaccine
 FDA makes decisions on vaccine
licensure once phase III trials are
concluded and demonstrate safety and
efficacy.
 FDA relies on guidance from the
Vaccines and Related Biologic Products
Advisory Committee (VRBPAC), a
standing advisory group of experienced
clinicians, vaccine experts,
epidemiologists, and other subject
matter experts.
 Similar approaches are taken by
regulatory bodies in Canada and
European countries for the licensure of
their vaccines.

53. Emergency Use Authorization
 Emergency Use Authorization (EUA) is designed to
make products available during public health
emergencies.
 substantial evidence of safety and effectiveness
 A median of 2 months of follow-up for half of the vaccine
participants following vaccine receipt
 Clinicians are obliged to inform potential recipients that
the vaccine is not licensed, why it is not licensed, and
what information the FDA is waiting for before granting a
full license.
 Signed informed consent documents is not necessary.

54. Manufacturing & storage
 Several vaccine producers have started
commercial production prior to the availability
of phase III trial efficacy data.
 This is unusual, since vaccine production
facilities for widespread use of vaccines are
typically not developed until after vaccine
efficacy has been established, to minimize
financial risk.
 Enhanced by the infusion of government funds.
 Some mRNA vaccines require ultra-cold storage
in specialized freezers. (Pfizer -94°F, Moderna -
4°F).
 The need for vials used to hold the vaccines
may also pose supply chain issues.

55. Pfizer Vaccine Ingredients
Active Ingredient
nucleoside-modified messenger RNA (modRNA) encoding the
viral spike glycoprotein (S) of SARS-CoV-2
Lipids (protect the mRNA and help it slide inside cells.)
(4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis (ALC-3015)
(2- hexyldecanoate),2-[(polyethylene glycol)-2000]-N,N-
ditetradecylacetamide (ALC-0159)
1,2-distearoyl-snglycero-3-phosphocholine (DPSC)
cholesterol
Salts (keeps the pH of the vaccine close to that of a person’s body)
potassium chloride
monobasic potassium phosphate
sodium chloride
basic sodium phosphate dihydrate
Other (cryoprotectant)
sucrose
No preservatives

56. Why Super-Cold Storage?!
 Pfizer vaccine requires storage at -70°C.
 RNA can be easily destroyed by enzymes.
 Lower temperatures slow these reactions.
 The “M&M” analogy.
 The lipid protective shell of the vaccine.
 Moderna vaccine requires less cold
temperatures.
 might be a better option for smaller
centers unable to afford colder storage
equipment.

57. Thank
You!