Clinical evaluation of vaccine

1. 1
VACCINE TRIAL
Presenter : Dr Nipa Mendapara
Moderator : Dr Sudhir Chandra Sarangi

2. Overview
• Definitions
• First vaccine trial
• Historical path of the vaccine designs
• Various types of licensed vaccines
• Drug vs vaccine development
• Vaccine development process
• Clinical phases
• Accelerated vaccine development strategies
2

3. Vaccine
• A preparation that is used to stimulate the body’s immune
response against diseases
3

4. Vaccine trial
 Vaccine trial is a clinical trial that aims at establishing the safety and efficacy of
a vaccine prior to it being licensed.
• New candidate vaccine: A vaccine that is regarded in national regulations as
separate and distinct from other candidate and licensed vaccines
• It could include a vaccine that contains :
■ New antigenic component
■ Contains a new adjuvant;
■ Antigen(s) ± adjuvant(s) not previously combined
4

5. First documented Vaccine trial
5
May
1796
“Variola”:
smallpox
Inoculation
or
variolation
Cowpox lesions
on Sarah Nelms
(a dairymaid)
Inoculated
James Phipps
Vaccination
1798
“Vaccinia”:
cowpox
Edward Jenner
Ref: Reidel; BUMC proceedings (2005) 18: 21-25
The World
Health
Assembly
announced
that the
world was
free of
smallpox
May 8,
1980

6. 6
Major milestones in vaccine design
Delany I, Rappuoli R, De Gregorio E. Vaccines for the 21st century. EMBO Mol Med. 2014
Jun;6(6):708-20.

7. 7
Strategies used for the development of COVID-19 vaccines, and the pathway each
one follows to induce T cell and B cell immune response.
Khuroo MS et al., 2020

8. Adjuvant
8
• A components capable of enhancing and/or
shaping antigen-specific immune responses.
• To boost the immune response when an antigen
has low immunogenicity (Recombinant, subunit,
inactivated)
Functions :
• Prolongs antigen persistence
• Increases local inflammation and formation of
granuloma
• Stimulate nonspecific proliferation of lymphocytes
• Stimulate Toll-like receptors on the surface of
macrophages. This results in cytokine production
(such as IL-12) that enhances the response of T
cells and B cells to the immunogen.
Reed, S., Orr, M. & Fox, C. Key roles of adjuvants in modern vaccines. Nat Med 19, 1597–1608 (2013)

9. 9

10. Reverse vaccinology (RV)
10
• It is a technique to predict vaccine candidates from
pathogen's genome(s)
• Vaxign-ML (Vaxign - Machine Learning) is the first web-
based vaccine design program using RV
Ex.
1. Three protective antigens that are common to
multiple MenB strains were expressed as
recombinant proteins and combined with a MenB
outer membrane vesicle (OMV), resulting in the first
universal vaccine against type B meningococcus
2. Vaxign-ML results suggested S protein as a promising
vaccine antigen target for SARS COV-2

11. National Immunization schedule
11
https://www.nhp.gov.in/universal-immunisation-programme_pg

12. Covid-19 Vaccines approved for Use in India
No. Type Name Manufacturer
1 Protein Subunit COVOVAX (Novavax
formulation)
Serum Institute of India
2 Protein Subunit Corbevax Biological E Limited
3 DNA ZyCoV-D Zydus Cadila
4 RNA GEMCOVAC-19 Gennova Biopharmaceuticals
Limited
5 RNA Spikevax Moderna
6 Non Replicating Viral
Vector
iNCOVACC Bharat Biotech
7 Non Replicating Viral
Vector
Sputnik Light Gamaleya
8 Non Replicating Viral
Vector
Sputnik V Gamaleya
9 Non Replicating Viral
Vector
Jcovden Janssen (Johnson & Johnson)
10 Non Replicating Viral
Vector
Vaxzevria Oxford/AstraZeneca
11 Non Replicating Viral
Vector
Covishield (Oxford/
AstraZeneca formulation)
Serum Institute of India
12 Inactivated Covaxin Bharat Biotech
12
https://covid19.trackvaccines.org/country/india

13. 13
Drug Development Process
Vaccine Development Process
Age de-escalation
Healthy Participants
Patients
Healthy volunteers
Healthy volunteers
Either patients or
healthy volunteers

14. 14
Development of New Vaccines
Exploratory
stage
Pre-clinical
stage
Clinical
development
Regulatory
review and
approval
Manufacturing Quality
control
Identify
natural/
synthetic
antigens,
Often lasts
2-4 years
Safety,
Immunogenicity,
Challenge
studies,
Last 1-2 years
IND
Applicatio
n
FDA has 30 days to approve
the application
Post-
Licensure
Monitoring of
Vaccines
Biologic licence
application(BLA)
3 phase process
Marketing of
vaccine
Exploratory
stage
Pre-clinical
stage
Clinical
development
Identify
natural/
synthetic
antigens,
Often lasts
2-4 years
Exploratory
stage
Pre-clinical
stage
Clinical
development

15. 15
Clinical
development
SAFETY
IMMUNOGENICITY
EFFICACY
SAFETY
IMMUNOGENICITY
EFFICACY
SAFETY
IMMUNOGENICITY
EFFICACY
SAFETY
IMMUNOGENICITY
EFFICACY
EFFECTIVENESS

16. Immunogenicity, efficacy and safety trials
16
VACCINATION
IMMUNE RESPONSE
PREVENTION OF
INFECTION
May lead to
ADVERSE EVENTS
VACCINATION
IMMUNE RESPONSE
PREVENTION OF
INFECTION
VACCINATION
VACCINATION
IMMUNE RESPONSE
VACCINATION

17. Phase I
17
• Data required: appropriate animal challenge data or in vitro data
• Primary focus on determination of clinical tolerance and safety
• Determination of the type and extent of immune response that the vaccine
provokes.
• Exploration of safety of different amounts of antigen, with/without adjuvant
• Participants: HEALTHY ADULT VOLUNTEERS (usually between 20-80 subjects)
(preferably confined to subjects who have no history of previous exposure to the
organism(s) against which vaccine is intended to protect)
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017

18. SAFETY TRIALS
18
May be primary, co-primary or
secondary objective
PRE-LICENSURE
Assessment of safety done to
analyse AEs (predefined/ SAEs/
AESI)
Categorization of events (causality,
severity and frequency)
Appropriate reporting of AEFI
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017
AE: Adverse Event
SAE: Serious Adverse Event
AESI: Adverse Event of Special Interest
(Adverse Event Following Immunization)

19. ADR and causality assessment scales
19
https://innovareacademics.in/journals/index.php/ijpps/article/view/37209/22408

20. ADR severity scale
20

21. SAFETY TRIALS
21
• RECORDING AND REPORTING ADVERSE EVENTS
• By investigators and sponsors
• According to defined procedures in the protocol, collected for defined periods
ADVERSE EVENT DESCRIPTION PERIOD OF COLLECTION
IMMEDIATE
REACTIONS
Such as hypersensitivity reactions Defined period (commonly 20-60
minutes)
SOLICITED AE • Information on their occurrence is
actively sought
• Through “Diary Cards”
• At least 4-7 days after each dose
• Longer periods if components
replicate
UNSOLICITED AE Not prespecified Collected for entire period between
doses till approx. 4 weeks post dose
SAEs or pre-specified
AESI
SAE: Serious adverse event
AESI: adverse event of special interest
For at least 6 months after last
assigned dose
IMMUNE MEDIATED
AE
For vaccines that contain new adjuvant At least 12 months after last dose
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017

22. 22

23. 23

24. 24
• Open-label, multicenter, randomized phase 1 study ongoing in US
• Subjects : All 18 Years to 55 Years healthy (Adult) Volunteers (total = 108)
• Hypothesis : BG505 MD39.3 soluble and membrane-bound trimer mRNA vaccines will be safe and well-
tolerated among HIV-uninfected individuals and will elicit autologous neutralizing antibodies.
• Vaccine : BG505 MD39.3 mRNA or BG505 MD39.3 gp151 mRNA or BG505 MD39.3 gp151 CD4KO mRNA, at
doses of 100 mcg or 250mcg, administered via intramuscular (IM) at months 0, 2, and 6
• A dose escalation plan will be implemented whereby sentinel safety groups for each of the three low-dose
groups in Part A would be enrolled and evaluated for safety 2 weeks after the first vaccination.
• If safety criteria are met, then enrollment of the Part B sentinel safety groups and the remainder of the Part
A participants would commence
• Safety for the sentinel groups in Part B will be assessed after the first vaccination prior to full enrollment of
Part B.

25. Phase II
25
• Primary Focus: Immunogenicity (includes safety as secondary endpoint)
• Participants: HEALTHY VOLUNTEERS in TARGET POPULATION (several hundred
individuals participates )
• AGE DE-ESCALATION studies are done
VACCINE FACTORS HOST FACTORS
- Dose - age
- Sequence/interval - gender
- Number of doses - ethnicity
- Route of administration - presence of interfering antibodies
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017

26. Age de-escalation
• It means that phase I and II trials are conducted first in healthy adults, then in
older children, and finally, if relevant, in small children.
• if a new vaccine is only for infants, trials in older children may expose them to
unnecessary risks without giving any benefit to these too “old” vaccinees. Ex.
Rotavirus vaccines
• Sometimes adult participants can be used in the first trials, although they are of
no help in the efficacy trials.
26
Kulkarni PS. Current topics in research ethics in vaccine studies. Perspect Clin Res. 2013 Jan;4(1):80-3.

27. Immunogenicity trials
27
• Immunogenicity: capacity of a vaccine to elicit a measurable immune
response
• Purpose:
1. Characterize the immune response
a) Measuring functional antibody
b) Induction of immune memory
c) Exploration of factors that can affect humoral immunity
d) Assessment of cell-mediated immunity
2. Identifying Immune correlates of protection (ICPs)
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017

28. Immunogenicity trials
28
Trial Design:
Comparative
• Comparator:
Placebo / Licensed
Vaccine/ Different
doses
• Preferably double-
blind design
• Lab staff kept
unaware of
treatment
assignment
Endpoints
Analysis
To support
maternal
immunization
Support co-
administration of
other vaccines
Select formulation
and posology
To assess lot-to-lot
consistency
• When ICP is
established: %age of
subjects achieving the
antibody level
• ICP not established:
seroconversion rate or
magnitude of immune
response
• Superiority:
compared to no
vaccination or
placebo
• Non-inferiority:
according to a
predefined inferiority
margin
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017
(ICP: Immune Correlate of
Protection )

29. 29

30. 30
1st dose
2nd dose
2 wk 2nd dose
4 wk 2nd dose

31. RTS,S/AS01 (Mosquirix)
• Recombinant protein-based malaria vaccine.
• In October 2021, the vaccine was endorsed by
the WHO for "broad use" in children in sub-
Saharan Africa and in other regions with
moderate to high P. falciparum malaria
transmission
• RTS because it was engineered using genes from
the repeat ('R') and T-cell epitope ('T') of the
pre-erythrocytic circumsporozoite protein (CSP)
of the Plasmodium falciparum malaria parasite
together with a viral surface antigen ('S') of the
hepatitis B virus (HBsAg)
31

32. 32
Study Design & site : Phase 2a, double-blind, randomized challenge trial at WRAIR Clinical Trials Center
from 2003 through 2006
(Enrolled and allocated N =138) : 2 cohorts of 52 & 50 adults each who received RTS,S/AS01B or
RTS,S/AS02A in a 1:1 ratio along with 36 control
Study subjects : men and women 18–45 years of age with good health, no history of malaria, and the ability
to comply with the study schedule.
Immunizations : 0-, 1-, and 2-month schedule, with P. falciparum challenge occurring 2–3 weeks after
the last immunization and rechallenge occurring 5 months later for vaccine recipients who were protected
at the time of the initial challenge
Vaccines : The lyophilized pellet contained 62.5 mg of RTS,S per single-dose vial.
Adjuvant : Just before administration the pellet was reconstituted with liquid AS01B or AS02A 0.5-mL dose
contained 50 mg

33. 33
RTS,S/AS02A (shaded columns) and RTS,S/AS01B (open columns)
Result : At the time of initial challenge, the RTS,S/AS01B group had :
higher (Ig) G titers, higher numbers of CSP-specifi CD4+ T cells expressing
≥ 2 activation markers (interleukin-2, interferon [IFN]–g, tumor necrosis
factor–a, or CD40L), and more ex vivo IFN-g enzyme-linked immunospots
(ELISPOTs) than did the RTS,S/AS02A group
At rechallenge : 4 of 9 vaccine recipients in each group were still completely
protected.
Efficacy : RTS,S/AS01B and RTS,S/AS02A was 50% (95% confidenc interval
[CI], 32.9%–67.1%) and 32% (95% CI, 17.6%–47.6%), respectively.

34. 34
• Using immunogenicity to predict efficacy when
• Design: comparative
• Two main situations should be considered when using immunogenicity data
to bridge to estimates of vaccine efficacy obtained in prior clinical trials
Bridging trials
Well-established
ICP
ICP can be used to interpret immune
responses to a specific antigen component
EFFICACY
a) Modifying the use of vaccine:
different age, posology, geo-graphical areas
b) Inferring the efficacy of new candidate vaccine
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017

35. Phase III (Pivotal trials)
35
• Large-scale clinical trials
• Primary Focus: Efficacy
• Participants: HEALTHY VOLUNTEERS in TARGET AGE RANGE (involving
thousands to tens of thousands of people)
• Gold standard for ascertaining efficacy: prospective randomized double-blind
controlled trial of protective efficacy
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017

36. EFFICACY TRIALS
36
1. EFFICACY DATA NOT
REQUIRED
If it is established that clinical
immunological data can be
used to predict protection
against disease (i.e. there is
an established ICP)
EFFICACY: ability of the vaccine to prevent clinical disease
IMMUNE CORRELATE OF PROTECTION (ICP):
A type and amount of immunological response that
correlates with vaccine-induced protection against
an infectious disease and that is considered
predictive of clinical efficacy
Ex: antibody titre for hepatitis B virus
antitoxin levels against diphtheria and tetanus toxins
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017

37. EFFICACY TRIALS
37
2. EFFICACY DATA USUALLY
REQUIRED
- No established ICP
- No existing licensed vaccine
with documented efficacy
- When immune response elicited
is different from licensed
vaccine
- Cannot be assumed that vaccine
efficacy demonstrated against
disease due to specific strains
TYPES OF EFFICACY TRIALS
a) Human challenge trials : Subjects are
deliberately exposed to an infectious agent in
a controlled setting
b) Preliminary efficacy trials: provide an
estimate of magnitude of protection that can
be achieved by new vaccine candidate
c) Pivotal efficacy trials: designed and powered
to provide statistically robust estimates of
vaccine efficacy to support licensure
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017

38. EFFICACY TRIALS
38
3. EFFICACY DATA CANNOT BE PROVIDED
Disease:
- Does not occur- smallpox
- Unpredictable and short-lived outbreak-
viral haemorrhagic fevers
- Occurs at a rate too low for vaccine
efficacy to be evaluated
1. Natural rarity of the infectious disease-
plague, anthrax and meningitis due to
N. meningitidis group B
2. Rarity of the disease resulting from the
widespread use of effective vaccines
Non-Clinical
efficacy trials
Human challenge
trials
Passive protection
trials
Comparison with
previously proven
protective immune
responses
WHO Guidelines on clinical evaluation of vaccines, 2017
Derive an immunological marker of protection
from one or more of the following

39. EFFICACY TRIALS
39
• Geographical area with sufficient disease burden
• Account for feasibility, accessibility, representative numbers
TRIAL SITE
SELECTION
• TEST: candidate vaccine (one or more groups)
• REFERENCE: placebo/ licensed vaccine for same disease
TEST AND
REFERENCE
GROUPS
• Preferred: Randomized controlled (double blind)
• Alternative: Stepped wedge trial/ ring vaccination trial
TRIAL DESIGN
• PRIMARY: prevention of clinically apparent infections that fit the
primary case definition
• SECONDARY: cases occurring in groups/ due to different subtypes/
due to non vaccines; duration and/or severity of illness
CLINICAL END
POINTS
• During time of primary analysis could be relatively short (6-12
months)
DURATION OF
FOLLOW-UP
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017

40. Measure of protective efficacy
• Protective efficacy of a vaccine is the index VE = (ARU - ARV)/ARU = 1 – ARV/ARU
• (where ARV and ARU, respectively, are the attack rates of the disease under study among the
vaccinated and unvaccinated cohorts)
40
'Neill RT. On sample sizes to estimate the protective efficacy of a vaccine. Stat Med. 1988
Dec;7(12):1279-88.

41. 41

42. 42

43. 43
Results :

44. • Biologics License Application(BLA) is FDA’s
standard “full approval” mechanism for
biological products (therapeutics and
vaccines)
• Must demonstrate that the product is “safe,
pure, and potent,” which generally means
completing robust, well-controlled clinical
trials.
• A BLA also has no defined end date —
assuming no significant problems emerge, the
product can stay on the market indefinitely.
• Emergency Use Authorization(EUA) is just that
— an authorization to distribute an
otherwise unapproved product during
an emergency
• “Based on the totality of scientific evidence
available,” “it is reasonable to believe that the
product may be effective” and that the
“known and potential benefits… outweigh the
known and potential risks.”
• EUA lasts only as long as the underlying
emergency. FDA may “revise or revoke” an
EUA if the substantive evidence for granting it
no longer exists.
44
https://blog.petrieflom.law.harvard.edu/2021/06/15/whats-the-difference-between-vaccine-approval-bla-and-authorization-eua/
BLA EUA

45. 45
OBSERVATIONAL
COHORT STUDIES
STEPPED WEDGE DESIGN CASE TEST-NEGATIVE STUDY
DESIGN
Occurrence of disease to
be prevented in the
target population
Phased introduction in to
the target population
reduced. (for ex, in
sequential age or risk
groups)
Modification of a case control
study
SUBJECTS WITH SYMPTOMS
Cases: positive for disease
Controls : negative for pathogen of
interest
ESTABLISHING EFFECTIVENESS
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017

46. Vaccine development
46
Phase IV
• PURPOSE:
1. Monitor vaccine safety in routine use
2. Studies designed to address specific safety issues that were identified as
potential concerns
3. Studies designed specifically to estimate vaccine effectiveness
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017

47. Phase I
SAFETY
SAFETY TRIALS
47
May be primary, co-primary or
secondary objective
PRE-LICENSURE POST-LICENSURE
Assessment of safety done at all
phases to analyse AEs (predefined/
SAEs/ AESI)
To detect AE that occur too
infrequently for detection in pre-
licensure studies
Categorization of events (causality,
severity and frequency)
1. Appropriate reporting of AEFI
2. Size of pre-licensure safety database
Phase IV
POST MARKETING
Ref: WHO Guidelines on clinical evaluation of vaccines, 2017

48. 48
Uttarilli A, Amalakanti S, Kommoju PR, Sharma S, Goyal P, Manjunath GK, Upadhayay V, Parveen A, Tandon R, Prasad KS, Dakal TC, Ben Shlomo I, Yousef
M, Neerathilingam M, Kumar A. Super-rapid race for saving lives by developing COVID-19 vaccines. J Integr Bioinform. 2021 Mar 25;18(1):27-43.

49. Accelerated vaccine development
strategies
• As scientists sequenced the genome of the novel coronavirus and developed
several promising vaccine candidates with extraordinary speed
• Moderna’s mRNA-based SARS-CoV-2 candidate entered phase I trials on March
16, less than 10 weeks after the first genetic sequences were released.
a. Bioinformatics tools
b. Parallel studies of screening trials
c. Global cooperation within the scientific community
d. Access to COVID-19 tools (ACT) Accelerator
49
Uttarilli A, Amalakanti S, Kommoju PR, Sharma S, Goyal P, Manjunath GK, Upadhayay V, Parveen A, Tandon R, Prasad KS, Dakal TC, Ben Shlomo I, Yousef
M, Neerathilingam M, Kumar A. Super-rapid race for saving lives by developing COVID-19 vaccines. J Integr Bioinform. 2021 Mar 25;18(1):27-43.

50. References:
• https://www.who.int/publications/m/item/WHO-TRS-1004-web-annex-9
• Delany I, Rappuoli R, De Gregorio E. Vaccines for the 21st century. EMBO Mol Med. 2014
Jun;6(6):708-20.
• https://blog.petrieflom.law.harvard.edu/2021/06/15/whats-the-difference-between-vaccine-
approval-bla-and-authorization-eua/
• https://www.nhp.gov.in/universal-immunisation-programme_pg
• Reed, S., Orr, M. & Fox, C. Key roles of adjuvants in modern vaccines. Nat Med 19, 1597–1608
(2013)
• Ong E, Wong MU, Huffman A, He Y. COVID-19 coronavirus vaccine design using reverse
vaccinology and machine learning. bioRxiv [Preprint]. 2020 Mar 21:2020.03.20.000141. doi:
10.1101/2020.03.20.000141. Update in: Front Immunol. 2020 Jul 03;11:1581.
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