Brief on various designs of phase 1 trials for vaccines

1. 1
Phase-1 Vaccine Trials
Dr Palvi Kudyar
DM Resident
03-05-2021
Department of Clinical Pharmacology, kem

2. 2
VACCINE DEVELOPMENT V/S DRUG DEVELOPMENT
High safety
margin Compatibility of
adjuvant with
vaccine antigen
03-05-2021
Department of Clinical Pharmacology, kem

3. 3
Cross reactive antibodies
Cell mediated immune response
03-05-2021
Department of Clinical Pharmacology, kem

4. 4
Step – down approach
03-05-2021
Department of Clinical Pharmacology, kem

5. 5
POPULATION OF INTEREST
Pre-defined Selected in accordance to
study objectives
03-05-2021
Department of Clinical Pharmacology, kem

6. • Observational cohort studies
describe the occurrence of the disease to be prevented in the target
population over time
• Phased (e.g. in sequential age or risk groups) introduction of the
vaccine into the target population in which the groups might form the
units of randomization
• Prospective case control studies
6
03-05-2021
Department of Clinical Pharmacology, kem

7. 7
• Placebo
• Adjuvant
• Alternative vaccine
Control Group
• No treatment
• Licensed vaccine
03-05-2021
Department of Clinical Pharmacology, kem

8. 8
Double
blind
Single
blind
Control of Bias
03-05-2021
Department of Clinical Pharmacology, kem

9. 9
Phase 1 trial of a 20-valent pneumococcal
conjugate vaccine in healthy adults
Example 1
03-05-2021
Department of Clinical Pharmacology, kem

10. 10
Phase-I open label, dose-escalation clinical trial to evaluate
the safety, tolerability and immunogenicity of Chikungunya
vaccine in healthy adults of 18 to 50 years
10 µg 20µg 30µg Placebo
N=15
(dosing at
0,28,56 day)
N=15
(dosing at
0,28,56 day)
N=15
(dosing at
0,28,56 day)
N=15
(dosing at
0,28,56 day)
Example 2
03-05-2021
Department of Clinical Pharmacology, kem

11. 11
POPULATION
10-100 healthy volunteers
Exclusion of those at risk of severe COVID
Older adults with no comorbidities
Include diverse group of populations
At maximum risk of infection both ethnic & racial
03-05-2021
Department of Clinical Pharmacology, kem

12. 12
Trial Design
Expedite by adaptive/seamless
designs
Include placebo and blinding
Multiple dosing regimes
Safe effective vaccine established-
control
03-05-2021
Department of Clinical Pharmacology, kem

13. 13
Safety and Efficacy of the BNT162b2 mRNA
Covid-19 Vaccine (Pfizer)
03-05-2021
1
Department of Clinical Pharmacology, kem

14. 14
Safety and immunogenicity of an rAd26 and rAd5 vector-
based heterologous prime-boost COVID-19 vaccine in two
formulations: two open, non-randomised phase 1/2 studies
from Russia (Sputnik-V)
frozen lyophilized
03-05-2021
2
Department of Clinical Pharmacology, kem

15. 15
Early
follow
ups
Received
booster
immunogenicity
Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine
against SARS-CoV-2: a preliminary report of a phase 1/2, single-
blind, randomised controlled trial (Astrazeneca)
03-05-2021
3
Department of Clinical Pharmacology, kem

16. Pharmacokinetic studies
• Usually not required for vaccines
• New delivery systems are employed
• Vaccine contains novel adjuvants or excipients
Pharmacodynamic studies
• Immunogenicity studies characterize the immune response to the vaccine
16
03-05-2021
Department of Clinical Pharmacology, kem

17. 17
IMMUNOLOGICAL STUDIES
• Amount
• class, sub-class
• function of specific antibody
• Lag-time for onset antibody persistence
• Seroconversion rate
• Induction of immune memory
 Relationship between
functional and non-
functional antibody
assays
 Quality of the antibody
response: specificity epitope
recognition and avidity
03-05-2021
Department of Clinical Pharmacology, kem

18. 18
Changes in these
parameters over time
and/or with subsequent
doses
• Age
• Prematurity
• maternal antibody
• nutritional status
• genetics
• coexisting disease
• immunosuppression
03-05-2021
Department of Clinical Pharmacology, kem

19. To antigen(s) in a candidate vaccine vs. similar antigen(s) in licensed
comparator(s)
To antigens in a candidate vaccine when administered to different
populations or at different doses or schedules
 To antigens when given separately vs. administration as components of a
candidate combined vaccine
antigens in a candidate vaccine when given alone or concomitantly with
other vaccine(s)
 To antigens in different formulations (including different antigen or
adjuvant doses) or lots of a candidate vaccine
Immunogenicity studies for Immune responses 19
03-05-2021
Department of Clinical Pharmacology, kem

20. 03-05-2021
Department of Clinical Pharmacology, kem
20
A phase 1 randomized open-label clinical study
to evaluate the safety and tolerability of a novel
recombinant hepatitis E vaccine

21. 21
03-05-2021
Department of Clinical Pharmacology, kem

22. 22
Primary Aim
demonstrate non-inferiority between treatment
groups with respect to immune responses to each
antigen of interest
demonstrate superiority of the immune response
to at least one antigen in the formulation
03-05-2021
Department of Clinical Pharmacology, kem

23. 03-05-2021
Department of Clinical Pharmacology, kem
23
Established immunological correlates of protection  Sero protection Rate
None Established immunological correlates of protection  Seroconversion Rate

24. 03-05-2021
Department of Clinical Pharmacology, kem
24
• % of Responders/those who Seroconvert [with 95% confidence interval
(CI)]
• GMC/GMT (with 95% CI) and pre/postvaccination ratios provide
absolute values and increase in antibody titers
• Antigen-specific T cell responses including cluster of differentiation
(CD)4+ and CD8+cytotoxic T lymphocytes (CTLs)
ANALYSIS OF IMMUNOLOGICAL STUDIES

25. DOSE FINDING STUDIES
• Explore schedules
• To minimize risk suboptimal dose/dose regimens are used
• lowest amount of antigen that elicits a protective immune response (if known)
should be explored
• To evaluate booster doses in case of more than one dosing required
25
03-05-2021
Department of Clinical Pharmacology, kem

26. EFFICACY STUDIES
an established
immunological correlate of
protection against a
specific infection (e.g.
diphtheria, tetanus)
infectious disease does not
occur ( smallpox)
occurs at too low a rate (
brucellosis, Q fever)
comparison of
immunological responses
with past studies of similar
vaccines with proven
protective efficacy
(acellular pertussis
vaccines)
efficacy study is not
feasible and there is no
established immunological
correlate of protection or
previous efficacy study
(anthrax)
26
03-05-2021
Department of Clinical Pharmacology, kem

27. vaccinated vs control groups
demonstrate superiority for the
vaccinated group
new vaccine vs approved vaccine
non-inferiority in terms of
protection
PRIMARY AIM 27
03-05-2021
Department of Clinical Pharmacology, kem

28. 28
SAFETY REQUIREMENTS
• Diary cards/Questionnaires
including intervals for collection of the data & duration of follow up
• Safety data to be collected after each dose of the vaccine
• any adverse event that occurs within approximately 5-7 days (longer for
live vaccines)
• Recording of later events (e.g. up to 14 days post-dose) by telephone
contact or when vaccinees actually attend for the next dose
03-05-2021
Department of Clinical Pharmacology, kem

29. CLINICAL ENDPOINTS
• Reactogenicity
• Protective efficacy ability of the vaccine to prevent clinically apparent infections
• Alternative primary endpoints :
 Clinical manifestations of latent infection (e.g. vaccines intended to prevent
herpes zoster)
 Laboratory evidence that a candidate vaccine reduces primary infection rates.
(e.g. candidate vaccines against hepatitis C infection).
 Other markers that predict progression to clinically apparent disease
29
03-05-2021
Department of Clinical Pharmacology, kem

30. SPECIAL CONSIDERATIONS FOR VACCINE STUDIES
• Immune interference
• Vaccines with more than one antigen
• Cross reacting immune responses
• Bridging studies
30
03-05-2021
Department of Clinical Pharmacology, kem

31. 31
03-05-2021
Department of Clinical Pharmacology, kem
Phase 1/2a Trial of Plasmodium vivax Malaria Vaccine
Candidate VMP001/AS01B in Malaria-Naive Adults:
Safety, Immunogenicity, and Efficacy