Vaccine clinical trial

‘ Presented by’-
Piyush A. Bafna
2013H146077H
M. Pharm.(Pharmaceutics)-1st year
28th October 2013

• A ‘Vaccine’ is biological preparation that improves immunity to
particular disease.
• A Vaccine may be prophylactic or therapeutic.
• A Vaccines can be made of Live, Killed or attenuated micro
organisms.
• The term vaccine was firstly used by Edward Jenner in 1796.
• Edward Jenner is thus well known as ‘Father of Immunology’.
Vaccine Clinical trial

Year Discovery
1796 Edward Jenner introduced Small pox vaccine
1880 Louis Pasteur developed attenuated cholera vaccine
1882 Robert Koch isolated tubercle bacilli
1882 Louis pasteur successfully prevented rabies by post
exposure vaccination
1908 Karl Landsteiner and Erwin Popper discovered poliovirus
1924 BCG is introduced as live tuberculosis vaccine

Year Discovery
1961 Albert Sabin developed oral attenuated polio vaccine
1960-
1969
Live attenuated vaccines for Measles , Mumps and Rubella were
developed
2006 First HPV (Human papilloma virus) vaccine is licensed
2012 Polio was eliminated from India

1. Phase I trial- are usually small scale.
2. Phase II trial- are to assess the safety, early efficacy of
selected dose of vaccine.
3. Phase III trial- are usually large in scale and are to
confirm the Efficacy of vaccine in target population.

4.Phase IV- are usually conducted for
collecting information regarding long term
safety or efficacy of vaccine to full fill with
regulatory requirement.

1.Safety studies – Acc.to FDA guidelines, the
studies should be randomized and controlled.
Follow up safety should be actively monitored and
planned. Follow up should be continued at least
30 days for live or killed vaccines.
2.Immunogenicity- The main objective of
comparative immunogenicity study is to rule out
the difference between response to study vaccine
and a control. The differences between Geometric
Mean Titers and/or Sero conversion rates are
studied.

3.Efficacy-Endpoint used to evaluate efficacy
could range from disease incidence to well
established marker with activity.
4.Statistical Considerations- Stratified –
Randomization may be recommended .
For sample size, the FDA requires that sample
size calculation for each study endpoint should be
performed and …

And accordingly the sample size should be
selected.

What is TBE-: It is the disease condition
which is caused by the TBE viruses which
are positive-stranded RNA viruses.
Infectious TBE Viruses enters cells by
receptor mediated endocytosis.
TBE Virus is the Flavi virus infection, that
has been known from more than 50 yrs.

TBE has recently joined the diseases under
surveillance in the European Union; on 5
September 2012, it was included in the list
of notifiable diseases in the European
Union.

TBEV is transmitted by 11 tick species, but
only 2 species are important vectors: Ixodes
ricinus for TBEV-Eu and Ixodes persulcatus
for TBEV-Sib.
Ticks act as both the vector and reservoir for
TBEV.

Sponsor of trial- Novartis vaccines
Estimated Enrollment – 300
Location countries- Germany
Status of study- Completed

- Prepare protocol(s) for human studies.
-Apply for investigational New drug (IND) approval.
-Submit Product Licensure Application MCC
approval .
-Advisory Committees review and make
recommendations.

- Post Marketing Surveillance for safety and
effectiveness (Phase IV).
- Long term process and Usually takes 10- 15
years.

Official title of study-
A Phase IV, Randomized, Controlled, Single-Blind,
Multi-Center Study in Children to Evaluate the
Safety, Tolerability and Immunogenicity of
Two TBE Vaccines Administered According to Two
Different Schedules.
Purpose/Objective of study- The purpose of
this study is to evaluate the safety, immunogenicity
and tolerability of TBE vaccines administered to
children.

Primary Outcome Measures:
Immunogenicity of two pediatric TBE vaccines as
measured by neutralization test and ELISA on days
28, 42, 300, and 321.
Secondary Outcome Measures:
Tolerability of two paediatric TBE vaccines with
respect to local and systemic reactions including fever.

Study type- Interventional
Study phase- Phase IV
Study Design-
Sr.no. Design
1. Allocation- Randomized
2. End point classification- Safety/Efficacy
3. Intervention Model: Parallel Assignment

Sr. no. Design
4. Type- Single blinded
5. 1° purpose- Prevention

The administration scheme for both
vaccines is three doses given intra
muscularly, the first two given with a gap of
three week to 3 month apart and the third
one given nine to twelve months after the
second. Thereafter, a booster dose every
fifth year is recommended.

Sr. No. Vaccination stage Age
1. Primary immunization ≥ 1 year
2. 1st booster ≥ 1 year
3. 2nd booster ≤ 49 years *

All subjects who already had pre immunization
TBE titers showed at least a fourfold increase
post immunization. The latter subjects had
naturally acquired immunity against TBE and
therefore can be regarded as protected against
TBE disease.
Substantial level of neutralizing TBE antibodies
were already be detected.

1.Healthy male and female children, age
group in between 1 to 10 years.
2. Willingness to sign written informed
consent form.
3. Subject agrees to enroll into protocol-
driven long- term follow up for 2 years after
randomization.

1. Age more than 18 years.
2. Pregnancy or lactation.
3. History of autoimmune disease.
4. Administration of other vaccine 4 weeks before or
after day zero.
5. Administration of immuno globulins 6
Weeks prior to any vaccination.
6. Any contraindication specified by manufacturer.

% reduction in attack rate of disease-:
VE (%) = (ARU-ARV) X 100
(ARU)
Where; ARU-unvaccinated individual
ARV- vaccinated individual

Vaccine efficacy- Is given as Reduction in
the incidence of a disease.
VE =1-θ
where;
θ =Relative risk of infection

Marketed formulations-:
1. TBE Moscow Vaccine ® (Russia)
2. FSME-Immun ® (Baxter,Austria)
3. Encepur ® (Novartis Vaccine, Germany)

Vaccines Adjuvant Shelf life Age limit
FSME-IMMUN 0.5ML
Adults
Al(OH)3
24 months MT 16 years
FSME-IMMUN 0.25ML
Junior.
Al(OH)3
24 months 1-16 years
Encepur adults Al(OH)3
24 months MT 14 years
Encepur children Al(OH)3
24 months 1-12 years

-Subjects are analyzed for immunogenicity
achieved after post immunization levels of
TBE antibodies.
-Common range of the side effects already
noted for licensed TBE vaccines was
reported. After the distribution of more than
five million vaccine doses,no potential safety
risk was noted.

Vaccination is the most effective protective
measure against TBE.
Immunization against TBE has also proved cost
effective. It is advisable to increase vaccination
coverage not only among people living in
regions considered at risk of TBE, but also
among travelers who plan to spend some time
in countries where TBE is endemic.

Post-marketing experience supports results
from clinical trials showing that these new TBE
vaccines may safely be used for the
vaccination of children, adolescents, and
adults.
The evaluation of safety and tolerability in
adolescents and adults in the present clinical
program was focused on the monitoring of local
and systemic reactions and the detection of
uncommon or unexpected side effects.

No serious or unexpected adverse events
related to vaccination were reported in these
comprehensive clinical studies involving
more than 7,500 voluntary subjects.
Post-marketing experience has confirmed
the generally high degree of safety and
acceptance of the new TBE vaccines.

1. Low to High grade fever
2. Fatigue and appetite loss
3. Hypersensitivity and local reactions.

1. Liposomal delivery systems
2. Polymeric nanoparticle delivery systems
3. Virosomes
4. Micellar delivery systems
5. Dendrimer based delivery system

Webpages-:
1. Clinicaltrials.gov
2. www.ncbi.nlm.nih.gov/pubmed
3. Par Anderson , Immunological Effects of
TBE Vaccination, 2008.
4. CH Saroja , PK Lakshmi, Shyamala
Bhaskaran, Recent trends in vaccine
delivery systems, vol. I,April 2001.
5. Daniela Amicizia, A. Domnich;
Epidemiology of TBE, Italy, May 2013.Vaccine Clinical trial

Books-:
1. Design and Analysis of clinical trials, 2nd
edition, S. Chung Chow and J. P. Liu.
2. Fundamentals of Clinical trials, 3rd edition, L.
M. Friedman, C. D. Furberg , D. L. DeMets.

Thank u For listening…
Any Question ?

Vaccine clinical trial

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