Vaccine Overdose of Undetermined Intent Clinical Trial
Official title:
Safety and Efficacy of a Novel Candidate Peptide Vaccine Against HCV Infection in Healthy Volunteers and in Treated (Non-responders/ Responders) Chronic HCV Patients. Clinical Trials Phases I and II
Description: A randomized Placebo-controlled study to evaluate safety and efficacy of Cenv3
peptide vaccine in normal volunteers. This study is designed to test safety of 3 consecutive
monthly escalating doses of the immunogen ( 0.324 mg, 0.648 and 3.240 mg / 70 kgm body
weight) in 40 healthy male subjects (15,15 and10 subjects respectively) plus 10 subjects on
placebo. Bioavailability of Cenv3 will be tested throughout the duration of the experiment.
In the study hyperimmune state will be achieved via 3 subcutaneous injections (0.648 mg
each), once every 4 weeks. A placebo treated healthy subjects ( n= 10) will serve as
controls. Chronic HCV patients ( n=50) who did not respond to IFN + RBV combined therapy
will be recruited to test therapeutic efficacy of the compound via 6 consecutive injections
( 0.648 mg each ) every 2 weeks. ( NB : this group of patients has been already recruited in
the first part of this project where evaluation of the compound is currently underway).
Immunized healthy volunteers will be followed for a year compared with placebo group, where
all biochemical, hematological, immunological and allergic parameters are recorded. Treated
CHC patients will be evaluated for virological, hematological, biochemical and immunological
states at the end of treatment.
Subject : Cenv3 potential prophylactic and therapeutic immunogens in healthy volunteers and
against chronic HCV infection respectively.
In the present work, we plan to study the safety and efficacy of a peptide vaccine termed
Cenv3 ( C for HCV, en for envelop, v for vaccine, 3 for 3 epitopes). The main outlines of
the current study include: 1) Examining the safety parameters throughout the vaccination
period including acute and chronic reactions if present in a phase 1 clinical study ( i.e.
in healthy volunteers). The vaccine will be administered sc at 3 escalating doses in
presence and absence of adjuvant. Bioavailability of the vaccine throughout the experiment
duration will also be determined. 2) Assessment of the humoral and cellular immune responses
towards Cenv3 in healthy volunteers ( higher risk for acquiring HCV infection). 3)
Evaluation of the neutralizing capacity of the generated Abs to interfere with intracellular
replication of HCV in permissive cell lines
ii) Objective The present proposal aims at:-
1. Examining safety and tolerability towards the candidate HCV peptide vaccine in healthy
volunteers.
2. Testing cell mediated immunity via cytotoxic T lymphocyte responses in vaccinated
healthy subjects ( CMI).
3. Determining epitope specific B cell response and antibody titers in vaccinated
individuals (humoral Immunogenicity).
4. Testing the viral neutralization by antibodies against the vaccine epitopes.
(Efficacy).
5. Studying the bioavailability of the peptides in subjects' circulation throughout the
vaccination time and 90 days post vaccination.
iii) Study population
Subjects with any cardiovascular problems, asthma, or allergies, should be excluded from the
study. Also, any subject who has participated in any experimental medicine clinical trial in
the past 3 months will be excluded. Healthy volunteers including subjects from both sexes,
18-55 years of age will be enrolled. All subjects had to fulfill all inclusion criteria as
follows: mentally and physically healthy, no clinically relevant pathological findings in
any of the investigations of the pre-study examination including blood chemistry ( liver and
kidney function tests), differential blood counts, coagulation test, ultrasensitive
C-reactive protein levels. Subjects should be able to provide written informed consents. The
exclusion criteria included pregnant or breast feeding women, patients with chronic
viral-infections (e.g., HBV, HCV, HIV, CMV, HSV), evidence of decompensated liver disease,
pre-existing hematuria, or proteinuria, cryoglobulin levels >1% or other immunologically
driven diseases, schistosomiasis, acute infectious illness, severe psychiatric disorders,
current or past history of malignancy and patients who received treatment with interferon or
any investigational therapy for hepatitis during the 3 months prior to study entry.
iv) Consent The volunteers will be provided with a written information sheet on the vaccine
and the requirements of this trial. They will
, in return, give written consent to participate in the study. Subjects will be paid an
honorarium for their participation. They will also be provided with transport money to and
from the hospital.
v) Outlines of the study : In the proposed study, we aim at evaluating tolerability, safety,
immunogenicity and efficacy of Cenv3 peptide vaccine in 112 healthy volunteers as a placebo
controlled open labeled phase 1 clinical trial. Tolerability and safety parameters include
clinical signs ( acute and chronic), biochemical assays ( hepatic and renal functions as
well as other metabolic parameters) and hematological tests ( all blood cell parameters).
Both humoral and cellular responses to the immunization protocols will be evaluated.
Neutralizing capacities of specific Abs generated in response to the vaccine will also be
determined after vaccination.
vi) Vaccination
Preparation of vaccine will be performed under the principles of Good Manufacturing
Practice. The lyophilized peptides are manufactured in an eight arm multiple antigenic
peptide (MAP) in a commercial facility specialized in peptide synthesis and structure
modification ( .e.g AnaSpec USA). Peptides will be dissolved in PBS made for human use. The
whole procedure will be done in sterilized areas of drug/vaccine industry ( e.g. VACSERA,
MOH Wezaret Al Zera'a street Agouza). The lyophilized peptides will be stored in regular
fridge, while dissolved peptides will be stored at -80 0 C as aliquots ( in sealed ampoules
each contains 1X dose) ready for injection and transported to the hospital in dry ice just
before use. Note : These storage and transportation precautions are followed during these
early stages of the study. While the strategy would be modified at a commercial scale when
the current product proves effective. In this later case a lyophilized powder with the
recommended dose will be packaged in a sealed ampoules and dissolved just before use. HCV
peptide vaccine Cenv3 will be injected subcutaneously in 3 different doses ( 1x i.e. 324 ug
, 2x i.e. 648 ug or 3x 1296 ug/ 70 kgm body weight adult). It should be noted here, that
dose 1X equals to the calculated pharmaceutical dose from mice experiments, therefore 324
ug/ 70 kg body weight is the Minimum Available Biologically Effective dose Level (MABEL).
Based on other laboratories experience with peptide vaccine administration to man ( Tanaka
and Manns) who used up to 5000 ug of peptide vaccine for their immunization experiments. The
highest dose used in our protocol is 4X ( 1296 ug/ 70 kg bw) and therefore considered the No
Observable Adverse Effect Level ( NOAEL) in this protocol. The vaccine will be administered
either as a MAP form ( self adjuvanted) or supplemented with adjuvant ( MF59) in a common
protocol of monthly injection for 3 consecutive months.
vii) Sample collection
All immunization and sampling procedures will be performed in Ahmed Maher Educational
Hospital ( MOH). Subject enrollment, consenting, vaccination, sampling and clinical
observation post vaccination will be done under close medical supervision by trained
clinicians in the hospital. Seven blood samples will be taken from subjects prior to the
first immunization and at days 30, 60, 90 ( during vaccination period) and days 135, 180 and
360 thereafter. At day 360 subjects will be immunized with a booster dose equal to the
original dose given to the same subject and an 8th blood sample will be collected 30 days
after the booster dose. Each time 15 ml venous blood will be withdrawn. Eight ml will be
used for serum separation for humoral response determination, neutralization assays and
biochemical testing. Seven ml on EDTA for CBC and lymphocyte separation for EliSpot assay.
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Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Single Blind (Investigator), Primary Purpose: Prevention