| Protocol No: | ECCT/19/04/01 | Date of Protocol: | 09-07-2019 |
| Study Title: | Safety and immunogenicity of a Shigella-tetravalent bioconjugate vaccine: A phase 1/2 randomized controlled and age descending study including dose finding in 9-month-old infants |
| Study Objectives: |
Study objectives
- The primary objective of this Phase 1/2 study is to obtain first-in-human data (safety
and immunogenicity) following administration of 9-month-old infants and to identify
the preferred dose of Shigella4V.
Secondary objectives:
- To further evaluate safety of Shigella4V through collection of laboratory values from
safety laboratory tests.
- To evaluate immunogenicity of Shigella4V when administered to adults and in 2-5-
year-old children.
- To evaluate persistence of the vaccine-induced immune response, 6 months after the
primary vaccination schedule.
- To evaluate the immunological response and immune persistence induced by a booster
dose of Shigella4V in children and infants.
Exploratory objectives:
In this study, additional investigations may include, but are not limited to, the following
immunological and efficacy objectives:
- IgA immunological response induced by vaccination with Shigella4V (i.e. Serum IgA
responses and fold-increases between post- and pre-vaccination samples, from
participants of step 1 and 2).
- Functionality of the antibodies generated following vaccination with Shigella4V (i.e
measuring serum bactericidal activity (SBA) post and pre-vaccination from
participants of step 1 and 2).
- Development of B-memory response in the vaccinated participants, against serotypes
included in Shigella4V.
- Impact of vaccination toward incidence of diarrhoea episodes caused by Shigella
strains of vaccine serotypes (i.e. Number of participants with Shigella positive
(culture or PCR confirmed) diarrhoea in vaccinated vs. control group).
- Impact of vaccination on the severity of symptoms associated with Shigella-positive
diarrhoea in vaccinated vs. control groups.
- To evaluate concomitant administration of measles-rubella vaccine in 9-month-oldinfants.
The study team will administer the measles-rubella vaccine to allow for its
co-administration with the Shigella vaccine. The team will work with the county
officials to make arrangements for the study participants to receive the measlesrubella
vaccine in the study sites
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| Laymans Summary: |
What is the problem/background?
LimmaTech Biologics Ab (LMTB) develops vaccines called “glycoprotein bioconjugates”
through a new process. Bioconjugates are sugar/protein mixtures that are made using bacterial
cells. Although this is a first in human trial of this precise bioconjugate, six previous clinical
studies have been conducted with the same technology and protein component as used for this
vaccine. Vaccination with bioconjugates in more than 1000 healthy adults has been reported
as safe and well tolerated. This trial will evaluate a vaccine against Shigella, a disease that
causes diarrhoeal illness. The vaccine targets a disease of major importance for
children/infants in low and middle-income countries (LMICs). According to the Global
Burden of Disease study 2015, diarrhoea is the fourth leading cause of death for children and
is responsible for 8.6% of all deaths of children aged under 5years. The impact of diarrheal
disease (DD) goes well beyond mortality, causing a significant amount of disease that mostly
affects children under 5 years of age. Shigella is the leading pathogen causing DD in LMICs
in children > 1 year of age and is among the top six causes of diarrhoea in children < 1 year.
What questions are we trying to answer?
We plan to evaluate if Shigella4V, a candidate shigella vaccine, is safe at different doses in
healthy Kenyan adults (aged 18-50 years), young children (aged 2-5 years) and infants (8-10
months) and investigate the immune response following vaccination. We will also determine
the ideal dose for an adequate immune response and the associated safety profile in infants.
Where is the study taking place, how many people does it involve and how are they
selected?
The study is taking place in two research sites; CGMR-C (Kilifi site) and in CCR (Kericho
site). We aim to recruit healthy participants, exclusion will include conditions such as HIV,
hepatitis B and C, heart, lung and conditions, pregnancy amongst others. This study will
evaluate the safety and immune responses to the vaccine in 2 steps. The 1st step will recruit 16
adults, 48 young children and 60 infants at one research site. Once safety has been
established in this first step, we will progress to determine the best dose in 468 infants at both
sites until the target number is enrolled. We will screen potential participants until we identify
the required number of healthy participants from the different age groups.
What does the study involve for those who are in it?
Individuals who provide consent and pass screening examination will be enrolled in the study.
Screening will involve a series of blood tests to check for good health, an examination and a
urine test for pregnancy in women. All participants will have pre-test counselling for
Hepatitis and HIV as per local practices and guidelines. Additionally, participants at the
KEMRI/CGMRC site will be screened for sickle cell disease (SCD) after pre-test counselling.
Such test will not be routinely done at the site in Kericho as not supported by the geographical
incidence of SCD. For individuals who are selected for participation, blood will be drawn at
the different time-points (infant volumes will be described in SSA and will be within the
limits stipulated by the World Health Organisation/National Institute of Health Guidelines).
Adults will have an average 459mls taken over 8-10 months, Children 120mls over 13-16
months and infants 90mls over 15-18 months in Kilifi and 130 mls in Kericho. Adults will
have 75 mls of blood taken at each visit except screening when 9 mls will be taken. Children
will have 12 mls taken at all visits. Infants in Kilifi will have 5mls taken at 6 visits and 12 mls
at 5 visits. Infants in Kericho will have on average 12mls taken at 11 visits. The higher blood
volumes collected in a subpopulation of infants (Kericho site) will allow exploratory analyses
for further evaluation of the immune response to the Shigella vaccine. Repeat blood samples
may be taken to verify abnormal results. Urine samples will be collected for adult females to
test for pregnancy and medical history will also be obtained in addition to undergoing a
clinical assessment. Listening to the heart will serve as an assessment of heart function with further investigations if clinically indicated. Those that pass screening will be enrolled in the
trial and for those that don’t if a clinically significant condition is identified they will be
counselled as appropriate then referred to a government facility. Eligible participants will be
randomised to receive Shigella 4V or a control vaccine. Blood will be taken at screening,
prior to each vaccination (to check baseline immunity to Shigella4V in all participants and for
rabies in a small group of the children receiving rabies as a control vaccine), and at several
time points (2 to 3 time points) post each vaccination (to evaluate response to vaccination).
There will be a total of 7 clinic visits for adults, 10 for children and 11 for infants, plus home
visits whenever needed in the week following each vaccination. Should a participant develop
diarrhoea during the course of the study 4mls of blood will be collected in children and
infants and 9 mls of blood will be collected in adults and a stool sample to determine if
diarrhea was caused by Shigella and treatment will be provided. The study duration for each
participant will be approximately 8 to 10 months for adults, 13 to 16 months for children and
15 to 18 months for infants.
What are the benefits and risks/costs of the study for those involved?
Participants may benefit from receipt of the vaccine if the immune response is favourable and
the vaccine is safe. Participants will also have close oversight and treatment support from the
study team although this will primarily be for risk monitoring. Participants will benefit from a
vaccine against meningitis (adults and infants), rabies (children) or an additional dose of
DTaP vaccine that will be administered to the infants of the control group and offered free of
charge at the end of the study, to the infants randomized to Shigella4V. Although the
administration schedule of the rabies vaccine being used has been evaluated in clinical trials it
is currently not standard practice, therefore for all children we will recommend that should
they have exposure to high risk bite they get full post-exposure prophylaxis.
There will also be wider benefit in the field of shigella vaccine development and in building
on data available on safety and immune responses to bioconjugate vaccines. Although 1 of the
4 components of the vaccine has been evaluated in humans before this will be the first study
of Shigella 4V in humans, however 6 very similar vaccines have been evaluated in >1000
healthy adults and been found to be safe and illicit a good immune response. A careful
approach to vaccinate a small number of adults sequentially then children and infants with increasing doses and with close follow up in the days and months following vaccination have
been planned to safeguard the safety of all participants.
At its first administration, Shigella4V will be co-administered with the measles-rubella
vaccine in infants which is routinely given at 9 months of age. Several trials have shown an
acceptable safety profile and non-inferiority in the immune-response when conjugate vaccines
are co-administrated together with measles and rubella vaccine. Furthermore immune
response to measles and rubella will be analysed. Higher volumes of blood are being collected
from infants at KEMRI/MRD-K, Kericho to allow for detailed analysis of the immune
response to all components of the Shigella 4V vaccine. Recurrent venepuncture can lead to
anaemia and as such we will monitor heamoglobin levels to ensure we only collect the
volumes of blood planned at the KEMRI/MRD-K, Kericho site if the haemoglobin (Hb) is
10g/dL or above. Hemoglobin monitoring will be done at the clinic using HemoCue method
prior to the visit blood draw. Should the level fall below 10g/dL blood volumes will be taken
as specified at KEMRI-CGMRC.
Participants will not have any costs associated to their participation to this trial.
How will the study benefit society?
Diarrhoea is a big problem all around the world and there is a need to develop vaccines for
vulnerable populations-such as infants and young children, particularly in endemic areas. This
study will build on safety and immunogenicity data of Shigella4V and will provide safety and
immune responses which will inform the nature and need of clinical development of this
vaccine. There is reason to believe this is a promising candidate vaccine given components of
the vaccine and vaccines made using a similar technology have been shown to be safe and to
raise an immune response.
When does the study start and finish?
The study will start on receipt of ethical and regulatory approvals and will take approximately
2.5 years.
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| Abstract of Study: | ABSTRACT Shigella species are one of the leading causes of diarrhoea in our region affecting primarily infants and children and diarrhoeal disease accounts for close to half a million under five deaths per year worldwide. Following an acute infection shigellosis is associated with post infective complications, developmental repercussions, cognitive impairment and a negative impact on growth. We propose to evaluate the safety and reactogenicity of a candidate Shigella vaccine. Shigella4V, is composed of O-antigen polysaccharides (PS) from four different Shigella strains representing the most epidemiologically relevant strains: S. sonnei, S. flexneri 2a, 3a and 6, conjugated to the exoprotein A of P. aeruginosa EPA. This will be a first-in human trial. However, several biconjugate vaccines, and one component of Shigella4V have already been evaluated and have been found to be safe and immunogenic. We will conduct a double blind, multi-site trial in KEMRI-CGMRC and KEMRI/MRD-K, Kericho in 2 steps. Step 1 will involve a safety cohort at KEMRI-CGMRC-. We will use a randomised control, age descending, dose-escalating approach to evaluate safety and reactogenicity in 16 adults (18-50 years), 48 young children (aged 2-5 years) and 60 infants aged 8-10 months of age. The second step will aim to enrol 468 infants to further evaluate safety and identify the optimum immunogenic dose. Infants in step 2 will be randomised on enrolment to 1 of 4 vaccine doses of (4 ,12, 24, 48 µg) or control vaccines. Adults will receive a 2 dose schedule, 1 month apart with a total of 7 visits in clinic, and they will be in the trial for about 8 months; children will receive a 3 dose schedule (2 doses 1 month apart then a booster dose 6 months after the 2nd dose) with a total of 10 visits in clinic and they will be in the trial for about 13 months; infants will receive a 3 dose schedule (2 doses three months apart then a booster dose 6 months after the 2nd dose) and a total of 11 visits in clinic, and they will be in the trial for approximately 15 months. For each vaccine dose, formulation with and without Aluminium adjuvant will be tested. |