| Protocol No: | ECCT/24/08/02 | Date of Protocol: | 27-05-2024 |
| Study Title: |
Safety and immunogenicity of a second generation Shigella bioconjugate vaccine: a phase II randomized, controlled, and blinded study in 9-month-old infants
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| Study Objectives: |
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| Laymans Summary: |
Lay Title
A study to expand safety and immunogenicity data with the second generation of the Shigella bioconjugate tetravalent (Shigella4V2) in 9-month-old Kenyan infants.
What is the problem/background?
Bioconjugates are “glycoproteins-like” vaccines made using bacterial cells, and developed at LimmaTech
Biologics (LMTB) through a well established process, that has generated more than 7 products
successfully tested in 10 clinical trials (Table 1). Generally, vaccination with bioconjugates in around 2000
participants ranging from adults to infants has been reported as safe and well tolerated. This trial will
evaluate a vaccine against Shigella, a disease of major importance for children/infants in low and middle
income countries (LMICs). According to the Global Burden of Disease 2019, diarrheal diseases (DDs) are
the fourth leading cause of death for children under 5 years. The impact of DDs 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 the second cause of
diarrhea in children under 5 years (1). A clinical phase I/II trial (NCT04056117) using the first generation
(Shigella4V) of this bioconjugate vaccine (Shigella4V2) has already been conducted in Kenya enrolling
around 600 participants, mostly infants but also adults and children. The results of this study showed that
the Shigella4V bioconjugate is safe and immunogenic in the target population of 9 months infants for all 4
vaccine serotypes. Following the positive results, a 2nd generation S. sonnei bioconjugate has been
produced to further increase yield leading to the development of the Shigella4V2 vaccine being used in the
upcoming S4V02 study. This second generation vaccine also comes preformulated with AL(OH)3 adjuvant
and, for enabling multidose presentations, 2-Phenoxyethanol as a preservative, making this Shigella 4V2
drug product phase III ready.
What questions are we trying to answer?
Following the good safety and immunogenicity data obtained in the phase I/II with Shigella4V, this new
trial aims to expand and confirm the available data in Kenyan infants (9 ± 1 months old) , including the
optimized S. sonnei bioconjugate component. Testing the 2 doses, considering all serotypes, showing the
best immunogenicity following the S4V01 trial (see section 0), we will confirm which of these 2 doses
will be selected for phase III by looking at the vaccine immunogenicity and safety.
Where is the study taking place, how many people does it involve and how are they selected?
The study is being carried out by KEMRI at their Clinical Research Center located at the Siaya County
Referral Hospital, western Kenya. We aim to recruit healthy participants. Exclusion will include
conditions such as HIV, hepatitis B and C, heart and lung conditions, amongst others. Unlike the S4V01
study, which was the first-in-human trial and was therefore designed in two steps using an age-descending
and dose escalation approach, this study will be conducted in infants only and with concurrent
randomization to either of the two vaccine doses or to the control. A total of 110 infants will be enrolled .
What does the study involve for those who are in it?
Individuals who pass screening examination and meet the eligibility criteria will be consented for
voluntary participation and then enrolled in the study. Screening will involve a series of blood tests to
check for good health. All participants will have pre-test counselling for Hepatitis B and C and HIV-1/2 as
per local practices and recommended national guidelines.
For individuals who are selected for participation, blood will be drawn at the different time-points
according to the Schedule of Events. These samples will range between 5ml and 12ml over approximately
9 months. Should there be any vaccination visits (V1) occurring within one week from screening (VS),
blood collection at V1 could be omitted because of the proximity with blood draw that occurred at
screening. For these cases, baseline values from screening will be used for further analyses unless there is
any clinical concern or change in medical history in which case relevant investigations would be repeated
(e.g., haematology or biochemistry). Repeat blood samples may be taken to verify abnormal results.
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. Study
participants who pass screening and are eligible to take part in the study will be enrolled in the trial. Those
who don’t, if due to a clinically significant condition, will be counselled as appropriate and then referred to
relevant clinics for further management in line with the local referral systems. Eligible participants will be
randomised to receive either Shigella4V2 or a control vaccine. Blood will be taken at screening, prior to
vaccination (to check baseline antibodies against Shigella serotypes included in the vaccine), and at 2 or 3
time points post each vaccination in order to check 1701 for safety and evaluate the study participants immune
response to vaccination. There will be a total of 6 clinic visits, plus home visits whenever needed in the
week following each vaccination. Should a participant develop diarrhea during the course of the study, 4ml
of blood will be collected to check immune response, together with a stool sample to determine if diarrhea
was caused by Shigella. Free treatment will be provided according to antibiotic susceptibility test results
and as further advised by Kenya’s Ministry of Health guidelines on Control and Management of
Diarrhoeal Diseases in Children Below Five Years. The study duration for each participant will be
approximately 9 months. As previously done in the S4V01 phase I/II trial, at its first administration,
Shigella4V2 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 the measles and rubella
vaccine, and this was also reported in our phase I trial with the Shigella bioconjugate.
What are the benefits and risks/costs of the study for those involved?
It is expected that the Shigella4V2 bioconjugate will lead to further significant progress in the prevention
of Shigella infections caused by the O-antigen serotypes of S. sonnei and S. flexneri 2a, 3a and 6. This
investigational vaccine is no longer in the early stages of clinical development, as efficacy of the
tetravalent first generation product (Shigella4V) has already been demonstrated in the same population.
The anticipated benefits for participants participating in the S4V02 trial may include the following:
• Participants will contribute to the further advancement of medical and scientific knowledge
on a candidate Shigella vaccine that may have in the future a key role in the prevention of a disease
for which there is a high medical burden in LMICs.
• Participants will benefit from receiving free regular health checks and medical care access
to the clinic during the entire study although this will be primarily for risk monitoring
• All participants in the investigational groups will be offered a licensed vaccine (namely
MenACWY) not included in the regular EPI schedule (Men ACWY is the S4V02 study control
vaccine administered during the study to the control groups and at the end of study to those
participants that received Shigella4V2), without costs.
How will the study benefit society?
Diarrhea is a big problem all around the world and there is a need to develop vaccines for vulnerable
populations such as infants and children under 5 years, particularly in endemic areas. Furthermore, the
emergence of resistance among Shigella isolates to commonly used antibiotic agents limits the therapeutic
options in some settings. Vaccines can reduce the use of antibiotics and can curb the spread of
antimicrobial resistance in the society. This study will confirm immunogenicity and safety of Shigella4V2,
and will provide information for the subsequent stages of its clinical development. The S4V01 study has
already shown this vaccine to be safe and immunogenic against Shigella flexneri serotypes 2a, 3a, 6 and S.
sonnei. This has given reason to believe that this product is a promising candidate Shigella vaccine
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 the Shigella bioconjugate, which is currently the most
advanced vaccine candidate against Shigella. All 4 components of the vaccine have already been tested in
adults, children, and infants during the S4V01 trial (see Investigator’s Brochure for more details) . Out of
the four bioconjugates included in Shigella4V2, three are the same previously tested with Shigella4V in
the phase I/II S4V01 trial, the fourth bioconjugate is an optimised version of the previously tested S.
sonnei component (O-antigen structure and protein carrier are the same, but product yield has been
improved by increasing number of glycosides on the protein carrier, see IB for further details). In addition,
6 very similar bioconjugate vaccines have also already been evaluated in around 1500 healthy adults and
have been found to be safe and elicit a good immune response.
When does the study start and finish?
The study will start on receipt of ethical and regulatory approvals and will take approximately 1 year until Last Subject Last Visit.
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| Abstract of Study: |
Shigella species are one of the leading causes of diarrhea in our region affecting primarily
infants and children under 5 years of age. Diarrheal diseases account 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 confirm the immunogenicity and
safety of the second generation of the Shigella bioconjugate vaccine. Shigella4V2 is
composed of O-antigen polysaccharides (PS) from the four different Shigella strains
representing the most epidemiologically relevant serotypes: S. sonnei, S. flexneri 2a, 3a, and
6, conjugated to the exoprotein A of P. aeruginosa (EPA). All four serotypes included in this
product have already been evaluated and have been found to be safe and immunogenic in
Kenyan infants. We want to confirm these results in the second generation Shigella
bioconjugate, which includes an optimized S. sonnei component, and to select one
formulation out of the two doses which performed the best (immunogenicity- and safetywise)
in the S4V01 trial. Therefore, we will conduct a double blind, single-site trial at
KEMRI’s Clinical Research Center at Siaya County Referral Hospital in western Kenya. We
will evaluate immunogenicity and safety in 110 infants aged 9 ± 1 months. Participants will
be randomised into 3 different arms: 2 investigational groups (12 or 24 μg PS doses including
Alum) and 1 one control group (MenACWY). Study participants will receive 2 doses three
months apart, will undergo a total of 8 visits in clinic, and will be part of the trial for
approximately 9 months.
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