• To characterize the systemic response to mucosal immunization with an oral cholera vaccination challenge.• To characterize the local response to intranasal rechallenge after cholera vaccination as outcome measure for nasal mucosal immunity.• To…
ID
Source
Brief title
Condition
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Serum cholera antigen specific IgA levels at Day 1, 14, 18, 20 and 28.
• Serum cholera antigen specific IgG levels at Day 1, 14, 18, 20 and 28.
Secondary outcome
• Cholera antigen specific IgA in nasal secretion (measured by nasosorption) at
-2 hours before and 1, 2, 7 and 10 days after nasal rechallenge.
• Treatment-emergent (serious) adverse events (S)AEs.
• Clinical safety laboratory measurements.
• Vital signs measurements.
• Physical examinations.
Background summary
The mucosal immune system is a relatively new and promising target for IMPs.
These mucosa-associated lymphoid tissues (MALT), containing a specialized
innate and adaptive immune system, are located in all mucous membranes covering
the digestive, respiratory and urogenital tracts. Amongst the MALT are
anatomically defined lymphoid compartments that are the main mucosal inductive
sites for initiating the immune response, such as the Peyer*s patches,
mesenteric lymph nodes and the appendix (gastrointestinal tract), tonsils and
adenoids (nose and airway). The mucosal immune system protects against
colonization and invasion by pathogenic microbes, but also provides tolerance
against non-pathogenic antigens from commensal bacteria or food. Contrary to
the systemic immune reaction, the mucosal immune system functions in
surroundings containing several foreign antigens and therefore immunological
reactions have to be strictly regulated. The mucosal immune reaction is
regulated by nature of the antigen, type of antigen presenting cell (APC) and
the local microenvironment. Another difference between the mucosal immune
system and systemic immune system is the production of secretory IgA (SIgA) as
most abundant immunoglobulin. SIgA is a dimer of two IgA monomers coupled by a
J-chain, which also protects against the breakdown by proteolytic enzymes
present in the digestive system.
When luminal antigens are taken up by absorptive epithelial cells (M cells) and
presented by antigen presenting cells (APCs), cytokines and B cell stimulating
factors will be produced, after which activation and class switching by B cells
is induced. Non-pathogen antigens (such as food proteins) usually result in
suppression of the immune reaction (tolerance), while pathogenic antigens are
recognized by mucosal APCs (e.g. by toll-like receptors) and will lead to a
broader humoral and cellular immune response. After sensitization, B- and T
cells leave the mucosal site where they have encountered the antigen, and enter
the circulation via the lymph vessels. Next, they return to the MALT
(*homing*), where differentiation into memory or effector cells takes place.
The principal location where lymphocytes are homing is determined by expression
of their homing receptors, and locally produced chemokines. More specifically,
the homing receptor integrin α4β1 binds to vascular cell adhesion molecule 1
(VCAM-1), that is mainly expressed at the bronchial and nasal mucosa. Integrin
α4β7 binds to the mucosal addressin cell adhesion molecule 1 (MAdCAM-1), that
is mainly located in the gastrointestinal mucosa. Local chemokines such as
chemokine (C-C motif) ligand (CCL)-25 and CCL28 further attract lymphocytes via
their chemokine receptors (C-C motif Chemokine Receptor [CCR]-9, CCR10). The
presence of retinoic acid (RA) imprints IgA-producing cells with gut-homing
properties; without RA homing receptors to other parts of the MALT are formed.
Despite the extensive functions of the mucosal immune system, which provide new
opportunities for IMPs targeting - amongst others - gut immunity, possibilities
for quantifying the mucosal immune reaction are still limited. Measuring the
effect of novel immunomodulatory drugs targeting the mucosal immune system is
challenging, as the immune reaction first needs to be activated to be able to
measure pharmacodynamic effects, and measuring local response is not possible.
Therefore, a well-characterized immune challenge driving a mucosal immune
response is needed.
Oral vaccinations such as the cholera vaccine interact with the mucosal immune
system, particularly the Waldeyer*s ring in the oral cavity and the Peyer*s
patches in the small intestine. Therefore, inducing the mucosal immune system
by oral cholera vaccination may be used to measure the effect of new compounds
on the mucosal immune system. In order to study the effect of IMPs on the
mucosal immune response via oral cholera vaccination, firstly the effect of
well-known compounds should be characterized. It is already known that use of
immunosuppressive medication by renal transplant recipients results in a much
lower increase in IgA antibody level after oral cholera vaccination. More
specifically, in healthy controls the anti-cholera toxin subunit B (CBT) titer
is 13.4 times higher post-vaccination compared to pre-vaccination, while it is
4.3 times higher post-vaccination in renal transplant recipients using
immunosuppressive medication (prednisolone and either a calcineurine inhibitor
or mycophenolate).
Although the mucosal immune system is spread all over the internal mucosa,
particular mucosal inductive sites are associated with corresponding effector
sites. Differences in expression of chemokines, integrins (the aforementioned
*homing receptors*) and cytokines over the mucosal surface result in a
compartmentalization of the mucosal immune system. Therefore, the mucosal
immune response can be induced by different vaccination routes, resulting in
segmentalized antibody production. Oral vaccination mainly induces antibody
responses in the small intestine, ascending colon and salivary glands, but
there is little IgA production in the tonsils or genital tract. Conversely,
nasal immunization results in an antibody response in the upper airway, saliva
and nasal secretion and does not have much effect on immune responses in the
gut. Therefore, nasal vaccinations may be used to study compounds targeting the
nasal cavity and upper respiratory tract. Nasal vaccinations have already been
investigated with a diphtheria and tetanus vaccination8, influenza vaccination9
and cholera toxin vaccination. It has been shown that nasal vaccination is
superior to oral vaccination in obtaining local antibodies in the respiratory
tract. In this study, the use of nasal cholera rechallenge as model for
compounds targeting the nasal mucosa will be investigated.
Study objective
• To characterize the systemic response to mucosal immunization with an oral
cholera vaccination challenge.
• To characterize the local response to intranasal rechallenge after cholera
vaccination as outcome measure for nasal mucosal immunity.
• To evaluate safety and tolerability of nasal rechallenge after oral cholera
vaccination.
Study design
The study will be a single-blind, randomized, placebo controlled, single center
study including 12 healthy subjects (groups: 6 MMF, 6 placebo). Subjects will
receive an oral cholera vaccination at Day 1 and Day 14. Intranasal rechallenge
will take place at Day 18. Immunosuppression (MMF or placebo) will be
administered for 6 days around the initial oral cholera vaccination (i.e. 2
days before, 4 days after).
Intervention
For oral cholera vaccination Dukoral will be used, combined with recombinant
cholera toxin subunit B. Subjects will receive a dose (3 mL) at Day 1 and at
Day 14. At Day 18, nasal rechallenge with the cholera vaccination will take
place. For nasal rechallenge, 0.375 mL containing 125 µg recombinant cholera
toxin subunit B, a total dosage of 250 ug in 0.75 mL will be administered in
two nostrils.
As immunosuppressive agent, MMF will be used. Dosing will be 2 dd 1g, according
to standard treatment protocols.
As comparative drugs, placebo tablets will be used.
Study burden and risks
The oral cholera vaccination (Dukoral®) that is used in this study is already
registered and is known to have good safety profile with few side effects.
Also, the intranasal administration of the cholera vaccination has already been
performed in earlier studies, with mild and self-limiting adverse events. More
risks are involved in the use of MMF as benchmarking drug. MMF will be used for
a short period (6 days) and in healthy subjects. During the study, subjects
will be monitored closely for signs of infection by the study physician, and
will be instructed to contact the study physician in case of any complaints.
After MMF use, haematology blood tests will be performed to ensure lymphocytes
have returned to their normal levels. Given the short use of MMF and the close
monitoring of subjects, the risks of administration to healthy volunteers is
acceptable in this study. To limit the period of immunosuppression, MMF will
only be used around the initial oral cholera vaccination, to inhibit the
initial immune response. It was hypothesized that the lack of initial immune
priming and inhibited T and B cell proliferation will result in a substantially
lower response to the second oral cholera vaccination and intranasal
rechallenge. In case an infection occurs within a subject, MMF treatment will
be stopped immediately. If needed, infections may be treated with antibiotics
or antiviral medication. As shown in the CHDR1902 study, proliferation will be
restored rapidly. Lastly, both MMF and the oral cholera vaccination may cause
gastrointestinal side effects, which may also result in interaction between
these drugs. However, the oral cholera vaccination has already been
administered to different patient groups under immunosuppressive therapy and to
patients with inflammation of the gut, where no serious safety concerns were
raised.
For a structured risk assessment see Section 10 of the protocol.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Signed informed consent prior to any mandated procedure.
2. Healthy male and female subjects, 18 to 45 years of age, inclusive at
screening.
3. Body mass index (BMI) between 18 and 35 kg/m2, inclusive, and with a minimum
weight of 50 kg.
4. All subjects must practice effective contraception during the study and be
willing and able to continue contraception for at least 90 days after their
last dose of study treatment.
5. The participant has clinical laboratory evaluations (including clinical
chemistry, haematology and complete urine analysis) within the reference range
for the testing laboratory, unless the results are deemed not clinically
significant by the investigator.
6. Participants who are overtly healthy as determined by medical evaluation
including medical history, vital signs, physical examination, laboratory tests
and ECGs at Screening and on Day -2.
7. The participant should be able to take MMF / placebo 2 times per day for 6
days, and to refrain from eating 2 hours before intake.
8. Has the ability to communicate well with the Investigator in the Dutch
language and willing to comply with the study restrictions.
Exclusion criteria
1. The participant has signs and/or symptoms of an infection 2 weeks prior to
dosing, or recurrent infection, or has had an infection requiring antibiotic
treatment (e.g. sepsis, pneumonia, abscess) within 42 days prior to start of
MMF / placebo administration.
2. The participant has (a history of) autoimmune disease such as multiple
sclerosis, inflammatory bowel disease, rheumatoid arthritis or other
immune-inflammatory disease.
3. The participant has a history of trauma with likely damage to the spleen, or
has had surgery to the spleen or splenectomy.
4. The participant has a known immunodeficiency.
5. Positive Hepatitis B surface antigen (HBsAg), anti-hepatitis B core,
hepatitis C, or human immunodeficiency virus antibody (HIV-Ab) at screening.
6. Serious psychiatric or medical conditions that, in the opinion of the
investigator, could interfere with treatment, compliance, or the ability to
give consent.
7. The participant has taken any over-the-counter (OTC) or any prescription
medication (with the exception of paracetamol) less than 5 half lives prior to
the first oral cholera vaccination, and considered as relevant by the
investigator.
8. Participant has received live attenuated vaccination within 42 days prior to
Screening or intends to have vaccinations during the course of the study.
SARS-CoV-2 vaccinations are not allowed 1 week prior to Screening and from 2
weeks before dosing until EOS.
9. Participant has received any investigational drug of experimental procedure
within 90 days or 5 half-lives, whichever is longer, prior to study
intervention administration, or participant was enrolled in an investigational
drug or device study within 90 days prior to first IMP dosing.
10. The participant has a history of hypersensitivity or allergies to any drug
or to any of the components of the study interventions (i.e. Dukoral oral
cholera vaccination, MMF or placebo).
11. The participant has lost or donated more than 400 mL of blood or blood
products within 90 days prior to start of MMF or placebo treatment (Day -2) or
plans to donate blood during the study.
12. The participant has had an acute, clinically significant illness or
intervention by surgeon or dentist within 14 days prior to screening.
13. Current (or within past 6 months) nicotine use in excess of 5 cigarettes
per day, or unable not to smoke during visits.
14. History of abuse of addictive substances (alcohol, illegal substances) or
current use of more than 14 units alcohol per week, drug abuse, or regular user
of sedatives, hypnotics, tranquillisers, or any other addictive agent.
15. Previous vaccination against cholera or enterotoxigenic Escherichia coli.
16. Travel in the last 3 years to a country where cholera or enterotoxigenic E.
coli is prevalent.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2023-000084-31-NL |
| CCMO | NL83700.056.23 |