To screen the immune repertoire of healthy volunteers for broadly reactive fusion-inhibiting antibodies directed against coronavirus S protein, including SARS-CoV-2 f and (if found) to isolate/clone and further characterize such antibodies with the…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* B-cell response as assessed by enzyme-linked immunosorbent assay (ELISA)
and/or enzyme-linked immunosorbent spot assay (ELISpot) and/or flow cytometry
methods
* Serology: peptide library scanning
Secondary outcome
* Prevalence of common cold as assessed by PCR-based assay for respiratory
pathogens panel
Background summary
Two processes are key to infection by any virus: attachment and entry. Viral
attachment is achieved through binding of a protein on the surface of the viral
particle to a specific receptor (i.e. protein or glycan structure) on the
surface of a host cell, whereas entry is defined as the release of the viral
proteins and genetic material in the cytosol of the host cell.
In the case of enveloped viruses, attachment and entry are mediated through
distinct domains of a single surface protein. Typically, a globular *head*
region of this protein contains the Receptor Binding Domain (RBD) while a
membrane-proximal *stem* region contains the machinery that mediates viral
entry by triggering fusion of the viral and host cell membranes, the so called
*fusion domain* (1).
As the globular head region is much more exposed than the stem region, both
natural infection and vaccination primarily induce antibodies that block
infection by binding to the RBD and prevent viral attachment. While such
antibodies have high neutralizing potency, they are typically highly specific
for one virus strain (or a small set of closely related strains) as a
consequence of the fact that the RBD is prone to mutate and varies
significantly between individual virus strains.
In contrast, the fusion domain is highly conserved among virus families. This
is due to the fact that in order to trigger fusion of the virus* and host cell
membranes, the fusion domain needs to undergo extensive conformational
rearrangements. This molecular machine consists of many moving parts which
imposes strong evolutionary constraints on many residues in the stem region (2).
For Coronaviruses, attachment and entry are mediated by the *Spike* (S)
protein. The S1 subunit contains the variable RBD while the S2 subunit contains
the conserved fusion machinery (3-5). There is ample evidence in the literature
that the S2 domain of coronaviruses is antigenic, and antibodies able to
inhibit membrane fusion by Coronavirus S proteins have been described (6-10).
In order to find human monoclonal antibodies with broad neutralizing activity,
the current research will be focusing on interrogating the B-cell repertoire of
healthy human donors for antibodies directed against the S, S1, and
particularly the S2 domains of the coronavirus S protein able to block the
membrane fusion process using state-of-the-art technology such as flow
cytometry.
If broadly neutralizing antibodies are identified using the above-mentioned
techniques, Leyden Labs will develop mAb-based fusion-inhibition product(s) for
prevention of infection and respiratory disease by members of the corona virus
family, including SARS-CoV-2.
Study objective
To screen the immune repertoire of healthy volunteers for broadly reactive
fusion-inhibiting antibodies directed against coronavirus S protein, including
SARS-CoV-2 f and (if found) to isolate/clone and further characterize such
antibodies with the ultimate goal of developing an antibody for prophylactic
and/or therapeutic use against coronavirus infections.
Study design
This is an exploratory study that is part of the development trajectory of a
therapeutic antibody. A total of 20 healthy subjects will be enrolled. The
study will consist of a single visit, the total duration of the study for each
subject will not be more than half a day. During the visit, subject*s
eligibility for this study will be assessed prior to sample collection, and
blood will be collected for the study endpoints.
Study burden and risks
No investigational drug will be administered to the volunteers. The invasive
procedures under this protocol will be restricted to blood sample collection
(venipuncture). The burden for the volunteer related to the study procedures is
limited. Only well-established methods of sample collection will be applied,
with a known and limited risk and no or mild discomfort for the volunteer. In
addition, all collections will be performed by qualified medical staff.
No clinical benefit can be expected from this study for the participating
subjects. A study population of 20 healthy volunteers (10 males; 10 females) is
deemed appropriate to investigate in vitro the immune response for epitope
based therapeutic SARS-CoV-2 antibody development.
Keizersgracht 290a
Amsterdam 1016EW
NL
Keizersgracht 290a
Amsterdam 1016EW
NL
Listed location countries
Age
Inclusion criteria
1. Participant must sign the study informed consent form prior to any
study-mandated procedure indicating that he or she understands the purpose,
procedures and potential risks, and is willing to participate in the study;
2. Participant is male or female and between 40 and 65 years of age, inclusive,
at the time of enrollment;
3. Participant is willing and able to complete the study procedures;
4. Participant has a primary care physician at the time of enrollment;
5. Participant is generally healthy in the investigator*s clinical judgment, as
determined by medical history evaluation, including no clinically significant
disorder, condition, infection or disease that would interfere with the study
evaluation, procedures or completion.
Exclusion criteria
1. Participant has current clinical symptoms of COVID-19 (including, but not
limited to: cough, fever, shortness of breath, sudden onset of anosmia, ageusia
or dysgeusia). Note that a participant who reports a previous positive
diagnostic test result for SARS-CoV-2 infection (serological testing or viral
RNA detection by PCR testing) and who is recovered from COVID-19 for at least
three weeks prior to blood sampling is allowed to participate in the study as
deemed by the investigator;
2. Participant had recent close contact with a SARS-CoV-2 infected person or
someone in their household tested positive for SARS-CoV-2, has travelled to a
country/area that has been designated as a COVID-19 risk area according to the
effective policies/guidelines of the National Institute for Public Health and
the Environment (Dutch: RIVM) or otherwise meet criteria for home isolation;
3. Participant received immunosuppressive medication or other immunomodulating
agents (including investigational drugs) in the 3 weeks prior to study blood
sampling or received immunoglobulins or blood products in the 3 months prior to
study blood sampling;
4. Participant with a whole blood donation or loss of >500 ml within 21 days
before study blood sampling;
5. Any known factor, condition, or disease that might interfere with
compliance, study conduct or interpretation of the results, as deemed by the
investigator.
Design
Recruitment
metc-ldd@lumc.nl
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In other registers
| Register | ID |
|---|---|
| CCMO | NL75505.058.20 |