This project ultimately aims to demonstrate that a 1-visit rabies PrEP vaccination course induces immunological memory as evidenced by protective antibody titres within 7 days after revaccination at one year. In the current phase, a dose-finding…
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Memory response to standard booster vaccination (IM d0 d3) at 1 year post
primary vaccination (defined as 100% seroprotection [RVNA >0,5 IU/mL as
measured by FAVN] for all subjects in the dose level within or at 7 days
post-booster). In case all subjects within a dose group are still protected at
the booster baseline of day 365, the primary endpoint will be a 4-fold increase
in RVNA GMT for that group.
Secondary outcome
7.1.2 Secondary endpoints related with immunogenicity:
- Rabies seroprotection rate in each group at baseline, d14-16 and d28-35 after
primary vaccination; defined as seroconversion.
- Geometric mean titres of rabies virus neutralizing antibody (RVNA GMT by
FAVN) in each group at D14, D28-35, D365 and D368, D372.
7.1.3 Secondary endpoints of safety:
- Loss of vaccine at the injection site.
- Size of intradermal wheal after vaccination
- Discomfort caused by vaccination technique;
- Number of vaccination technique failures;
- Frequency and severity of local and systemic adverse events.
Background summary
The main purpose of rabies pre-exposure (PrEP) vaccination is the formation of
immunologic memory. The rapid memory response to booster vaccination eliminates
the need for rabies immunoglobulin treatment (RIG) after possible exposure.
Pre-exposure vaccination also induces a transient protective antibody level
that may protect against unnoticed exposure during the at-risk period.
Injection of a reduced dose of rabies vaccine into the skin (intradermal, ID)
has previously been shown to be as safe and effective as traditional
intramuscular vaccination, and is endorsed by the WHO for both pre- and
post-exposure prophylaxis. [1,2,27]
Administering vaccines into the skin is thought to enhance the immunogenicity
of vaccines due to the high density of antigen presenting cells (APC) that
enable a strong immune response. Furthermore, the skin facilitates rapid
trafficking of antigen and the activated APC to draining lymph nodes where
subsequent T-cell and B-cell activation and initiation of an adaptive immune
response can occur. Administration into the skin in general may enable the use
of vaccine doses with lower antigenic contents than is used for intramuscular
or subcutaneous administration, saving costs and increasing availability in
resource-poor regions of the world. [3-17]
The LUMC Travel Clinic performs 1500 intradermal rabies administrations
annually. Many travellers don*t have sufficient time to complete a full 3-week,
3-visit PrEP vaccination course before they commence their travels. Several
studies indicate that the PrEP course could be shortened to 2 visits while
maintaining an adequate seroconversion rate and memory formation, by using
multi-site ID injection of the vaccine. Schedules were either 1-site ID d0-d3
or d0-d7, and at 7-14 days more than 98% of vaccinees were seroprotected
Indications for adequate protection after only 1 visit using multi-site ID
injection also exist in literature: 2 ID injections on d0 resulted in 71-74%
seroprotection rate at d35 and 4 ID injections on d0 resulted in 100%
seroprotection rate at d14. There was no difference between 4-site and 8-site
d0 regimens.HDCV vaccine appeared to be most immunogenic among all
vaccines.[18-26]
Traditionally, ID vaccination is more painful than IM vaccination and takes
longer to perform due to vaccine preparation logistics. It*s also more
technically demanding to perform than intramuscular injection (IM), and success
often depends on the individual skill of the person performing the injection.
To enable reduction of the number of visits in the PrEP course with multi-site
ID injections while maintaining reliability, the ID administrations in this
trial will be performed by 1 experienced practitioner.
Study objective
This project ultimately aims to demonstrate that a 1-visit rabies PrEP
vaccination course induces immunological memory as evidenced by protective
antibody titres within 7 days after revaccination at one year. In the current
phase, a dose-finding trial will be performed to establish proof of principle.
To determine the optimum dose level for a one-visit multi-site rabies
pre-exposure intradermal rabies vaccination schedule, in rabies naïve healthy
adults. A small series of different doses will be used to construct the
dose-response relationship for the new schedule. Immunological memory formation
will be assessed with boostability at 1 year. With the optimal dose
demonstrated from this study, a larger non-inferiority trial will be performed.
Study design
A 4-arm randomized controlled open-label vaccination trial. Time between the
first visit and the last visit is approximately 1 year. Subjects will visit the
investigator 8 times . Each subject will receive multi-site intradermal
administration of rabies vaccine in 1/5th of the normal dose or 1 IM injection
(control group). Subjects will be required to complete a diary (booklet or
web-based) during the first 5 days following the pre-exposure vaccination, in
which local and systemic side effects are to be recorded.
Blood samples will be drawn on days 0, 3, 7, 14-16, 28-35, 365, 365+3 and 365+7.
After interim analysis of the seroprotection rate, the 2 arms with the lowest
seroprotection rate will be extended to include an additional 5 subjects each.
Intervention
Study group A: 1-site intradermal injection of 0,1 mL rabies vaccine
per site at d0 using N&S.
Study group B: 2-site intradermal injection of 0,1 mL rabies vaccine per site
at d0 using N&S.
Study group C: 3-site intradermal injection of 0,1 mL rabies vaccine per site
at d0 using N&S.
Study group D: IM vaccination of 1 mL rabies vaccine at d0 using N&S.
Each group consists of 5 evaluable healthy adult volunteers. After
interim-analysis, the 2 experimental arms with the lowest seroconversion rates
will be extended to include an additional 5 subjects.
Study burden and risks
In total, 1 to 3 intradermal injections will be given with a registered
vaccine. A total of 308 mL of blood will be collected during 8 sampling
moments. Eight visits are required for the study. The participants are asked to
complete a diary for safety evaluation during the study. Rabies vaccine in
intradermal administration is currently in use in many countries without
incident. No risks are associated with participation in this study other than
those of routine vaccination and minimal to moderate physical discomfort that
can be experienced after vaccination or the collection of blood. Participants
will receive financial compensation for their participation.
Albinusdreef 2
Leiden 2333ZA
NL
Albinusdreef 2
Leiden 2333ZA
NL
Listed location countries
Age
Inclusion criteria
Subjects are required to fulfill all of the following criteria:
• Age >= 18 years
• Good health according to the investigator
• Willingness and ability to adhere to the study regimen
• Able to give informed consent
Exclusion criteria
Exclusion criteria for this study are:
• Known or suspected previous vaccination against rabies
• Known or suspected allergy against any of the vaccine components
• History of unusual or severe reactions to any previous vaccination
• History of (pre)syncope associated with medical procedures involving needles
• Immunocompromized state due to illness or medication
• Administration of plasma or blood products three months prior to inclusion in the study
• (hydroxy)chloroquine or mefloquine use
• History of any neurological disorder including epilepsy or febrile seizures
• Pregnancy or breastfeeding
• Any current infectious disease other than seasonal cold
• Bleeding disorders or use of anticoagulants
• Temporary exclusion criterion for vaccination: Body temperature >= 38.5ºC or acute illness will lead to postponement of participation and vaccination. Screening may continue when the temperature has normalized.
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 | EUCTR2013-002999-40-NL |
| CCMO | NL45544.058.13 |