Simplifying the Rabies Pre-exposure Vaccination

• Sponsor: Institute of Tropical Medicine, Belgium (Other)
• Overall Status: Completed
• CT.gov ID: NCT01388985
• Collaborator: Military Hospital, Brussels (Other), Sciensano (Other)
• Enrollment: 500
• Location: 1
• Arms: 2
• Duration (Months): 51
• Patients Per Site Per Month: 9.8

Study Details

Study Description

Brief Summary

Rabies is a viral zoonosis that causes an encephalitis, almost invariably fatal. It is widely distributed across the globe: the World Health Organization (WHO) estimates that about 2,4 billion people live in endemic areas for canine rabies. Vaccination of domestic animals is limited to industrialized and middle-income countries.

The development of clinical rabies can be prevented through timely immunization after exposure: however, preventive vaccination simplifies the post-exposure procedure considerably, as immunoglobulins are no longer needed and less vaccine administrations are scheduled. Pre-exposure prophylaxis consists of an intramuscular (IM)of intradermal (ID) dose given on days 0, 7 and 21 or 28. The development of immunological memory after this vaccination is critical for the establishment of long lasting immunity. Subjects receiving a booster dose 1 year after pre-exposure prophylaxis segregate themselves into 'good' and 'poor' responders; the former may not need further boosters for 10 years, whereas the latter may need more frequent boosters.

Until recently, guidelines in travel medicine recommended pre-exposure vaccination only for some risk groups. Since recent studies have shown the effectiveness of the ID vaccination, the policies are changing towards pre-exposure vaccination for a larger population, including travelers to endemic regions, where immunoglobulins and vaccine are often not readily available.

Based on the above, the investigators must stress the concept of "boostability" after a risk exposure. However, the current pre-exposure vaccination scheme could be improved: a schedule of 1 week would be less time consuming, would improve compliance and give less interference with other prophylaxis measures, e.g. mefloquine. Two small studies suggest that a schedule of 1 week interval is as effective and immunogenic as the standard one.

The investigators will investigate whether the accelerated schedule is as effective as the classical schedule, by carrying out a randomized, non-inferiority study.

Condition or Disease	Intervention/Treatment	Phase
Rabies	Biological: Human Diploid Cell Vaccine (HDCV) rabies vaccine	Phase 3

Detailed Description

Rabies is a viral infection that affects the central nervous system and causes an encephalitis which is almost invariably fatal. Being a zoonosis, the infection usually occurs following a transdermal bite or scratch by an infected animal, but contamination may also occur when infectious material, usually saliva, comes into direct contact with the victim's mucosa or with fresh skin wounds. Human-to-human transmission is extremely uncommon.

Rabies is widely distributed across the globe: the World Health Organization (WHO) estimates that 87 countries with a total population of about 2,4 billion people are afflicted with endemic canine rabies, and the inclusion of all species poses a potential threat to >3.3 billion people. The number of rabid wild animals that die without being detected is however estimated to be more than 90% of the total, so identified infections represent only a small fraction of wild animal rabies cases. Vaccination of domestic animals is limited to industrialized nations, the most urbanized areas of Latin America and some Asian countries such as Thailand.

The development of clinical rabies can be prevented through timely immunization after exposure to the infecting agent: preventive vaccination alone implies no complete protection, but it simplifies the post-exposure procedure considerably, as immunoglobulins are no longer needed and less vaccine administrations are scheduled. Pre-exposure prophylaxis consists of an intramuscular (IM)of intradermal (ID) dose given on days 0, 7 and 21 or 28. The development of immunological memory after this vaccination is therefore critical for the establishment of long lasting immunity against rabies in humans. If a booster dose is given 1 year after pre-exposure prophylaxis, subjects segregate themselves into 'good' and 'poor' responders; the former group, who represent 75% of subjects, may not need further booster vaccination for 10 years, whereas the latter may need more frequent boosters.

Until recently, guidelines in travel medicine recommended the pre-exposure vaccination only to the classic risk groups. Since recent studies have shown the effectiveness of the ID vaccination, the policies are changing towards the recommendation of pre-exposure vaccination for a larger population, including all travelers to endemic regions, where rabies immunoglobulins and vaccine are often not readily available. The ID pre-exposure vaccination, which is more cost-effective, could also become an affordable alternative to protect the local population in high endemic regions.

Based on all the above, the investigators must stress the concept of "boostability" after a risk exposure: the main target of travel medicine today is to get a sufficient serological response on day 7 after a risk in prevaccinated persons (accelerated immune response through memory cells) and after two post-exposure vaccinations (day 0 and 3). It should also be noted that a schedule of 1 week would be preferable to the current schedule, because it would be less time consuming, would improve compliance and gives less interference with the intake of other prophylaxis measures, e.g. mefloquine. Two recent but small studies from Thailand suggest that an accelerated schedule of three intradermal injections within 1 week interval is as effective and immunogenic as administered within 4 weeks.

Therefore, this randomized, non-inferiority study will investigate whether the accelerated schedule is as effective as the classical schedule. The investigators will also increase the number of sites of injection, from one to two, to stimulate several different groups of lymph nodes on the same time to initiate more antibody production.

Study Design

• Study Type: Interventional
• Actual Enrollment: 500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Simplifying the Rabies Pre-exposure Vaccination
• Study Start Date: Oct 1, 2011
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Standard vaccination schedule One injection will be given on three different days (day 0, day 7 and day 21 or 28)	Biological: Human Diploid Cell Vaccine (HDCV) rabies vaccine; Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites
Experimental: Accelerated vaccination schedule Two injections will be given on the same day (day 0 and day 7): one on each forearm.	Biological: Human Diploid Cell Vaccine (HDCV) rabies vaccine; Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites

Outcome Measures

Primary Outcome Measures

1. Number of Participants With a Boostability of the Rabies Antibodies After Booster Vaccination [Day 7 after booster vaccination]

   The primary endpoint is the number of particpants with a boostability of the rabies antibodies on day 7 after booster vaccination, carried out at years 1 to 3 after initial vaccination. A rabies serology value of more than 0,5 IU/ml (international unit/milliliter) on day 7 after booster vaccination is considered to be protective. Subjects showing this serology value at day 7 are considered to be boostable.

Secondary Outcome Measures

1. Number of Participants With a Rabies Serology More Than 0.5IU/ml After Primary Vaccination [Day 35 after primary (initial) vaccination]

   Number of participants that have a Rabies serology more than 0,5 IU/ml on day 35 after primary vaccination.

2. Number of Particpants With a Rabies Serology More Than 10IU/ml After Primary and Booster Vaccination [Day 35 after primary (initial) vaccination, and after booster vaccination]

   Number of participants that have a Rabies serology more than 10 IU/ml on day 35 after primary vaccination, and after booster vaccination.

3. Number of Particpants Experiencing Adverse Events [One week after initial and booster vaccination]

   Number of participants experiencing Adverse events within one week after initial and booster vaccinations

4. Number of Participants Experiencing Serious Adverse Events [28 days after initial and booster vaccination]

   Number of participants experiencing a Serious adverse event within 28 days after initial and booster vaccinations

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 47 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Willingness to provide written consent

• Seronegative for rabies

• Belgian soldiers who are deployable and visit the Travel clinic in Brussels during their preparation phase before deployment OR military students at the schools of Belgian Defense are eligible in preparation of an overseas exercise or during the scheduled vaccination program at the end of their studies

• Prepared to follow the study schedule

Exclusion Criteria:

• Subjects who have had rabies vaccination (complete or incomplete) in the past due to post-exposure prophylaxis.

• Subjects with a known allergy to one of the components of the vaccine.

• Immune depressed persons or intake of immunodepressant medication.

• Subjects who take mefloquine

• Planned deployment to overseas areas within 35 days.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Military Hospital	Bruxelles		Belgium	B-1000

Sponsors and Collaborators

• Institute of Tropical Medicine, Belgium
• Military Hospital, Brussels
• Sciensano

Investigators

• Principal Investigator: Patrick Soentjens, MD, ITM and Military Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• EudraCT entry for the trial 2011-001612-62

Publications

None provided.

• Responsible Party: Institute of Tropical Medicine, Belgium
• ClinicalTrials.gov Identifier: NCT01388985
• Other Study ID Numbers: ITMC0211; 2011-001612-62
• First Posted: Jul 7, 2011
• Last Update Posted: May 14, 2019
• Last Verified: Apr 1, 2019

• Keywords provided by Institute of Tropical Medicine, Belgium: Rabies; Vaccination; Boostability
• Additional relevant MeSH terms: Rabies; Vaccines

Study Results

Participant Flow

Pre-assignment Detail	2 participants (1 in each group) signed the ICF and were randomized, but withdrew their consent before the first vaccination. They are not included in any of the analyses.

Arm/Group Title	Standard Vaccination Schedule	Accelerated Vaccination Schedule
Arm/Group Description	One injection will be given on three different days (day 0, day 7 and day 21 or 28) Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites	Two injections will be given on the same day (day 0 and day 7): one on each forearm. Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites
Period Title: Overall Study
STARTED	249	249
Primary Vaccination Period	231	238
COMPLETED	200	211
NOT COMPLETED	49	38

Baseline Characteristics

Arm/Group Title	Standard Vaccination Schedule	Accelerated Vaccination Schedule	Total
Arm/Group Description	One injection will be given on three different days (day 0, day 7 and day 21 or 28) Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites	Two injections will be given on the same day (day 0 and day 7): one on each forearm. Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites	Total of all reporting groups
Overall Participants	249	249	498
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	29	28	29
Sex: Female, Male (Count of Participants)
Female	12 4.8%	8 3.2%	20 4%
Male	237 95.2%	241 96.8%	478 96%
Serology at baseline (Count of Participants)
0.5 IU/mL or less	245 98.4%	248 99.6%	493 99%
more than 0.5 IU/mL	4 1.6%	1 0.4%	5 1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With a Boostability of the Rabies Antibodies After Booster Vaccination
Description	The primary endpoint is the number of particpants with a boostability of the rabies antibodies on day 7 after booster vaccination, carried out at years 1 to 3 after initial vaccination. A rabies serology value of more than 0,5 IU/ml (international unit/milliliter) on day 7 after booster vaccination is considered to be protective. Subjects showing this serology value at day 7 are considered to be boostable.
Time Frame	Day 7 after booster vaccination

Outcome Measure Data

Analysis Population Description

From the total number of participants that completed the study (200 in the standard vaccination schedule and 211 in het accelerated vaccination schedule), not all were included in het per protocol analysis. 15 participants were excluded from the standard vaccination schedule group and 28 were excluded from the accelerated schedule group.

Arm/Group Title	Standard Vaccination Schedule	Accelerated Vaccination Schedule
Arm/Group Description	One injection will be given on three different days (day 0, day 7 and day 21 or 28) Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites	Two injections will be given on the same day (day 0 and day 7): one on each forearm. Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites
Measure Participants	185	183
Count of Participants [Participants]	185 74.3%	183 73.5%

2. Secondary Outcome

Title	Number of Participants With a Rabies Serology More Than 0.5IU/ml After Primary Vaccination
Description	Number of participants that have a Rabies serology more than 0,5 IU/ml on day 35 after primary vaccination.
Time Frame	Day 35 after primary (initial) vaccination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard Vaccination Schedule	Accelerated Vaccination Schedule
Arm/Group Description	One injection will be given on three different days (day 0, day 7 and day 21 or 28) Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites	Two injections will be given on the same day (day 0 and day 7): one on each forearm. Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites
Measure Participants	231	238
Count of Participants [Participants]	231 92.8%	238 95.6%

3. Secondary Outcome

Title	Number of Particpants With a Rabies Serology More Than 10IU/ml After Primary and Booster Vaccination
Description	Number of participants that have a Rabies serology more than 10 IU/ml on day 35 after primary vaccination, and after booster vaccination.
Time Frame	Day 35 after primary (initial) vaccination, and after booster vaccination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard Vaccination Schedule	Accelerated Vaccination Schedule
Arm/Group Description	One injection will be given on three different days (day 0, day 7 and day 21 or 28) Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites	Two injections will be given on the same day (day 0 and day 7): one on each forearm. Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites
Measure Participants	231	238
Count of Participants [Participants]	189 75.9%	167 67.1%

4. Secondary Outcome

Title	Number of Particpants Experiencing Adverse Events
Description	Number of participants experiencing Adverse events within one week after initial and booster vaccinations
Time Frame	One week after initial and booster vaccination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard Vaccination Schedule	Accelerated Vaccination Schedule
Arm/Group Description	One injection will be given on three different days (day 0, day 7 and day 21 or 28) Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites	Two injections will be given on the same day (day 0 and day 7): one on each forearm. Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites
Measure Participants	249	249
Count of Participants [Participants]	190 76.3%	190 76.3%

5. Secondary Outcome

Title	Number of Participants Experiencing Serious Adverse Events
Description	Number of participants experiencing a Serious adverse event within 28 days after initial and booster vaccinations
Time Frame	28 days after initial and booster vaccination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard Vaccination Schedule	Accelerated Vaccination Schedule
Arm/Group Description	One injection will be given on three different days (day 0, day 7 and day 21 or 28) Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites	Two injections will be given on the same day (day 0 and day 7): one on each forearm. Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites
Measure Participants	249	249
Count of Participants [Participants]	1 0.4%	2 0.8%

Adverse Events

Time Frame	Adverse events are collected until 1 week after the vaccination. Serious adverse events (SAEs) are collected until 28 days after the vaccination.
Arm/Group Title	Standard Vaccination Schedule		Accelerated Vaccination Schedule
Arm/Group Description	One injection will be given on three different days (day 0, day 7 and day 21 or 28) Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites		Two injections will be given on the same day (day 0 and day 7): one on each forearm. Human Diploid Cell Vaccine (HDCV) rabies vaccine: Human Diploid Cell Vaccine (HDCV) rabies Merieux 1 ml vaccine for rabies, provided by Sanofi-Pasteur, administered zvia ID route at two sites
All Cause Mortality
	Standard Vaccination Schedule		Accelerated Vaccination Schedule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/249 (0%)		1/249 (0.4%)
Serious Adverse Events
	Standard Vaccination Schedule		Accelerated Vaccination Schedule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/249 (0.4%)		2/249 (0.8%)
Eye disorders
Diplopia	1/249 (0.4%)		0/249 (0%)
Gastrointestinal disorders
Oesophagitis	0/249 (0%)		1/249 (0.4%)
Nervous system disorders
Hemianopia	1/249 (0.4%)		0/249 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/249 (0%)		1/249 (0.4%)
Skin and subcutaneous tissue disorders
Angioedema	0/249 (0%)		1/249 (0.4%)
Urticaria	0/249 (0%)		2/249 (0.8%)
Other (Not Including Serious) Adverse Events
	Standard Vaccination Schedule		Accelerated Vaccination Schedule
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/249 (0%)		0/249 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.