RABVAX: Immunogenicity of Rabies Vaccine for Pre Exposure Prophylaxis

• Sponsor: State University of New York - Upstate Medical University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02374814
• Collaborator: Walter Reed Army Institute of Research (WRAIR) (U.S. Fed)
• Enrollment: 60
• Location: 1
• Arms: 6
• Actual Duration (Months): 18
• Patients Per Site Per Month: 3.3

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the effectiveness of a two dose versus a three dose schedule and intramuscular versus intradermal injection for pre-exposure prophylaxis.

Condition or Disease	Intervention/Treatment	Phase
Rabies	Drug: Rabies vaccine; Drug: Placebo	Phase 4

Detailed Description

This is an exploratory vaccine trial to evaluate immunogenicity of a non-licensed dosing schedule and route of administration for a currently FDA licensed rabies vaccine for pre-exposure prophylaxis against rabies infection. The goal of this study is to characterize the immune response and persistence of immunity to a shortened dose schedule and intradermal (ID) administration, relative to the current licensed dosing schedule of the rabies vaccine (3 dose (0, 7, 21 days) IM). Rabies virus is endemic throughout the world due to high rates of both wild and domestic animal rabies and the risk to deployed military in endemic areas is considerable. Currently the commonly supported pre-exposure prophylaxis regimen for rabies, in the United States is comprised of three, 1.0 ml intramuscular (IM) injections of the human diploid cell vaccine (HDCV) or purified chick embryo cell (PCEC) rabies vaccine on days 0, 7, and 21 or 28. Modified, two and three dose schedules of intradermal (ID) injections of 0.1 ml of HDCV and PCEC are utilized outside the US. These two and three dose intradermal schedules share a similar safety and immunogenicity profile to intramuscular vaccinations and are easily boosted at one year after vaccination. A death, from rabies, of a US Soldier returned from Afghanistan underscores the importance of rabies pre-exposure prophylaxis for soldiers and the need to evaluate the safest, most effective means of vaccinating large deploying forces. While the current three dose, 1 ml IM rabies series is effective, a shortened, equally effective vaccination series with significantly smaller dose per injection would greatly improve the logistics and cost associated with universal or even targeted coverage of deploying soldiers. Evaluation of a shorter, smaller-dose, pre-exposure vaccination series for rabies is the goal of this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Immunogenicity of a Two vs Three Dose, Intradermal (ID) vs Intramuscular (IM) Administration of a Licensed Rabies Vaccine for Pre-Exposure Vaccination
• Actual Study Start Date: Mar 24, 2015
• Actual Primary Completion Date: Sep 22, 2016
• Actual Study Completion Date: Sep 22, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Rabies vaccine IM 3 dose Intramuscular injection: 1mL at 0, 7 and 21 days. An additional 1 mL intramuscular dose at day 365	Drug: Rabies vaccine; Compare dose schedule and route of administration; Other Names: Rabavert
Experimental: Rabies vaccine ID 3 dose Intradermal injection: 0.1mL at 0, 7 and 21 days. A single intramuscular 1 mL dose at day 365	Drug: Rabies vaccine; Compare dose schedule and route of administration; Other Names: Rabavert
Experimental: Rabies vaccine IM 2 dose Intramuscular injection: 1mL at 0, 7 days. An additional 1 mL intramuscular dose at day 365	Drug: Rabies vaccine; Compare dose schedule and route of administration; Other Names: Rabavert
Experimental: Rabies vaccine ID 2 dose Intradermal injection: 0.1mL at 0, 7 days. A single intramuscular 1 mL dose at day 365	Drug: Rabies vaccine; Compare dose schedule and route of administration; Other Names: Rabavert
Placebo Comparator: Placebo IM 1 dose Albumin and saline comparator, Intramuscular injection: 1mL	Drug: Placebo; Placebo; Other Names: Albumin
Placebo Comparator: Placebo ID 1 dose Albumin and saline comparator, Intradermal injection: 0.1mL	Drug: Placebo; Placebo; Other Names: Albumin

Outcome Measures

Primary Outcome Measures

1. Protective Humoral Immune Response at 1 Month Post First Vaccination. [1 month post first vaccination]

   Percentage of subjects achieving the protective titer of ≥ 0.5 IU/ml against rabies virus

2. Protective Humoral Immune Response 12 Months Post First Vaccination. [12 months post first vaccination]

   Percentage of subjects achieving the protective titer of ≥ 0.5 IU/ml against rabies virus 12 months post vaccinations (prior to boost).

Secondary Outcome Measures

1. Protective Humoral Immune Response 7 Days Post Booster at 12 Months Post First Vaccination. [up to 13 months post first vaccination]

   Percentage of subjects achieving the protective titer of ≥ 0.5 IU/ml against rabies virus at 7 days post boost.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

Male and non-pregnant females aged ≥ 18 to ≤ 60 years on the day of inclusion Able to comprehend and give informed consent Able to attend all scheduled visits and to comply with all trial procedures Subject in good health, based on medical history and physical examination

Exclusion Criteria:

1. Subject is pregnant, or lactating, or of childbearing potential (to be considered of non-childbearing potential, a female must be post- menopausal for at least 1 year, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to the first vaccination and until at least 4 weeks after the last vaccination).

2. Participation in the 4 weeks preceding the first trial vaccination, or planned participation during the present trial period, in another clinical trial investigating a vaccine, drug, medical device, or medical procedure.

3. Previous history of receiving the rabies vaccine.

4. Previous history of receiving rabies immune globulin.

5. Any major psychiatric disorder, such as severe depression, severe anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures. History of mild depression or anxiety disorder that is well controlled is not an exclusion criteria.

6. Any history of cardiac arrhythmias, such as: Bradycardia, tachycardia, heart block, SVT, PAC, VF, VT, or any other conduction abnormalities.

7. Use of any immunosuppressive drug , including topical steroids of potency groups I, II or III within 30 days of the study period.

8. Any immunosuppressive disorder, such as HIV, common variable, active cancers or chemotherapy.

9. History of renal insufficiency or requiring dialysis.

10. Any condition that would, in the opinion of the site investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol.

11. Identified as an employee of the Investigator or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as family members (i.e., immediate, husband, wife and their children, adopted or natural) of the employee or the Investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	State University of New York, Upstate Medical University (SUNY-UMU)	Syracuse	New York	United States	13210

Sponsors and Collaborators

• State University of New York - Upstate Medical University
• Walter Reed Army Institute of Research (WRAIR)

Investigators

• Principal Investigator: Mark Polhemus, MD, State University of New York - Upstate Medical University

Study Documents (Full-Text)

• Study Protocol - Jun 2, 2016
• Statistical Analysis Plan - Dec 5, 2016
• Informed Consent Form - Mar 26, 2015

More Information

Publications

None provided.

• Responsible Party: Timothy Endy, MD MPH, Chair, Microbiology and Immunology, State University of New York - Upstate Medical University
• ClinicalTrials.gov Identifier: NCT02374814
• Other Study ID Numbers: 568085
• First Posted: Mar 2, 2015
• Last Update Posted: Jun 13, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Rabies

Study Results

Participant Flow

Pre-assignment Detail	One subject in group 4 was lost to follow up prior to receiving vaccine.

Arm/Group Title	Rabies Vaccine IM 3 Dose	Rabies Vaccine ID 3 Dose	Rabies Vaccine IM 2 Dose	Rabies Vaccine ID 2 Dose	Placebo IM 1 Dose	Placebo ID 1 Dose
Arm/Group Description	Rabies vaccine: 1.0 ml delivered Intramuscularly (IM) on day 0, 7, 21 and 365.	Rabies vaccine: 0.1 ml of rabies vaccine delivered intradermal (ID) on days 0, 7, and 21 with a 1.0ml boost delivered IM on day 365.	Rabies vaccine: 1.0ml delivered IM on day 0, 7 and 365.	Rabies vaccine: 0.1ml delivered on day 0 and 7 with a 1.0ml IM boost on day 365	Placebo: 1.0ml delivered IM on day 0	Placebo: 0.1ml delivered on day 0
Period Title: Overall Study
STARTED	12	12	12	11	6	6
COMPLETED	11	11	11	9	6	6
NOT COMPLETED	1	1	1	2	0	0

Baseline Characteristics

Arm/Group Title	Rabies Vaccine IM 3 Dose	Rabies Vaccine ID 3 Dose	Rabies Vaccine IM 2 Dose	Rabies Vaccine ID 2 Dose	Placebo IM 1 Dose	Placebo ID 1 Dose	Total
Arm/Group Description	This is standard FDA approved schedule Rabies vaccine: Compare dose schedule and route of administration	This is using alternative administration method Rabies vaccine: Compare dose schedule and route of administration	This is using alternative dose schedule Rabies vaccine: Compare dose schedule and route of administration	This is using alternative dose schedule and administration Rabies vaccine: Compare dose schedule and route of administration	Albumin and saline comparator Placebo: Placebo	Albumin and saline comparator Placebo: Placebo	Total of all reporting groups
Overall Participants	12	12	12	11	6	6	59
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	1 9.1%	0 0%	0 0%	1 1.7%
Between 18 and 65 years	12 100%	12 100%	12 100%	10 90.9%	6 100%	6 100%	58 98.3%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	31.7 (7.0)	29.3 (9.5)	32.3 (10.0)	31.8 (12.6)	38.5 (15.3)	35.7 (10.6)	32.4 (10.5)
Sex: Female, Male (Count of Participants)
Female	7 58.3%	8 66.7%	8 66.7%	8 72.7%	4 66.7%	3 50%	38 64.4%
Male	5 41.7%	4 33.3%	4 33.3%	3 27.3%	2 33.3%	3 50%	21 35.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%	2 33.3%	2 3.4%
Not Hispanic or Latino	12 100%	12 100%	12 100%	11 100%	6 100%	4 66.7%	57 96.6%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 8.3%	1 8.3%	0 0%	0 0%	0 0%	2 3.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	2 16.7%	1 8.3%	0 0%	0 0%	0 0%	3 5.1%
White	12 100%	9 75%	10 83.3%	11 100%	6 100%	6 100%	54 91.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%	12 100%	12 100%	11 100%	6 100%	6 100%	59 100%

Outcome Measures

1. Primary Outcome

Title	Protective Humoral Immune Response at 1 Month Post First Vaccination.
Description	Percentage of subjects achieving the protective titer of ≥ 0.5 IU/ml against rabies virus
Time Frame	1 month post first vaccination

Outcome Measure Data

Analysis Population Description

Placebo groups were used for adverse event data collection only. It was not expected that placebo group would elicit any antibody titer to rabies. Samples in groups 5 and 6 were not analyzed for primary or secondary outcome measures.

Arm/Group Title	Rabies Vaccine IM 3 Dose	Rabies Vaccine ID 3 Dose	Rabies Vaccine IM 2 Dose	Rabies Vaccine ID 2 Dose	Placebo IM 1 Dose	Placebo ID 1 Dose
Arm/Group Description	Rabies vaccine: Intramuscular injection: 1mL at 0, 7 and 21 days. An additional 1 mL intramuscular dose at day 365.	Rabies vaccine: Intradermal injection: 0.1mL at 0, 7 and 21 days. A single intramuscular 1 mL dose at day 365.	Rabies vaccine: Intramuscular injection: 1mL at 0, 7 days. An additional 1 mL intramuscular dose at day 365.	Rabies vaccine: Intradermal injection: 0.1mL at 0, 7 days. A single intramuscular 1 mL dose at day 365.	Albumin and saline comparator Placebo: A single 1mL intramuscular injection at day 0	Albumin and saline comparator Placebo: A single intradermal injection of 0.1mL at day 0
Measure Participants	12	12	12	11	0	0
Count of Participants [Participants]	12 100%	12 100%	12 100%	11 100%

2. Primary Outcome

Title	Protective Humoral Immune Response 12 Months Post First Vaccination.
Description	Percentage of subjects achieving the protective titer of ≥ 0.5 IU/ml against rabies virus 12 months post vaccinations (prior to boost).
Time Frame	12 months post first vaccination

Outcome Measure Data

Analysis Population Description

One subject in each of groups 1, 2, and 4 were lost to follow up prior to vaccination boost. Placebo groups were used for adverse event data collection only. It was not expected that placebo group would elicit any antibody titer to rabies. Samples in groups 5 and 6 were not analyzed for primary or secondary outcome measures.

Arm/Group Title	Rabies Vaccine IM 3 Dose	Rabies Vaccine ID 3 Dose	Rabies Vaccine IM 2 Dose	Rabies Vaccine ID 2 Dose	Placebo IM 1 Dose	Placebo ID 1 Dose
Arm/Group Description	Rabies vaccine: Intramuscular injection: 1mL at 0, 7 and 21 days. An additional 1 mL intramuscular dose at day 365.	Rabies vaccine: Intradermal injection: 0.1mL at 0, 7 and 21 days. A single intramuscular 1 mL dose at day 365.	Rabies vaccine: Intramuscular injection: 1mL at 0, 7 days. An additional 1 mL intramuscular dose at day 365.	Rabies vaccine: Intradermal injection: 0.1mL at 0, 7 days. A single intramuscular 1 mL dose at day 365.	Albumin and saline comparator Placebo: A single 1mL intramuscular injection at day 0	Albumin and saline comparator Placebo: A single 0.1mL intradermal injection at day 0
Measure Participants	11	11	12	10	0	0
Count of Participants [Participants]	7 58.3%	5 41.7%	7 58.3%	6 54.5%

3. Secondary Outcome

Title	Protective Humoral Immune Response 7 Days Post Booster at 12 Months Post First Vaccination.
Description	Percentage of subjects achieving the protective titer of ≥ 0.5 IU/ml against rabies virus at 7 days post boost.
Time Frame	up to 13 months post first vaccination

Outcome Measure Data

Analysis Population Description

One subject in group 3 and one in 4 withdrew consent not due to adverse events. Placebo groups were used for adverse event data collection only. It was not expected that placebo group would elicit any antibody titer to rabies. Samples in groups 5 and 6 were not analyzed for primary or secondary outcome measures.

Arm/Group Title	Rabies Vaccine IM 3 Dose	Rabies Vaccine ID 3 Dose	Rabies Vaccine IM 2 Dose	Rabies Vaccine ID 2 Dose	Placebo IM 1 Dose	Placebo ID 1 Dose
Arm/Group Description	Rabies vaccine: Intramuscular injection: 1mL at 0, 7 and 21 days. An additional 1 mL intramuscular dose at day 365.	Rabies vaccine: Intradermal injection: 0.1mL at 0, 7 and 21 days. A single intramuscular 1 mL dose at day 365.	Rabies vaccine: Intramuscular injection: 1mL at 0, 7 days. An additional 1 mL intramuscular dose at day 365	Rabies vaccine: Intradermal injection: 0.1mL at 0, 7 days. A single intramuscular 1 mL dose at day 365.	Albumin and saline comparator Placebo: 1mL intramuscular at day 0	Albumin and saline comparator Placebo: 0.1 mL intradermal at day 0
Measure Participants	11	11	11	9	0	0
Count of Participants [Participants]	11 91.7%	11 91.7%	11 91.7%	9 81.8%

Adverse Events

Time Frame	372 days for all groups (1-4) receiving rabies vaccine; 7 days for groups 5-6 receiving control
Arm/Group Title	Rabies Vaccine IM 3 Dose		Rabies Vaccine ID 3 Dose		Rabies Vaccine IM 2 Dose		Rabies Vaccine ID 2 Dose		Placebo IM 1 Dose		Placebo ID 1 Dose
Arm/Group Description	Intramuscular injection: 1mL at 0, 7 and 21 days. An additional 1 mL intramuscular dose at day 365		Intradermal injection: 0.1mL at 0, 7 and 21 days. A single intramuscular 1 mL dose at day 365		Intramuscular injection: 1mL at 0, 7 days. An additional 1 mL intramuscular dose at day 365		Intradermal injection: 0.1mL at 0, 7 days. A single intramuscular 1 mL dose at day 365		Albumin and saline comparator Intramuscular injection: 1ml		Albumin and saline comparator Intradermal injection: 0.1ml
All Cause Mortality
	Rabies Vaccine IM 3 Dose		Rabies Vaccine ID 3 Dose		Rabies Vaccine IM 2 Dose		Rabies Vaccine ID 2 Dose		Placebo IM 1 Dose		Placebo ID 1 Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/12 (0%)		0/11 (0%)		0/6 (0%)		0/6 (0%)
Serious Adverse Events
	Rabies Vaccine IM 3 Dose		Rabies Vaccine ID 3 Dose		Rabies Vaccine IM 2 Dose		Rabies Vaccine ID 2 Dose		Placebo IM 1 Dose		Placebo ID 1 Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/12 (0%)		0/11 (0%)		0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Rabies Vaccine IM 3 Dose		Rabies Vaccine ID 3 Dose		Rabies Vaccine IM 2 Dose		Rabies Vaccine ID 2 Dose		Placebo IM 1 Dose		Placebo ID 1 Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/12 (83.3%)		12/12 (100%)		8/12 (66.7%)		11/11 (100%)		1/6 (16.7%)		0/6 (0%)
Blood and lymphatic system disorders
Lymph node pain	1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/11 (0%)		0/6 (0%)		0/6 (0%)
Ear and labyrinth disorders
Tinnitus	0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/11 (0%)		0/6 (0%)		0/6 (0%)
Gastrointestinal disorders
Nausea	0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/11 (0%)		0/6 (0%)		0/6 (0%)
Abdominal Pain	0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/11 (0%)		0/6 (0%)		0/6 (0%)
Diarrhea	0/12 (0%)		0/12 (0%)		0/12 (0%)		1/11 (9.1%)		0/6 (0%)		0/6 (0%)
General disorders
Injection site reaction	7/12 (58.3%)		11/12 (91.7%)		6/12 (50%)		10/11 (90.9%)		1/6 (16.7%)		0/6 (0%)
Fatigue	2/12 (16.7%)		1/12 (8.3%)		0/12 (0%)		1/11 (9.1%)		0/6 (0%)		0/6 (0%)
Flu-like symptoms	2/12 (16.7%)		0/12 (0%)		1/12 (8.3%)		3/11 (27.3%)		0/6 (0%)		0/6 (0%)
Malaise	0/12 (0%)		1/12 (8.3%)		1/12 (8.3%)		0/11 (0%)		0/6 (0%)		0/6 (0%)
Fever	1/12 (8.3%)		0/12 (0%)		1/12 (8.3%)		0/11 (0%)		0/6 (0%)		0/6 (0%)
Infections and infestations
Upper respiratory infection	1/12 (8.3%)		0/12 (0%)		2/12 (16.7%)		2/11 (18.2%)		0/6 (0%)		0/6 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	2/12 (16.7%)		0/12 (0%)		0/12 (0%)		1/11 (9.1%)		0/6 (0%)		0/6 (0%)
Nervous system disorders
Dizziness	1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/11 (0%)		0/6 (0%)		0/6 (0%)
Headache	1/12 (8.3%)		1/12 (8.3%)		0/12 (0%)		1/11 (9.1%)		0/6 (0%)		0/6 (0%)
Reproductive system and breast disorders
Menorrhagia	1/12 (8.3%)		0/12 (0%)		0/12 (0%)		0/11 (0%)		0/6 (0%)		0/6 (0%)
Skin and subcutaneous tissue disorders
Rash	0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/11 (0%)		0/6 (0%)		0/6 (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.