Clinical trial NCT00415051: Safety/Immunogenicity/Genetic Drift of MP-12 Rift Valley Fever Vaccine
Official title: Safety and Immunogenicity of Live-Attenuated MP-12 Rift Valley Fever Vaccine in Humans, and Genetic Characterization of Virus Isolates Recovered From the Blood of Vaccinated Volunteers: A Phase II Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rift Valley Fever
Keywords: Rift Valley Fever, vaccine
Lead sponsor: U.S. Army Medical Research and Development Command
Sponsor class: FED
First posted: 2006-12-22
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: This study is to determine if a vaccine for Rift Valley Fever (RVF) is safe to give to humans. The study will examine how well the vaccine (RVF MP-12) stimulates the body's immune response (which fights off infection) and if the vaccine is stable or if the virus used to make the vaccine changes into a different form once injected into the body. Twenty healthy volunteers (18-50 years old) will be vaccinated with a single dose of undiluted RVF MP-12, injected into a muscle.

Detailed description: Rift Valley Fever (RVF) is a mosquito-borne disease in Africa that affects both humans and animals. The disease poses a significant endemic disease threat, and the etiologic agent (RVF virus) possesses physical and biochemical characteristics that have resulted in its classification as a Category A Agent. Historically, this disease was confined to Africa. In September 2000, however, RVF appeared in the western part of the Kingdom of Saudi Arabia (843 cases with 114 deaths) and in Yemen (1,087 suspected cases with 121 deaths). It is thought that Rift Valley fever was introduced into this new geographic area through importation of infected livestock from Djibouti. Mosquito transmission has been subsequently demonstrated in these areas, suggesting that the disease may have become permanently established. A safe and effective RVF vaccine capable of inducing protective immunity after a single injection is urgently needed. Currently, no drug is available that will alter the course of the disease in humans or animals, nor is any licensed vaccine for RVF approved for human use. This protocol is an open-label, Phase II study to assess the safety, immunogenicity and genetic stability of RVF MP-12 vaccine in humans. The objectives of this study are to collect safety and immunogenicity data for an intramuscular (IM) injection of live, attenuated, mutagenized RVF 12th mutagenesis passage (MP-12) vaccine and characterize isolates of the Rift Valley fever (RVF) MP-12 vaccine recovered from blood of vaccinated volunteers using in vitro systems to evaluate genetic stability. A total of 20 volunteers will be recruited from among military and civilian persons at and around USAMRIID and from the general population in and around Frederick, Maryland, who expect to remain in the area for the duration of the study. Volunteers will be vaccinated with undiluted RVF MP-12 vaccine. Safety will be evaluated by recording the frequency and severity of clinical reactions to the vaccine, as well as by measuring complete blood counts and selected serum biochemistry (enzyme) values. Immunogenicity will be evaluated by measuring 80% plaque reduction neutralization (PRNT80) antibodies to RVF virus for periods up to 1 year following vaccination. Genetic stability of the vaccine will be evaluated by examining isolates recovered from blood of vaccinated volunteers by molecular sequencing techniques, and comparing these findings with those from the vaccine virus inoculum. Subjects will participate in the study for up to 1 year.

Eligibility criteria: Inclusion Criteria:

* Between 18 and 50 years old
* Free of chronic medical conditions requiring ongoing therapy and in general good health as determined by a physician investigator
* Have a current (within 30 days of scheduled blood donation for this study) complete blood (cell) count (CBC) to include a Hct and Hgb that show no evidence of anemia, and total white blood cell with differential platelet counts that are within normal range, as well as hepatic enzyme (AST, ALT, LDH) values that are within normal laboratory ranges
* Negative human immunodeficiency virus (HIV) antibody test within 3 months preceding vaccination
* No evidence of pre-existing liver disease or current infection with Hepatitis A, B, or C virus as determined by serology
* No evidence for pre-existing eye disease, as determined by fundoscopic/slit lamp examination by the study ophthalmologist other than refractory changes
* No evidence by history or serologic testing for previous infection with RVF virus or RVF vaccine
* Subjects must agree to refrain from intimate contact (sexual activity), or use barrier contraception (e.g., condoms), for the 2-week period following vaccination
* Females of child-bearing potential must have a negative serum pregnancy test on screening and the morning of vaccination prior to receipt of the vaccine and must agree to use a highly effective method of birth control during the first 3 months following receipt of the MP-12 vaccine. A highly effective method of birth control is defined as one with a failure rate of less than 1% per year. Acceptable birth control methods that meet this criterion include hormonal implants and injectables (Norplant, Dep-Provera, Lunelle, and Etonogestrel); combined oral contraceptives; the intrauterine devices (IUDs) Copper T (380-A) or Mirena (Levonorgestrel Intrauterine System); female sterilization (tubal ligation); sexual abstinence; or a vasectomized partner.
* Subjects must be medically cleared for participation by an investigator
* Subjects must expect to remain in the area for the duration of the study
* Volunteer must sign an approved informed consent
* Volunteer must be willing to return for all follow-up visits including a post-vaccination ophthalmologic visit
* Volunteer must be willing to refrain from excessive (more than individual's normal routine) exercise for a period of at least 2 weeks prior to and following vaccination
* Volunteer must be willing to abstain from drinking alcoholic beverages for a period of at least 2 weeks prior to and following vaccination. Volunteer must not be a "weekend" drinker or normally drink more than 2 drinks a day if male or 1 drink a day if female.
* Volunteer must agree to report any adverse event (AE) that may or may not be associated with administration of the test article during their participation in the study.

Exclusion Criteria:

* History or evidence of liver disease/abnormality
* History of pre-existing thymic disease or thymic dysfunction (any cellular immune or antibody disorders)
* Be taking any medication, prescription or non-prescription (excluding dietary supplements), on a regular basis with the exception of contraceptive pills. This includes the regular use of statins, non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressive agents, antivirals, topical steroidal creams, and nasal sprays. Conditions requiring intermittent medications and other decisions regarding eligibility due to medication use will be deferred to physician investigators.
* Elevation above the upper limit of laboratory normal values in liver enzymes, or history of unexplained elevation in liver enzymes
* History or evidence of eye disease (excluding changes in refraction and strabismus)
* Abnormal clinical lab results indicating evidence of anemia, immunosuppression, or immune deficiency disease
* Have donated 1 unit (500 cc) or more of blood for any reason during the 2 months (56 days) preceding administration of the vaccine (as assessed by query)
* Plan to donate blood within 1 year following receipt of the vaccine
* History or evidence of previous infection with RVF or vaccination against RVF
* Any known allergies to components of the vaccine: Human serum albumin (stabilizer), Sol-U-Pro, Neomycin (antibiotic), sorbitol, L-proline, L-arginine, monosodium glutamate (MSG), or Urea
* Administration of another vaccine within 4 weeks of RVF MP-12 vaccination
* "Weekend" drinkers, males who drink more than 2 drinks a day and females who drink more than 1 drink a day, will be excluded
* Individuals who plan to start a new exercise program within two weeks of vaccination (either two weeks prior to or two weeks following vaccination) will be excluded. Individuals who are already on a regular exercise program and who have normal transaminase levels will not be excluded but will be advised not to increase their level of activity for a period of one month (for two weeks prior to until two weeks after vaccination). Individuals who do not exercise regularly and who participate in this study will be advised not to embark on an exercise program for the same time period.
* Volunteers will be cautioned against salivary contact and contact with infants, children under the age of 8 years, adults over the age of 64 years, and anyone who is immunocompromised or in poor health. Volunteers who feel unable to comply with these restrictions will be excluded from the study.

Primary outcomes:
measure: Safety as Measured by the Number of Adverse Events
timeFrame: up to 1 year
Secondary outcomes:
measure: Immune Response Assessed by Measuring Days to Peak Response for PRNT80 Antibodies to RVF Virus
timeFrame: Days 0, 1, 2, 3, 7, 10, 14 and 28, Months 3, 6 and 12
measure: Immune Response Assessed by Measuring Days to Peak Response for (PRNT50) RVP MP-12 Vaccine
timeFrame: Days 0, 1, 2, 3, 7, 10, 14 and 28, Months 3, 6 and 12
measure: Genetic Stability - Characterize Viral Isolate (Plasma) Frequency
timeFrame: Days 0-14
Other outcomes:
Locations:
city: Fort Deterick
country: United States
facility: US Army Medical Research Institute of Infectious Diseases
state: Maryland
Study officials:
affiliation: USAMRIID Medical Division
name: Phillip Pittman, MD
role: PRINCIPAL_INVESTIGATOR
References: