Vaccine Study for Tick-Borne Encephalitis Virus (TBEV)

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Brief Title

Vaccine Study for Tick-Borne Encephalitis Virus (TBEV)

Official Title

A Phase II, Open Label Trial of a Vaccine (FSME-IMMUN 0.5 mL) Against Tick-Borne Encephalitis (TBE) for NIAID Workers Manipulating Tick-Borne Encephalitis Virus (TBEV) in the Laboratory

Brief Summary

      This was an open label trial of a non-US licensed vaccine for tick-borne encephalitis. The
      vaccine was licensed by Baxter, and now following an acquisition by Pfizer Inc in Vienna,
      Austria since 2001, and has an extensive safety record in multiple European countries. Field
      effectiveness studies suggest > 99 percent protection against disease transmitted by the
      natural routes of either tick bite or ingestion of contaminated, unpasteurized milk. The
      vaccine is also considered to be effective against laboratory exposures and is used routinely
      for this purpose in European laboratories. The US Centers for Disease Control and Prevention
      and the National Institutes of Health acknowledge the effectiveness of the vaccine by
      allowing those who have received it to study tick-borne encephalitis virus (TBEV) in
      isolation facilities rated at BSL-3 rather than the more stringent BSL-4, with the exception
      of the Russian Spring-Summer Encephalitis strain. Subjects were recruited from personnel at 2
      intramural campuses of the National Institute of Allergy and Infectious Diseases who may be
      exposed accidentally to any strain or serotype of viable TBEV. Approximately 160 individuals
      were eligible to participate. The rapid immunization schedule (injections on Days 0, 14, and
      161) was used and subjects had labs drawn 21 days after the 2nd, 3rd and 4th vaccine
      injections to determine seroconversion. Subjects that seroconverted to TBEV were offered a
      booster dose of the vaccine 3 years from the date of receipt of the third dose of the
      vaccine. Subjects that were seropositive at entry into the study were offered a booster dose
      of the vaccine every 3 years from Day 0.
    

Detailed Description

      Infection by tick-borne encephalitis virus (TBEV) is a significant health concern for humans
      in Europe and Asia. A vaccine is available in these regions and in Canada, but not in the
      United States. Research studies in Europe have shown the vaccine to be effective in
      preventing infection among the general population, where disease is transmitted either by the
      bite of an infected tick (most common) or by ingestion of contaminated unpasteurized milk or
      milk products. Persons who work with the virus in a research setting, however, have the
      potential of being exposed in unnatural ways, and may come into contact with concentrations
      of virus higher than those found naturally in ticks. The Food and Drug Administration is
      investigating the effectiveness of the existing vaccine. It is a killed vaccine, which means
      that it has been treated to ensure that it does not contain live agents (bacteria or virus).
      The manufacturer has tested the product for other possible contaminating agents and none have
      been detected. However, there is an unknown but small risk of exposure to undetected
      contaminating agents in the vaccine. This was an open label trial of a non-US licensed
      vaccine for tick-borne encephalitis. The vaccine has been licensed by Baxter, and now
      following an acquisition by Pfizer Inc in Vienna, Austria since 2001, and has an extensive
      safety record in multiple European countries. Field effectiveness studies suggest > 99
      percent protection against disease transmitted by the natural routes of either tick bite or
      ingestion of contaminated, unpasteurized milk. The vaccine is also considered to be effective
      against laboratory exposures and is used routinely for this purpose in European laboratories.
      The US Centers for Disease Control and Prevention and the National Institutes of Health
      acknowledge the effectiveness of the vaccine by allowing those who have received it to study
      tick-borne encephalitis virus (TBEV) in isolation facilities rated at BSL-3 rather than the
      more stringent BSL-4, with the exception of the Russian Spring-Summer Encephalitis strain.

      Subjects were recruited from personnel at 2 intramural campuses of the National Institute of
      Allergy and Infectious Diseases who may be exposed accidentally to any strain or serotype of
      viable TBEV. Approximately 160 individuals were eligible to participate.

      Objectives: To test the safety and immune response to a vaccine against tick-borne
      encephalitis virus (TBEV). To add a level of protection to persons who may have occupational
      exposure to TBEV to reduce their chances of developing infection from that exposure.

      Eligibility: Individuals 18 years of age or older who are in generally good health and have
      the potential for occupational exposure to TBEV at one of the two National Institute of
      Allergy and Infectious Diseases campuses.

      Design: The full series of the vaccine included at least three doses by injection in the
      upper arm. The first and third dose of study vaccine were given in the muscle of the
      nondominant arm. The second dose was given in the dominant arm. Participation included at
      least 12 scheduled visits to the study center over approximately 3.5 years. An initial visit
      took place 7 to 21 days prior to the first injection. Blood samples were taken to test liver
      and kidney function, baseline antibody levels, and for possible pregnancy in female
      participants. Vaccine doses were given on days 0, 14, and 161. Participants were asked to
      complete a diary card on each day for one week following the vaccination to assess any
      reactions or side effects. At each visit after receipt of a vaccine, participants were asked
      about any side effects. Blood was drawn 14 days after the second injection and 21 days after
      the third injection in order to measure the level of antibodies and overall response to the
      vaccine. Subjects that developed a sufficiently high level of antibodies may (at the
      discretion of the laboratory chief) be allowed to work with strains of TBEV at Biosafety
      Level (BSL) 3 rather than BSL-4. Blood was drawn annually for 3 years to determine antibody
      level and response to the vaccine. Booster doses were provided if required.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

TBEV Viral Neutralization Titer >1:10


Condition

Tick-Borne Encephalitis

Intervention

FSME-IMMUN 0.5ml Baxter

Study Arms / Comparison Groups

 FSME-IMMUN 0.5mL Baxter
Description:  FSME-IMMUN 0.5mL Baxter is non-US licensed vaccine for tick-borne encephalitis virus. The FSME-IMMUN 0.5mL Baxter is available as 0.5mL in a pre-loaded vaccine syringe. All participants received active vaccine using a rapid immunization schedule, with vaccine administration on Days 0, 14, 161 and 245. Participants that tested seropositive for tick-borne encephalitis virus or subjects that developed positive viral neutralizer titers after the 3rd or 4th vaccine were given a booster of FSME-IMMUN 0.5mL Baxter vaccine at 3, 6 and 9 years after enrollment.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

69

Start Date

September 25, 2009

Completion Date

December 23, 2016

Primary Completion Date

December 23, 2016

Eligibility Criteria

        -  INCLUSION CRITERIA:

        All subjects must meet the following criteria at study entry:

          -  Be engaged in activities that place them at potential risk of occupational exposure to
             TBEV in its viable form at one of the participating intramural laboratories of NIAID

          -  Be 18 years of age or older at the time of the first immunization.

          -  Comprehend the study requirements.

          -  Provide written informed consent to participate in this study.

          -  Be in good health as determined by the Investigator, based upon medical history and a
             targeted physical examination.

          -  Have a stable health status as determined by the Investigator.

          -  Have access to a consistent means of telephone contact, which may be either in the
             home or at the workplace, land line or mobile, but NOT a pay phone or other
             multiple-user device (i.e., a common use phone serving multiple rooms or apartments).

          -  Express availability for the required study period, and ability to attend scheduled
             visits.

        EXCLUSION CRITERIA:

        The following criteria should be checked at the time of the study entry. If any apply, the
        subject will not be included in the study:

          -  The subject must not be participating in any other trial of an investigational drug or
             vaccine for 1 month prior to the first injection through until 21 days after the third
             injection. (Given the nature of the work these study subjects engage in, exemptions to
             this proscription may be granted on a case by case basis after discussion between the
             Investigator and the IRB.)

          -  The presence on the day of immunization of an oral temperature of >101.2 degrees F or
             acute symptoms other than mild severity.

          -  Active systemic infectious process as determined by review of systems and physical
             examination. The subject may be enrolled at a later date once the illness has
             resolved.

          -  Known immune suppression, such as that associated with human immunodeficiency virus
             infection, or other condition, to the extent that, in the opinion of the Investigator,
             the subject is likely to have a poor response to the vaccine. This information will be
             obtained by history only. Serologic screening for these diseases will not be
             performed.

          -  Presence of evidence of substance abuse or of neurological or psychiatric diagnoses
             which, even if clinically stable, are deemed by the Investigator to render the
             potential subject unable/unlikely to report promptly any adverse reactions to the
             vaccine.

          -  Current diagnosis of leukemia, Hodgkin s disease, non-Hodgkin s lymphoma, or any other
             cancer, autoimmune disease such as lupus, which is in and of itself a cause of
             immunosuppression to the point that, in the opinion of the Investigator, the subject
             is likely to have a poor response to the vaccine.

          -  Currently receiving systemic immunosuppressive chemotherapy or immunotherapy
             (including glucocorticoids) resulting in immune suppression to the point that, in the
             opinion of the Investigator, the subject is likely to have a poor response to the
             vaccine.

          -  Any neurological condition in which (in the opinion of the Investigator) the integrity
             of the blood brain barrier may have been compromised.

          -  Licensed vaccines are not exclusionary but should be given at least 14 days before or
             after immunization (applies to each of the 3 scheduled TBEV injections) for
             inactivated vaccines and 30 days before or after immunization with any live vaccines.
             This is in order to avoid potential confusion of adverse reactions. (Given the nature
             of the work these study subjects engage in, exemptions to this proscription may be
             granted on a case-by-case basis after discussion between the Investigator and the
             IRB.).

          -  Previous anaphylactic reaction to any TBE vaccine.

        Known or suspected anaphylactic reaction to any constituent of FSME IMMUN, to include
        formaldehyde, protamine sulfate, gentamicin and neomycin, or current egg allergy.

          -  Known pregnancy, or anticipating becoming pregnant in the first 8 months of the study
             or a positive urine beta-human chorionic gonadotropin (beta hCG) test result prior to
             immunization. If subjects become pregnant at some point in time after the 1st
             injection, no further injections will be given until after the pregnancy is completed,
             they are no longer nursing or have a negative beta-hCG result.

          -  Lactating or nursing.

          -  Women of child bearing potential (defined as pre-menopausal who have not undergone
             either hysterectomy or tubal ligation) who lack a history of reliable contraceptive
             practices. Reliable contraceptive practices (for the first 8 months of the study and
             within 21 days prior to or 42 days after booster immunizations) include:

               -  Consistent abstinence from heterosexual activity

               -  Consistent use of combined or progestogen oral contraceptives

               -  Injectable progestogen

               -  Implants of levonorgestrel

               -  Estrogen or estrogen/progestogen vaginal ring

               -  Percutaneous contraceptive patches

               -  Intrauterine device (IUD) or intrauterine system (IUS)

               -  Successful vasectomy of the sole male partner, or

               -  Double barrier method (condom or occlusive cap plus spermicidal agent)

          -  A history of a prior infection with TBEV or previously receiving a TBE vaccine will
             not be considered as an exclusionary criterion for immunization through this protocol.
             However, these subjects antibody titer data will not be included in the statistical
             analysis.

          -  Any other conditions, which in the Investigator s judgment, might result in an
             increased risk to the subject, or would affect their participation in the study.
             Additionally the Investigator has the ability to exclude a subject if for any reason
             he/she feels the subject is not a good candidate for the study or will not be able to
             follow study procedures.
      

Gender

All

Ages

18 Years - 100 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

James M Schmitt, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01031537

Organization ID

090246

Secondary IDs

09-I-0246

Responsible Party

Sponsor

Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborators

 National Institutes of Health (NIH)

Study Sponsor

James M Schmitt, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)


Verification Date

April 2018