Staphylococcus Aureus Toxoids Phase 1-2 Vaccine Trial

Study Overview
=================
Brief Summary
-----------------
This study involves the use of investigational vaccines. A vaccine is a medicine that causes the body to make antibodies. Antibodies help destroy foreign substances that enter the body. The purpose of this study is to find the right dose of a new vaccine that is safe and produces a good immune response (how well your body recognizes and defends itself against harmful foreign substances). There are two Staphylococcus aureus toxoids (components or antigens) under investigation in this study; one of them is a protein known as rAT and the other is a protein known as rLukS-PV. They are being developed to see if they are effective at preventing infections caused by the bacteria Staphylococcus aureus.

Detailed Description
-----------------
Staphylococcus aureus is a leading cause of skin and soft tissue infections. Antibiotic resistance, such as seen with new community-acquired methicillin-resistant strains, presents a major challenge in treating and preventing these infections. Therefore, a preventative vaccine is considered a potentially better approach. This study assesses the safety and immunogenicity of monovalent and bivalent S. aureus vaccine components. Healthy adult subjects will be randomized to receive 1 dose of monovalent or bivalent toxoid vaccine, or placebo in a dose escalation schedule. Antigen-specific antibody will be measured by ELISA in sera collected for three months after injection. Safety data will be collected as 7 day reactogenicity diaries after each injection, adverse events and Staphylococcus aureus and skin and soft tissue infections will be collected through Day 84, and serious adverse events and chronic illnesses will be collected for the full 6 month study period. To evaluate the possible utility of booster doses, the cohort receiving the highest dose of bivalent antigen will have a 2nd dose administered at Day 84, with a new 7-day reactogenicity diary and sera collected after the 2nd dose. All subjects will be followed up with a 6 month phone call after vaccination or booster. The total subject observation period will be for 24 weeks from Day 0, plus 12 additional weeks for the cohorts that receive a 2nd dose. With a recruitment period of 4 months, the study duration is expected to be approximately 13 months.

Official Title
-----------------
A Randomized, Multi-Center Trial to Evaluate the Safety & Immunogenicity of Staphylococcus Aureus Toxoids, rAT and rLukS-PV, in Healthy Volunteers

Conditions
-----------------
Staphylococcus Aureus

Intervention / Treatment
-----------------
* Biological: Monovalent rAT
* Biological: Monovalent rLukS-PV
* Biological: Bivalent rLukS-PV / rAT
* Biological: Placebo with adjuvant
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy adult males or females, DoD beneficiaries, including active duty members, 18-55 years of age. Negative urine pregnancy test for female subjects of child bearing potential (negative test within 24 hours prior to investigational product injection) or documented surgical sterility. Female subjects of child-bearing potential must use an acceptable method of birth control, as determined by the PI. Willingness to participate in this study as evidenced by written informed consent. Exclusion Criteria: Prior receipt of S. aureus rAT or rLukS-PV Known S. aureus infection requiring medical treatment within the 3 months prior to investigational drug product injection Known active viral or bacterial infection Seropositivity for HIV infection Known or suspected abuse of prescribed or illicit drugs, or alcohol in the past year Use of any new medications (except oral contraceptives, over-the-counter medications, or vitamin supplements) within the 7 days prior to investigational drug product injection Use of investigational drugs, vaccines, or devices during the study or within the 30 days prior to each dose of investigational drug product injection, or anticipated use of such items during the study Use of systemic steroids (any dose) or high daily dose inhaled steroids within the last month. Use of low or medium daily dose inhaled, intranasal, or low potency topical steroid creams/ointments is allowed unless such medication was begun within the previous 7 days. History of a bleeding or coagulation disorder; or use of anti-coagulant medications within 7 days prior to investigational product injection Actively breastfeeding Presence of grade I or higher abnormality in laboratory or vital signs parameter at time of screening Presence of any condition which, in the opinion of the investigator, places the subject at undue risk or potentially jeopardizes the quality of the data to be generated

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Vaccine<br>Monovalent rAT or Monovalent rLukS-PV or Bivalent rLukS-PV / rAT | Biological: Monovalent rAT<br>* 10, 25, 50 or 100 μg<br>Biological: Monovalent rLukS-PV<br>* 10, 25, 50 or 100 μg<br>Biological: Bivalent rLukS-PV / rAT<br>* 10, 25 or 50 μg<br>|
| Placebo Comparator: Placebo with Alum<br> | Biological: Placebo with adjuvant<br>* Placebo with adjuvant<br>|
| Placebo Comparator: Saline Placebo<br> | Biological: Placebo<br>* Placebo saline<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Safety Through Clinical Examinations, Clinical Laboratory Results, Self-reported Diary Reactogenicity Data and Adverse Event Reports | Adverse events, local reactogenicity, and systemic reactogenicity were assessed through clinical examination by study providers, clinical lab results, as well as review of subject-completed diary | Up to 6 months | 
| Immunogenicity: Geometric Mean Concentrations After First Injection, Completer Population | Immunogenicity is the ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal. Immunogenicity was determined on the basis of anti-rAT and anti-rLukS-PV IgG concentrations assessed by enzyme-linked immunosorbent assay (ELISA) in sera from blood samples collected on Days 0 (baseline), 14, 28 and 84 for those receiving a single dose of vaccine. For those receiving a second dose of vaccine, immunogenicity assessments were also conducted on Days 98 and 112. Immunogenicity was evaluated using the following metrics: geometric mean concentrations (GMCs), geometric mean fold increase (GMFIs) and seroresponse status. Seroresponse variables are normally defined in terms of exceeding a threshold. | Up to 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Staphylococcus aureus, Skin and soft tissue infection, Methicillin-resistant Staphylococcus aureus, Recombinant alpha-toxoid (rAT), Recombinant LukS subunit of Panton-Valentine Leukocidin (rLukS-PV)