A Phase 1 Dose Escalation Study to Examine the Safety of the P2-VP8 Rotavirus Vaccine

Study Overview
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Brief Summary
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This study will evaluate 3 doses of a new vaccine for rotavirus infection in healthy adult volunteers to determine if it is safe and if the immune systems of healthy adults respond to this vaccine.

Detailed Description
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The trial will be a double-blinded, randomized, placebo-controlled dose-escalation study in which three dose-levels of vaccine will be tested in adults. Cohorts of 16 individuals (12 vaccine recipients and 4 placebo recipients) per dose level will receive three intramuscular injections four weeks apart. The three dose levels of vaccine to test will be 10 microgram (μg), 30 μg and 60 μg.

Official Title
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A Phase 1 Double Blinded, Randomized, Placebo-controlled Dose Escalation Study to Examine the Safety, Reactogenicity, Tolerability and Immunogenicity of the P2-VP8 Subunit Rotavirus Vaccine in Healthy Adult Volunteers

Conditions
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Rotavirus Infection

Intervention / Treatment
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* Biological: P2-VP8 subunit rotavirus vaccine
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A qualified volunteer must be: Healthy male or female between 18 and 45 (inclusive) years of age at time of enrollment. Willing and able to give informed consent - must pass test of comprehension with > 70% correct within two attempts. If female and of childbearing potential, be not breastfeeding and not pregnant (based on a negative serum pregnancy test at screening and a negative urine pregnancy test during the 24 hours prior to first injection), planning to avoid pregnancy for at least 4 weeks after the last injection, and willing to use an adequate method of contraception consistently and have repeated pregnancy tests prior to second and third injections. Willing to comply with study restrictions and study schedule (as evidenced by a signed informed consent form (ICF) and assessment by the Principal Investigator (PI) or designee). Able and willing to be contacted by telephone or text, and willing for study staff to record telephone voice or text messages as needed. Exclusion Criteria: A qualified volunteer must not: Have received an investigational product during the 30 days prior to randomization. Intend to receive another investigational product during this study. Have any contraindication to parenteral injections (e.g., history of bleeding disorder). Have previously received a marketed or investigational rotavirus vaccine. Have a history of severe local or systemic reaction to any vaccine. Have a history of recurrent urticaria of unknown cause. Have a history of any allergic or infusion reaction that was severe (e.g., anaphylactic or anaphylactoid), generalized (e.g., drug rash, urticaria, angioedema) or that, in the opinion of the PI, significantly increases risk of severe local or systemic reaction to an investigative vaccine. Have a history of reaction to any vaccine that, in the opinion of the PI, significantly increases risk of severe reaction to an investigative vaccine. Have received any vaccine within 4 weeks prior to randomization or planned vaccination through Day 84. Have received any blood product or any immunomodulating agent (e.g., immunoglobulin, interferon, growth factor) within 12 weeks prior to randomization. Have received immunosuppressive medications (e.g., prolonged use of systemic corticosteroid or cytotoxic agent) within the 24 weeks prior to randomization. Eligible if a short course (≤10 days) of systemic corticosteroid concluded more than 2 weeks prior to randomization, use of inhaled corticosteroid for asthma, and use of topical corticosteroid for a skin condition. Have a history of any clinically significant (in the opinion of the PI) immunosuppressive or autoimmune condition. Anticipate need for administration of any blood product, immunosuppressive (e.g., systemic corticosteroid), or immunomodulatory treatment during the study. Have a history of malignancy, excluding basal cell carcinoma. Have Diabetes Mellitus Type I or II. Have a positive test for human immunodeficiency virus 1 (HIV-1), Hepatitis B surface antigen (HBsAg) or (Hepatitis C Antibody Test) anti-HepC. Have significant abnormalities in screening laboratory test results or clinical assessment as determined by the PI or by the PI in consultation with the Sponsor's medical officer.* Have abnormal vital signs deemed clinically relevant by the Principle Investigator (PI). Evidence of current or recent (within past 12 months) excessive alcohol consumption or drug dependence. Have any condition of hand, arm or related lymph nodes that may confound post-dose assessments. Have any condition (medical, psychiatric or behavioral) that, in the opinion of the PI, would increase the volunteer's health risks in study participation or would increase the risk of not achieving the study's objectives

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 μg P2-VP8<br>3 doses of P2-VP8 subunit rotavirus vaccine (Lot # 1746) produced in E. coli was adsorbed onto aluminum hydroxide (0.6 mg/dose) adjuvant prior to administration. Each dose contained 10 μg of active ingredient. | Biological: P2-VP8 subunit rotavirus vaccine<br>* P2-VP8 subunit rotavirus vaccine was made by inserting a codon optimized synthetic gene for the VP8 region of rotavirus VP4 fused to the P2 T-cell epitope of tetanus toxin into the Pj411 proprietary cloning vector developed by DNA 2.0, Menlo Park, CA. The vector carries a kanamycin resistance gene as a selection marker. The vector was transfected into the BL21 strain of E. coli. The fusion protein was purified from Isopropyl β-D-1-thiogalactopyranoside (IPTG)-induced and physically lysed cultures using standard column chromatographic techniques employing Q-Sepharose and Butyl 650 as resins in addition to ultrafiltration and diafiltration.<br>|
| Experimental: 30 μg P2-VP8<br>3 doses of P2-VP8 subunit rotavirus vaccine (Lot # 1746) produced in E. coli was adsorbed onto aluminum hydroxide (0.6 mg/dose) adjuvant prior to administration. Each dose contained 30 μg of active ingredient. | Biological: P2-VP8 subunit rotavirus vaccine<br>* P2-VP8 subunit rotavirus vaccine was made by inserting a codon optimized synthetic gene for the VP8 region of rotavirus VP4 fused to the P2 T-cell epitope of tetanus toxin into the Pj411 proprietary cloning vector developed by DNA 2.0, Menlo Park, CA. The vector carries a kanamycin resistance gene as a selection marker. The vector was transfected into the BL21 strain of E. coli. The fusion protein was purified from Isopropyl β-D-1-thiogalactopyranoside (IPTG)-induced and physically lysed cultures using standard column chromatographic techniques employing Q-Sepharose and Butyl 650 as resins in addition to ultrafiltration and diafiltration.<br>|
| Experimental: 60 μg P2-VP8<br>3 doses of P2-VP8 subunit rotavirus vaccine (Lot # 1746) produced in E. coli was adsorbed onto aluminum hydroxide (0.6 mg/dose) adjuvant prior to administration. Each dose contained 60 μg of active ingredient. | Biological: P2-VP8 subunit rotavirus vaccine<br>* P2-VP8 subunit rotavirus vaccine was made by inserting a codon optimized synthetic gene for the VP8 region of rotavirus VP4 fused to the P2 T-cell epitope of tetanus toxin into the Pj411 proprietary cloning vector developed by DNA 2.0, Menlo Park, CA. The vector carries a kanamycin resistance gene as a selection marker. The vector was transfected into the BL21 strain of E. coli. The fusion protein was purified from Isopropyl β-D-1-thiogalactopyranoside (IPTG)-induced and physically lysed cultures using standard column chromatographic techniques employing Q-Sepharose and Butyl 650 as resins in addition to ultrafiltration and diafiltration.<br>|
| Placebo Comparator: Placebo<br>3 doses of placebo delivered intramuscularly. | Other: placebo<br>* Sodium Chloride 0.9%, USP for Injection was used to dilute the active P2-VP8 vaccine to final dosing concentration and was used for the Placebo for the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Severity of Adverse Events After Any Vaccination | Adverse events were collected through 28 days following the final study injection and were graded for severity. Unsolicited adverse events were also assessed for relationship to vaccine. A final follow-up contact was attempted 6 months following the final study injection to inquire about new chronic health conditions, serious health events, and hospitalizations. | 6 months after final vaccination (224 days) | 
| Maximum Local or Systemic Reactogenicity After Any Vaccination | For all cohorts, local and systemic reactogenicity data for all vaccinations were collected by subjects via diary card up to 7 days post each vaccination. Solicited systemic reactogenicity events included headache, muscle pain, fever, nausea, vomiting, fatigue, joint aches, and chills. Solicited local systemic reactogenicity events included injection site pain, tenderness, redness, swelling, itching, and local lymphadenopathy. | 7 days after each vaccination (Day 7, 35, 63) | 
| Maximum Local or Systemic Reactogenicity After the First Vaccination | For all cohorts, local and systemic reactogenicity data for all vaccinations were collected by subjects via diary card up to 7 days post each vaccination. Solicited systemic reactogenicity events included headache, muscle pain, fever, nausea, vomiting, fatigue, joint aches, and chills. Solicited local systemic reactogenicity events included injection site pain, tenderness, redness, swelling, itching, and local lymphadenopathy. | 7 days post Vaccination #1 on Day 0 | 
| Maximum Local or Systemic Reactogenicity After the Second Vaccination | For all cohorts, local and systemic reactogenicity data for all vaccinations were collected by subjects via diary card up to 7 days post each vaccination. Solicited systemic reactogenicity events included headache, muscle pain, fever, nausea, vomiting, fatigue, joint aches, and chills. Solicited local systemic reactogenicity events included injection site pain, tenderness, redness, swelling, itching, and local lymphadenopathy. | 7 days post Vaccination #2 on Day 35 | 
| Maximum Local or Systemic Reactogenicity After the Third Vaccination | For all cohorts, local and systemic reactogenicity data for all vaccinations were collected by subjects via diary card up to 7 days post each vaccination. Solicited systemic reactogenicity events included headache, muscle pain, fever, nausea, vomiting, fatigue, joint aches, and chills. Solicited local systemic reactogenicity events included injection site pain, tenderness, redness, swelling, itching, and local lymphadenopathy. | 7 days post Vaccination #3 on Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Subjects With Anti-P2-VP8 Immunoglobulin G (IgG) and Immunoglobulin A (IgA) Seroresponses | Seroresponse was defined as as a four-fold increase in antibody titers between baseline and 4-weeks post-third injection. | 4 weeks post 3rd immunization (84 days) | 
| Geometric Mean Titer (GMT) of Anti-P2-VP8 Immunoglobulin G (IgG) | Measured from sera taken on Days 0, 28, 56 and 84 (before the first injection and 4 weeks after each injection). | Days 0, 28, 56 and 84 (before the first injection and 4 weeks after each injection) | 
| Geometric Mean Titer (GMT) of Anti-P2-VP8 Immunoglobulin A (IgA) | Measured from sera taken on Days 0, 28, 56 and 84 (before the first injection and 4 weeks after each injection). | Days 0, 28, 56 and 84 (before the first injection and 4 weeks after each injection) | 
| Number and Percentage of Subjects With Serum Neutralizing Antibody Seroresponse, by Rotavirus Strain | Seroresponse was defined as as a four-fold increase in antibody titers between baseline and 4-weeks post-third injection. | 4 weeks post 3rd immunization (84 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rotavirus, vaccine