Safety and Immunogenicity of Norovirus Bivalent Virus-Like Particle Vaccine in Healthy Adults

Phase II, Randomized, Placebo-controlled, Double-blind, Safety and Immunogenicity Trial of Intramuscular Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine in Healthy Adults

The purpose of this study is to evaluate the safety of the norovirus bivalent virus-like particle (VLP) vaccine for further development by assessing the rates of serious adverse events (SAEs), unsolicited adverse events (AEs), solicited local and solicited systemic AEs, Adverse Events of Special Interest (AESIs) and AEs leading to participant's withdrawal from the trial.

Study Overview

• Status: Completed
• Conditions: Norovirus Prevention
• Intervention / Treatment: Biological: Norovirus Bivalent VLP Vaccine; Drug: Placebo (Saline)

Detailed Description

The vaccine being tested in this study is called norovirus GI.1/GII.4 bivalent virus-like particle (VLP) vaccine adjuvanted with or without monophosphoryl lipid A (MPL) and with aluminum hydroxide. The norovirus vaccine is being tested to provide additional safety and immunogenicity data to enable the vaccine to be further developed. This study will look at the side effects in people who take different formulations of the norovirus vaccine.

The study will enroll approximately 450 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the 3 treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

• one dose of GI.1/GII.4 (15 µg/50 µg) adjuvanted with MPL (50 µg) and aluminum hydroxide (500 µg) on Day 1 followed by one dose of GI.1/GII.4 (15 µg/15 µg) adjuvanted with aluminum hydroxide (500 µg) (without MPL) on Day 365
• one dose of GI.1/GII.4 (50 µg/50 µg) adjuvanted with MPL (50 µg) and aluminum hydroxide (500 µg) on Day 1 followed by one dose of GI.1/GII.4 (15 µg/15 µg) adjuvanted with aluminum hydroxide (500 µg) (without MPL) on Day 365
• one dose of Saline Placebo (dummy inactive injection) - this is a liquid that has no active ingredient-on Day 1 + GI.1/GII.4 (15 µg/15 µg) adjuvanted with aluminum hydroxide (500 µg) (without MPL) as primary vaccination on Day 365

All participants will be administered vaccine or placebo on Day 1 of the study and will receive a vaccination dose (reduced antigen content) of the norovirus vaccine on Day 365. Participants will be asked to record any symptoms that may be related to the vaccine or the injection site in a diary card for 7 days after each vaccination.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is up to 18 months. Participants will make 11 visits to the clinic including a follow-up visit 6 months after the last dose of study medication.

• Study Type: Interventional
• Enrollment (Actual): 454
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92103-6204
      • California Research Foundation
    • San Francisco, California, United States, 94108
      • Benchmark Research San Francisco
  • Florida
    • Coral Gables, Florida, United States, 33134
      • Clin Research of South Florida
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • SNBL
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • St. Louis University, School of Medicine
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Rochester, New York, United States, 14609
      • Rochester Clinical Research
  • Ohio
    • Cincinnati, Ohio, United States, 45206
      • Cincinnati Childrens Hospital Medical Center
  • Texas
    • Austin, Texas, United States, 78705
      • Benchmark Research Austin
    • Houston, Texas, United States, 77030-3498
      • Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 49 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male and female participants aged 18 to 49 years of age at the time of enrollment.
2. Are in good health at the time of entry into the trial as determined by medical history, physical examination and clinical judgment of the investigator.
3. Participants with a signed informed consent form and any required privacy authorization prior to the initiation of any trial procedures and after the nature of the trial has been explained according to local regulatory requirements.
4. Can comply with trial procedures and are available for the duration of the trial.

Exclusion Criteria:

1. Has a history of acute gastroenteritis within 14 days of enrollment.
2. Has a clinically significant active infection (as assessed by the investigator) or oral body temperature 38°C (100.4°F) or higher within 3 days of the intended date of vaccination.
3. Has received antipyretic/analgesic medications within 24 hours prior to the intended vaccine administration.
4. Has known hypersensitivity or allergy to any of the bivalent norovirus virus-like particle (VLP) vaccine components (including excipients of the investigational vaccines).
5. Has behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may interfere with the participant's ability to participate in the trial.
6. Has a history of any progressive or severe neurologic disorder, seizure disorder, or neuro-inflammatory disease (e.g., Guillain-Barré syndrome).
7. Has history or any illness that, in the opinion of the investigator, might interfere with the results of the trial or pose additional risk to the participants due to participation in the trial.

8. Has known or suspected impairment/alteration of immune function including the following:

   1. Chronic use of oral steroids (Equivalent to 20 mg/day prednisone for ≥ 12 weeks / ≥2 mg/kg body weight /day for ≥ 2 weeks) within 60 days prior to Day 1 (use of inhaled, intranasal, or topical corticosteroids is allowed).
   2. Receipt of parenteral steroids (equivalent to 20 mg/day prednisone ≥ 12 weeks / ≥2 mg/kg body weight /day for ≥2 weeks) within 60 days prior to Day 1.
   3. Receipt of immunostimulants within 60 days prior to Day 1.
   4. Receipt of parenteral, epidural, or intra-articular immunoglobulin preparation, blood products, and/or plasma derivatives within 3 months prior to Day 1 or planned during the full length of the trial.
   5. Receipt of immunosuppressive therapy within 6 months prior to Day 1.
   6. Human immunodeficiency virus (HIV) infection or HIV-related disease.
   7. Heritable immunodeficiency.
9. Has abnormalities of splenic or thymic function.
10. Has a history of any autoimmune disease.
11. Has a known bleeding diathesis or any condition that may be associated with a prolonged bleeding time.
12. Has any serious chronic or progressive disease according to judgment of the investigator (e.g., neoplasm, insulin dependent diabetes, cardiac, renal, or hepatic disease).
13. Has a body mass index (BMI) greater than or equal to 35 kg/m^2 (= weight in kg / [height in meters * height in meters]).
14. Is participating in any clinical trial with another investigational product 30 days prior to first trial visit or intent to participate in another clinical trial at any time during the conduct of this trial.
15. Participants who received any inactivated vaccines within 14 days or any live vaccines for 28 days prior to enrollment in this trial.
16. Are first degree relatives of individuals involved in trial conduct.
17. Has a history of substance or alcohol abuse within the past 2 years.

18. If female, "of childbearing potential", sexually active, and has not used any of the "acceptable contraceptive methods" for at least 2 months prior to trial entry:

    1. Of childbearing potential is defined as status post onset of menarche and not meeting any of the following conditions: menopausal for at least 2 years, status after bilateral tubal ligation for at least 1 year, status after bilateral oophorectomy, or status after hysterectomy.
    2. Acceptable birth control methods are defined as 1 or more of the following:

    i. Hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring).

    ii. Barrier (condom with spermicide or diaphragm with spermicide) each and every time during intercourse.

    iii. Intrauterine device (IUD). iv. Monogamous relationship with vasectomized partner. Partner must have been vasectomized for at least 6 months prior to the participant's trial entry.

19. Female participants of childbearing potential and sexually active, who refuse to use an "acceptable contraceptive method" from Day 1 through 6 months after the last dose of investigational vaccine.
20. Female participants who plan to donate ova from Day 1 through 6 months after the last dose of investigational vaccine.
21. Female participants with any positive pregnancy test.
22. Female participants who are pregnant or breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GI.1/GII.4 15/50 μg - MPL 50 μg + GI.1/GII.4 15/15 μg (no MPL); Intramuscular (IM) norovirus bivalent virus like particle (VLP) vaccine (15 µg of GI.1 norovirus VLP and 50 µg GII.4 norovirus VLP) adjuvanted with 50 µg monophosphoryl lipid A (MPL) and 500 µg aluminum hydroxide, on Day 1, followed by IM norovirus bivalent VLP vaccine (15 µg of GI.1 norovirus VLP and 15 µg GII.4 norovirus VLP) adjuvanted with 500 µg aluminum hydroxide (no MPL), on Day 365.	Biological: Norovirus Bivalent VLP Vaccine; Norovirus GI.1/GII.4 bivalent VLP vaccine adjuvanted with or without MPL and/or aluminum hydroxide IM injection
Experimental: GI.1/GII.4 50/50 μg - MPL 50 μg + GI.1/GII.4 15/15 μg (no MPL); IM norovirus bivalent VLP vaccine (50 µg of GI.1 norovirus VLP and 50 µg GII.4 norovirus VLP) adjuvanted with 50 µg monophosphoryl lipid A (MPL) and 500 µg aluminum hydroxide, on Day 1, followed by IM norovirus bivalent VLP vaccine (15 µg of GI.1 norovirus VLP and 15 µg GII.4 norovirus VLP) adjuvanted with 500 µg aluminum hydroxide (no MPL), on Day 365.	Biological: Norovirus Bivalent VLP Vaccine; Norovirus GI.1/GII.4 bivalent VLP vaccine adjuvanted with or without MPL and/or aluminum hydroxide IM injection
Placebo Comparator: Saline Placebo + GI.1/GII.4 15/15 μg (No MPL); IM saline placebo on Day 1, followed by IM norovirus bivalent VLP vaccine (15 µg of GI.1 norovirus VLP and 15 µg GII.4 norovirus VLP ) adjuvanted with 500 µg aluminum hydroxide (no MPL), on Day 365.	Biological: Norovirus Bivalent VLP Vaccine; Norovirus GI.1/GII.4 bivalent VLP vaccine adjuvanted with or without MPL and/or aluminum hydroxide IM injection; Drug: Placebo (Saline); Placebo-matching norovirus bivalent VLP vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Solicited Local Adverse Events (AEs) at Injection Site After the First Injection	Solicited local AEs at injection site are defined as: pain, erythema, induration, and swelling that occurred within 7 days after the primary injection.	Days 1 through 7
Percentage of Participants With Solicited Systemic Adverse Events (AEs) After the First Injection	Solicited systemic AEs are defined as: headache, fatigue, myalgia, arthralgia, vomiting, and diarrhea that occurred within 7 days after the primary injection.	Days 1 through 7
Percentage of Participants With Elevated Daily Oral Temperature (Fever) After the First Injection	Fever is defined as greater than or equal to 38°C (100.4°F). Oral body temperature measurement was performed using the thermometer provided by the site for 7 days after each injection. The highest body temperature observed each day was recorded on the Diary Card also provided by the site.	Days 1 through 7
Percentage of Participants With Unsolicited Adverse Events (AEs) After the First Injection	Unsolicited AEs are any AEs that are not solicited local or systemic AEs, as defined by this study.	Days 1 through 28
Percentage of Participants With Serious Adverse Events (SAEs) After the First Injection	A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria.	From first injection (Day 1) to second injection pre-dose (Up to Day 365)
Percentage of Participants With Serious Adverse Events (SAEs) After the Second Injection	A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria.	From second injection (Day 365) to 6 months after second injection (Up to Day 545)
Percentage of Participants With Adverse Events of Special Interest (AESI) After the First Injection	AESIs are AEs that are not solicited local or systemic AEs, they are predefined AEs that required close monitoring and prompt reporting to the sponsor. AESI included protocol specified Cardiac Disorders, Gastrointestinal Disorders, Immune System Disorders, Infections and Infestations, Musculoskeletal and Connective Tissue Diseases, Neuroinflammatory Disorders, Renal and Urinary Disorders, Skin Disorders, Thyroid Disorders, Vascular Disorders and Other Disorders.	From first injection (Day 1) to second injection pre-dose (Up to Day 365)
Percentage of Participants With Adverse Events of Special Interest (AESI) After the Second Injection	AESIs are AEs that are not solicited local or systemic AEs, they are predefined AEs that required close monitoring and prompt reporting to the sponsor. AESI included protocol specified Cardiac Disorders, Gastrointestinal Disorders, Immune System Disorders, Infections and Infestations, Musculoskeletal and Connective Tissue Diseases, Neuroinflammatory Disorders, Renal and Urinary Disorders, Skin Disorders, Thyroid Disorders, Vascular Disorders and Other Disorders.	From second injection (Day 365) to 6 months after second injection (Up to Day 545)
Percentage of Participants With Any Adverse Event (AE) Leading to Withdrawal From the Study	Withdrawal due to an AE occurred if the participant experienced an AE that required early termination because continued participation imposed an unacceptable risk to the participant's health or the participant was unwilling to continue because of the AE.	Unsolicited AEs 28 days after each injection (Days 1 to 28 and Days 365 to 393), and Serious Adverse Events (SAEs) throughout the trial (Up to Day 545)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Solicited Local Adverse Events (AEs) at Injection Site After the Second Injection	Solicited local AEs at injection site are defined as: pain, erythema, induration, and swelling that occurred within 7 days after the vaccination on Day 365.	Days 365 through 371
Percentage of Participants With Solicited Systemic Adverse Events (AEs) After the Second Injection	Solicited systemic AEs are defined as: headache, fatigue, myalgia, arthralgia, vomiting, and diarrhea that occurred within 7 days after the vaccination on Day 365.	Days 365 through 371
Percentage of Participants With Elevated Daily Oral Temperature (Fever) After the Second Injection	Fever is defined as greater than or equal to 38°C (100.4°F). Oral body temperature measurement was performed using the thermometer provided by the site for 7 days after each vaccination. The highest body temperature observed each day was recorded on the Diary Card also provided by the site.	Days 365 through 371
Percentage of Participants With Unsolicited Adverse Events (AEs) After the Second Injection	Unsolicited AEs are any AEs that are not solicited local or systemic AEs, as defined by this study.	Days 365 through 393
Percentage of Participants With a Seroresponse in Both Serum Anti-norovirus GI.1 VLP and GII.4 VLP (Pan-Ig ELISA)	Seroresponse is defined as 4-fold rise or greater in serum anti-norovirus antibody titers for both GI.1 virus-Like particle (VLP) and GII.4 VLP as measured by pan immunoglobulin (Pan-Ig) enzyme-linked immunosorbent assay (ELISA).	Baseline and Day 28
Percentage of Participants With a Seroresponse in Serum Anti-norovirus GI.1 VLP (Pan-Ig ELISA)	Seroresponse is defined as 4-fold rise or greater in serum anti-norovirus antibody titers for GI.1 virus-Like particle (VLP) as measured by pan immunoglobulin (Pan-Ig) enzyme-linked immunosorbent assay (ELISA).	Baseline and Day 28
Percentage of Participants With a Seroresponse in Serum Anti-norovirus GII.4 VLP (Pan-Ig ELISA)	Seroresponse is defined as 4-fold rise or greater in serum anti-norovirus antibody titers for GII.4 virus-like particles (VLP) as measured by pan immunoglobulin (Pan-Ig) enzyme-linked immunosorbent assay (ELISA).	Baseline and Day 28
Geometric Mean Titer (GMT) of GI.1 VLP Antibody Titers (Pan-Ig ELISA)	Geometric mean titer (GMT) of anti-norovirus GI.1 VLP antibody titers as measured by Pan-Ig ELISA.	Day 28
Geometric Mean Titer (GMT) of GII.4 VLP Antibody Titers (Pan-Ig ELISA)	Geometric mean titer (GMT) of anti-norovirus GII.4 VLP antibody titers as measured by Pan-Ig ELISA.	Day 28
Geometric Mean Fold Rise (GMFR) of GI.1 VLP Antibody Titers (Pan-Ig ELISA)	Geometric mean fold rise (GMFR) of anti-norovirus GI.1 VLP antibody titers as measured by Pan-Ig ELISA.	Day 28
Geometric Mean Fold Rise (GMFR) of GII.4 VLP Antibody Titers (Pan-Ig ELISA)	Geometric mean fold rise (GMFR) of anti-norovirus GII.4 VLP antibody titers as measured by Pan-Ig ELISA.	Day 28
Percentage of Participants With a Seroresponse in Both Serum Anti-norovirus GI.1 VLP and GII.4 VLP (HBGA)	Seroresponse is defined as 4-fold rise or greater in serum anti-norovirus antibody titers for both GI.1 virus-Like particle (VLP) and GII.4 VLP as measured by histoblood group antigen (HBGA) binding assay.	Baseline and Day 28
Percentage of Participants With a Seroresponse in Serum GI.1 VLP Antibody Titers (HBGA)	Seroresponse is defined as 4-fold rise or greater in serum anti-norovirus antibody titers for GI.1 virus-Like particle (VLP) as measured by HBGA binding assay.	Baseline and Day 28
Percentage of Participants With a Seroresponse in Serum GII.4 VLP Antibody Titers (HBGA)	Seroresponse is defined as 4-fold rise or greater in serum anti-norovirus antibody titers for GII.4 virus-Like particle (VLP) as measured by HBGA binding assay.	Baseline and Day 28
Blocking Titers 50 (BT50) of Anti-Norovirus GI.1 VLP Antibody Titers (HBGA)	Blocking titers 50 (BT50) of anti-norovirus GI.1 VLP antibody titers as measured by HBGA binding assay.	Day 28
Blocking Titers 50 (BT50) of Anti-Norovirus GII.4 VLP Antibody Titers (HBGA)	Blocking titers 50 (BT50) of anti-norovirus GII.4 VLP antibody titers as measured by HBGA binding assay.	Day 28
Geometric Mean Fold Rise (GMFR) of GI.1 VLP Antibody Titers (HBGA)	Geometric mean fold rise (GMFR) of anti-norovirus GI.1 VLP antibody titers as measured by HBGA binding assay.	Day 28
Geometric Mean Fold Rise (GMFR) of GII.4 VLP Antibody Titers (HBGA)	Geometric mean fold rise (GMFR) of anti-norovirus GII.4 VLP antibody titers as measured by the HBGA binding assay.	Day 28

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• Atmar RL, Baehner F, Cramer JP, Lloyd E, Sherwood J, Borkowski A, Mendelman PM; NOR-201 Study Group. Persistence of Antibodies to 2 Virus-Like Particle Norovirus Vaccine Candidate Formulations in Healthy Adults: 1-Year Follow-up With Memory Probe Vaccination. J Infect Dis. 2019 Jul 19;220(4):603-614. doi: 10.1093/infdis/jiz170.
• Atmar RL, Baehner F, Cramer JP, Song E, Borkowski A, Mendelman PM; NOR-201 Study Group. Rapid Responses to 2 Virus-Like Particle Norovirus Vaccine Candidate Formulations in Healthy Adults: A Randomized Controlled Trial. J Infect Dis. 2016 Sep 15;214(6):845-53. doi: 10.1093/infdis/jiw259. Epub 2016 Jun 28.

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2014
• Primary Completion (Actual): January 6, 2016
• Study Completion (Actual): January 6, 2016

Study Registration Dates

• First Submitted: May 9, 2014
• First Submitted That Met QC Criteria: May 15, 2014
• First Posted (Estimate): May 20, 2014

Study Record Updates

• Last Update Posted (Actual): August 21, 2017
• Last Update Submitted That Met QC Criteria: August 18, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Drug therapy
• Other Study ID Numbers: NOR-201; U1111-1155-8803 (Other Identifier: World Health Organization)