Bivalent Norovirus Vaccine Study

Phase 1, Randomized Controlled Dose Escalation, Safety and Immunogenicity Study of Intramuscular Norovirus GI.1/GII.4 Bivalent Virus-Like Particle (VLP) Vaccine Adjuvanted With Monophosphoryl Lipid A (MPL) and Aluminum Hydroxide [Al(OH)3] in Adults

Randomized, multi-site, dose-escalation study of the safety and immunogenicity of four dosage levels of Intramuscular (IM) Norovirus Bivalent VLP Vaccine adjuvanted with MPL and Al(OH)3 compared to controls. Participants will receive two doses, by IM injection, 28 days apart.

The hypotheses for this study are:

• The incidence of adverse events after vaccination with IM Norovirus Bivalent VLP Vaccine will be similar to the incidence of adverse events after other IM vaccines including CERVARIX® which contains MPL and Al(OH)3.
• Two doses of IM Norovirus Bivalent VLP Vaccine will be more immunogenic than one dose.
• The post-vaccination serum antibody responses, the number of antibody secreting cells (ASC), including homing markers, and memory B-cell responses directed against norovirus antigens will be increased after IM Norovirus Bivalent VLP Vaccine compared to controls.

Study Overview

• Status: Completed
• Conditions: Gastroenteritis
• Intervention / Treatment: Biological: NoV GI.1/GII.4 Bivalent VLP Vaccine; Biological: Saline

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Silver Springs, Maryland, United States, 20910
      • Navy Medical Research Center
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • Saint Louis University
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Participants must meet all of the inclusion criteria listed below:

1. Signed written informed consent.

2. Age:

   • Cohort A: 18-49 years, inclusive
   • Cohort B: 50-64 years, inclusive
   • Cohort C: 65-85 years, inclusive
   • Cohort D: 18-49 years, inclusive

3. Health Status:

   • Cohort A and D: In good health as determined by a screening evaluation that includes vital signs, medical history, and physical exam within 45 days before administration of IM Norovirus Bivalent VLP Vaccine or control.
   • Cohorts B and C: In good health as determined by a screening evaluation that includes vital signs, medical history, and physical exam within 45 days before administration of IM Norovirus Bivalent VLP Vaccine or control. Any existing medical diagnoses or conditions must be stable based on medical history and targeted physical examination. A stable medical condition is defined as: (A) Clinically acceptable health outcomes for the specific condition over the prior 6 months and (B) No change in prescription medication(s), dose, or frequency over the prior 3 months. Acceptable changes in medications are: a change of health care provider or insurance company or that is made for financial reasons as long as the medications are in the same class and/or a change due to improvement in a disease outcome.
4. Expressed interest and availability to fulfill the study requirements.
5. Female participants must be of non-childbearing potential (surgically sterile or post-menopausal for greater than or equal to [>=] 12 months), or if of childbearing potential (as determined by the investigator) must be practicing abstinence or using an effective licensed method of birth control (example oral contraceptives; diaphragm or condom in combination with contraceptive jelly, cream, or foam; intrauterine contraceptive device, or Depo-Provera; skin patch; vaginal ring or cervical cap) for 30 days prior to vaccination and must agree to continue such precautions for at least 60 days after the last vaccination. A woman is eligible if she is monogamous with a male who has had a vasectomy. Male participants must agree not to father a child for at least 60 days after the last vaccination and to practice abstinence or use an effective method of birth control as noted above.
6. Agrees not to participate in another clinical trial with an investigational product for the entire duration of the study one year after the last study dose that is 393 days.
7. Agrees to storage of unused clinical specimens for an indefinite period of time for future norovirus research or research on other gastrointestinal pathogens.

Exclusion Criteria:

Participants who meet any of the exclusion criteria at baseline will be excluded from study participation. The exclusion criteria are:

1. History of any of the following medical illnesses:

   • Diabetes
   • Cancer (malignancy other than resolved/excised skin lesion)
   • Heart disease (hospitalization for a heart attack, arrhythmia, or syncope)
   • Unconsciousness (other than a single brief "concussion")
   • Seizures (other than febrile seizures as a child less than [<] 5 years old)
   • Recurrent infections (more than 3 hospitalizations for invasive bacterial infections such as pneumonia or meningitis)
   • Any condition associated with immunodeficiency or participants taking immunosuppressant medication
   • Neuroinflamatory or auto-immune disease

2. Any current illness requiring daily medication other than the following:

   • Cohort A and D: Vitamins, birth control, anti-hypertensive medication, antihistamines or anti-depressant medication. The Principal Investigator (PI) should consult with the Central Safety Monitor and/or the sponsor for any clarification of medications allowable.
   • Cohorts B and C: Vitamins, birth control, anti-hypertensive medication, antihistamines or anti-depressant medication or any current illness requiring daily medication other than as noted above in inclusion criteria 3. The PI should consult with the Central Safety Monitor and/or the sponsor for any clarification of medications allowable.
3. Allergies or hypersensitivity to any component of the vaccine including MPL and Al(OH)3 adjuvants.

4. Any clinically significant abnormality detected on physical examination, including:

   • Murmur (other than a functional murmur)
   • Focal neurological abnormality
   • Hepatosplenomegaly
   • Lymphadenopathy
   • Jaundice
5. Hypertension (Blood Pressure [BP] greater than [>] 140/90 millimeter of mercury [mm Hg] on two separate days)

6. Any lab abnormality (per the site local laboratory), as listed below:

   • Absolute Neutrophil Count (ANC) outside the normal range (may be repeated if outside this limit)
   • Total white blood cells (WBC) outside the normal range (may be repeated if outside this limit)
   • Hemoglobin outside the normal range (may be repeated if outside this limit)
   • Platelet count outside the normal range (may be repeated if outside this limit)
   • Blood urea nitrogen (BUN) > upper limit of normal (ULN) (may be repeated if outside this limit)
   • Creatinine > ULN (may be repeated if outside this limit)
   • Glucose (fasting or random) outside the normal range (may be repeated if outside this limit)
   • Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) > ULN (may be repeated if outside this limit)
7. Positive serology for hepatitis C or Human Immunodeficiency Virus (HIV) antibody or hepatitis B surface antigen.
8. For women of child bearing potential, positive serum pregnancy test within 14 days and urine pregnancy test within 24 hours of administering either dose of IM Norovirus Bivalent VLP Vaccine or control.
9. Nursing mother.
10. Temperature >100.4 degree Fahrenheit (F) or symptoms of an acute self-limited illness such as an upper respiratory infection or gastroenteritis within 3 days of administration of IM Norovirus Bivalent VLP Vaccine or control.
11. Previous participation in a Norovirus vaccine or challenge study.
12. Study site personnel or their family members.
13. Significant history of psychiatric hospitalization, alcohol abuse, or illicit drug use in the prior 5 years.
14. Completion of an investigational vaccine or drug study within 28 days before administration of IM Norovirus Bivalent VLP Vaccine or control.
15. Have a history of receiving immunoglobulin or other blood product within the 3 months prior to vaccination in this study.
16. Other condition that in the clinical judgment of the investigator would jeopardize the safety or rights of a participant participating in the trial, would render the participant unable to comply with the protocol or would interfere with the evaluation of the vaccine.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Saline	Biological: Saline; Two doses 28 days apart
Experimental: NoV GI.1/GII.4 Bivalent VLP Vaccine; Norovirus Bivalent GI.1 and GII.4 VLP Vaccine, adjuvanted with 50 microgram (mcg) MPL and 500 mcg Al(OH)3, IM, on Days 0 and 28.	Biological: NoV GI.1/GII.4 Bivalent VLP Vaccine; 2 Doses 28 days apart Cohort A: 18-49 Years Cohort A1: IM Norovirus Bivalent GI.1/GII.4 VLP Vaccine (5/5 mcg) Cohort A2: IM Norovirus Bivalent GI.1/GII.4 VLP Vaccine (15/15 mcg) Cohort A3: IM Norovirus Bivalent GI.1/GII.4 VLP Vaccine (50/50 mcg) Cohort A4: IM Norovirus Bivalent GI.1/GII.4 VLP Vaccine (150/150 mcg) Cohort B: 50-64 Years IM Norovirus Bivalent GI.1/GII.4 VLP Vaccine (50/50 mcg) Cohort C: 65-85 Years IM Norovirus Bivalent GI.1/GII.4 VLP Vaccine (50/50 mcg) Cohort D: 18-49 Years IM Norovirus Bivalent GI.1/GII.4 VLP Vaccine (50/50 mcg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Solicited Local Adverse Events (AEs) Post Dose 1	The solicited local adverse events were reported using a memory aid. Pain was scaled as Mild (did not interfere with activity); Moderate (repeated use of non-narcotic pain reliever greater than (>) 24 hours [24h] or interfered with activity); and Severe (any use of narcotic pain reliever or prevented daily activity). Tenderness was scaled as Mild (mild discomfort to touch); Moderate (discomfort with movement); and Severe (significant discomfort at rest). Swelling and redness were scaled as Mild (2.5-5 centimeter [cm] and did not interfere with activity); Moderate (5.1-10 cm or interfered with activity); and Severe (>10 cm or prevented daily activity).	Day 0 up to Day 7
Number of Participants With Solicited Local AEs Post Dose 2	The solicited local adverse events were reported using a memory aid. Pain was scaled as Mild (did not interfered with activity); Moderate (repeated use of non-narcotic pain reliever >24h or interfered with activity); and Severe (any use of narcotic pain reliever or prevented daily activity). Tenderness was scaled as Mild (mild discomfort to touch); Moderate (discomfort with movement); and Severe (significant discomfort at rest). Swelling and redness were scaled as Mild (2.5-5 cm and did not interfere with activity); Moderate (5.1-10 cm or interfered with activity); and Severe (>10 cm or prevented daily activity).	Day 28 up to Day 35
Number of Participants With Solicited Systemic AEs Post Dose 1	Elevated oral temperature:Mild(38-38.4 Celsius[C]);Moderate(38.5-38.9 C);Severe(39-40 C).Headache:Mild(no interference with activity);Moderate(repeated use of non-narcotic pain reliever>24h/some interference with activity);Severe(significant;any use of narcotic pain reliever/prevented daily activity).Fatigue,Malaise:Mild(no interference with activity);Moderate(some interference with activity);Severe(significant;prevented daily activity).Diarrhea:Mild(2-3loose stools/<400gram[g]/24h);Moderate(4-5stools/400-800g/24h);Severe(>=6watery stools/>800g/24h/required intravenous[IV]hydration).Nausea/Vomiting:Mild(no interference with activity/1-2 episodes/24h);Moderate(some interference with activity/>2 episodes/24h);Severe(prevented daily activity,required IV hydration).Muscle ache,chills,joint ache,abdominal cramp/pain:Mild(no interference with activity);Moderate(some interference with activity,not required medical intervention);Severe(prevented daily activity,required medical intervention).	Day 0 up to Day 7
Number of Participants With Solicited Systemic AEs Post Dose 2	Elevated oral temperature:Mild(38-38.4 C);Moderate(38.5-38.9 C);Severe(39-40 C).Headache:Mild(no interference with activity);Moderate(repeated use of non-narcotic pain reliever>24h/some interference with activity);Severe(significant;any use of narcotic pain reliever/prevented daily activity).Fatigue,Malaise:Mild(no interference with activity);Moderate(some interference with activity);Severe(significant;prevented daily activity).Diarrhea:Mild(2-3loose stools/<400g/24h);Moderate(4-5stools/400-800g/24h);Severe(>=6watery stools/>800g/24h/required IV hydration).Nausea/Vomiting:Mild(no interference with activity/1-2 episodes/24h);Moderate(some interference with activity/>2 episodes/24h);Severe(prevented daily activity,required IV hydration).Muscle ache,chills,joint ache,abdominal cramp/pain:Mild(no interference with activity);Moderate(some interference with activity,not required medical intervention);Severe(prevented daily activity,required medical intervention).	Day 28 up to Day 35
Number of Participants With Unsolicited AEs Post Dose 1		Baseline up to Day 28 (Pre-dose 2)
Number of Participants With Unsolicited AEs Post Dose 2		Day 28 up to Day 56 (Post dose 2)
Number of Participants With Clinically Significant Change From Baseline in Markedly Abnormal Laboratory Values	The number of participants with any markedly abnormal standard safety laboratory values (serum chemistry or hematology) collected throughout study.	Baseline up to Day 35
Number of Participants With Serious Adverse Events (SAEs), Onset of Significant New Medical Conditions, Including Adverse Events of Special Interest (AESI)		Baseline up to 365 Days after post dose 2 (Day 393)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric Mean Titer (GMT) of Serum Anti-norovirus GI.1 and GII.4 VLP Ig (Immunoglobulin) A	Run I was defined as the initial analysis performed once Day 56 post dose data was available. Run II was defined as final analysis performed after all later time points were achieved.	First (I) run: predose 1 and 7, 21, 28 days postdose (PD)1, and 7 and 28 days PD2; second (II) run: predose 1 and 28, 152 and 365 days PD2 (up to Day 393)
GMT of Serum Anti-norovirus GI.1 and GII.4 VLP IgG	Run I was defined as the initial analysis performed once Day 56 post dose data was available. Run II was defined as final analysis performed after all later time points were achieved.	I run: predose 1 and 7, 21, 28 days PD1, and 7 and 28 days PD2; II run: predose 1 and 28, 152 and 365 days PD2 (up to Day 393)
GMT of Serum Anti-norovirus GI.1 and GII.4 VLP IgM	Run I was defined as the initial analysis performed once Day 56 post dose data was available. Run II was defined as final analysis performed after all later time points were achieved.	I run: predose 1 and 7, 21, 28 days PD1, and 7 and 28 days PD2; II run: predose 1 and 28, 152 and 365 days PD2 (up to Day 393)
Geometric Mean Fold Rise (GMFR) of Serum Anti-norovirus GI.1 and GII.4 VLP IgA as Compared to Baseline	Run I was defined as the initial analysis performed once Day 56 post dose data was available. Run II was defined as final analysis performed after all later time points were achieved.	I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
GMFR of Serum Anti-norovirus GI.1 and GII.4 VLP IgG as Compared to Baseline	Run I was defined as the initial analysis performed once Day 56 post dose data was available. Run II was defined as final analysis performed after all later time points were achieved.	I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
GMFR of Serum Anti-norovirus GI.1 and GII.4 VLP IgM as Compared to Baseline	Run I was defined as the initial analysis performed once Day 56 post dose data was available. Run II was defined as final analysis performed after all later time points were achieved.	I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
Percentage of Participants With Seroresponse for Serum Anti-norovirus GI.1 and GII.4 VLP IgA	Seroresponse was defined as a 4-fold increase in antibody titer compared to pre-immunization titers. Run I was defined as the initial analysis performed once Day 56 post dose data was available. Run II was defined as final analysis performed after all later time points were achieved.	I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
Percentage of Participants With Seroresponse for Serum Anti-norovirus GI.1 and GII.4 VLP IgG	Seroresponse was defined as a 4-fold increase in antibody titer compared to pre-immunization titers. Run I was defined as the initial analysis performed once Day 56 post dose data was available. Run II was defined as final analysis performed after all later time points were achieved.	I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
Percentage of Participants With Seroresponse for Serum Anti-norovirus GI.1 and GII.4 VLP IgM	Seroresponse was defined as a 4-fold increase in antibody titer compared to pre-immunization titers. Run I was defined as the initial analysis performed once Day 56 post dose data was available. Run II was defined as final analysis performed after all later time points were achieved.	I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
GMT of Anti-norovirus GI.1 and GII.4 VLP IgA, IgG, and IgM Combined Using Pan-Ig Enzyme-Linked Immunosorbent Assay (ELISA)	GMTs were assessed for Anti-norovirus GI.1 and GII.4 VLP by Pan-Ig ELISA. A pan ELISA assay captured IgG, IgA and IgM combined. Run I was defined as the initial analysis performed once Day 56 post dose data was available. Run II was defined as final analysis performed after all later time points were achieved.	I run: predose 1, 7, 21, 28 days PD1, 7 and 28 days PD2; II run: predose 1, 28, 152 and 365 days PD2 (up to Day 393)
GMFR of Anti-norovirus GI.1 and GII.4 VLP IgA, IgG, and IgM Combined Using Pan-Ig ELISA as Compared to Baseline	GMFRs in GMTs of Anti-norovirus GI.1 and GII.4 VLP by Pan-Ig ELISA. A pan ELISA assay captured IgG, IgA and IgM combined. Run I was defined as the initial analysis performed once Day 56 post dose data was available. Run II was defined as final analysis performed after all later time points were achieved.	I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
Percentage of Participants With Seroresponse (4-Fold Rise) of Anti-norovirus GI.1 and GII.4 VLP IgA, IgG, and IgM Combined Using Pan-Ig ELISA	Seroresponse was defined as a 4-fold increase in antibody titer compared to pre-immunization titers. Run I was defined as the initial analysis performed once Day 56 post dose data was available. Run II was defined as final analysis performed after all later time points were achieved.	I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• Ramani S, Neill FH, Ferreira J, Treanor JJ, Frey SE, Topham DJ, Goodwin RR, Borkowski A, Baehner F, Mendelman PM, Estes MK, Atmar RL. B-Cell Responses to Intramuscular Administration of a Bivalent Virus-Like Particle Human Norovirus Vaccine. Clin Vaccine Immunol. 2017 May 5;24(5):e00571-16. doi: 10.1128/CVI.00571-16. Print 2017 May.
• Lindesmith LC, Ferris MT, Mullan CW, Ferreira J, Debbink K, Swanstrom J, Richardson C, Goodwin RR, Baehner F, Mendelman PM, Bargatze RF, Baric RS. Broad blockade antibody responses in human volunteers after immunization with a multivalent norovirus VLP candidate vaccine: immunological analyses from a phase I clinical trial. PLoS Med. 2015 Mar 24;12(3):e1001807. doi: 10.1371/journal.pmed.1001807. eCollection 2015 Mar.
• Treanor JJ, Atmar RL, Frey SE, Gormley R, Chen WH, Ferreira J, Goodwin R, Borkowski A, Clemens R, Mendelman PM. A novel intramuscular bivalent norovirus virus-like particle vaccine candidate--reactogenicity, safety, and immunogenicity in a phase 1 trial in healthy adults. J Infect Dis. 2014 Dec 1;210(11):1763-71. doi: 10.1093/infdis/jiu337. Epub 2014 Jun 20.

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2010
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): January 9, 2013

Study Registration Dates

• First Submitted: July 21, 2010
• First Submitted That Met QC Criteria: July 22, 2010
• First Posted (Estimate): July 23, 2010

Study Record Updates

• Last Update Posted (Actual): November 23, 2018
• Last Update Submitted That Met QC Criteria: April 27, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Vaccine, norovirus, acute gastroenteritis
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis
• Other Study ID Numbers: LV03-104; U1111-1187-1052 (Registry Identifier: WHO)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No