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.

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.

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.