Safety and Immunogenicity of Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine in an Elderly Population

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

The purpose of this study is to further develop a formulation and dose regimen of the norovirus GI.1/GII.4 bivalent virus-like particle (VLP) vaccine that is immunogenic and safe in an elderly population aged 60 years and above.

The vaccine being tested in this study is called norovirus GI.1/GII.4 bivalent virus-like particle (VLP) vaccine adjuvanted with aluminum hydroxide (Formulation A) or adjuvanted with monophosphoryl lipid A (MPL) and aluminum hydroxide (Formulation B). Two norovirus vaccine formulations are being tested to select for further development the formulation that will generate an optimal specific antibody response that may provide protection against norovirus and is safe in a population aged 60 years and above. This study will look at side effects and the level of antibodies to norovirus formed in people who will be injected with different formulations of the norovirus vaccine candidate.

The study will enroll approximately 325 patients. Participants will be randomly assigned (by chance) to one of five treatment groups.

• Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation A) 1-dose, participants ≥ 60 years
• Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation A) 2-dose, participants ≥ 60 years
• Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation B) 1-dose, participants ≥ 60 years
• Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation B) 2-dose, participants ≥ 60 years
• Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation A) 1-dose, participants 18 to 49 years All participants in the age of 60 years and older will be administered either NoV vaccine (Formulation A or B) or placebo on Day 1 and NoV vaccine (Formulation A or B) on Day 29 of the study. In order to keep the treatment arms undisclosed to the patient and the doctor, those randomized to the one dose groups will receive a dose of placebo (this is a saline solution that has no active ingredient) on Day 1 followed by the NoV vaccine on Day 29. Those randomized to 2 doses with receive the NoV vaccine on Day 1 and Day 29. In case of an urgent medical need a participant can be unblinded.

Adults aged 18 to 49 will receive placebo on Day 1 followed by NoV vaccine Formulation A on Day 29.

Participants will be asked to record any reactions/ symptoms that may be related or not to the vaccine in a diary card for 28 days after each vaccination.

This multi-center trial will be conducted in the United States of America. The overall time to participate in this study is up to 393 days. Participants will make multiple visits to the clinic including a final follow-up visit on Day 393.

Inclusion Criteria:

1. Is aged 18 to 49 years, or 60 years and older at the time of enrollment;
2. Participants who are in good health, or in stable health status with no exclusionary medical or neuropsychiatric conditions at the time of entry into the trial as determined by medical history, physical examination (including vital signs) and clinical judgment of the Investigator;
3. Participant signs and dates a written, Informed Consent Form (ICF) and any required privacy authorization prior to the initiation of any trial procedures, after the nature of the trial has been explained according to local regulatory requirements;
4. Participants who can comply with trial procedures and are available for the duration of follow-up.

Exclusion Criteria:

1. Has a known hypersensitivity or allergy to any of the Norovirus (NoV) GI.1/GII.4 Bivalent virus-like particle (VLP) Vaccine components;

2. Has a clinically significant active infection (as assessed by the Investigator) or body temperature ≥38°C/100.4°F within 3 days of the intended date of vaccination;

3. Participants with the presence of significant acute or chronic, uncontrolled medical or neuropsychiatric illness. Uncontrolled was defined as:

   Requiring institution of new medical or surgical treatment within 3 months prior to immunization, or Requiring a change in medication dosage in the 3 months prior to immunization due to uncontrolled symptoms or drug toxicity (elective dosage adjustments in stable participants were acceptable), or Hospitalization or an event fulfilling the definition of a serious adverse event within 3 months prior immunization.

4. Has any unstable medical or neuropsychiatric condition, which in the Investigator's opinion poses a risk of unusual magnitude for the participant's age group of hospitalization, death, or an event meeting the definition of a serious adverse event within 2 months of immunization. The intent of this criterion is to recognize and allow for the frequent existence of significant health concerns in this population; but exclude those participants who are experiencing an acute decline in health status;

5. Has any medical or neuropsychiatric condition, which in the Investigator's opinion, rendered the participant incompetent to provide informed consent or unable to provide valid safety observations and reports;

6. 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;

7. Participants with any history of progressive or severe neurologic disorder, history of seizure, or history of neuro-inflammatory disease (e.g. Guillain-Barre syndrome);

8. Participants with 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;

9. Has known or suspected autoimmune disease;

10. Has known or suspected impairment/alteration of immune function, including:

    Chronic use of oral steroids (Equivalent to 20 mg/day prednisone ≥ 12 weeks/≥ 2 mg/kg body weight/day prednisone ≥ 2 weeks) within 60 days prior to Day 1 (use of inhaled, intranasal, or topical corticosteroids is allowed).

    Receipt of parenteral steroids (Equivalent to 20 mg/day prednisone ≥ 12 weeks/≥ 2 mg/kg body weight/day prednisone ≥ 2 weeks) within 60 days prior to Day 1.

    Receipt of immunosuppressive therapy within 3 months prior to Day 1. Receipt of immunostimulants within 60 days prior to Day 1. 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.

    Human Immunodeficiency Virus (HIV) infection or HIV-related disease. Genetic immunodeficiency.

11. Has abnormalities of splenic or thymic function;

12. Has any significant disorder of coagulation or treatment with anticoagulant therapy that would increase the risk of intramuscular (IM) injection. Persons receiving prophylactic antiplatelet medication such as low dose of acetylsalicylic acid are eligible;

13. Has any serious chronic or progressive disease according to judgment of the Investigator: cancer (malignancy other than resolved/excised skin lesion), insulin dependent Type I diabetes (Type II diabetes is accepted), cardiac, renal or hepatic disease;

14. Has body mass index (BMI) greater than or equal to 35 kg/m^2 (= weight in kg/[height in meters^2]);

15. 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;

16. Participants who received any other vaccines within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to enrollment in this trial or who are planning to receive any vaccine within 28 days of investigational vaccine administration;

17. Participants involved in trial conduct or their first degree relatives;

18. Has history of substance or alcohol abuse within the past 2 years;

19. Females who are pregnant or breastfeeding;

20. If female of childbearing potential, sexually active with a male partner who has not been sterilized, and has not used any of the "acceptable contraceptive methods" for at least 2 months prior to trial entry:

    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.

    Acceptable birth control methods are defined as one 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 six months prior to the participants' trial entry.

21. If female of childbearing potential and sexually active, refusal to use an "acceptable contraceptive method" from Day 1 and throughout the duration of the trial. In addition, they must be advised not to donate ova during this period;

22. Females with any positive or indeterminate pregnancy test.