Two Doses of Multimeric-001 (M-001) Followed by Influenza Vaccine

This is a Phase II randomized, double-blind, placebo-controlled trial in 120 males and non-pregnant females, 18 to 49 years old, inclusive, who are in good health and meet all eligibility criteria. This clinical trial will be conducted at 3 United States sites and is designed to assess the safety, reactogenicity, and immunogenicity of two priming doses of M-001 followed by a seasonal quadrivalent inactivated influenza vaccine (IIV4). The duration of this trial for each subject will be approximately 7 months. The entire study duration will be approximately 24 months. The primary objectives are: 1) To assess the safety as measured by vaccine related adverse events, reactogenicity, and laboratory adverse events of two doses of M-001 vaccine, each dose administered approximately 21 days apart; and 2) To assess the T cell responses to M-001 component peptides following two doses of M-001.

This is a Phase II randomized, double-blind, placebo-controlled trial in 120 males and non-pregnant females, 18 to 49 years old, inclusive, who are in good health and meet all eligibility criteria. This clinical trial will be conducted at 3 United States sites and is designed to assess the safety, reactogenicity, and immunogenicity of two priming doses of M-001 followed by a seasonal quadrivalent inactivated influenza vaccine (IIV4). The duration of this trial for each subject will be approximately 7 months. The entire study duration will be approximately 24 months. The primary objectives are: 1) To assess the safety as measured by vaccine related adverse events, reactogenicity, and laboratory adverse events of two doses of M-001 vaccine, each dose administered approximately 21 days apart; and 2) To assess the T cell responses to M-001 component peptides following two doses of M-001. The secondary objectives are: 1) To assess all serious adverse events (SAEs) following receipt of each dose of M-001 vaccine or placebo, each dose separated by approximately 21 days, through the end of the study; 2) To assess all unsolicited non-serious AEs following receipt of each dose of M-001 or placebo, each dose separated by approximately 21 days, through 21 days after each dose of M-001 or placebo; and 3) To assess the serum HAI and Neut antibody responses to the 2018-2019 IIV4 vaccine viruses.

Eligibility Criteria:
Inclusion Criteria:

1. Provide written informed consent prior to initiation of any study procedures.
2. Are able to understand and comply with planned study procedures and be available for all study visits.
3. Are males or non-pregnant females, 18 to 49 years old, inclusive.
4. Are in good health\*.

   \*As determined by medical history and targeted physical examination to evaluate acute or currently ongoing chronic medical diagnoses or conditions, defined as those that have been present for at least 90 days, which would affect the assessment of the safety of subjects or the immunogenicity of study vaccinations. Chronic medical diagnoses or conditions should be stable for the last 60 days prior to investigational vaccine study product administration. This includes no change in chronic prescription medication, dose, or frequency as a result of deterioration of the chronic medical diagnosis or condition in the 60 days prior to enrollment and investigational vaccine study product administration. Any prescription change that is due to change of health care provider, insurance company, etc., or that is done for financial reasons, as long as in the same class of medication, will not be considered a deviation of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome, as determined by the site principal investigator or appropriate sub-investigator, will not be considered a deviation of this inclusion criterion. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the site principal investigator or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition. Similarly, medication changes subsequent to enrollment and investigational study product vaccination are acceptable provided there was no deterioration in the subject's chronic medical condition that necessitated a medication change. All chronic medical condtions should pose no additional risk to the subject or interference with the evaluation of responses to study vaccination. Note: Topical, nasal, and inhaled medications (with the exception of inhaled corticosteroids as outlined in the Subject Exclusion Criteria), herbals, vitamins, and supplements are permitted.
5. Oral temperature is less than 100.0 degrees F.
6. Pulse\*\* is 50 to 100 bpm, inclusive.

   \*\*Acceptable pulse range prior to IIV4 dose is 45 to 115 bpm, inclusive and no symptoms.
7. Systolic blood pressure\*\*\* is 85 to 150 mmHg, inclusive. \*\*\*Acceptable systolic blood pressure range prior to IIV4 dose is 80 to 155 mm Hg, inclusive and no symptoms.
8. Diastolic blood pressure\*\*\*\* is 55 to 95 mmHg, inclusive.

   \*\*\*\*Acceptable diastolic blood pressure range prior to IIV4 dose is 50 to 100 mm Hg, inclusive and no symptoms.
9. Women of childbearing potential\* must use an acceptable method of contraception\*\* from 30 days prior to vaccination until 60 days after the second of dose of M-001 or placebo.
10. Women of childbearing potential\*\*\*\*\* must use an acceptable method of contraception\*\*\*\*\*\* from 30 days prior to receipt of IIV vaccination, and must plan to use until 28 days after the IIV.

    \*\*\*\*\*Not sterilized via tubal ligation, bilateral oophorectomy, hysterectomy, or successful Essure(R) placement (permanent, non-surgical, non-hormonal sterilization with history of documented radiological confirmation test achieved or with use of another approved birth control method if confirmation test not confirmed) and still menstruating or \< 1 year of the last menses if menopausal).

    \*\*\*\*\*\*Includes, but is not limited to, non-male sexual relationships, abstinence from sexual intercourse with a male partner, monogamous relationship with a vasectomized partner, male condoms with the use of applied spermicide, intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables, contraceptive patches or oral contraceptives ("the pill"). Method of contraception will be captured on the appropriate data collection form.
11. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 24 hours prior to study vaccination.

Exclusion Criteria:

1. Have an acute illness\*, as determined by the site PI or appropriate sub-investigator, within 72 hours prior to study vaccination.

   * An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the site PI or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety parameters as required by the protocol.
2. Have any medical disease or condition that, in the opinion of the site PI or appropriate sub-investigator, is a contraindication to study participation\*\*.

   \*\*Including acute or chronic medical disease or condition, defined as persisting for at least 90 days, that would place the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or the subject's successful completion of this study.
3. Have immunosuppression as a result of an underlying illness or treatment, or use of anticancer chemotherapy or radiation therapy (cytotoxic) within 3 years prior to study vaccination.
4. Have known active neoplastic disease or a history of any hematologic malignancy. Non-melanoma skin cancers that are not active are permitted.
5. Have known HIV, hepatitis B, or hepatitis C infection.
6. Have known hypersensitivity or allergy to eggs, egg or chicken protein, or other components of the study vaccine.
7. Have a history of severe reactions following previous immunization with licensed or unlicensed influenza vaccines.
8. Have a history of Guillain-Barré Syndrome.
9. Have a history of alcohol or drug abuse within 5 years prior to study vaccination.
10. Have any diagnosis, current or past, of schizophrenia, bipolar disease, or other psychiatric diagnosis that may interfere with subject compliance or safety evaluations.
11. Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others within 10 years prior to study vaccination.
12. Have taken oral or parenteral (including intraarticular) corticosteroids of any dose within 30 days prior to study vaccination.
13. Have taken high-dose\*\*\* dose inhaled corticosteroids within 30 days prior to study vaccination\*\*\*\*.

    \*\*\*High-dose defined as per age as using inhaled high dose per reference chart https://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/quick-reference-html#estimated-comparative-daily-doses.

    \*\*\*\*Topical and nasal steroids are permissible.
14. Received any licensed live vaccine or plan to receive a licensed live vaccine within 30 days prior or 21 days after each M-001 study vaccination.
15. Received a licensed inactivated vaccine within 14 days prior to or 21 days after each M-001 study vaccination.
16. Plans to or received the current 2018-2019 influenza vaccine (inactivated or live prior to ordering the study (the 2018-2019 influenza vaccine will be given during the trial.))
17. Received immunoglobulin or other blood products (with exception of Rho D immunoglobulin) within 90 days prior to study vaccination.
18. Received an experimental agent\*\*\*\*\* within 30 days prior to the first study vaccination, or expects to receive an experimental agent\*\*\*\*\*\* during the 7-month trial-reporting period.

    \*\*\*\*\*Including vaccine, drug, biologic, device, blood product, or medication.

    \*\*\*\*\*\*Other than from participation in this study.
19. Are participating or plan to participate in another clinical trial with an interventional agent\*\*\*\*\*\*\* that will be received during the 7-month trial-reporting period.

    \*\*\*\*\*\*\*Including agent (licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication) during the 9-month study period.
20. Plan to travel outside the U.S. (continental U.S., Hawaii and Alaska) in the time between the first study vaccination and 21 days after the last study vaccination\*\*\*\*\*\*\*\*.

    \*\*\*\*\*\*\*\*Study vaccination refers to investigational study product vaccination.
21. Female subjects who are breastfeeding or plan to breastfeed at any given time from the first study vaccination until 30 days after the last study vaccination.
22. Blood donation or planned blood donation within 30 days prior to the study vaccination through 30 days after the last blood drawn for this study.
23. Have signs or symptoms that could confound or confuse assessment of study vaccine reactogenicity\*\*\*\*\*\*\*\*\*.

    \*\*\*\*\*\*\*\*\*The study vaccination should be postponed/deferred until signs or symptoms have resolved and if within the acceptable protocol-specified window for that visit.
24. Have a history of convulsions or encephalomyelitis within 90 days prior to study vaccination.