Safety Study of Hepatitis E Vaccine (HEV239)

This is a Phase I double-blind, randomized, placebo controlled trial (1:4 ratio of placebo to vaccine) of Hepatitis E virus vaccine containing a 239 amino acid subfragment of Hecolin(R) (HEV-239) in 25 US males and non-pregnant females ages 18 - 45 (inclusive) to assess the safety, reactogenicity, and immunogenicity of HEV-239. Subjects will receive 3 doses of study product on Days 1, 29, and 180. Subjects will remain in the study for up to 13 months (including screening). The study duration will be approximately 15 months. Subjects will be observed for 30 minutes after vaccination. The occurrence of solicited injection site and systemic reactogenicity events will be measured from the time of study vaccination through Day 8 after each vaccination. These will be ascertained through use of an electronic memory (e-memory) aid, a telephone call on day 4 after each dose of vaccine, a Day 8 clinic visit, and potentially at the Day 15 clinic visit after each dose of vaccine. Unsolicited adverse events will be collected from vaccination through Day 29 after each vaccination. Serious adverse events will be collected from the time of the first study vaccination through the last study visit (Day 360). The study includes multiple phlebotomy time points for immunogenicity and blood collection for future use at visit 1 and Days 8, 15, and 29 after each vaccination. The durability of the immune response and future use collection will be assessed at 5 months after the first boost (Day 180) and at 6 months after the second boost (Day 360). The primary objectives of the study are to; 1) assess the safety and reactogenicity of HEV-239 following delivery of each vaccine dose; and 2) assess the number of subjects with \> / = 4 fold rise in Hepatitis E virus (HEV) immunoglobulin G (IgG) at any time after vaccination.

This is a Phase I double-blind, randomized, placebo controlled trial (1:4 ratio of placebo to vaccine) of Hepatitis E virus vaccine containing a 239 amino acid subfragment of Hecolin(R) (HEV-239) in 25 US males and non-pregnant females ages 18 - 45 (inclusive) to assess the safety, reactogenicity, and immunogenicity of HEV-239. Subjects will receive 3 doses of study product on Days 1, 29, and 180. Subjects will remain in the study for up to 13 months (including screening). The study duration will be approximately 15 months. Subjects will be observed for 30 minutes after vaccination. The occurrence of solicited injection site and systemic reactogenicity events will be measured from the time of study vaccination through Day 8 after each vaccination. These will be ascertained through use of an electronic memory (e-memory) aid, a telephone call on day 4 after each dose of vaccine, a Day 8 clinic visit, and potentially at the Day 15 clinic visit after each dose of vaccine. Unsolicited adverse events will be collected from vaccination through Day 29 after each vaccination. Serious adverse events will be collected from the time of the first study vaccination through the last study visit (Day 360). The study includes multiple phlebotomy time points for immunogenicity and blood collection for future use at visit 1 and Days 8, 15, and 29 after each vaccination. The durability of the immune response and future use collection will be assessed at 5 months after the first boost (Day 180) and at 6 months after the second boost (Day 360). The primary objectives of the study are to; 1) Assess the safety and reactogenicity of HEV-239 following delivery of each vaccine dose; and 2) Assess the number of subjects with \> / = 4 fold rise in Hepatitis E virus (HEV) immunoglobulin G (IgG) at any time after vaccination. The secondary objectives are to; 1) Assess the number of subjects with HEV immunoglobulin M (IgM) seroconversion at any time after vaccination; 2) Assess the number of subjects with HEV IgG seroconversion at any time after vaccination; and 3) Assess the HEV IgG geometric mean concentrations (GMCs) at any time after vaccination.

Eligibility Criteria:
Inclusion Criteria:

1. Subject must provide written informed consent.
2. Subject must be able to comprehend and willing to comply with all study visits and procedures (up to 13 months from enrollment).
3. Subject must be a man or a non-pregnant woman\* aged 18-45 years (inclusive).

   \*Females of childbearing potential must have a negative serum human chorionic gonadotropin (beta-HCG) pregnancy test at screening and negative urine beta-HCG pregnancy test within 24 hours prior to (each) vaccination.
4. Subject must be in good general health as determined by medical history, vital signs\*, body mass index (BMI)\*\*, physical examination, and clinical judgment of the investigator.

   \*Oral temp \< 38.0 Degrees Celsius /100.4 Degrees Fahrenheit; pulse 51 to 100 bpm; systolic blood pressure 90 to 140 mm Hg, and diastolic blood pressure 55 to 90 mm Hg.

   \*\*BMI \> / = 18.5 and \< 35 kg/m\^2.
5. Subject's screening laboratory values\*,\*\* must be within site normal limits\*\*\* within 28 days of enrollment.

   \*Screening labs will include: White blood cell (WBC) count; Hemoglobin (HgB); Platelets; Absolute neutrophil count (ANC); Absolute eosinophil count (AEC); Creatinine; Glucose (random, must be \< 140); Alanine Aminotransferase (ALT); HIV 1/2 antibody/antigen test, Hepatitis B surface antigen (HBsAg), and Hepatitis C virus (HCV) antibody.

   \*\*Minor abnormalities are considered acceptable if not clinically significant (e.g., Mean Corpuscular Volume (MCV)). Repeating the screening tests once is permitted for out-of-range values provided there is an alternative explanation for the out-of-range value. The alternative explanation for the out-of-range value should be documented in the subject's source documents.

   \*\*\*Creatinine, glucose, and ALT values lower than the normal range may be acceptable if the PI or a designated licensed clinician determines that these laboratory findings are not clinically significant. The HIV 1/2 antibody/antigen test, Hepatitis B surface antigen (HBsAg), and Hepatitis C virus (HCV) antibody must be non-reactive.
6. Subject's Hepatitis E Virus (HEV) - specific Immunoglobulin G (IgG) and Immunoglobulin M (IgM) are negative by ELISA at screening.
7. Subject agrees to not to participate in another clinical trial during the study period.
8. Subject agrees not to donate blood from screening through Day 270.
9. Female subjects must be of non-childbearing potential\* OR must use an acceptable method of contraception\*\* from 28 days before prime vaccination until at least 3 months after the last vaccination.

   \*Surgically sterile via tubal ligation, bilateral oophorectomy, hysterectomy or postmenopausal for \> / = 1 year.

   \*\*Abstinence (defined as refraining from heterosexual intercourse), monogamous relationship with vasectomized partner, barrier methods such as male or female condoms with spermicide or diaphragms with spermicide, intrauterine devices, and licensed hormonal methods (such as birth control pills, skin patches, Implanon(R), Nexplanon(R), DepoProvera(R), or NuvaRing(R)).
10. Male subjects must be surgically sterile via vasectomy OR must use an acceptable method of contraception\* from prime vaccination until at least 3 months after the last boost vaccination.

    * Abstinence (defined as refraining from heterosexual intercourse), or condoms with spermicide.
11. Subjects must have consistent access to the internet to perform electronic data entry.

Exclusion Criteria:

1. Has a previous HEV infection or chronic liver disease.
2. Has received any experimental agent\* within 30 days prior to first vaccination, or the expected recipient of any experimental agent during this trial-reporting period.

   \*Including vaccines, drugs, biologics, devices, and/or blood products.
3. Female subject is pregnant (or has a positive pregnancy test prior to vaccination) or breast feeding, or planning to become pregnant within 3 months after the last boost vaccination.
4. Fever (\> / = 38.0 Degrees Celsius / 100.4 Degrees Fahrenheit) or other acute illness within 3 days prior to first vaccination.
5. Infection requiring systemic antibiotics or antiviral treatment within the 7 days prior to first vaccination.
6. Has a positive urine drug screen for amphetamines\*, cocaine, opiates, or phencyclidine.

   \*Prescription amphetamines are not exclusionary.
7. Chronic, clinically significant medical or psychiatric conditions\* that, in the opinion of the investigator, may pose additional risk to the subject if she/he participates in the study.

   \*Permissible conditions include but are not limited to mild, well-controlled asthma, well-controlled depression, well-controlled anxiety, seasonal allergies, and well-controlled hypertension.
8. Receipt of immunosuppressive drugs\*,\*\*,\*\*\* or biologic agents within the 30 days prior to enrollment.

   \*This includes use of oral or parental prednisone. This also includes allergy desensitization injections from 14 days prior to each vaccination through 14 days after each vaccination. The use of topical steroids for mild uncomplicated dermatitis permissible after therapy is completed. Over-the-counter (OTC) corticosteroid nasal sprays for allergic rhinitis are permissible. The use of low or moderate dose inhaled steroids is permissible. Doses are defined as per age as using inhaled high-dose per reference chart in the National Heart, Lung and Blood Institute Guidelines for the Diagnosis and Management of Asthma (EPR-3) or other lists published in UPTODATE.

   \*\*Receipt of systemic, prescription medications for the treatment of chronic medical conditions or variations of normal physiologic functions may be permissible if, in the opinion of the investigator, they are used for conditions that are not clinically significant and would not impact the safety of the subject or the safety and immunogenicity outcomes of the protocol.

   \*\*\*Use of systemic, over-the-counter medications and PRN systemic, prescription medication may be allowed if, in the opinion of the investigator, they pose no additional risk to subject safety or assessment of immunogenicity/reactogenicity.
9. Has known neoplastic disease\* anticancer therapy, or radiation therapy within 3 years prior to first study vaccination.

   \*Excluding non-melanoma skin cancer, such as squamous cell skin cancer or basal cell skin cancer, cured by surgical excision.
10. Has a history of any hematologic malignancy at any time.
11. Has a known or suspected congenital or acquired disease that impairs the immune system, including functional asplenia or immunosuppression as a result of underlying illness or treatment.
12. Has prior organ and/or stem cell transplant.
13. Has a history of abuse of alcohol or drugs that, in the opinion of the investigator, may interfere with the subject's ability to comply with the protocol.
14. Has behavioral or cognitive impairment or psychiatric conditions that, in the opinion of the investigator, may interfere with the subject's ability to participate in the trial.
15. Has received blood products or immunoglobulin within six months prior to vaccination.
16. Travel to Asia, the Middle East, Africa, or Central America or to an area with an active Hepatitis E outbreak\* within the last 90 days or intention to travel to such areas during the study.

    \*Outbreaks within the last 3 years.
17. Receipt of any inactivated vaccine from 2 weeks prior to each vaccination through 2 weeks after each vaccination.
18. Receipt of any live vaccine from 4 weeks prior to each vaccination through 4 weeks after each vaccination.
19. Known hypersensitivity or allergy to aluminum, any component of the vaccine, or other serious adverse reactions to vaccines or vaccine products.
20. Subject who, in the opinion of the investigator, is unlikely to adhere to the requirements of the study.
21. Any condition that, in the opinion of the investigator, might interfere with assessing the study objectives.