Safety and Immunogenicity of Hecolin® in Healthy Pregnant Women

Study Overview
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Brief Summary
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This is a phase II randomized, observer-blinded, placebo-controlled study with 3 arms enrolling a total of 2,358 participants. The arms are composed of Arm 1, pregnant participants receiving Hecolin® (N=1,104) with immunogenicity subset (n=150), Arm 2, pregnant participants receiving placebo (N=1,104) with immunogenicity subset (n=150), and Arm 3, non-pregnant participants receiving Hecolin® (N=150) of which all participants in this arm will be included in the immunogenicity subset.

Detailed Description
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Hecolin® is licensed in China and Pakistan indicated to be used for prevention of hepatitis E in healthy adult. The primary goal of this clinical trial is to establish the safety and immunogenicity of Hecolin® during pregnancy. As secondary and exploratory objectives, infant immune response through passive immunization of infants achieved through transplacental transfer of maternal IgG antibodies from the pregnant mother who has received Hecolin® in the second or third trimester will be evaluated. Hecolin® follows a 3-dose schedule (0-1-6 months). For Arm 1 and 2, pregnant participants will receive 2 doses of Hecolin® or placebo at a 4 weeks interval and the third dose will be administered postpartum, approximately 20 weeks after the second dose. The neonates from these Arms will be followed for 24 weeks after birth. For Arm 3, non-pregnant participants will receive Hecolin® at 0-1-6 months schedule. After each dose of IP injection to pregnant/non-pregnant participants, immediate AE (30 minutes post injection), solicited AE (7 days post injection), unsolicited AE (28 days post injection) and AESI/SAE (during the whole study period) will be collected. For the immunogenicity subset, the participants' blood will be drawn before and 4 weeks post each dose of IP injection. At delivery, maternal blood will be drawn. Breast milk samples will be taken at delivery, 6 weeks, and 24 weekss after delivery. All infant AESI/SAE will be collected throughout the study period and developmental assessment will be performed at age of 6 weeks, and 24 weeks. Blood will be drawn from infant immunogenicity subset at the same time points, umbilical cord blood (neonate blood will be collected if cord blood is not available for collection) at delivery, venous blood at age of 6 weeks and 24 weeks.

Official Title
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A Phase II, Randomized, Observer-blinded, Placebo Controlled Trial to Evaluate the Safety and Immunogenicity of Hecolin® in Healthy Pregnant Women Between Gestational Age 14-34 Weeks and Non-Pregnant Women of 16-45 Years Old.

Conditions
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Hepatitis E Infection

Intervention / Treatment
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* Biological: Hecolin® (Recombinant Hepatitis E Vaccine (Escherichia coli)).
* Other: Isotonic Sodium Chloride injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be eligible to participate in this study, a pregnant/non-pregnant woman must meet all of the following criteria: Pregnant women only: Healthy women 16-45 years of age who are between 14 0/7 and 34 6/7 weeks gestation1 on the day of planned vaccination with an uncomplicated, singleton pregnancy, who are at no known increased risk for complications for herself and her infant. Individual willing to provide written informed consent for herself and her infant to participate in the study. Individual who can be followed up during the study period and can comply with the study requirements. Individual and fetus in good health as determined by the outcome of medical history, physical examination, obstetric history, prenatal care (by ultrasound and other prenatal assessment subject to gestational age), vital signs, laboratory evaluations at screening and the clinical judgment of the investigator. Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Non-pregnant women only: Healthy women 16-45 years of age. Individual willing to provide written informed consent to participate in the study. Individual who can be followed up during the study period and can comply with the study requirements. Individual in good health as determined by the outcome of medical history, physical examination, vital signs, laboratory evaluations at screening and the clinical judgment of the investigator. Individuals who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Females of childbearing potential with negative urinary pregnancy test on the day of screening. Females of childbearing potential who are using an effective birth control method2 for at least 4 weeks before the screening and up to 4 weeks after the last vaccination. Exclusion Criteria: A pregnant/non-pregnant woman who meets any of the following criteria will be excluded from participation in this study: Has received any hepatitis E vaccine in the past. Febrile illness (axillary temperature ≥ 38.5°C) or acute illness within 3 days prior to the study vaccination. Known history or allergy to study vaccine components and/or excipients or other medications, or any other allergies or medical history deemed by the investigator to increase the risk of an adverse event if they were to participate in the trial (e.g., Guillain-Barre Syndrome). Major congenital abnormalities which in the opinion of investigator may affect the participant's participation in the study. Known history of immune function disorders including immunodeficiency diseases (known HIV infection or other immune function disorders) and lupus. Chronic use of systemic steroids (>2 mg/kg/day or >20 mg/day prednisone equivalent for periods exceeding 10 days), cytotoxic or other immunosuppressive drugs within past 6 weeks. Any abnormality or chronic disease which in the opinion of the investigator might be detrimental for the safety of the participant and interfere with the assessment of the study objectives. Behavioral or cognitive impairment, or chronic substance abuse, or psychiatric disease or neural disorders, that, in the opinion of the investigator, could interfere with the participant's ability to participate in the trial. History of splenectomy. Past history of thrombocytopenia and/or thrombosis, myocarditis or pericarditis or any other significant cardiac condition. With a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time resulting in contraindication for IM injections/blood extractions. (Those who receive low dose aspirin (less than 100mg/day) are not excluded) Receipt of blood or blood-derived products in the past 3 months. Receipt of other vaccines from 4 weeks prior to test vaccination or planned to receive any vaccine within 4 weeks of last dose of study vaccine As per Investigator's medical judgement, an individual could be excluded from the study in spite of meeting all inclusion/exclusion criteria mentioned above. Concomitantly enrolled or scheduled to be enrolled in another trial. Research staff involved with the clinical study or family/household members of research staff. Body mass index (BMI) of ≥ 40, at the time of the screening visit. Pregnant women only: 1. Plans to terminate her pregnancy. Pregnancy complications (in the current pregnancy) such as preterm labor, gestational diabetes, hypertension (blood pressure (BP) > 140/90 in the presence of proteinuria or BP > 150/100 with or without proteinuria), or currently on an antihypertensive therapy, or pre-eclampsia, or evidence of intrauterine growth restriction. 3. Prior stillbirth or neonatal death, or multiple (≥ 3) spontaneous abortions. 4. Prior preterm delivery ≤ 34 weeks gestation or having ongoing intervention (medical/surgical) in current pregnancy to prevent preterm birth. 5. Previous infant with a known genetic disorder or major congenital anomaly. 6. History of major gynecologic or major abdominal surgery (previous Caesarean section is not an exclusion) 7. Current pregnancy results from in vitro fertilization (IVF). 8. Current pregnancy results from rape or incest. 9. Plans to release the neonate for adoption or the neonate to be a ward of the state. 10. Greater than 5 prior deliveries Non-pregnant women only: 1. Pregnant or plan to be pregnant during the study period.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pregnant participant receiving Hecolin®<br>1 (N=1,104): Pregnant participants receiving Hecolin® (n=150 immunogenicity subset). For Arm 1, pregnant participants will receive 2 doses of Hecolin® at a 4 weeks interval and the third dose will be administered postpartum, approximately 20 weeks after the second dose. | Biological: Hecolin® (Recombinant Hepatitis E Vaccine (Escherichia coli)).<br>* Hecolin® will be administered 2 doses administered 4 weeks apart during pregnancy and 1 dose administered after delivery at least 20 weeks following the second dose for the pregnant participants (arm 1), and 0, 1 and 6 months for the non-pregnant participant (arm 3).<br>* Other names: 26 kDa protein (239 amino acids, aa368 to aa606) encoded by ORF2 of the HEV1 (Chinese HEV strain, genotype 1) and is expressed in Escherichia coli as a non-fusion protein.;|
| Placebo Comparator: Pregnant participants receiving placebo<br>Arm 2 (N=1,104): Pregnant participants receiving placebo (n= 150 immunogenicity subset). For Arm 2, pregnant participants will receive 2 doses of placebo at a 4 weeks interval and the third dose will be administered postpartum, approximately 20 weeks after the second dose. | Other: Isotonic Sodium Chloride injection<br>* Placebo will be administered 2 doses administered 4 weeks apart during pregnancy and 1 dose administered after delivery at least 20 weeks following the second dose for the pregnant participants (arm 2)<br>* Other names: Sterile 0.9% sodium chloride;|
| Active Comparator: Non-Pregnant participants receiving Hecolin®<br>Arm 3 (N=150): Non-Pregnant participants receiving Hecolin® (n= 150 immunogenicity subset). For Arm 3, non-pregnant participants will receive Hecolin® at 0-1-6 months schedule. | Biological: Hecolin® (Recombinant Hepatitis E Vaccine (Escherichia coli)).<br>* Hecolin® will be administered 2 doses administered 4 weeks apart during pregnancy and 1 dose administered after delivery at least 20 weeks following the second dose for the pregnant participants (arm 1), and 0, 1 and 6 months for the non-pregnant participant (arm 3).<br>* Other names: 26 kDa protein (239 amino acids, aa368 to aa606) encoded by ORF2 of the HEV1 (Chinese HEV strain, genotype 1) and is expressed in Escherichia coli as a non-fusion protein.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of pregnancy-related AESI and SAE from vaccination in pregnant participant. | Proportion of pregnancy-related AESI from the vaccination throughout the entire study in pregnant participants. Proportion of SAE from the vaccination throughout the entire study in pregnant participants. | Throughout the study period, approximately 24 months. | 
| Immunogenicity in pregnant and non-pregnant participants | GMC of anti-HEV IgG at 4 weeks post second dose of Hecolin® administered 4 weeks apart in pregnant women and non-pregnant women. | 4 weeks post second dose of Hecolin® | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of AESIs and SAE in neonate/infant participants. | Proportion of neonatal/infant AESIs. Proportion of SAE through the 6 months of life in neonate/infant. | 6 months of life in neonate/infant | 
| Proportion of immediate adverse events in pregnant and non-pregnant participants | Proportion of immediate adverse events within 30 minutes post each dose of vaccination in pregnant and non-pregnant participants. | Within 30 minutes post each dose of vaccination. | 
| Proportion of Solicited local and system adverse events in pregnant and non-pregnant participants | Proportion of solicited local and systemic adverse events within 7 days post each dose of vaccination in pregnant and non-pregnant participants. | Within 7 days post each dose of vaccination. | 
| Proportion of unsolicited adverse events in pregnant and non-pregnant participants | Proportion of unsolicited adverse events within 28 days post each dose of vaccination in pregnant and non-pregnant participants. | Within 28 days post each dose of vaccination. | 
| Immunogenicity in pregnant and non-pregnant participants | SCR (antibody response greater than four times or more increase of anti-HEV IgG in paired sera) at 4 weeks post second dose of Hecolin® administered 4 weeks apart in pregnant and non-pregnant participants. | 4 weeks post second dose of vaccination. | 
| Immunogenicity in pregnant and non-pregnant participants | GMC of anti-HEV IgG at 4 weeks post third dose of Hecolin® (2 doses in pregnancy and 1 dose after delivery) in pregnant and non-pregnant participants. | 4 weeks post third dose of vaccination. | 
| Immunogenicity in pregnant and non-pregnant participants | SCR (antibody response greater than four times or more increase of anti-HEV IgG in paired sera) at 4 weeks post third dose of Hecolin® (2 doses in pregnancy and 1 dose after delivery) in pregnant and non-pregnant participants. | 4 weeks post third dose of vaccination. | 
| Immunogenicity in pregnant and non-pregnant participants | GMC of anti-HEV IgG at 4 weeks post first dose of Hecolin® in pregnant and non-pregnant participants. | 4 weeks post first dose of vaccination. | 
| Immunogenicity in pregnant and non-pregnant participants | SCR (antibody response greater than four times or more increase of anti-HEV IgG in paired sera) at 4 weeks post first dose of Hecolin® in pregnant and non-pregnant participants. | 4 weeks post first dose of vaccination. | 
| Immunogenicity in pregnant and non-pregnant participants | GMC of anti-HEV IgG at 4 weeks post second dose of Hecolin® in pregnant participants of GA 14-27 weeks (second trimester) and 28-34 weeks (third trimester) and non-pregnant participants as measured by anti HEV IgG ELISA. | 4 weeks post second dose of vaccination. | 
| Immunogenicity in pregnant and non-pregnant participants | SCR (antibody response greater than four times or more increase of anti-HEV IgG in paired sera) at 4 weeks post second dose of Hecolin® in pregnant participants of GA 14-27 weeks (second trimester) and 28-34 weeks (third trimester) and non-pregnant participants. | 4 weeks post second dose of vaccination. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis E infection, Hepatitis E virus, Hepatitis E vaccine, Hepatitis E in pregnancy