A Study to Determine the Safety and Efficacy of the RSV F Vaccine to Protect Infants Via Maternal Immunization

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy of maternal immunization with the RSV F vaccine against symptomatic RSV lower respiratory tract infection (LRTI) with hypoxemia through the first 90 days of life in infants.

Detailed Description
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This is a randomized, observer-blind, placebo-controlled trial enrolling third-trimester pregnant women in the Northern and Southern hemispheres, for up to four consecutive RSV seasons in each hemisphere. The trial will enroll 4636 third-trimester pregnant subjects. Women in the third trimester of a singleton uncomplicated pregnancy and 18 to 40 years of age (inclusive) will be enrolled and randomized in a 1:1 ratio into one of two treatment groups, active or placebo, over approximately the three months prior to peak RSV season. After the first global season of enrollment, the randomization scheme will be changed to a 2:1 (active/placebo) ratio to enable more efficient accrual of the safety database. All maternal subjects will receive a single intramuscular (IM) injection on Day 0 with the assigned test article, the RSV F vaccine or placebo. Study participation for maternal subjects will span approximately nine (9) months from the first dose, ending six (6) months post-delivery. Study follow-up for infant subjects who are consented will span approximately one (1) year post-delivery.

Official Title
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A Phase 3, Randomized, Observer-Blind, Placebo-Controlled Study to Determine the Immunogenicity and Safety of a Respiratory Syncytial Virus (RSV) F Nanoparticle Vaccine With Aluminum in Healthy Third-trimester Pregnant Women; and Safety and Efficacy of Maternally Transferred Antibodies in Preventing RSV Disease in Their Infants

Conditions
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Respiratory Syncytial Virus Infections

Intervention / Treatment
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* Biological: RSV F vaccine with adjuvant
* Biological: Formulation buffer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 and ≤40 years-of-age Singleton pregnancy of 28 to 36 0/7 weeks gestation on the day of planned vaccination Documentation of gestational age will be based on one of the following composite criteria. (Note: The Investigator should use the earliest ultrasound data available to establish the study-specific gestational age dating): Gestational Age Dating Based on First Trimester Data (data obtained ≤13 6/7 weeks): The date of the first day of the reported last menstrual period (LMP) may be used to estable the gestational age if corroborated by a first trimester ultrasound. If the gestational age estimation derived using the LMP and the first trimester ultrasound are discrepant >7 days, the ultrasound will be used to establish gestational age. If LMP is uncertain or unknown, the ultrasound-established gestational age estimation will be used to establish the gestational age of the pregnancy. Gestational Age Dating Based on Early Second Trimester Data (data obtained 14 0/7 to 21 6/7 weeks): The day of the first reported LMP may be used to establish the gestational age if corroborated by an early second trimester ultrasound (that estimates the gestational age between 14 0/7 and 21 6/7 weeks). If the gestational age estimation derived using the LMP and the early second trimester ultrasound are discrepant >10 days, the ultrasound will be used to establish the gestational age. If LMP is uncertain or unknown, the ultrasound-established gestational age estimation will be used to establish the gestational age of the pregnancy. Gestation Age Dating Based on Later Second Trimester Data (data obtained 22 0/7 and 27 6/7 weeks by LMP): The date of the first day of the reported LMP may be used to establish the gestation age if corroborated by a later second trimester ultrasound (that estimates the gestational age between 22 0/7 and 27 6/7 weeks). If the gestational age estimation derived using the LMP and the later second trimester ultrasound are discrepant >14 days, the ultrasound will be used to establish the gestational age. If LMP is uncertain or unknown, the ultrasound-established gestational age estimation will be used to establish the gestational age of the pregnancy. Gestational Age Dating When the LMP is Uncertain or Unknown AND No Prior First or Second Trimester Ultrasound Has Been Performed: An ultrasound performed at screening within the second trimester (≤27 6/7 weeks) will be used to establish the gestational age of the pregnancy. Documentation of a second or third (between 18 0/7 weeks and prior to randomization) trimester ultrasound with no major fetal anomalies identified. Good general maternal health as demonstrated by: Medical history (including history of adverse reactions to prior vaccines and allergies). Physical examination including at least vital signs (blood pressure, pulse, respirations, and oral temperature); weight; height; examination of the HEENT, cardiovascular, pulmonary, gastrointestinal (abdominal), musculoskeletal, lymphatic, and dermatologic organ systems; and documentation of fetal heart tones. Note that abnormal vital signs may be repeated at the investigator's discretion since these measures may be labile. Vital signs should be assessed in the context of normal values for the third trimester of pregnancy (see the Study Operations Manual). Clinical laboratory parameters that include: For the first year of study conduct in any country, normal/clinically insignificant blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase (ALP), hemoglobin, white blood count, and platelet count. Note that normal ranges for clinical laboratory parameters will be based on reference ranges appropriate for the subject population under study (i.e., third trimester of pregnancy) and as defined in the toxicity grading scale (TGS) (see the Study Operations Manual). For all subjects, serologic exclusion of infection with hepatitis B (HBV) and C (HCV) viruses, syphilis, and HIV as documented by testing (performed at the central or local laboratory) at screening or by medical records during the current pregnancy. Able to understand, and both willing and physically able to comply with study procedures. This includes anticipation of reasonable geographic proximity to the study clinic and adequate transportation to comply with scheduled and unscheduled study follow-up visits. Able and willing to provide written informed consent for themselves and infant. Exclusion Criteria: Symptomatic cardiac or pulmonary disease requiring chronic drug therapy, including hypertension and asthma. Asthma will be exclusionary if the subject is receiving chronic systemic glucocorticoids at any dose or inhaled glucocorticoids at any dose >500µg per day of beclomethasone or fluticasone, or >800μg per day of budesonide. Pregnancy complications (in the current pregnancy) such as preterm labor, 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. Grade 2 or higher clinical laboratory or vital sign abnormality. Exclusion of subjects with grade 1 abnormalities will be based on the subject's prior medical history and the investigator's clinical judgment that the abnormality is indicative of a meaningful physiologic event. Receipt of any licensed vaccine (e.g., Tdap, inactivated influenza vaccine) within 14 days of study vaccination. Received any RSV vaccine at any time. Body mass index (BMI) of ≥40, at the time of the screening visit. Hemoglobinopathy (even if asymptomatic) or blood dyscrasias. Hepatic or renal dysfunction. Established diagnosis of seizure disorder, regardless of therapy. Known, active auto-immune disease or immunodeficiency syndrome. Endocrine disorders, including (but not limited to) untreated hyperthyroidism, untreated hypothyroidism (unless due to auto-immune disease), and glucose intolerance (e.g., diabetes mellitus type 1 or 2) antedating pregnancy, or occurring during pregnancy and requiring interventions other than diet for control. History of major gynecologic or major abdominal surgery, including bariatric surgery (previous Caesarean section is not an exclusion). Known HIV, syphilis, HBV, or HCV infection, as assessed by serologic tests conducted during the current pregnancy or as a procedure during the screening period of the study. Primary genital Herpes simplex virus (HSV) infection during the current pregnancy. Current alcohol or drug abuse based on the Investigator's knowledge of present or recent (within the last 2 years) use/abuse of alcohol or illegal or non-prescription drugs. Documentation that the current pregnancy results from in vitro fertilization (IVF). Documentation that the current pregnancy results from rape or incest. Documentation that the infant will be a ward of the state or be released for adoption. History/presence of deep venous thrombosis or thromboembolism, or the use of anticoagulants during pregnancy (the use of low-dose aspirin as prophylaxis [e.g., for the prevention of morbidity and mortality from preeclampsia] is acceptable is dosages consistent with local standards of care). Red blood cell allo-immunization. Prior stillbirth or neonatal death, or multiple (≥3) spontaneous abortions. Prior preterm delivery ≤34 weeks gestation or having ongoing intervention (medical/surgical) in current pregnancy to prevent preterm birth. Greater than five (5) prior deliveries. Previous infant with a known genetic disorder or major congenital anomaly. Receipt of investigational drugs or immune globulins (with the exception of prophylactic anti-Rho D immune globulin) within six (6) months prior to the administration of the study vaccine. Chronic administration (defined as more than 14 continuous days) of immunosuppressants or other immune-modifying drugs within 6 months prior to the administration of the study vaccine. An immunosuppressant dose of glucocorticoid will be defined as a systemic dose ≥10mg of prednisone per day or equivalent. The use of topical, inhaled, and nasal glucocorticoids will be permitted except for the limit established in exclusion criterion #1. Neuro-psychiatric illness deemed likely to interfere with protocol compliance, safety reporting, or receipt of pre-natal care; or requiring treatment with psychotropic drugs (excluding treatment for depression and anxiety). Any other physical, psychiatric or social condition which may, in the investigator's opinion, increase the risks of study participation to the maternal subject or the fetus/infant; or may lead to the collection of incomplete or inaccurate safety data. Acute disease within 72 hours of the day of the planned vaccination (defined as the presence of a moderate or severe illness with or without fever, or an oral temperature >38.0°C). History of a serious adverse reactions (e.g., anaphylaxis) to any prior vaccine.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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 |
| --- | --- |
| Placebo Comparator: Treatment Group A<br>Formulation buffer (0.5mL injection) | Biological: Formulation buffer<br> <br> |
| Active Comparator: Treatment Group<br>RSV F vaccine with adjuvant (0.5mL injection) | Biological: RSV F vaccine with adjuvant<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of medically significant RSV LRTI with either hypoxemia (SpO2 <95% at sea level or <92% at altitudes >1800 meters) or tachypnea in infants through 90 days of life |  | Delivery to 90 days after delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of RSV LRTI with severe hypoxemia (Sp02 <92% at sea level or <87% at altitudes >1800 meters) or documented use of oxygen by high flow nasal cannula or other advanced respiratory support in infants through 90 days of life |  | Delivery to 90 days after delivery | 
| Incidence of RSV LRTI with hospitalization in infants through 90 days of life |  | Delivery to 90 days after delivery | 
| RSV F protein antibody expressed as ELISA Units | Geometric Mean Concentrations as EU (GMEU) Geometric Mean Ratio (GMFR) Seroresponse Rate (SRR) | Day 0 to 180 days after delivery | 
| Palivizumab-competitive antibody (PCA) expressed as ug/mL as detected in a competitive ELISA | Geometric Mean Concentrations as EU (GMEU) Geometric Mean Fold Rise (GMFR) | Day 0 to 180 days after delivery | 
| Neutralizing antibody titer to at least one RSV/A and one RSV/B virus strain | Geometric Mean Titer (GMT) Geometric Mean Ratio (GMR) | Delivery to 90 days after delivery | 
| Counts and percentages of term, healthy infants , APGAR scores, length, birth weight, frontal-occipital head circumference (FOC), and physical examination |  | Delivery | 
| Counts and percentages of infants with adverse events and serious adverse events during the neonatal period and through the first year of life |  | Delivery to 364 days after delivery | 
| Counts and percentages of infants with developmental delay |  | Day 180 to Day 364 after delivery | 
| Counts and percentages of maternal subjects with solicited injection site and systemic reactogenicity within seven days of vaccination |  | Day 0 to Day 7 | 
| Counts and percentages of maternal subjects with unsolicited adverse events, medically-attended adverse events (MAEs), significant new medical conditions (SNMCs) and serious adverse events (SAEs) |  | Delivery to 180 days after delivery | 
| Clinical safety laboratory assessments of select serum chemistry and hematology parameters |  | Day 0 to Delivery | 
| Counts and percentages of subjects with Caesarean, vaginal, or instrument assisted vaginal modes of delivery |  | Delivery | 
| Counts and percentages of maternal subjects with post-immunization onset of specific complications of third-trimester pregnancy and delivery |  | Day 0 to Delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RSV