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

Phase 3

Completed

Conditions: Respiratory Syncytial Virus Infections

Interventions: Biological: RSV F vaccine with adjuvant
Biological: Formulation buffer

Registration Number: NCT02624947

Lead Sponsor: Novavax

Brief Summary: The purpose of this study is to determine the efficacy of maternal immunization during the third trimester of pregnancy with the RSV F vaccine against medically-significant RSV lower respiratory tract infection (LRTI), as defined by hypoxemia or tachypnea at rest, through the first 90, 120, 150, and 180 days of life in infants.

Detailed Description: 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 could enroll up to 8618 third-trimester pregnant subjects, of which 4,636 were actually enrolled. Women in the third trimester of a singleton uncomplicated low-risk pregnancy and 18 to 40 years of age (inclusive) were enrolled and randomized in a 1:1 ratio into one of two treatment groups, active or placebo, over approximately three months prior to peak RSV season in their locale. After the first global season of enrollment, the randomization scheme was changed to a 2:1 (active/placebo) ratio to enable a more efficient accrual of the safety database.

All maternal subjects were to 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 spanned approximately nine (9) months from the first dose, ending six (6) months post-delivery. Study follow-up for live-born infant subjects spanned approximately one (1) year post-delivery.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 4636

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 was to use the earliest ultrasound data available to establish the study-specific gestational age dating):
  1. 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 establish 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.
  2. 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.
  3. 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.
  4. 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment Group	RSV F vaccine with adjuvant	RSV F vaccine with adjuvant (0.5mL injection)
Treatment Group A	Formulation buffer	Formulation buffer (0.5mL injection)

Primary Outcome Measures

Name	Time	Method
Infants: Percentages of Participants With Medically Significant RSV LRTI With Either Hypoxemia (SpO2 <95% at Sea Level or <92% at Altitudes >1800 Meters) or Tachypnea	Delivery to 180 days after delivery	Percentages of infants with medically-significant RSV LRTI from delivery through 90, 120,150, and 180 days of life, as defined by: * The presence of RSV infection confirmed by detection of RSV genome by RT-PCR on respiratory secretions (obtained within the continuous illness episode which fulfills the other criteria listed below); AND * At least one manifestation of lower respiratory tract infection (LRTI) from among the following: cough, nasal flaring, lower chest wall indrawing, subcostal retractions, stridor, rales, rhonchi, wheezing, crackles/crepitations, or observed apnea; AND * Evidence of medical significance as defined by the presence of: * EITHER hypoxemia (peripheral oxygen saturation \[SpO2\] \< 95% at sea level or \< 92% at altitudes \> 1800 meters) OR * Tachypnea (≥ 70 breaths per minute \[bpm\] in infants 0 to 59 days of age and ≥ 60 bpm in infants ≥ 60 days of age).

Secondary Outcome Measures

Name	Time	Method
Infants: Mean Frontal-occipital Head Circumference of Participants at Birth	At Delivery	Frontal-occipital Head Circumference measured in infant participants at delivery expressed as centimeters
Infants: Mean APGAR (Appearance, Pulse, Grimace, Activity, Respiration) Score of Participants at Birth	At Delivery	The APGAR test measures the infant's Appearance, Pulse, Grimace, Activity, and Respiration. Any score of 7 or above is considered a good APGAR score. The maximum APGAR score is 10 and the minimum score is 1.
Maternal: Number of Participants With Post-immunization Onset of Specific Complications of Third-trimester Pregnancy and Delivery	Day 0 to Delivery	Number of maternal participants with post-immunization onset of specific complications of third-trimester pregnancy and delivery including Pregnancy complications, Labor and delivery complications.
Infants: Number of Participants With Developmental Delay	Day 364 after delivery	Number of infants with developmental delay (a term used to describe a delay in a child's development.), as measured by the outcome of testing at 1 year, in infants of RSV F vaccinees as compared to placebo.
Maternal: Immunogenicity of Anti-RSV F IgG and Placebo Expressed as GMEU (Geometric Mean ELISA Units/mL)	Pre-dose to Delivery +180 days	Immunogenicity of RSV F Vaccine and Placebo (Anti-F IgG) among Maternal Participants from Screening until Delivery
Maternal: Immunogenicity of RSV F Vaccine and Placebo Expressed as GMC (Geometric Mean Concentration)	Pre-dose to Delivery +180 days	Immunogenicity of RSV F Vaccine and Placebo (Palivizumab-competitive antibodies (PCA)) among Maternal Participants from Screening until Delivery
Maternal: Immunogenicity of RSV F Vaccine and Placebo Expressed as GMT (Geometric Mean Titers)	Pre-dose to Delivery +180 days	Immunogenicity of RSV F Vaccine and Placebo (RSV/A microneutralization titers expressed as GMT) among Maternal Participants from Screening until Delivery
Maternal: Immunogenicity of RSV F Vaccine and Placebo Expressed as GMTs	Pre-dose to Delivery +180 days	Immunogenicity of RSV F Vaccine and Placebo (RSV/B microneutralization titers expressed as GMT) among Maternal Participants from Screening until Delivery
Infants: Mean Length of Participants at Birth	At Delivery	Length of Infant participants measured at delivery expressed in centimeters
Infants: Mean Weight of Participants at Birth	At Delivery	Weight of infant participants measured at delivery expressed in kilograms.
Infants: Number of Participants With 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 Through 90 Days of Life	Delivery to 180 days after delivery	The number of infants with RSV LRTI with EITHER severe hypoxemia (SpO2 \< 92% at sea level or \< 87% at altitudes \> 1800 meters) OR the documented use of oxygen by high flow nasal cannula OR CPAP OR BiPAP OR Bubble CPAP OR bag-mask ventilation OR intubation with subsequent mechanical (or manual) ventilation OR ECMO from delivery through 90, 120, 150, and 180 days of life.
Infants: Percentages of Participants With RSV LRTI With Hospitalization From Delivery	Delivery to 180 days after delivery	Percentages of infants with RSV LRTI with hospitalization from delivery through 90, 120, 150, and 180 days of life.
Infant: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the Neonatal Period and Through the First Year of Life	Delivery to 364 days after delivery	Number of infants with AEs and SAEs (with special attention to congenital anomalies; respiratory failure other than RSV-associated hospitalization; neonatal death; infant death; sudden infant death syndrome; asphyxia; neonatal or hypoxic-ischemic encephalopathy; or other adverse events or complications of adverse events that necessitate hospitalization) during the neonatal period and through the first year of life.
Infants: Number of Participants With Potential Developmental Delay	Day 180 after delivery	Number of infants with potential developmental delay (a term used to describe a delay in a child's development), as measured by the outcome of testing with the Ages and Stages Questionnaire-3 at 6 months and at 1 year, in infants of RSV F vaccinees as compared to placebo.
Maternal: Number of Participants With Solicited Injection Site and Systemic Reactogenicity	Day 0 to Day 7	A number of maternal participants with solicited injection site and systemic reactogenicity within seven days of vaccination.
Maternal: Number of Participants 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	Number of maternal participants with unsolicited (local and systemic) adverse events (AEs), unscheduled medically-attended adverse events (MAEs), significant new medical conditions (SNMCs), and serious adverse events (SAEs) through delivery and six (6) months thereafter.
Maternal: Number of Participants With Caesarean, Vaginal, or Instrument Assisted Vaginal Modes of Delivery	Delivery	Number of maternal subjects that had either Caesarean, vaginal, or instrument-assisted vaginal modes of delivery.
Maternal: Immunogenicity of RSV F Vaccine and Placebo Expressed as GMFR	Day 14 to Delivery	Immunogenicity of RSV F Vaccine and Placebo (Anti-F IgG, PCA, and RSV Types A and B - MN assays) among Maternal Participants from Day 14 until Delivery
Maternal: Percentage of Participants With a Seroresponse to RSV F Vaccine and Placebo	Day 14 to Delivery	Immunogenicity of RSV F Vaccine and Placebo (Anti-F IgG, PCA, and RSV Types A and B - MN assays) among Maternal Participants from Day 14 until Delivery
Maternal: Percentage of Participants Who Seroconverted (2 Fold Increase) as Determined by Immunogenicity of RSV F Vaccine and Placebo	Day 14 to Delivery	Immunogenicity of RSV F Vaccine and Placebo (Anti-F IgG, PCA, and RSV Types A and B - MN assays) among Maternal Participants from Day 14 until Delivery
Maternal: Percentage of Participants Who Seroconverted (4 Fold Increase) as Determined by Immunogenicity of RSV F Vaccine and Placebo	Day 14 to Delivery	Immunogenicity of RSV F Vaccine and Placebo (Anti-F IgG, PCA, and RSV Types A and B - MN assays) among Maternal Participants from Day 14 until Delivery
Immunogenicity of RSV F Vaccine and Placebo Expressed as GMT	Delivery to Day 180	Immunogenicity of RSV F Vaccine and Placebo (Anti-F IgG, PCA, and RSV Types A and B - MN assays) among Infant Participants from Delivery until Day 180
Infants: Percentage of Participants With a Seroresponse to RSV F Vaccine and Placebo	Delivery to Day 180	Immunogenicity of RSV F Vaccine and Placebo (Anti-F IgG, PCA, and RSV Types A and B - MN assays) among Infant Participants from Delivery until Day 180
Infant: Immunogenicity of RSV F Vaccine and Placebo Expressed as GMR	Day 14 to Day 180	Immunogenicity of RSV F Vaccine and Placebo (Anti-F IgG, PCA, and RSV Types A and B - MN assays) among Infant Participants from Day 14 until Day 180

Trial Locations

Locations (88): Research Site US095
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Chicago, Illinois, United States
Research Site US087
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Johnson City, New York, United States
Research Site US126
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Alexandria, Louisiana, United States
Research Site US090
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West Des Moines, Iowa, United States
Research Site US098
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Biloxi, Mississippi, United States
Research Site US097
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Fort Bragg, North Carolina, United States
Research Site ES002
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Barcelona, Spain
Research Site ES004
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Santiago de Compostela, Spain
Research Site US088
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Neptune, New Jersey, United States
Research Site UK003
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Southampton, United Kingdom
Research Site ES001
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Sevilla, Spain
Research Site ES003
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Madrid, Spain
Research Site NZ001
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Papatoetoe, Aukland, New Zealand
Research Site ZA001
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Soweto, South Africa
Research Site AR006
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Cordoba, Argentina
Research Site BD001
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Sylhet, Sylhet Division, Bangladesh
Research Site US094
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Longview, Texas, United States
Research Site US100
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Richmond, Virginia, United States
Research Site ZA006
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Benoni, South Africa
Research Site ZA008
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Bloemfontein, South Africa
Research Site AR011
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Mendoza, Argentina
Research Site US116
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Beaumont, Texas, United States
Research Site ZA004
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Parow, Cape Town, South Africa
Research Site ZA003
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Hillbrow, Johannesburg, South Africa
Research Site AU010
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Brisbane, Queensland, Australia
Research Site AR002
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Buenos Aires, Argentina
Research Site UK004
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Bristol, United Kingdom
Research Site NZ003
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Grafton, Auckland, New Zealand
Research Site ZA007
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Thabazimbi, Limpopo Providence, South Africa
Research Site US127
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Los Angeles, California, United States
Research Site US091
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Madera, California, United States
Research Site US086
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Syracuse, New York, United States
Research Site US089
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Englewood, Ohio, United States
Research Site US021
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Pittsburgh, Pennsylvania, United States
Research Site US019
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Houston, Texas, United States
Research Site US128
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Houston, Texas, United States
Research Site US041
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Seattle, Washington, United States
Research Site AU007
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Adelaide, South Australia, Australia
Research Site US038
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Augusta, Kansas, United States
Research Site US031
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Hutchinson, Kansas, United States
Research Site AU009
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Perth, Western Australia, Australia
Research Site US020
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Durham, North Carolina, United States
Research Site US042
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San Antonio, Texas, United States
Research Site US035
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Cullman, Alabama, United States
Research Site US130
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Fort Defiance, Arizona, United States
Research Site US092
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Colton, California, United States
Research Site US125
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Lampasas, Texas, United States
Research Site MX001
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Monterrey, Nuevo Leon, Mexico
Research Site NZ002
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Christchurch, New Zealand
Research Site NZ004
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Wellington, New Zealand
Research Site PH001
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Alabang, Manila, Philippines
Research Site US115
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Birmingham, Alabama, United States
Research Site US036
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Denver, Colorado, United States
Research Site UK001
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London, United Kingdom
Research Site UK002
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Oxford, United Kingdom
Research Site US119
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Idaho Falls, Idaho, United States
Research Site US102
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Lincoln, Nebraska, United States
Research Site US103
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Tucson, Arizona, United States
Research Site US008
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Salt Lake City, Utah, United States
Research Site AU008
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Melbourne, Victoria, Australia
Research Site US032
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Nampa, Idaho, United States
Research Site US123
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Phoenix, Arizona, United States
Research Site US039
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Metairie, Louisiana, United States
Research Site US129
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Whiteriver, Arizona, United States
Research Site US040
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Washington, District of Columbia, United States
Research Site US037
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Blackfoot, Idaho, United States
Research Site US101
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Detroit, Michigan, United States
Research Site AR008
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Salta, Argentina
Research Site US025
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Norfolk, Nebraska, United States
Research Site AR003
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Tucuman, Argentina
Research Site US121
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Salt Lake City, Utah, United States
Research Site US099
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Salt Lake City, Utah, United States
Research Site CL002
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Osorno, X Region, Chile
Research Site AU011
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Clayton, Victoria, Australia
Research Site CL001
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Santiago, Region Metropolitana (RM), Chile
Research Site ZA010
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Bellville, Western Cape, South Africa
Research Site CL003
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Concepcion, VIII Region, Chile
Research Site ZA011
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Worcester, Western Cape, South Africa
Research Site PH002
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Muntinlupa, Metro Manila, Philippines
Research Site ZA009
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Paarl, Western Cape, South Africa
Research Site ZA002
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Soshanguve, South Africa
Research Site US134
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Aurora, Colorado, United States
Research Site US093
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Riverside, California, United States
Research Site US083
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Fort Worth, Texas, United States
Research Site US114
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Huntington Park, California, United States
Research Site US096
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Louisville, Kentucky, United States
Research Site US043
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Galveston, Texas, United States
Research Site US131
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Gallup, New Mexico, United States