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

NCT ID: NCT02624947

Last Updated: 2025-05-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 4636 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-12-31
• Study Completion Date: 2019-07-12

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.

Conditions

Respiratory Syncytial Virus Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Treatment Group A

Formulation buffer (0.5mL injection)

Group Type: PLACEBO_COMPARATOR

Formulation buffer

Intervention Type: BIOLOGICAL

Treatment Group

RSV F vaccine with adjuvant (0.5mL injection)

Group Type: ACTIVE_COMPARATOR

RSV F vaccine with adjuvant

Intervention Type: BIOLOGICAL

Interventions

RSV F vaccine with adjuvant

Intervention Type: BIOLOGICAL

Formulation buffer

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

1. ≥18 and ≤40 years-of-age

2. 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.

3. Documentation of a second or third (between 18 0/7 weeks and prior to randomization) trimester ultrasound with no major fetal anomalies identified.

4. 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.

5. 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.

6. Able and willing to provide written informed consent for themselves and infant.

Exclusion Criteria

1. 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.

2. 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.

3. 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.

4. Receipt of any licensed vaccine (e.g., Tdap, inactivated influenza vaccine) within 14 days of study vaccination.

5. Received any RSV vaccine at any time.

6. Body mass index (BMI) of ≥40, at the time of the screening visit.

7. Hemoglobinopathy (even if asymptomatic) or blood dyscrasias.

8. Hepatic or renal dysfunction.

9. Established diagnosis of seizure disorder, regardless of therapy.

10. Known, active auto-immune disease or immunodeficiency syndrome.

11. 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.

12. History of major gynecologic or major abdominal surgery, including bariatric surgery (previous Caesarean section is not an exclusion).

13. 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.

14. Primary genital Herpes simplex virus (HSV) infection during the current pregnancy.

15. 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.

16. Documentation that the current pregnancy results from in vitro fertilization (IVF).

17. Documentation that the current pregnancy results from rape or incest.

18. Documentation that the infant will be a ward of the state or be released for adoption.

19. 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).

20. Red blood cell allo-immunization.

21. Prior stillbirth or neonatal death, or multiple (≥3) spontaneous abortions.

22. Prior preterm delivery ≤34 weeks gestation or having ongoing intervention (medical/surgical) in current pregnancy to prevent preterm birth.

23. Greater than five (5) prior deliveries.

24. Previous infant with a known genetic disorder or major congenital anomaly.

25. 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.

26. 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.

27. 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).

28. 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.

29. 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).

30. History of a serious adverse reactions (e.g., anaphylaxis) to any prior vaccine.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Bill and Melinda Gates Foundation

OTHER

Sponsor Role: collaborator

Novavax

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Development

Role: STUDY_DIRECTOR

Novavax Inc

Locations

Research Site US115

Birmingham, Alabama, United States

Research Site US035

Cullman, Alabama, United States

Research Site US130

Fort Defiance, Arizona, United States

Research Site US123

Phoenix, Arizona, United States

Research Site US103

Tucson, Arizona, United States

Research Site US129

Whiteriver, Arizona, United States

Research Site US092

Colton, California, United States

Research Site US114

Huntington Park, California, United States

Research Site US127

Los Angeles, California, United States

Research Site US091

Madera, California, United States

Research Site US093

Riverside, California, United States

Research Site US134

Aurora, Colorado, United States

Research Site US036

Denver, Colorado, United States

Research Site US040

Washington D.C., District of Columbia, United States

Research Site US037

Blackfoot, Idaho, United States

Research Site US119

Idaho Falls, Idaho, United States

Research Site US032

Nampa, Idaho, United States

Research Site US095

Chicago, Illinois, United States

Research Site US090

West Des Moines, Iowa, United States

Research Site US038

Augusta, Kansas, United States

Research Site US031

Hutchinson, Kansas, United States

Research Site US096

Louisville, Kentucky, United States

Research Site US126

Alexandria, Louisiana, United States

Research Site US039

Metairie, Louisiana, United States

Research Site US101

Detroit, Michigan, United States

Research Site US098

Biloxi, Mississippi, United States

Research Site US102

Lincoln, Nebraska, United States

Research Site US025

Norfolk, Nebraska, United States

Research Site US088

Neptune City, New Jersey, United States

Research Site US131

Gallup, New Mexico, United States

Research Site US087

Johnson City, New York, United States

Research Site US086

Syracuse, New York, United States

Research Site US020

Durham, North Carolina, United States

Research Site US097

Fort Bragg, North Carolina, United States

Research Site US089

Englewood, Ohio, United States

Research Site US021

Pittsburgh, Pennsylvania, United States

Research Site US116

Beaumont, Texas, United States

Research Site US083

Fort Worth, Texas, United States

Research Site US043

Galveston, Texas, United States

Research Site US019

Houston, Texas, United States

Research Site US128

Houston, Texas, United States

Research Site US125

Lampasas, Texas, United States

Research Site US094

Longview, Texas, United States

Research Site US042

San Antonio, Texas, United States

Research Site US121

Salt Lake City, Utah, United States

Research Site US008

Salt Lake City, Utah, United States

Research Site US099

Salt Lake City, Utah, United States

Research Site US100

Richmond, Virginia, United States

Research Site US041

Seattle, Washington, United States

Research Site AR002

Buenos Aires, , Argentina

Research Site AR006

Córdoba, , Argentina

Research Site AR011

Mendoza, , Argentina

Research Site AR008

Salta, , Argentina

Research Site AR003

San Miguel de Tucumán, , Argentina

Research Site AU010

Brisbane, Queensland, Australia

Research Site AU007

Adelaide, South Australia, Australia

Research Site AU011

Clayton, Victoria, Australia

Research Site AU008

Melbourne, Victoria, Australia

Research Site AU009

Perth, Western Australia, Australia

Research Site BD001

Sylhet, Sylhet Division, Bangladesh

Research Site CL002

Osorno, Los Lagos Region, Chile

Research Site CL001

Santiago, Region Metropolitana (RM), Chile

Research Site CL003

Concepción, Región del Biobío, Chile

Research Site MX001

Monterrey, Nuevo León, Mexico

Research Site NZ003

Grafton, Auckland, New Zealand

Research Site NZ001

Papatoetoe, Aukland, New Zealand

Research Site NZ002

Christchurch, , New Zealand

Research Site NZ004

Wellington, , New Zealand

Research Site PH001

Alabang, Manila, Philippines

Research Site PH002

Muntinlupa, National Capital Region, Philippines

Research Site ZA004

Parow, Cape Town, South Africa

Research Site ZA003

Hillbrow, Johannesburg, South Africa

Research Site ZA007

Thabazimbi, Limpopo Providence, South Africa

Research Site ZA010

Bellville, Western Cape, South Africa

Research Site ZA009

Paarl, Western Cape, South Africa

Research Site ZA011

Worcester, Western Cape, South Africa

Research Site ZA006

Benoni, , South Africa

Research Site ZA008

Bloemfontein, , South Africa

Research Site ZA002

Soshanguve, , South Africa

Research Site ZA001

Soweto, , South Africa

Research Site ES002

Barcelona, , Spain

Research Site ES003

Madrid, , Spain

Research Site ES004

Santiago de Compostela, , Spain

Research Site ES001

Seville, , Spain

Research Site UK004

Bristol, , United Kingdom

Research Site UK001

London, , United Kingdom

Research Site UK002

Oxford, , United Kingdom

Research Site UK003

Southampton, , United Kingdom

Countries

United States; Argentina; Australia; Bangladesh; Chile; Mexico; New Zealand; Philippines; South Africa; Spain; United Kingdom

References

Madhi SA, Polack FP, Piedra PA, Munoz FM, Trenholme AA, Simoes EAF, Swamy GK, Agrawal S, Ahmed K, August A, Baqui AH, Calvert A, Chen J, Cho I, Cotton MF, Cutland CL, Englund JA, Fix A, Gonik B, Hammitt L, Heath PT, de Jesus JN, Jones CE, Khalil A, Kimberlin DW, Libster R, Llapur CJ, Lucero M, Perez Marc G, Marshall HS, Masenya MS, Martinon-Torres F, Meece JK, Nolan TM, Osman A, Perrett KP, Plested JS, Richmond PC, Snape MD, Shakib JH, Shinde V, Stoney T, Thomas DN, Tita AT, Varner MW, Vatish M, Vrbicky K, Wen J, Zaman K, Zar HJ, Glenn GM, Fries LF; Prepare Study Group. Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants. N Engl J Med. 2020 Jul 30;383(5):426-439. doi: 10.1056/NEJMoa1908380.

Reference Type: DERIVED

PMID: 32726529 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://novavax.com

Novavax, Inc

Other Identifiers

RSV-M-301

Identifier Type: -

Identifier Source: org_study_id