| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Healthy Volunteers (prevention of lower respiratory tract illness) |
|
| E.1.1.1 | Medical condition in easily understood language |
| RSV is a very common virus that leads to mild, cold-like symptoms in adults and children. RSV can cause more serious disease in infants, such as inflammation of the lungs. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the safety and reactogenicity of a single IM dose of study vaccine administered to maternal subjects, from Visit 1 up to 6 weeks after delivery
To evaluate pregnancy outcomes and pregnancy-related AESIs after a single IM dose of study vaccine administered to maternal subjects, from Visit 1 up to 6 weeks after delivery (Visit 6)
To evaluate the safety of the study vaccine, including neonatal AEs of special interest, in infants born to maternal subjects who were vaccinated with a single IM dose of study vaccine, up to 6 weeks after birth
To evaluate the immunogenicity of a single IM dose of study vaccine in maternal subjects at Day 31 and at Delivery
To evaluate RSV-specific antibody levels at birth, in infants born to maternal subjects who were vaccinated with a single IM dose of study vaccine
To evaluate the transfer of RSV-specific antibodies from maternal subjects vaccinated with a single IM dose of study vaccine to their infants at delivery/birth |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate safety of:
● a single IM dose of study vaccine in maternal subjects, up to 6 months after delivery and in infants (born to vaccinated mothers), up to 1 year of age.
To estimate the incidence of:
● RSV-associated, medically attended RTIs in maternal subjects vaccinated with a single IM dose of study vaccine, from vaccination up to 6 months post-delivery
● RSV-associated lower respiratory tract illness (LRTI), severe LRTI, very severe LRTI and hospitalization in infants from birth up to 6 months of age.
To evaluate the immunogenicity of:
● single IM dose of study vaccine in maternal subjects in terms of RSVPreF3 IgG-specific antibody concentrations and neutralizing antibodies against RSV-A at Day 43 after delivery
● single IM dose of study vaccine in maternal subjects in terms of RSV-B neutralizing antibodies at Day 1 before vaccination, Day 31, at delivery and at Day 43 post-delivery.
● To evaluate RSV-specific antibodies in infants up to 6 months after birth. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Maternal subjects
●Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol.
●Subjects who give written or witnessed/thumb printed informed consent after the study has been explained according to local regulatory requirements, and before performing any study specific procedures are performed.
The informed consent given at screening should (consistent with local regulations / guidelines) either:
- include consent for both the maternal subject's participation and participation of the infant after the infant’s birth, or
- include consent for the maternal subject's participation and expressed willingness to consider permitting the infant to take part after the infant's birth.
Both mother and father should consent if local regulations/guidelines require it.
●Age 18 to 40 years, inclusive, when informed consent is given.
●Pre-pregnancy BMI 18.5 to 34.9, inclusive
●Healthy as established by medical history and clinical examination before entering into the study.
●At 28^0/7 to 33^6/7 weeks of gestation at the time of study vaccination (Visit 1), as established by last menstrual period (LMP) date corroborated by first or second trimester ultrasound examination (U/S).
* If LMP and U/S do not correlate, default to U/S gestational age assessment. The level of diagnostic certainty of the gestational age should be established by using the Global Alignment of Immunisation safety Assessment in pregnancy gestation age assessment tool
●Subject satisfying screening requirements
●Singleton pregnancy
●HIV negative, as assessed by local standard of care serologic tests conducted during the current pregnancy and before enrolment (Visit 1).
●No fetal genetic abnormalities.
●No significant congenital malformations, as assessed by level 2 ultrasound (also known as a fetal anomaly untrasound scan or fetal morphology assessment) conducted after 18 weeks of gestation
●Willing to provide cord blood
●Willing to have the infant followed-up after delivery for a period of 12 months
●Does not plan after delivery to give the infant for adoption or place the infant in care
Note that women whose pregnancies resulted from Assisted Reproductive Technologies may be enrolled if they meet all inclusion criteria and none of the exclusion criteria.
Infant subjects
●Live-born from the study pregnancy.
●Re-signed (confirmed) written or witnessed/thumb printed informed consent for study participation of the infant obtained from the infant’s mother and/or father and/or legally authorized representative, as applicable by local law, before performing any study specific procedure. |
|
| E.4 | Principal exclusion criteria |
Maternal subjects
Medical conditions
●History of allergic disease or reactions likely to be exacerbated by any component of the RSV vaccine
●Hypersensitivity to latex
●Significant complications in the current pregnancy such as:
Gestational hypertension at ≥20 weeks of gestation in the absence of proteinuria in a woman with a previously normal blood pressure
Gestational diabetes which is not controlled by diet and exercise
Pre-eclampsia
Eclampsia during current pregnancy
Intrauterine growth restriction
Placenta previa
Placental abruption, placenta accreta/percreta/increta, chorioamnionitis or any abnormalities that in the opinion of Investigator can impair the maternal-fetal circulation
Polyhydramnios
Oligohydramnios
Cervical suture in place
Preterm labour or history of preterm labour in the current pregnancy
Ongoing medical intervention to prevent preterm delivery or medical treatment for suspected preterm delivery
Cholestasis
Other pregnancy-related complications that in the Investigator’s judgement would preclude participation of the subjects in an investigational vaccine trial or might pose risk to the subject due to participation in the study
●Significant structural abnormalities of the uterus or cervix
●History of prior stillbirth or neonatal death
●History of preterm birth
●History of ≥2 spontaneous abortions
●Known or suspected HBV or HCV infection, based on medical history and clinical presentation
●Known or suspected infection during the current pregnancy with Toxoplasma, Parvovirus B19, Syphilis, Zika, Rubella, Varicella, CMV or primary genital Herpes Simplex, based on medical history and clinical presentation
●Active infection with tuberculosis, based on medical history and clinical presentation
●Known or suspected impairment of the immune system or autoimmune disorder (based on medical history and physical examination; no laboratory testing required)
●Lymphoproliferative disorder or malignancy within 5 years before vaccination (excluding effectively treated non-melanoma skin cancer)
●Any clinically significant grade 1 hematological and/or biochemical laboratory abnormalities identified at screening, which are clinically significant for pregnant women in the second and third trimester
●Grade ≥ 2 hematological and/or biochemical laboratory abnormalities identified at screening being clinically significant for pregnant women in the second and third trimester
●Acute or chronic clinically significant conditions, that might pose additional risk to the subject due to participation in the study
●Any conditions that, may interfere with subject’s ability to comply with study procedures or receipt of prenatal care
●Any condition which, would increase the risks of study participation to the unborn infant
Prior/Concomitant therapy
●Prior receipt of a COVID-19 vaccine
●Prior receipt of an RSV vaccine
●Use of any investigational or non-registered product other than the study vaccine(s)/product(s) during the period beginning 29 days before the dose of study vaccine/product or planned use during the study period
●Planned administration / administration of any vaccine within 29 days before study vaccine administration and through Day 43 post-delivery, except seasonal influenza vaccines and dTpa/Tdap or tetanus, which may be administered according to standard of care ≥ 15 days before or after study vaccination
●Administration of immunoglobulins, blood products or plasma derivatives within 3 months before study vaccination or planned administration through Visit 5
●Administration of immune-modifying therapy within 6 months before the study vaccine/product dose, or planned administration through delivery. This includes but is not limited to:
Azathioprine, mycophenolate mofetil, 6-mercaptopurine, cyclosporine, tacrolimus, monoclonal or polyclonal antibodies;
Prednisone, ≥5 mg/day or equivalent for ≥ 14 days. Topical, steroids are allowed. Inhaled steroids are allowed if ≤ 500µg/day of beclomethasone or fluticasone, or ≤ 800µg/day of budesonide
Prior/Concomitant clinical study experience
●Previous participation in a clinical trial of an RSV vaccine
●Concurrently participating in another clinical study, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product
Other exclusions
●Alcoholism or substance use disorder within the past 24 months based on the presence of two or more abuse criteria
●A local condition that precludes injection of the study drug or precludes assessment of local reactogenicity
●Consanguinity of maternal subject and her partner (second degree cousins or closer)
●Any study personnel or their immediate dependants, family or household members
Infant subjects
●Concurrently participating in another clinical study, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product
●Child in care
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Percentage of maternal subjects reporting solicited administration site events
2. Percentage of maternal subjects reporting solicited systemic events
3. Percentage of maternal subjects with hematological and biochemical laboratory abnormality at baseline
4. Percentage of maternal subjects with hematological and biochemical laboratory abnormality at Day 8
5. Percentage of maternal subjects with unsolicited adverse events (AEs)
6. Percentage of maternal subjects with at least one serious adverse event (SAE)
7. Percentage of maternal subjects with AEs leading to study withdrawal
8. Percentage of maternal subjects with at least one medically attended AE (MAE)
9. Percentage of maternal subjects with pregnancy outcomes
10. Percentage of maternal subjects with pregnancy-related Adverse Events of Special Interest (AESIs)
11. Percentage of infant subjects with neonatal AESIs
12. Percentage of infant subjects with at least one SAE
13. Percentage of infant subjects with AEs leading to study withdrawal
14. Percentage of infant subjects with at least one MAE
15. RSVPreF3 Immunoglobulin G (IgG)-specific antibody concentration in terms of Geometric Mean Concentrations (GMCs) at Day 1, before vaccination for each group and by age category
16. RSVPreF3 IgG antibody GMCs at Day 31
17. RSVPreF3 IgG antibody GMCs at delivery
18. RSV-A neutralizing antibody Geometric Mean Titers (GMTs) at Day 1, before vaccination
19. RSV-A neutralizing antibody GMTs at Day 31
20. RSV-A neutralizing antibody GMTs at delivery
21. RSVPreF3 IgG antibody GMCs in infants born to maternal subjects
22. RSV-A neutralizing antibody GMTs in infants born to maternal subjects
23. Geometric Mean Ratio between cord blood and maternal RSVPreF3 IgG-specific antibody concentrations |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From Day 1 to day 7
2. From Day 1 to day 7
3. At baseline (Day -15)
4. At Day 8 (visit 2)
5. From Day 1 to Day 30
6. From Day 1 to Day 43 post-delivery
7. From Day 1 to Day 43 post-delivery
8. From Day 1 to Day 43 post-delivery
9. From Day 1 to Day 43 post-delivery
10. From Day 1 to Day 43 post-delivery
11. From birth to Day 43 post-birth
12. From birth to Day 43 post-birth
13. From birth to Day 43 post-birth
14. From birth to Day 43 post-birth
15. At Day 1 (before vaccination)
16. At Day 31
17. At delivery (Visit 5)
18. At Day 1 (before vaccination)
19. At Day 31
20. At delivery (Visit 5)
21. At birth (Visit Day 1 for infants)
22. At birth (Visit Day 1 for infants)
23. At delivery (visit 5 for maternal subjects) or birth (visit Day 1 for infants) |
|
| E.5.2 | Secondary end point(s) |
1. Percentage of maternal subjects with at least one SAE
2. Percentage of maternal subjects with at least one MAE
3. Percentage of maternal subjects with at least one AE leading to study withdrawal
4. Percentage of infant subjects with at least one SAE from birth through 6 months after birth
5. Percentage of infant subjects with at least one AE leading to study withdrawal from birth through 6 months after birth
6. Percentage of infant subjects with at least one MAE from birth through 6 months after birth
7. Percentage of infant subjects with at least one SAE from birth through 1 year after birth
8. Percentage of infant subjects with at least one AE leading to study withdrawal from birth through 1 year after birth
9. Percentage of infant subjects with at least one MAE from birth through 1 year after birth
10. Percentage of maternal subjects with at least one RSV-associated Medically Attended RSV-associated Respiratory Tract Illnesses (MA-RTI)
11. Percentage of infant subjects with at least one RSV-associated LRTI
12. Percentage of infant subjects with at least one RSV-associated severe LRTI
13. Percentage of infant subjects with at least one RSV-associated very severe LRTI
14. Percentage of infant subjects with at least one RSV-associated hospitalisation
15. RSVPreF3 IgG antibody GMCs in maternal subjects, at day 43
16. RSV-A neutralizing antibody GMTs in maternal subjects, at day 43
17. RSV-B neutralizing antibody GMTs in maternal subjects at Day 1
18. RSV-B neutralizing antibody GMTs in maternal subjects at Day 31
19. RSV-B neutralizing antibody GMTs in maternal subjects at delivery
20. RSV-B neutralizing antibody GMTs in maternal subjects at Day 43 post-delivery
21. RSVPreF3 IgG antibody GMCs in infants born to maternal subjects, at Day 43 after birth
22. RSVPreF3 IgG antibody GMCs in infants born to maternal subjects, at Day 121 after birth
23. RSVPreF3 IgG antibody concentration at Day 181 after birth
24. RSV-A neutralizing antibody GMTs at Day 43 after birth
25. RSV-A neutralizing antibody GMTs at Day 121 after birth
26. RSV-A neutralizing antibody GMTs at Day 181 after birth
27. RSV-B neutralizing antibody GMTs at birth
28. RSV-B neutralizing antibody GMTs at Day 43 after birth
29. RSV-B neutralizing antibody GMTs at Day 121 after birth
30. RSV-B neutralizing antibody GMTs at Day 181 after birth |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
End points 1, 2, 3. From Day 1 to Day 181 post-delivery
End points 4, 5, 6. From birth to Day 181 post-birth
End points 7, 8, 9. From birth to Month 12 post-birth
End point 10. From delivery (visit 5) to Day 181 post-delivery
End points 11, 12, 13, 14. From birth (Visit at Day 1) to Day 181 post-birth
End points 15, 16, 20, 21, 24, 28. At Day 43 post-delivery
End point 17. At Day 1 (before vaccination)
End point 18. At Day 31
End point 19. At delivery (Visit 5)
End points 22, 25, 29. At Day 121 after birth
End points 23, 26, 30. At Day 181 after birth
End point 27. At birth (Visit at Day 1) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity, Reactogenicity |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Finland |
| France |
| New Zealand |
| Panama |
| South Africa |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| EoS occurs with the last (infant) subject last visit (LSLV; Visit 5-NB) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 19 |
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