Study to Evaluate Safety and Immunogenicity of COVID-19 Vaccine in Children 6 Months to < 12 Years

Study Overview
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Brief Summary
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This is a Phase 2/3 randomized, observer-blinded, placebo-controlled, age de-escalation trial to evaluate the safety and immunogenicity of 2 primary doses and a booster dose of NVX CoV2373 given 21 days apart in pediatric participants (3 age cohorts; 6 to < 12 years, 2 to < 6 years, and 6 to < 24 months of age). Each age cohort will be conducted in 2 parts starting with the oldest age cohort (6 to < 12 years of age).

Detailed Description
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This is a Phase 2/3 randomized, observer-blinded, placebo-controlled, age de-escalation trial to evaluate the safety and immunogenicity of 2 primary doses and a booster dose of NVX CoV2373 given 21 days apart in pediatric participants (3 age cohorts). Each age cohort will be conducted in 2 parts starting with the oldest age cohort (6 to < 12 years of age). Part 1 will enroll approximately 120 healthy or medically stable sentinel participants per age cohort (10% of the intended enrollment population per age cohort, for a total of 360 sentinel participants overall) who will be randomized in a 1:1 ratio to receive 2 doses of NVX-CoV2373 or placebo with doses given 21 days apart. Part 2 will enroll a larger number of healthy or medically stable participants (N= approximately 1,080 per age cohort), for a total of approximately 3,240 pediatric participants enrolled in Part 2, and a total of approximately 3,600 participants enrolled in the entire trial). Initial randomization in Part 2 will be in a 2:1 ratio, and the safety and effectiveness of 2 doses of NVX-CoV2373 given 21 days apart will be assessed.

Official Title
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A Phase 2/3 Age De-escalating Study to Evaluate the Safety and Immunogenicity of a SARS-CoV-2 Recombinant Spike Protein Vaccine (SARS-CoV-2 rS) With Matrix-M™ Adjuvant in Children 6 Months to < 12 Years of Age

Conditions
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COVID-19

Intervention / Treatment
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* Biological: Biological/Vaccine: SARS-CoV-2 rS/Matrix-M1 Adjuvant (Initial Vaccination Period)
* Biological: SARS-CoV-2 rS/Matrix-M1 Adjuvant (Open Label Crossover Vaccination period)
* Biological: SARS-CoV-2 rS/Matrix-M1 Adjuvant (Booster Vaccination)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be included in this study, each individual must satisfy all of the following criteria: Pediatric participants 6 months to < 12 years of age at randomization, determined to be healthy or medically stable by the investigator (based on review of health status, vital signs [to include body temperature], medical history, and targeted physical examination [to include body weight]). Vital signs must be within the normal range prior to the first vaccination, according to the child's age, sex, weight, and height/length. For children from 6 months to < 12 months of age: born at full-term (≥ 37 weeks gestation) with a minimum birth weight of 2.5 kilograms (kg). Participant and parent(s)/caregiver(s) or legally acceptable representative willing and able to give informed consent and assent, as required, prior to study enrollment and to comply with study procedures. Participants of childbearing potential (defined as any participant who has experienced menarche and who is NOT surgically sterile [ie, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy]) must agree to be heterosexually inactive from at least 28 days prior to enrollment and through 3 months after the last vaccination OR agree to consistently use a highly effective contraception method from at least 28 days prior to enrollment and through 3 months after the last vaccination. Agree not to participate in another SARS-CoV-2 prevention trial for the duration of the study. Exclusion Criteria: If an individual meets any of the following criteria, he or she is ineligible for this study: Any acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature ≥ 100.4°F [≥ 38.0°C]). A prospective subject should not be included in the study until the condition has resolved or the febrile event has subsided. Unstable acute or chronic illness. Criteria for unstable medical conditions include: Substantive changes in chronic prescribed medication (change in class or significant change in dose) in the past 2 months. Currently undergoing workup of undiagnosed illness that could lead to a diagnosis of a new condition. NOTE: Well-controlled human immunodeficiency virus [HIV] infection with undetectable HIV ribonucleic acid [RNA < 50 copies/mL] and CD4 count > 200 cells/µL for at least 1 year, documented within the last 6 months, is NOT considered an unstable chronic illness. Participant's or parent's/caregiver's verbal report will suffice as documentation. Participation in research involving an investigational product (drug/biologic/device) administered within 45 days prior to the first study vaccination. History of a previous laboratory-confirmed diagnosis of SARS-CoV-2 infection or COVID-19. Prior administration of an investigational, authorized, or approved Coronavirus vaccine (ie, against either SARS-CoV, SARS-CoV-2, or MERS CoV) or expected receipt during the period of study follow-up. Previous or current diagnosis of MIS-C. Receipt of medications intended to prevent or treat COVID-19. Received any vaccine within 14 days prior to first study vaccination or planned receipt of any vaccine before Day 49 (ie, 28 days after the second vaccination), except for influenza vaccination, which may be received > 14 days prior to or > 14 days after any study vaccination. Known or suspected congenital or acquired immunodeficiency or autoimmune disease/condition; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy; or long-term systemic corticosteroid therapy (prednisone or equivalent for > 14 continuous days) within 90 days prior to first study vaccination. NOTE: An immunosuppressant dose of glucocorticoid is defined as a systemic dose ≥ 20 mg of prednisone per day or equivalent. The use of topical, inhaled, and nasal glucocorticoids is permitted. Topical tacrolimus and ocular cyclosporin are permitted. Stable autoimmune endocrine disorders (eg, thyroiditis, pancreatitis), including stable diabetes mellitus type 1, or participants with a history of Kawasaki disease are NOT excluded. Received immunoglobulin or blood-derived products within 90 days prior to first study vaccination. Active cancer (malignancy) on chemotherapy within 1 year prior to first study vaccination (with the exception of malignancy cured via excision, at the discretion of the investigator). Any known allergies to products contained in the investigational product. Participants who are breastfeeding a child, pregnant or who plan to become pregnant within 3 months following the last study vaccination. Any other condition that, in the opinion of the investigator, would pose a health risk to the participant if enrolled or could interfere with the evaluation of the trial vaccine or interpretation of study results. Study team member or first-degree relative of any study team member (inclusive of Sponsor, and study site personnel involved in the study). Current participation in any other COVID-19 prevention clinical trial. Participants with a history of myocarditis or pericarditis.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 11 Years

Sexes Eligible for Study
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All

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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Originally Randomized to Vaccine, Immediate Booster Group<br>2 doses of 5 μg SARS-CoV-2 rS + 50 μg Matrix-M1 adjuvant (co-formulated), 1 dose each on Days 0 and 21 in Initial Vaccination Period.One dose of 5 μg SARS-CoV-2 rS + 50 μg Matrix-M1 adjuvant (co-formulated) on Day 201 in the Booster Vaccination Period. | Biological: Biological/Vaccine: SARS-CoV-2 rS/Matrix-M1 Adjuvant (Initial Vaccination Period)<br>* Alternating intramuscular (deltoid) injections of SARS-CoV-2 rS co-formulated with Matrix-M1 adjuvant (0.5 mL) (or fractional dose if necessary) on Days 0 and 21 in the Initial Vaccination Period.<br>* Other names: NVX-CoV2373;Biological: SARS-CoV-2 rS/Matrix-M1 Adjuvant (Booster Vaccination)<br>* In Booster Vaccination period, one dose of intramuscular (deltoid) injection of SARS-CoV-2 rS co-formulated with Matrix-M1 adjuvant (0.5 mL) on Day 0<br>* Other names: NVX-CoV2373;|
| Experimental: Originally Randomized to Vaccine, Delayed Booster Group<br>2 doses of 5 μg SARS-CoV-2 rS + 50 μg Matrix-M1 adjuvant (co-formulated), 1 dose each on Days 0 and 21 in the Initial Vaccination Period. 1 dose of 5 μg SARS-CoV-2 rS + 50 μg Matrix-M1 adjuvant (co-formulated) on Day 201 or Day 229 and 1 dose of Placebo (Saline) on Day 201 or Day 229 in the Booster Vaccination Period. | Biological: SARS-CoV-2 rS/Matrix-M1 Adjuvant (Booster Vaccination)<br>* In Booster Vaccination period, one dose of intramuscular (deltoid) injection of SARS-CoV-2 rS co-formulated with Matrix-M1 adjuvant (0.5 mL) on Day 0<br>* Other names: NVX-CoV2373;Other: Placebo<br>* Alternating intramuscular (deltoid) injections of placebo (0.5 mL) on Days 0 and 21 in the Initial Vaccination Period or on Days 201 or Day 229 in the Booster Vaccination Period<br>* Other names: Sodium chloride 0.9% (BP, sterile);|
| Experimental: Originally Randomized to Placebo<br>2 doses of Placebo (Saline),1 dose each on Days 0 and 21 in the Initial Vaccination Period. 2 doses of 5 μg SARS-CoV-2 rS + 50 μg Matrix-M1 adjuvant (co-formulated) 1 dose each on Day 201 and Day 229 in Open-Label Crossover Vaccination Period. One dose of 5 μg SARS-CoV-2 rS + 50 μg Matrix-M1 adjuvant (co-formulated) on Day 409 in the Booster Vaccination Period. | Biological: SARS-CoV-2 rS/Matrix-M1 Adjuvant (Open Label Crossover Vaccination period)<br>* Alternating intramuscular (deltoid) injections of SARS-CoV-2 rS co-formulated with Matrix-M1 adjuvant (0.5 mL) on Day 201 and Day 229 for the participants originally randomized to placebo.<br>* Other names: NVX-CoV2373;Biological: SARS-CoV-2 rS/Matrix-M1 Adjuvant (Booster Vaccination)<br>* In Booster Vaccination period, one dose of intramuscular (deltoid) injection of SARS-CoV-2 rS co-formulated with Matrix-M1 adjuvant (0.5 mL) on Day 0<br>* Other names: NVX-CoV2373;Other: Placebo<br>* Alternating intramuscular (deltoid) injections of placebo (0.5 mL) on Days 0 and 21 in the Initial Vaccination Period or on Days 201 or Day 229 in the Booster Vaccination Period<br>* Other names: Sodium chloride 0.9% (BP, sterile);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reactogenicity Incidence and Severity | Reactogenicity incidence, duration, and severity (mild, moderate, severe, or potentially life-threatening) recorded by parent(s)/caregiver(s) on an electronic patient-reported outcome diary application (eDiary) on days of vaccination and subsequent 6 days (total 7 days after each vaccine injection). | Day 0 to Day 7 | 
| Incidence and Severity of Medically Attended Adverse Events (MAAEs) | Incidence and severity of MAAEs through 28 days after second injection of each set of vaccinations (initial and crossover), and after a booster dose. | Day 0 to Day 28 | 
| Incidence and Severity of Unsolicited Adverse Events (AEs) | Incidence and severity of unsolicited AEs through 28 days after second injection of each set of vaccinations (initial and crossover), and after a booster dose. | Day 0 to Day 28 | 
| Incidence and Severity of MAAEs Attributed to Study Vaccine | Incidence and severity of MAAEs attributed to study vaccine after initial vaccination at Day 0 through Month 24 or the EoS. | Day 0 to Day 730 | 
| Incidence and Severity of Serious Adverse Events (SAEs) | Incidence and severity of SAEs after initial vaccination at Day 0 through Month 24 or the EoS. | Day 0 to Day 730 | 
| Incidence and Severity of Adverse Events of Special Interest (AESIs) | Incidence and severity of AESIs (including multisystem inflammatory syndrome in children [MIS-C], and myocarditis and/or pericarditis) after initial vaccination at Day 0 through Month 24 or the EoS. | Day 0 to Day 730 | 
| Death due to any cause | Death due to any cause occurring from Day 0 to EoS. | Day 0 to Day 730 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants with PCR positive mild, moderate or severe COVID-19 after the primary series of 2 doses | Incidence rate of participants with first episode of PCR-positive mild, moderate, or severe COVID-19 overall and per age cohort, with or without positive anti-NP serology at baseline after the primary series of 2 doses. | Day 0 to Day 730 | 
| Participants with PCR positive moderate or severe COVID-19 after the primary series of 2 doses | Incidence rate of participants with first episode of PCR-positive moderate or severe COVID-19 overall and per age cohort, with or without positive anti-NP serology at baseline, and by risk factors to develop severe COVID-19 after the primary series of 2 doses. | Day 0 to Day 730 | 
| Participants with diagnostic test - positive asymptomatic, mild, moderate or severe COVID-19 after the primary series of 2 doses | Incidence rate of participants with first episode of diagnostic test-positive asymptomatic, mild, moderate, or severe COVID-19 (regardless of confirmatory test used, ie, PCR or rapid antigen test, and of testing location, ie, central or externally tested) overall and per age cohort, with or without positive anti-NP serology at baseline after the primary series of 2 doses. | Day 0 to Day 730 | 
| Participants with diagnostic test - positive moderate or severe COVID-19 after the primary series of 2 doses | Incidence rate of participants with first episode of diagnostic test-positive moderate or severe COVID-19 (regardless of confirmatory test used, ie, PCR or rapid antigen test, and of testing location, ie, central or externally tested) overall and per age cohort, with or without positive anti NP serology at baseline, and by risk factors to develop severe COVID-19 after the primary series of 2 doses. | Day 0 to Day 730 | 
| Participants with PCR positive mild, moderate or severe COVID-19 after the booster dose | Incidence rate of participants with first episode of PCR-positive mild, moderate, or severe COVID-19 overall and per age cohort, with or without positive anti-NP serology at baseline after the booster dose. | Day 0 to Day 730 | 
| Participants with PCR positive moderate or severe COVID-19 after the booster dose | Incidence rate of participants with first episode of PCR-positive moderate or severe COVID-19 overall and per age cohort, with or without positive anti-NP serology at baseline, and by risk factors to develop severe COVID-19 after the booster dose. | Day 0 to Day 730 | 
| Participants with diagnostic test - positive asymptomatic, mild, moderate or severe COVID-19 after the booster dose | Incidence rate of participants with first episode of diagnostic test-positive asymptomatic, mild, moderate, or severe COVID-19 (regardless of confirmatory test used, ie, PCR or rapid antigen test, and of testing location, ie, central or externally tested) overall and per age cohort, with or without positive anti-NP serology at baseline after the booster dose. | Day 0 to Day 730 | 
| Participants with diagnostic test moderate or severe COVID-19 after the booster dose | Incidence rate of participants with first episode of diagnostic test-positive moderate or severe COVID-19 (regardless of confirmatory test used, ie, PCR or rapid antigen test, and of testing location, ie, central or externally tested) overall and per age cohort, with or without positive anti-NP serology at baseline after the booster dose, and by risk factors to develop severe COVID-19. | Day 0 to Day 730 | 
| Antibodies to SARS-CoV-2 Nucleoprotein (NP) at Specified Time Points | Antibodies to SARS-CoV-2 NP, regardless of whether the infection was symptomatic. Antibodies to SARS-CoV-2 NP at Days 0 and 35, at Crossover Visit 1, at Booster vaccination visit, and at Months 12 and 24 will be used to determine natural infection and to determine the incidence of asymptomatic infection acquired during study follow-up. | Day 0 to Day 730 | 
| Neutralizing antibody response, post-booster, by age cohort,seronegative to anti-SARS-CoV-2 NP antibodies at baseline and pre-booster | Neutralizing antibody response at 28 days post booster for pediatric participants in the Immunogenicity Population overall and by age cohort, seronegative to anti-SARS-CoV-2 NP antibodies at baseline and pre-booster, compared with that observed at 28 days post-booster vaccination in young adult participants 18 to < 26 years of age. | Day 0 to Day 28 | 
| Neutralizing antibody response, by age cohort, regardless of serostatus at baseline and pre-booster | Neutralizing antibody response at 28 days post-booster for pediatric participants in the Immunogenicity Population overall and by age cohort, regardless of serostatus at baseline and pre-booster, compared with that observed in pediatric participants at baseline (Day 0). | Day 0 to Day 28 | 
| Serum IgG levels to SARS-CoV-2 S protein, post-booster, by age cohort, regardless of serostatus at baseline and pre-booster vaccination | Serum IgG levels to SARS-CoV-2 S protein at 28 days post-booster vaccination for pediatric participants in the Immunogenicity Population overall and by age cohort, regardless of serostatus at baseline and pre-booster vaccination, compared with that observed at 28 days post-booster vaccination in young adult participants 18 to < 26 years of age. | Day 0 to Day 28 | 
| Serum IgG levels to SARS-CoV-2 S protein, post booster, by age cohort, regardless of serostatus at baseline and pre-booster | Serum IgG levels to SARS-CoV-2 S protein at 28 days post-booster for pediatric participants in the Immunogenicity Population overall and by age cohort, regardless of serostatus at baseline and pre-booster, compared with that observed in pediatric participants at baseline (Day 0). | Day 0 to Day 28 | 
| Serum IgG levels to SARS-CoV-2 S protein , post booster, by age cohort, regardless of serostatus at baseline and pre-booster | Serum IgG levels to SARS-CoV-2 S protein at 28 days post-booster for pediatric participants in the Immunogenicity Population overall and by age cohort, regardless of serostatus at baseline and pre-booster, compared with that observed in pediatric participants at Day 35, | Day 0 to Day 35 | 
| Percentage of pediatric participants by age cohort reporting SARS-CoV-2 infection (COVID-19) by severity | Proportion of pediatric participants by age cohort reporting SARS-CoV-2 infection (COVID-19) from Day 28 through 6 months, from Day 28 through end of Month 12, from Day 28 through EOS, from 6 months through end of Month 12, and from 6 months through EOS, by severity classification. | Day 28 to Day 730 | 
| Neutralizing antibody response in the Immunogenicity Population | Neutralizing antibody response at Day 35 for pediatric participants in the Immunogenicity Population by age cohort and with and without anti-SARS-CoV 2 NP antibodies at baseline. | Day 35 | 
| Serum IgG levels to SARS-CoV-2 S protein after second injection of the initial vaccination series | Serum IgG levels to SARS-CoV-2 S protein 14 days after second injection of the initial vaccination series (Day 35) in pediatric participants in the Immunogenicity Population by age cohort and subsets with and without anti-NP antibodies at baseline. | Day 35 | 
| Treatment and severity of COVID 19 after a PCR-confirmed case | Description of course, treatment and severity of COVID 19 reported after a PCR-confirmed case via the Case Form. | Day 0 to Day 730 | 
| Antibodies to SARS-CoV-2 NP, regardless of whether the infection was symptomatic. | Antibodies to SARS-CoV-2 NP, regardless of whether the infection was symptomatic. Antibodies to SARS-CoV-2 NP at Days 0 and 35, at Crossover Visit 1, at Booster vaccination visit, and at Months 12 and 24 will be used to determine natural infection and to determine the incidence of asymptomatic infection acquired during study follow-up. | Day 0 to Day 730 | 
| Serum IgG levels to SARS-CoV-2 S protein expressed as GMT | Serum IgG levels to SARS-CoV-2 S protein at Months 6 (pre- booster), 7/8 (1-month post-booster), 12, and 24 post-vaccination with NVXCoV2373. | Day 180 to Day 730 | 
| MN titers to SARS-CoV-2 S protein expressed as GMT | MN titers at Months 6 (pre- booster), 7/8 (1-month post-booster), 12, and 24 post-vaccination with NVXCoV2373. | Day 180 to Day 730 |