Evaluation of the Safety and Immunogenicity of a Recombinant Trivalent Nanoparticle Influenza Vaccine With Matrix M-1 Adjuvant (NanoFlu)

Study Overview
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Brief Summary
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This was a Phase 1/2, randomized, observer-blinded, active-controlled trial to assess the Safety and Tolerability of a Recombinant Trivalent Nanoparticle Influenza Vaccine (Tri-NIV) with Matrix M1™ Adjuvant in Healthy Older Adults ≥ 60 Years of Age

Detailed Description
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Study tNIV-E-101 a randomized, observer-blinded, active-controlled trial designed to evaluate the safety and immunogenicity of Novavax's insect cell-derived, egg-free, influenza vaccine (Tri-NIV) based on recombinant HA nanoparticle antigens, representing the 3 major influenza types/subtypes recommended for inclusion in the 2017 - 2018 seasonal influenza vaccine by the World Health Organization (WHO) and the Center for Biologics Evaluation and Research (CBER) Approximately 330 eligible subjects were enrolled and randomized into 1 of 3 treatment groups Each group consisted of approximately 110 subjects total, stratified by age, gender, and history of receipt of the 2016 - 17 influenza vaccine. On Day 0, subjects in Groups A and B were administered an IM injection of NanoFlu at one of two dose levels; subjects in Group C received the preconfigured comparator (Fluzone HD) at the manufacturer's recommended dose and volume. On Day 21, all Group A and B subjects were administered a rescue injection with a licensed seasonal influenza vaccine. In contrast, all Group C subjects were administered an injection with a sterile saline placebo to maintain the trial blind. Trial follow-up for each subject spanned approximately 1 year from Day 0.

Official Title
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A Phase 1/2, Randomized, Observer-Blinded, Active-Controlled Trials to Evaluate the Safety and Immunogenicity of a Recombinant Trivalent Nanoparticle Influenza Vaccine With Matrix-M1 Adjuvant (NanoFlu) in Healthy Older Adults

Conditions
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Influenza

Intervention / Treatment
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* Biological: NanoFlu
* Biological: Fluzone HD - Day 0
* Biological: Fluzone HD - Day 21
* Other: Saline - Day 21


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy older adults, male or female, Willing and able to give informed consent prior to trial enrollment, and Able to attend trial visits, comply with trial requirements, and provide reliable and complete reports of adverse events. Exclusion Criteria: Any ongoing, symptomatic acute or chronic illness requiring medical or surgical care. Asymptomatic chronic conditions or findings (eg, mild hypertension, dyslipidemia) that are not associated with evidence of end-organ damage are not exclusionary provided that they are being appropriately managed and are clinically stable (ie, unlikely to result in symptomatic illness within the time-course of this trial) in the opinion of the investigator. Acute or chronic illnesses or conditions which may be reasonably predicted to become symptomatic if treatment were withdrawn or interrupted are exclusionary, even if stable. Acute or chronic illnesses reasonably expected to be associated with increased risks in the event of influenza infection (eg, cardio-pulmonary diseases, diabetes mellitus, renal or hepatic dysfunction, hemoglobinopathies) are exclusionary, even if stable. Note that illnesses or conditions may be exclusionary, even if otherwise stable, due to therapies used to treat them (see exclusion criteria 2, 5, 8, 9). Participation in research involving investigational product (drug / biologic / device) within 45 days before planned date of first injection. History of a serious reaction to prior influenza vaccination, or known allergy to constituents of influenza vaccines - including egg proteins - or polysorbate 80. History of Guillain-Barré Syndrome (GBS) within 6 weeks following a previous influenza vaccine. Receipt of any vaccine in the 4 weeks preceding the trial vaccination and any influenza vaccine within 6 months preceding the trial vaccination. Any known or suspected immunosuppressive illness, congenital or acquired, based on medical history and/or physical examination. 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 trial vaccine. An immunosuppressant dose of glucocorticoid will be defined as a systemic dose ≥ 10 mg of prednisone per day or equivalent. The use of topical, inhaled, and nasal glucocorticoids will be permitted. Administration of immunoglobulins and/or any blood products within the 3 months preceding the administration of the trial vaccine or during the trial. Acute disease at the time of enrollment (defined as the presence of a moderate or severe illness with or without fever, or an oral temperature > 38.0°C, on the planned day of vaccine administration). Any condition that in the opinion of the investigator would pose a health risk to the subject if enrolled or could interfere with evaluation of the vaccine or interpretation of trial results (including neurologic or psychiatric conditions deemed likely to impair the quality of safety reporting). Known disturbance of coagulation. Suspicion or recent history (within one year of planned vaccination) of alcohol or other substance abuse.

Ages Eligible for Study
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Minimum Age: 60 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Low dose NanoFlu - Day 0; Fluzone HD - Day 21 | Biological: NanoFlu<br>* Vaccine<br>Biological: Fluzone HD - Day 21<br>* Vaccine<br>|
| Experimental: Group B<br>High dose NanoFlu - Day 0; Fluzone HD - Day 21 | Biological: NanoFlu<br>* Vaccine<br>Biological: Fluzone HD - Day 21<br>* Vaccine<br>|
| Active Comparator: Group C<br>Fluzone HD - Day 0; Saline - Day 21 | Biological: Fluzone HD - Day 0<br>* Vaccine<br>Other: Saline - Day 21<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With All Adverse Events (AEs), Medically Attended Adverse Events (MAAEs), Serious Adverse Events (SAEs), and Significant New Medical Conditions (SNMCs). | Number of participants that reported all adverse event (AE) profile (including adverse changes in clinical laboratory parameters) ; medically-attended adverse event (MAE), serious adverse event (SAE), and significant new medical condition (SNMC) post dosing. | Day 0 - Day 21 post dosing | 
| Number of Participants With Solicited Local and Systemic AEs | Number of participants with solicited local and systemic adverse events over the 7 days post-injection | Day 0 - Day 6 post-dosing | 
| Geometric Mean Titers (GMT) Specific for the Hemagglutinin (HA) Receptor Binding Domains of Each of the Virus Strains Included in the NanoFlu as Measured by the Hemagglutination Inhibition (HAI) Assay. | The immunogenicity of Tri-NIV at 2 different doses, and the licensed comparator Fluzone HD (Sanofi Pasteur), in healthy older adults ≥ 60 years of age, based on hemagglutination inhibition (HAI) responses to vaccine-homologous influenza A and B strains, as recommended for the 2017 - 18 Northern hemisphere vaccine, at Day 21 post-dosing expressed as GMTs. | Day 0 - Day 21 post dosing | 
| Geometric Mean Ratio (GMR) Specific for the HA Receptor Binding Domains of Each of the Virus Strains Included in the NanoFlu as Measured by the HAI Assay. | The immunogenicity of Tri-NIV at 2 different doses, and the licensed comparator Fluzone HD (Sanofi Pasteur), in healthy older adults ≥ 60 years of age, based on hemagglutination inhibition (HAI) responses to vaccine-homologous influenza A and B strains, as recommended for the 2017 - 18 Northern hemisphere vaccine, at Day 21 post-dosing expressed as GMR. | Day 0 - Day 21 post dosing | 
| Seroconversion Rate (SCR) Specific for the HA Receptor Binding Domains of Each of the Virus Strains Included in the NanoFlu as Measured by the HAI Assay. | The immunogenicity of Tri-NIV at 2 different doses, and the licensed comparator Fluzone HD (Sanofi Pasteur), in healthy older adults ≥ 60 years of age, based on hemagglutination inhibition (HAI) responses to vaccine-homologous influenza A and B strains, as recommended for the 2017 - 18 Northern hemisphere vaccine, at Day 21 post-dosing expressed as SCRs. | Day 0 - Day 21 post dosing | 
| Number of Participants With Seroprotection Specific for the HA Receptor Binding Domains of Each of the Virus Strains Included in the NanoFlu as Measured by the HAI Assay. | The immunogenicity of Tri-NIV at 2 different doses, and the licensed comparator Fluzone HD (Sanofi Pasteur), in healthy older adults ≥ 60 years of age, based on hemagglutination inhibition (HAI) responses to vaccine-homologous influenza A and B strains, as recommended for the 2017 - 18 Northern hemisphere vaccine, at Day 21 post-dosing expressed as SPRs. Seroprotection rate (SPR) - defined as the number of subjects with an HAI titer ≥ 1:40. | Day 0 - Day 21 post dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers (GMT) Specific for the HA Receptor Binding Domains of at Least 2 Historic A Virus Strains (One H1N1 and One H3N2) as Measured by the HAI Assay | The immunogenicity of Tri-NIV at 2 different doses and the licensed comparator Fluzone HD (Sanofi Pasteur) based on hemagglutination inhibition (HAI) responses to at least 2 historic and/or drifted A virus strains (one H1N1 and one H3N2) expressed as GMTs. | Day 0 - Day 21 | 
| Geometric Mean Ratio (GMR) Specific for the HA Receptor Binding Domains of at Least 2 Historic A Virus Strains (One H1N1 and One H3N2) as Measured by the HAI Assay | The immunogenicity of Tri-NIV at 2 different doses and the licensed comparator Fluzone HD (Sanofi Pasteur) based on hemagglutination inhibition (HAI) responses to at least 2 historic and/or drifted A virus strains (one H1N1 and one H3N2) expressed as GMRs. | Day 0 - Day 21 | 
| Seroconversion Rate (SCR) Specific for the HA Receptor Binding Domains of at Least 2 Historic A Virus Strains (One H1N1 and One H3N2) as Measured by the HAI Assay | The immunogenicity of Tri-NIV at 2 different doses and the licensed comparator Fluzone HD (Sanofi Pasteur) based on hemagglutination inhibition (HAI) responses to at least 2 historic and/or drifted A virus strains (one H1N1 and one H3N2) expressed as SCRs. | Day 0 - Day 21 | 
| Number of Participants With Seroprotection Specific for the HA Receptor Binding Domains of at Least 2 Historic A Virus Strains (One H1N1 and One H3N2) as Measured by the HAI Assay | The immunogenicity of Tri-NIV at 2 different doses and the licensed comparator Fluzone HD (Sanofi Pasteur) based on hemagglutination inhibition (HAI) responses to at least 2 historic and/or drifted A virus strains (one H1N1 and one H3N2) expressed as SPRs. Seroprotection rate (SPR) - defined as the percentage of subjects with an HAI titer ≥ 1:40. | Day 0 - Day 21 | 
| Geometric Mean Titers (GMT) for Neutralizing Antibody Titers Specific for the Virus Strains Included in NanoFlu and the Fluzone HD Comparator, as Well as Selected Historical A Strains, as Measured by a Microneutralization Assay. | The immunogenicity of Tri-NIV at 2 different doses, and the licensed comparator Fluzone HD (Sanofi Pasteur), based on microneutralization (MN) responses to vaccine-homologous and historic and/or drifted influenza A strains, and the vaccine-homologous B/Victoria lineage strain, at Day 21 post-dosing expressed as GMTs. | Day 0 - Day 21 post dosing | 
| Geometric Mean Ratio (GMR) for Neutralizing Antibody Titers Specific for the Virus Strains Included in NanoFlu and the Fluzone HD Comparator, as Well as Selected Historical A Strains, as Measured by a Microneutralization Assay. | The immunogenicity of Tri-NIV at 2 different doses, and the licensed comparator Fluzone HD (Sanofi Pasteur), based on microneutralization (MN) responses to vaccine-homologous and historic and/or drifted influenza A strains, and the vaccine-homologous B/Victoria lineage strain, at Day 21 post-dosing expressed as GMRs. | Day 0 - Day 21 | 
| Seroconversion Rate (SCR) for Neutralizing Antibody Titers Specific for the Virus Strains Included in NanoFlu and the Fluzone HD Comparator, as Well as Selected Historical A Strains, as Measured by a Microneutralization Assay. | The immunogenicity of Tri-NIV at 2 different doses, and the licensed comparator Fluzone HD (Sanofi Pasteur), based on microneutralization (MN) responses to vaccine-homologous and historic and/or drifted influenza A strains, and the vaccine-homologous B/Victoria lineage strain, at Day 21 post-dosing expressed as SPRs. | Day 0 - Day 21 |