Dose, Safety, Tolerability and Immunogenicity of an Influenza H1 Stabilized Stem Ferritin Vaccine in Healthy Adults

Study Design: This was a Phase I, open-label, dose escalation study to evaluate the dose, safety, tolerability, and immunogenicity of VRC-FLUNPF099-00-VP in two regimens. The hypotheses were that the vaccine is safe and tolerable and will elicit an immune response. The primary objective was to evaluate the safety and tolerability of the investigational vaccine in healthy adults. Secondary objectives were related to immunogenicity of the investigational vaccine and dosing regimen.

Study Products: The investigational vaccine, VRC-FLUNPF099-00-VP (H1ssF_3928), was developed by the Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID) and is composed of Helicobacter pylori non-heme ferritin assembled with influenza virus H1 haemagglutinin (HA) insert to form a nanoparticle displaying eight HA stabilized stem trimers from A/New Caledonia/20/1999 (H1N1) influenza. The vaccine was supplied in single-use vials at a concentration of 180 mcg/mL. H1ssF_3928 was administered intramuscularly (IM) in the deltoid muscle via needle and syringe.

Participants: Healthy adults between the ages of 18-70 years, inclusive.

Study Plan: The study evaluated the safety, tolerability and immunogenicity of 1 or 2 doses of the H1ssF_3928 vaccine in a dose-escalation design. In Group 1, five participants received a single low dose (20 mcg) of H1ssF_3928 on Day 0. For Group 1, the protocol required 1 vaccination visit, about 9 follow-up visits, and a telephone contact after vaccination.

Once the low dose was assessed as safe and well tolerated, enrollment began for Group 2A. Groups 2A, 2B, 2C, and 2D were stratified by age as shown in the vaccination schema below. In Group 2A, participants received a higher dose (60 mcg) of H1ssF_3928 on Day 0. Once this higher dose was assessed as safe and well tolerated, participants in Group 2A received a second vaccination at Week 16 and enrollment began for Groups 2B, 2C, and 2D. For Groups 2A, 2B, 2C, and 2D, the protocol required 2 vaccination visits, about 11 follow-up visits, and a telephone contact after each vaccination. Group 2A completed the product administration schedule per protocol. While most participants in Groups 2B-2D completed the second dose administration per protocol, one participant was not able to receive the second dose due to moving out of the area and 11 participants were not able to receive their second dose due to the COVID-19 pandemic.

For all groups, solicited reactogenicity was evaluated using a 7-day diary card. Assessment of vaccine safety included clinical observation and monitoring of hematological and chemical parameters at clinical visits throughout the study.

VRC 321 Vaccination Schema:

Group: 1; Age Cohort: 18-40; Participants: 5; Day 0: 20 mcg

Group: 2A; Age Cohort: 18-40; Participants: 12; Day 0: 60 mcg; Week 16: 60 mcg

Group: 2B; Age Cohort: 41-49; Participants: 12; Day 0: 60 mcg; Week 16: 60 mcg

Group: 2C; Age Cohort: 50-59; Participants: 12; Day 0: 60 mcg; Week 16: 60 mcg

Group: 2D; Age Cohort: 60-70; Participants: 11*; Day 0: 60 mcg; Week 16: 60 mcg

Total: 52*

*Recruitment for the final open group, Group 2D, was ongoing to meet the accrual target of 53 participants. However, due to the COVID-19 pandemic, enrollment was discontinued with a total of 52 participants enrolled.

Study Duration:

Group 1: Participants were evaluated for 52 weeks following the vaccine administration and through an influenza season.

Groups 2A, 2B, 2C, 2D: Participants were evaluated for 52 weeks following the last vaccine administration and through an influenza season.

Inclusion criteria

• Healthy adults between the ages of 18-70 years inclusive
• Based on history and examination, in good general health and without history of any of the conditions listed in the exclusion criteria
• Received at least one licensed influenza vaccine from 2014 to the present
• Able and willing to complete the informed consent process
• If enrolled in Group 1: Available for clinic visits for 52 weeks after enrollment and through an influenza season
• If enrolled in Group 2A, 2B, 2C, or 2D: Available for clinic visits for 68 weeks after enrollment and through an influenza season
• Willing to have blood samples collected, stored indefinitely, and used for research purposes
• Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process
• Physical examination and laboratory results without clinically significant findings and a Body Mass Index (BMI) less than or equal to 40 within the 28 days before enrollment

Laboratory Criteria within 28 days before enrollment

• White blood cells (WBC) and differential either within institutional normal range or accompanied by the site Principal Investigator (PI) or designee approval
• Total lymphocyte count greater than or equal to 800 cells/mm^3
• Platelets = 125,000 - 500,000/mm3
• Hemoglobin within institutional normal range
• Serum iron either within institutional normal range or accompanied by the site PI or designee approval
• Serum ferritin within institutional normal range or accompanied by the site PI or designee approval
• Alanine aminotransferase (ALT) less than or equal to 1.25 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) less than or equal to 1.25 x institutional ULN
• Alkaline phosphatase (ALP) <1.1 x institutional ULN
• Total bilirubin within institutional normal range
• Serum creatinine less than or equal to 1.1 x institutional ULN
• Negative for HIV infection by an FDA-approved method of detection

Criteria applicable to women of childbearing potential:

• Negative beta-human chorionic gonadotropin (beta-HCG) pregnancy test (urine or serum) on the day of enrollment
• Agreed to use an effective means of birth control from at least 21 days prior to enrollment through the end of the study

Exclusion criteria

• Breast-feeding or planning to become pregnant during the study.

Participant has received any of the following substances:

• More than 10 days of systemic immunosuppressive medications or cytotoxic medications within the 4 weeks prior to enrollment or any within the 14 days prior to enrollment
• Blood products within 16 weeks prior to enrollment
• Live attenuated vaccines within 4 weeks prior to enrollment
• Inactivated vaccines within 2 weeks prior to enrollment
• Investigational research agents within 4 weeks prior to enrollment or planned to receive investigational products while on the study
• Current allergy treatment with allergen immunotherapy with antigen injections, unless on maintenance schedule
• Current anti-TB (tuberculosis) prophylaxis or therapy
• Previous investigational H1 influenza vaccine
• Previous investigational ferritin-based vaccine
• Receipt of a licensed influenza vaccine within 6 weeks before trial enrollment

Participant has a history of any of the following clinically significant conditions:

• Serious reactions to vaccines that preclude receipt of study vaccinations as determined by the investigator
• Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema
• Asthma that is not well controlled
• Diabetes mellitus (type I or II), with the exception of gestational diabetes
• Thyroid disease that is not well controlled
• Idiopathic urticaria within the past year
• Autoimmune disease or immunodeficiency
• Hypertension that is not well controlled (baseline systolic > 140 mmHg or diastolic > 90 mmHg)
• Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with IM injections or blood draws
• Malignancy that is active or history of malignancy that is likely to recur during the period of the study.
• Seizure disorder other than 1) febrile seizures, 2) seizures secondary to alcohol withdrawal more than 3 years ago, or 3) seizures that have not required treatment within the last 3 years
• Asplenia, functional asplenia or any condition resulting in the absence or removal of the spleen
• Guillain-Barré Syndrome
• Any medical, psychiatric, social condition, occupational reason or other responsibility that, in the judgment of the investigator, is a contraindication to protocol participation or impairs a participant's ability to give informed consent.