Dose, Safety, Tolerability and Immunogenicity of an Influenza H10 Stabilized Stem Ferritin Vaccine, VRC-FLUNPF0103-00-VP, in Healthy Adults

Design: This was a Phase I, open-label, dose escalation study to evaluate the dose, safety, tolerability, and immunogenicity of VRC-FLUNPF0103-00-VP in two regimens. The hypotheses were that the vaccine is safe and tolerable and would 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-FLUNPF0103-00-VP (H10ssF-6473), was developed by the Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID) and is composed of the haemagglutinin (HA) stem domain from A/Jiangxi/IPB13/2013 (H10N8) influenza genetically fused to the ferritin protein from Helicobacter pylori. Purified H10ssF-6473 displays eight well-formed HA trimers that antigenically resemble the native H10 stem viral spikes. The vaccine was supplied in single-use vials at a concentration of 180 mcg/mL. VRC-PBSPLA043-00-VP consisting of sterile phosphate buffered saline (PBS) was the diluent for H10ssF-6473. Prepared study product was administered intramuscularly (IM) in the deltoid muscle via needle and syringe.

Participants:

Healthy adults between the ages of 18-70 were enrolled; adults born between 1965 and 1970 were excluded from the trial

Study Plan: This study evaluated the safety, tolerability and immunogenicity of 1 or 2 doses of H10ssF-6473 in a dose-escalation design.

In Group 1, three participants received a single low dose (20 mcg) of H10ssF-6473 on Day 0. For Group 1, the protocol required 1 vaccination visit, 8 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. In Group 2A, participants received a higher dose (60 mcg) of H10ssF-6473 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. Groups 2A and 2B were stratified by age as shown in the vaccination schema below. For Groups 2A and 2B, the protocol required 2 vaccination visits, 10 follow-up visits, and a telephone contact after each vaccination.

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 323 Vaccination Schema:

Group: 1; Age Cohort: 18-50; Participants: 3; Day 0: 20 mcg IM

Group: 2A; Age Cohort: 18-50; Participants: 14; Day 0: 60 mcg IM, Week 16: 60 mcg IM

Group: 2B; Age Cohort: 55-70; Participants: 8; Day 0: 60 mcg IM, Week 16: 60 mcg IM

Total Participants: 25

Study Duration:

Participants were evaluated for 40 weeks following the first vaccine administration.

Inclusion criteria

• Healthy adults between the ages of 18-70 years (excluding adults born between January 1, 1965 and December 31,1970)
• 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 2015 to the present
• Able and willing to complete the informed consent process
• Available for clinic visits for 40 weeks after enrollment
• 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 56 days before enrollment

Laboratory Criteria within 56 days before enrollment

• White blood cells (WBC) and differential 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/microL
• Platelets = 125,000 - 500,000 cells/microL
• Hemoglobin within institutional normal range or accompanied by the PI or designee approval
• Serum iron 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, except when otherwise consistent with Gilbert's syndrome
• 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
• Agrees 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

Individual 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 planning 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 H10 influenza vaccine
• Receipt of a licensed influenza vaccine within 6 weeks prior to enrollment

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

• Serious reactions to vaccines that preclude receipt of the study vaccination 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-Barre Syndrome
• Previous or current infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) documented by polymerase chain reaction (PCR) test
• 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.

INCLUSION OF VULNERABLE PARTICIPANTS

Children

Children were not eligible to participate in this clinical trial because the investigational vaccine had not been previously evaluated in adults. If the product is assessed as safe and immunogenic, other protocols designed for children may be conducted in the future.

NIH Employees

NIH employees and members of their immediate families could have participated in this protocol. If eligible, the Guidelines for the Inclusion of Employees in NIH Research Studies were followed for employees and each employee was given a copy of the 'NIH Information Sheet on Employee Research Participation' and a copy of the 'Leave Policy for NIH Employees Participating in NIH Medical Research Studies.'

Neither participation nor refusal to participate had an effect, either beneficial or adverse, on the participant's employment or work situation. The NIH information sheet regarding NIH employee research participation was distributed to all potential participants who are NIH employees. The employee participant's privacy and confidentiality was preserved in accordance with NIH Clinical Center and NIAID policies. For NIH employee participants, consent was obtained by an individual who is independent of the participant's team. If the individual obtaining consent is a co-worker to the participant, independent monitoring of the consent process will be included through the Bioethics Consultation Service. Protocol study staff were trained on obtaining potentially sensitive and private information from co-workers or subordinates.