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

NCT03814720 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 19003219-I-0032
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

Brief Summary

Background: The flu is a common viral infection that can be deadly for certain people. Vaccines against flu have been developed to teach the body to prevent or fight the infection. A new vaccine may help the body to make an immune response to H1 flu, a flu strain that infects humans. Objective: To test the safety and effectiveness of the H1 Stabilized Stem Ferritin vaccine (VRC-FLUNPF099-00-VP). Eligibility: Healthy people ages 18-70 years old who got at least 1 licensed flu vaccine since January 1, 2014. Design: Participants received 1 or 2 vaccinations by injections (shots) in the upper arm muscle over 4 months. Participants received a thermometer and recorded their temperature and symptoms every day a diary card for 7 days after each injection. The injection site was checked for redness, swelling, or bruising. Participants had 9-11 follow-up visits over 12-15 months. At follow-up visits, participants had blood drawn and were checked for health changes or problems. Participants who reported influenza-like illness had nose and throat swabs for evaluation of viral infection. Some participants had apheresis. A needle was placed into a vein in both arms. Blood was removed through a needle in the vein of one arm. A machine removed the white blood cells and then the rest of the blood was returned to the participant through a needle in the other arm. A separate consent was provided to participants for genetic testing on their samples.

Conditions

Influenza Infection

Keywords

Flu; Seasonal Allergy; Respiratory Illness; Flu Virus; Viral Infection

Outcome Measures

Primary Outcomes (7)

• Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of Each H1ssF_3928 Product Administration

  Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after each study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Local Symptom" is the number of participants reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, modified from FDA Guidance - September 2007.

  7 days after each H1ssF_3928 product administration, at approximately Week 1 and at approximately Week 17

• Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of Each H1ssF_3928 Product Administration

  Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after each study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Systemic Symptom" is the number of participants reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, modified from FDA Guidance - September 2007.

  7 days after each H1ssF_3928 product administration, at approximately Week 1 and at approximately Week 17

• Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following H1ssF_3928 Product Administration

  Unsolicited AEs and attribution assessments were recorded in the study database from receipt of the first study product administration through the visit scheduled for 4 weeks after each study product administration. At other time periods between study product administrations and when greater than 4 weeks after the last study product administration, only serious AEs (SAEs reported as a separate outcome and in the AE module), influenza-like illness (ILI) or influenza and new chronic medical conditions that required ongoing medical management (reported as separate outcomes) were recorded through the last study visit. The relationship between an AE and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.

  Day 0 through 4 weeks after each H1ssF_3928 product administration, up to Week 20

• Number of Participants With Serious Adverse Events (SAEs) Following H1ssF_3928 Product Administration

  SAEs were recorded from receipt of first study product administration through the last expected study visit at Week 68. The relationship between a SAE and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.

  Day 0 through the study participation, up to Week 68

• Number of Participants With Influenza or Influenza-like Illness (ILIs) Following H1ssF_3928 Product Administration

  Influenza or influenza-like illness (ILI) were recorded in the study database from receipt of the first study product administration through the last study visit.

  Day 0 through the study participation, up to Week 68

• Number of Participants With New Chronic Medical Conditions Following H1ssF_3928 Product Administration

  New chronic medical conditions that required ongoing medical management were recorded from receipt of first study product administration through the last expected study visit at Week 68. The relationship between a new chronic medical condition and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.

  Day 0 through the study participation, up to Week 68

• Number of Participants With Abnormal Laboratory Measures of Safety Following H1ssF_3928 Product Administration

  Any abnormal laboratory results recorded after product administration as unsolicited adverse events (AEs) are summarized. Safety laboratory parameters included hematology (hemoglobin, hematocrit, platelets, and white blood cell (WBC), red blood cell (RBC), neutrophil, lymphocyte, monocyte, eosinophil and basophil percents/counts) and chemistry (alanine aminotransferase (ALT), alanine aspartate (AST), alkaline phosphate (ALP), creatinine and total bilirubin). Complete blood count (CBC) with differential, total bilirubin, AST, ALT, and ALP results were collected at Days 14, 28, 280, 364 and 476. Iron and serum ferritin were collected at Day 28. Creatinine results were collected at Day 14. Institutional laboratory normal ranges as well as the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials FDA Guidance, September 2007 were used.

  Day 0 through the study participation, up to Week 68

Secondary Outcomes (1)

• Pseudoviral Neutralization Assay Geometric Mean Titer (GMT) Against Homologous A/New Caledonia/20/1999 Virus (H1N1) Following the Completion of Each Vaccination Regimen

  Baseline to 2 weeks after 1st dose for participants who received a single injection, at Week 2 or From Baseline to 2 weeks after 1st dose and from Week 16 to 2 weeks after 2nd dose for participants who received two injections, at Weeks 2 and 18

Study Arms (5)

Group 1: H1ssF_3928 (20 mcg), ages 18-40 years

EXPERIMENTAL

H1ssF\_3928 (20 mcg) administered intramuscularly (IM) by Needle/Syringe (Day 0)

Biological: VRC-FLUNPF099-00-VP (H1ssF_3928)

Group 2A: H1ssF_3928 (60 mcg), ages 18-40 years

EXPERIMENTAL

H1ssF\_3928 (60 mcg) administered IM by Needle/Syringe (Day 0 and Week 16)

Biological: VRC-FLUNPF099-00-VP (H1ssF_3928)

Group 2B: H1ssF_3928 (60 mcg), ages 41-49 years

EXPERIMENTAL

H1ssF\_3928 (60 mcg) administered IM by Needle/Syringe (Day 0 and Week 16)

Biological: VRC-FLUNPF099-00-VP (H1ssF_3928)

Group 2C: H1ssF_3928 (60 mcg), ages 50-59 years

EXPERIMENTAL

H1ssF\_3928 (60 mcg) administered IM by Needle/Syringe (Day 0 and Week 16)

Biological: VRC-FLUNPF099-00-VP (H1ssF_3928)

Group 2D: H1ssF_3928 (60 mcg), ages 60-70 years

EXPERIMENTAL

H1ssF\_3928 (60 mcg) administered IM by Needle/Syringe (Day 0 and Week 16)

Biological: VRC-FLUNPF099-00-VP (H1ssF_3928)

Interventions

VRC-FLUNPF099-00-VP (H1ssF_3928) BIOLOGICAL

The vaccine is composed of the HA stem domain from Influenza A/New Caledonia/20/1999 (H1N1) genetically fused to the ferritin protein from H. pylori. Purified H1ssF\_3928 particles display eight well-formed HA trimers that antigenically resemble the native H1 stem viral spikes.

Group 1: H1ssF_3928 (20 mcg), ages 18-40 years; Group 2A: H1ssF_3928 (60 mcg), ages 18-40 years; Group 2B: H1ssF_3928 (60 mcg), ages 41-49 years; Group 2C: H1ssF_3928 (60 mcg), ages 50-59 years; Group 2D: H1ssF_3928 (60 mcg), ages 60-70 years

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy adults between the ages of 18-70 years inclusive

You may not qualify if:

• 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)

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Krammer F, Palese P, Steel J. Advances in universal influenza virus vaccine design and antibody mediated therapies based on conserved regions of the hemagglutinin. Curr Top Microbiol Immunol. 2015;386:301-21. doi: 10.1007/82_2014_408.

  PMID: 25007847 BACKGROUND

• Kanekiyo M, Wei CJ, Yassine HM, McTamney PM, Boyington JC, Whittle JR, Rao SS, Kong WP, Wang L, Nabel GJ. Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature. 2013 Jul 4;499(7456):102-6. doi: 10.1038/nature12202. Epub 2013 May 22.

  PMID: 23698367 BACKGROUND

• Yassine HM, Boyington JC, McTamney PM, Wei CJ, Kanekiyo M, Kong WP, Gallagher JR, Wang L, Zhang Y, Joyce MG, Lingwood D, Moin SM, Andersen H, Okuno Y, Rao SS, Harris AK, Kwong PD, Mascola JR, Nabel GJ, Graham BS. Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nat Med. 2015 Sep;21(9):1065-70. doi: 10.1038/nm.3927. Epub 2015 Aug 24.

  PMID: 26301691 BACKGROUND

• Widge AT, Hofstetter AR, Houser KV, Awan SF, Chen GL, Burgos Florez MC, Berkowitz NM, Mendoza F, Hendel CS, Holman LA, Gordon IJ, Apte P, Liang CJ, Gaudinski MR, Coates EE, Strom L, Wycuff D, Vazquez S, Stein JA, Gall JG, Adams WC, Carlton K, Gillespie RA, Creanga A, Crank MC, Andrews SF, Castro M, Serebryannyy LA, Narpala SR, Hatcher C, Lin BC, O'Connell S, Freyn AW, Rosado VC, Nachbagauer R, Palese P, Kanekiyo M, McDermott AB, Koup RA, Dropulic LK, Graham BS, Mascola JR, Ledgerwood JE; VRC 321 study team. An influenza hemagglutinin stem nanoparticle vaccine induces cross-group 1 neutralizing antibodies in healthy adults. Sci Transl Med. 2023 Apr 19;15(692):eade4790. doi: 10.1126/scitranslmed.ade4790. Epub 2023 Apr 19.

  PMID: 37075129 DERIVED

• Andrews SF, Cominsky LY, Shimberg GD, Gillespie RA, Gorman J, Raab JE, Brand J, Creanga A, Gajjala SR, Narpala S, Cheung CSF, Harris DR, Zhou T, Gordon I, Holman L, Mendoza F, Houser KV, Chen GL, Mascola JR, Graham BS, Kwong PD, Widge A, Dropulic LK, Ledgerwood JE, Kanekiyo M, McDermott AB. An influenza H1 hemagglutinin stem-only immunogen elicits a broadly cross-reactive B cell response in humans. Sci Transl Med. 2023 Apr 19;15(692):eade4976. doi: 10.1126/scitranslmed.ade4976. Epub 2023 Apr 19.

  PMID: 37075126 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Influenza, Human; Rhinitis, Allergic, Seasonal; Virus Diseases

Condition Hierarchy (Ancestors)

Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Respiratory Tract Diseases; Rhinitis, Allergic; Rhinitis; Nose Diseases; Respiratory Hypersensitivity; Otorhinolaryngologic Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Limitations and Caveats

All 52 participants received at least one study product administration. Groups 1 and 2A completed the product administration schedule per protocol. While most participants in Groups 2B-2D completed the second product 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 because of visit interruptions due to the COVID-19 pandemic.

Results Point of Contact

• Title: Alicia T Widge, M.D.
• Organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health

alicia.widge@nih.gov

301-451-8715

Study Officials

• Alicia T Widge, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 23, 2019
• First Posted: January 24, 2019
• Study Start: April 1, 2019
• Primary Completion: April 6, 2021
• Study Completion: April 6, 2021
• Last Updated: April 29, 2022
• Results First Posted: April 29, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)