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

NCT ID: NCT03814720

Last Updated: 2022-04-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-04-01
• Study Completion Date: 2021-04-06

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.

Detailed Description

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.

Conditions

Influenza Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

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

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

Group Type: EXPERIMENTAL

VRC-FLUNPF099-00-VP (H1ssF_3928)

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

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

Group Type: EXPERIMENTAL

VRC-FLUNPF099-00-VP (H1ssF_3928)

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

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

Group Type: EXPERIMENTAL

VRC-FLUNPF099-00-VP (H1ssF_3928)

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

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

Group Type: EXPERIMENTAL

VRC-FLUNPF099-00-VP (H1ssF_3928)

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

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

Group Type: EXPERIMENTAL

VRC-FLUNPF099-00-VP (H1ssF_3928)

Intervention Type: 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.

Interventions

VRC-FLUNPF099-00-VP (H1ssF_3928)

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.

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

1. Healthy adults between the ages of 18-70 years inclusive

Exclusion Criteria

3. Received at least one licensed influenza vaccine from 2014 to the present

4. Able and willing to complete the informed consent process

5. If enrolled in Group 1: Available for clinic visits for 52 weeks after enrollment and through an influenza season

6. If enrolled in Group 2A, 2B, 2C, or 2D: Available for clinic visits for 68 weeks after enrollment and through an influenza season

7. Willing to have blood samples collected, stored indefinitely, and used for research purposes

8. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process

9. 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

10. White blood cells (WBC) and differential either within institutional normal range or accompanied by the site Principal Investigator (PI) or designee approval

11. Total lymphocyte count greater than or equal to 800 cells/mm^3

12. Platelets = 125,000 - 500,000/mm3

13. Hemoglobin within institutional normal range

14. Serum iron either within institutional normal range or accompanied by the site PI or designee approval

15. Serum ferritin within institutional normal range or accompanied by the site PI or designee approval

16. Alanine aminotransferase (ALT) less than or equal to 1.25 x institutional upper limit of normal (ULN)

17. Aspartate aminotransferase (AST) less than or equal to 1.25 x institutional ULN

18. Alkaline phosphatase (ALP) <1.1 x institutional ULN

19. Total bilirubin within institutional normal range

20. Serum creatinine less than or equal to 1.1 x institutional ULN

21. Negative for HIV infection by an FDA-approved method of detection

Criteria applicable to women of childbearing potential:

22. Negative beta-human chorionic gonadotropin (beta-HCG) pregnancy test (urine or serum) on the day of enrollment

23. Agreed to use an effective means of birth control from at least 21 days prior to enrollment through the end of the study

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

Participant has received any of the following substances:

2. 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

3. Blood products within 16 weeks prior to enrollment

4. Live attenuated vaccines within 4 weeks prior to enrollment

5. Inactivated vaccines within 2 weeks prior to enrollment

6. Investigational research agents within 4 weeks prior to enrollment or planned to receive investigational products while on the study

7. Current allergy treatment with allergen immunotherapy with antigen injections, unless on maintenance schedule

8. Current anti-TB (tuberculosis) prophylaxis or therapy

9. Previous investigational H1 influenza vaccine

10. Previous investigational ferritin-based vaccine

11. Receipt of a licensed influenza vaccine within 6 weeks before trial enrollment

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

12. Serious reactions to vaccines that preclude receipt of study vaccinations as determined by the investigator

13. Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema

14. Asthma that is not well controlled

15. Diabetes mellitus (type I or II), with the exception of gestational diabetes

16. Thyroid disease that is not well controlled

17. Idiopathic urticaria within the past year

18. Autoimmune disease or immunodeficiency

19. Hypertension that is not well controlled (baseline systolic > 140 mmHg or diastolic > 90 mmHg)

20. 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

21. Malignancy that is active or history of malignancy that is likely to recur during the period of the study.

22. 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

23. Asplenia, functional asplenia or any condition resulting in the absence or removal of the spleen

24. Guillain-Barré Syndrome

25. 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alicia T Widge, M.D.

Role: PRINCIPAL_INVESTIGATOR

National Institute of Allergy and Infectious Diseases (NIAID)

Locations

National Institutes of Health Clinical Center

Bethesda, Maryland, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 25007847 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23698367 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26301691 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37075129 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37075126 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Related Links

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2019-I-0032.html

NIH Clinical Center Detailed Web Page

Other Identifiers

19-I-0032

Identifier Type: OTHER

Identifier Source: secondary_id

190032

Identifier Type: -

Identifier Source: org_study_id