Two Doses of Multimeric-001 (M-001) Followed by Influenza Vaccine

• ClinicalTrials.gov Identifier: NCT03058692
• Recruitment Status: Completed
• First Posted: February 23, 2017
• Results First Posted: February 5, 2020
• Last Update Posted: June 18, 2020
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

Brief Summary:

This is a Phase II randomized, double-blind, placebo-controlled trial in 120 males and non-pregnant females, 18 to 49 years old, inclusive, who are in good health and meet all eligibility criteria. This clinical trial will be conducted at 3 United States sites and is designed to assess the safety, reactogenicity, and immunogenicity of two priming doses of M-001 followed by a seasonal quadrivalent inactivated influenza vaccine (IIV4). The duration of this trial for each subject will be approximately 7 months. The entire study duration will be approximately 24 months. The primary objectives are: 1) To assess the safety as measured by vaccine related adverse events, reactogenicity, and laboratory adverse events of two doses of M-001 vaccine, each dose administered approximately 21 days apart; and 2) To assess the T cell responses to M-001 component peptides following two doses of M-001.

Condition or disease	Intervention/treatment	Phase
Influenza; Influenza Immunisation	Biological: Influenza Multimeric-001 Vaccine; Other: Placebo; Biological: Quadrivalent Recombinant Seasonal Influenza Vaccine	Phase 2

Detailed Description:

This is a Phase II randomized, double-blind, placebo-controlled trial in 120 males and non-pregnant females, 18 to 49 years old, inclusive, who are in good health and meet all eligibility criteria. This clinical trial will be conducted at 3 United States sites and is designed to assess the safety, reactogenicity, and immunogenicity of two priming doses of M-001 followed by a seasonal quadrivalent inactivated influenza vaccine (IIV4). The duration of this trial for each subject will be approximately 7 months. The entire study duration will be approximately 24 months. The primary objectives are: 1) To assess the safety as measured by vaccine related adverse events, reactogenicity, and laboratory adverse events of two doses of M-001 vaccine, each dose administered approximately 21 days apart; and 2) To assess the T cell responses to M-001 component peptides following two doses of M-001. The secondary objectives are: 1) To assess all serious adverse events (SAEs) following receipt of each dose of M-001 vaccine or placebo, each dose separated by approximately 21 days, through the end of the study; 2) To assess all unsolicited non-serious AEs following receipt of each dose of M-001 or placebo, each dose separated by approximately 21 days, through 21 days after each dose of M-001 or placebo; and 3) To assess the serum HAI and Neut antibody responses to the 2018-2019 IIV4 vaccine viruses.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: A Phase II, Double-Blind, Multicenter, Randomized, Placebo-Controlled Trial to Assess the Safety, Reactogenicity and Immunogenicity of Two Doses of Multimeric-001 (M-001) Followed by Seasonal Quadrivalent Influenza Vaccine
• Actual Study Start Date: April 9, 2018
• Actual Primary Completion Date: January 14, 2019
• Actual Study Completion Date: January 14, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: M-001 + IIV4; 0.4 ml injection of M-001 (1 mg dose) intramuscularly on Day 1 and Day 22, followed by 0.5 ml injection of IIV4 (60 mcg HA) intramuscularly on Day 172 (n=60)	Biological: Influenza Multimeric-001 Vaccine; The M-001 vaccine consists of 3 repetitions of 9 conserved linear epitopes that are prepared as a single recombinant protein. The M-001 vaccine is expected to protect against existing as well as future seasonal and pandemic virus strains.; Biological: Quadrivalent Recombinant Seasonal Influenza Vaccine; Quadrivalent Inactivated Influenza Vaccine (IIV4) for intramuscular injection is indicated for active immunization against influenza disease caused by influenza virus subtypes A and type B present in the vaccine.
Placebo Comparator: Placebo+ IIV4; 0.4 ml injection of placebo intramuscularly on Day 1 and Day 22, followed by 0.5 ml injection of IIV4 (60 mcg HA) intramuscularly on Day 172 (n=60)	Other: Placebo; Placebo is saline injection; Biological: Quadrivalent Recombinant Seasonal Influenza Vaccine; Quadrivalent Inactivated Influenza Vaccine (IIV4) for intramuscular injection is indicated for active immunization against influenza disease caused by influenza virus subtypes A and type B present in the vaccine.

Outcome Measures

Primary Outcome Measures :

1. Mean Percentage of Perforin+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
   The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
2. Mean Percentage of Cluster of Differentiation 107a Positive (CD107a+) CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
   The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
3. Mean Percentage of Interleukin-2 Positive (IL-2+) CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
   The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
4. Mean Percentage of Tumor Necrosis Factor Positive (TNF+) CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
   The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
5. Mean Percentage of Interferon Gamma Positive (IFNg+) CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
   The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
6. Mean Percentage of Perforin+CD107a+IL-2+TNF+IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
   The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
7. Mean Percentage of Perforin+CD107a+IL-2+TNF+IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
   The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
8. Mean Percentage of Perforin+CD107a+IL-2+TNF- IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
   The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
9. Mean Percentage of Perforin+CD107a+IL-2+TNF- IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
   The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
10. Mean Percentage of Perforin+CD107a+IL-2-TNF+IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
11. Mean Percentage of Perforin+CD107a+IL-2- TNF+IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
12. Mean Percentage of Perforin+CD107a+IL-2-TNF- IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
13. Mean Percentage of Perforin+CD107a+IL-2-TNF- IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
14. Mean Percentage of Perforin+CD107a- IL-2+TNF+IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
15. Mean Percentage of Perforin+CD107a- IL-2+TNF+IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
16. Mean Percentage of Perforin+CD107a- IL-2+TNF- IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
17. Mean Percentage of Perforin+CD107a- IL-2+TNF- IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
18. Mean Percentage of Perforin+CD107a- IL-2- TNF+IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
19. Mean Percentage of Perforin+CD107a- IL-2- TNF+IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
20. Mean Percentage of Perforin+CD107a- IL-2- TNF- IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
21. Mean Percentage of Perforin+CD107a- IL-2- TNF- IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
22. Mean Percentage of Perforin- CD107a+IL-2+TNF+IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
23. Mean Percentage of Perforin- CD107a+IL-2+TNF+IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
24. Mean Percentage of Perforin- CD107a+IL-2+TNF- IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
25. Mean Percentage of Perforin- CD107a+IL-2+TNF- IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
26. Mean Percentage of Perforin- CD107a+IL-2- TNF+IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
27. Mean Percentage of Perforin- CD107a+IL-2- TNF+IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
28. Mean Percentage of Perforin- CD107a+IL-2- TNF- IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
29. Mean Percentage of Perforin- CD107a+IL-2- TNF- IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
30. Mean Percentage of Perforin- CD107a- IL-2+TNF+IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
31. Mean Percentage of Perforin- CD107a- IL-2+TNF+IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
32. Mean Percentage of Perforin- CD107a- IL-2+TNF- IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
33. Mean Percentage of Perforin- CD107a- IL-2+TNF- IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
34. Mean Percentage of Perforin- CD107a- IL-2- TNF+IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
35. Mean Percentage of Perforin- CD107a- IL-2- TNF+IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
36. Mean Percentage of Perforin- CD107a- IL-2- TNF- IFNg+ CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
37. Mean Percentage of Perforin- CD107a- IL-2- TNF- IFNg- CD4+ and CD8+ T Cells After Stimulation With M-001 Component Peptides [ Time Frame: Day 1 through Day 36 ]
    The percentages of CD4 and CD8 T cells expressing markers were determined using fluorescence-based flow cytometric assays from cryopreserved PBMCs collected and isolated from participants at Day 1 prior to initial vaccination and again at 14 days after the second vaccination. The percentages were calculated as the number of cells positive for these proteins divided by the total number of CD4+ or CD8+ T cells counted in each sample.
38. Number of Participants With Clinical Safety Laboratory Adverse Events After the First M-001 Vaccination [ Time Frame: Day 9 ]
    Blood was collected after first vaccination for assessment by a central clinical laboratory. Clinical safety laboratory adverse events included white blood cells (WBC) </=3900/uL or >/=10,600/uL; platelets </=139,000/uL or >/=416,000/uL; hemoglobin </=11.4 g/dL (female) or </=12.4 g/dL (male); alanine aminotransferase (ALT) >/=44 IU/L (female) or >/=61 IU/L (male); creatinine >/=1.1 mg/dL (female) or >/=1.4 (male); and total bilirubin >/=1.30 mg/dL.
39. Number of Participants With Clinical Safety Laboratory Adverse Events After Second M-001 Vaccination [ Time Frame: Day 22 through Day 29 ]
    Clinical safety laboratory adverse events included WBC less than or equal to 3900/uL or greater than or equal to 10,600/uL; platelets less than or equal to 139,000/uL or greater than or equal to 416,000/uL; hemoglobin less than or equal to 11.4 g/dL (female) or less than or equal to 12.4 g/dL (male); alanine aminotransferase (ALT) greater than or equal to 44 IU/L (female) or greater than or equal to 61 IU/L (male); creatinine greater than or equal to 1.1 mg/dL (female) or greater than or equal to 1.4 (male); and total bilirubin greater than or equal to 1.30 mg/dL.
40. Number of Participants Reporting Solicited Injection Site and Systemic Reactogenicity Events After the First M-001 Vaccination [ Time Frame: Day 1 through Day 8 ]
    Participants maintained a memory aid and thermometer to record daily oral temperatures and the occurrence of systemic reactions of feverishness, fatigue, malaise, myalgia, arthralgia, headache, and nausea, as well as local injection site reactions of pain, tenderness, redness, and swelling for 8 days after vaccination (Day 0-7) based on their interference with daily activities, with a severity grade of mild meaning no interference, moderate as some interference and severe as significant interference/prevented daily activity. Fever was defined as an oral temperature of 38 degree Celsius or higher. Participants are counted if they reported experiencing the symptom at any severity on any of the 8 days post vaccination.
41. Number of Participants Reporting Solicited Injection Site and Systemic Reactogenicity Events After the Second M-001 Vaccination [ Time Frame: Day 22 through Day 29 ]
    Participants maintained a memory aid and thermometer to record daily oral temperatures and the occurrence of systemic reactions of feverishness, fatigue, malaise, myalgia, arthralgia, headache, and nausea, as well as local injection site reactions of pain, tenderness, redness, and swelling for 8 days after vaccination (Day 0-7) based on their interference with daily activities, with a severity grade of mild meaning no interference, moderate as some interference and severe as significant interference/prevented daily activity. Fever was defined as an oral temperature of 38 degree Celsius or higher. Participants are counted if they reported experiencing the symptom at any severity on any of the 8 days post vaccination.
42. Number of Participants Reporting Vaccine-related Serious Adverse Events (SAEs) After M-001 Vaccination [ Time Frame: Day 1 through Day 200 ]
    SAEs included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation or a congenital anomaly/birth defect. Relationship (related or unrelated to the study product) was determined by a site principal investigator blinded to the study product received by the participant.

Secondary Outcome Measures :

1. Number of Participants Reporting Serious Adverse Events (SAEs) After M-001 Vaccination [ Time Frame: Day 1 through Day 200 ]
   SAEs included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation or a congenital anomaly/birth defect. All events are included regardless of relationship to the study product.
2. Incidence of Unsolicited Non-serious Adverse Events (AEs) After M-001 Vaccination [ Time Frame: Day 1 through Day 43 ]
   Unsolicited adverse events were collected from the time of first vaccination and at each follow-up visit through Day 43. Adverse events were defined as any untoward medical occurrence regardless of its causal relationship to the study treatment. Events were coded with MedDRA and are reported by System Organ Class.
3. The Percentage of Subjects Achieving HAI Seroconversion to IIV4 Vaccine Virus From Day 172 to Day 200 [ Time Frame: Day 172 to Day 200 ]
   Blood was collected from participants for testing in the HAI assay with the vaccine viruses as the assay antigens. Seroconversion was defined as a Day 172 titer less than 10 and Day 200 titer greater than or equal to 40, or for those with a Day 172 titer of 10 or greater, a minimum 4-fold rise in Day 200 antibody titer.
4. The Percentage of Subjects Achieving Neutralizing Antibody Seroconversion to IIV4 Vaccine Virus From Day 172 to Day 200 [ Time Frame: Day 172 to Day 200 ]
   Blood was collected from participants for testing in the neutralizing antibody assay with the vaccine viruses as the assay antigens. Seroconversion was defined as a Day 172 titer less than 10 and Day 200 titer greater than or equal to 40, or for those with a Day 172 titer of 10 or greater, a minimum 4-fold rise in Day 200 antibody titer.
5. The Percentage of Participants With an HAI Antibody Titer of 40 or Greater and GMTs vs. IIV4 Vaccine Viruses at Day 1 [ Time Frame: Day 1 ]
   Blood was collected from participants for testing in the HAI assay with the vaccine viruses as the assay antigens. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 40 or greater.
6. The Percentage of Participants With an HAI Antibody Titer of 40 or Greater and GMTs vs. IIV4 Vaccine Viruses at Day 43 [ Time Frame: Day 43 ]
   Blood was collected from participants for testing in the HAI assay with the vaccine viruses as the assay antigens. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 40 or greater.
7. The Percentage of Participants With an HAI Antibody Titer of 40 or Greater and GMTs vs. IIV4 Vaccine Viruses at Day 172 [ Time Frame: Day 172 ]
   Blood was collected from participants for testing in the HAI assay with the vaccine viruses as the assay antigens. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 40 or greater.
8. The Percentage of Participants With an HAI Antibody Titer of 40 or Greater and GMTs vs. IIV4 Vaccine Viruses at Day 200 [ Time Frame: Day 200 ]
   Blood was collected from participants for testing in the HAI assay with the vaccine viruses as the assay antigens. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 40 or greater.
9. The Percentage of Participants With a Neutralizing Antibody Titer of 40 or Greater and GMTs vs. IIV4 Vaccine Viruses at Day 1 [ Time Frame: Day 1 ]
   Blood was collected from participants for testing in the neutralizing antibody assay with the vaccine viruses as the assay antigens. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 40 or greater.
10. The Percentage of Participants With a Neutralizing Antibody Titer of 40 or Greater and GMTs vs. IIV4 Vaccine Viruses at Day 43 [ Time Frame: Day 43 ]
    Blood was collected from participants for testing in the neutralizing antibody assay with the vaccine viruses as the assay antigens. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 40 or greater.
11. The Percentage of Participants With a Neutralizing Antibody Titer of 40 or Greater and GMTs vs. IIV4 Vaccine Viruses at Day 172 [ Time Frame: Day 172 ]
    Blood was collected from participants for testing in the neutralizing antibody assay with the vaccine viruses as the assay antigens. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 40 or greater.
12. The Percentage of Participants With a Neutralizing Antibody Titer of 40 or Greater and GMTs vs. IIV4 Vaccine Viruses at Day 200 [ Time Frame: Day 200 ]
    Blood was collected from participants for testing in the neutralizing antibody assay with the vaccine viruses as the assay antigens. Each sample was tested at least twice according to standard operating procedures and the result of each replicate reported. A participant is counted if the geometric mean of the replicate values was 40 or greater.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 49 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Provide written informed consent prior to initiation of any study procedures.
2. Are able to understand and comply with planned study procedures and be available for all study visits.
3. Are males or non-pregnant females, 18 to 49 years old, inclusive.

4. Are in good health*.

   *As determined by medical history and targeted physical examination to evaluate acute or currently ongoing chronic medical diagnoses or conditions, defined as those that have been present for at least 90 days, which would affect the assessment of the safety of subjects or the immunogenicity of study vaccinations. Chronic medical diagnoses or conditions should be stable for the last 60 days prior to investigational vaccine study product administration. This includes no change in chronic prescription medication, dose, or frequency as a result of deterioration of the chronic medical diagnosis or condition in the 60 days prior to enrollment and investigational vaccine study product administration. Any prescription change that is due to change of health care provider, insurance company, etc., or that is done for financial reasons, as long as in the same class of medication, will not be considered a deviation of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome, as determined by the site principal investigator or appropriate sub-investigator, will not be considered a deviation of this inclusion criterion. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the site principal investigator or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition. Similarly, medication changes subsequent to enrollment and investigational study product vaccination are acceptable provided there was no deterioration in the subject's chronic medical condition that necessitated a medication change. All chronic medical condtions should pose no additional risk to the subject or interference with the evaluation of responses to study vaccination. Note: Topical, nasal, and inhaled medications (with the exception of inhaled corticosteroids as outlined in the Subject Exclusion Criteria), herbals, vitamins, and supplements are permitted.

5. Oral temperature is less than 100.0 degrees F.

6. Pulse** is 50 to 100 bpm, inclusive.

   **Acceptable pulse range prior to IIV4 dose is 45 to 115 bpm, inclusive and no symptoms.

7. Systolic blood pressure*** is 85 to 150 mmHg, inclusive. ***Acceptable systolic blood pressure range prior to IIV4 dose is 80 to 155 mm Hg, inclusive and no symptoms.

8. Diastolic blood pressure**** is 55 to 95 mmHg, inclusive.

   ****Acceptable diastolic blood pressure range prior to IIV4 dose is 50 to 100 mm Hg, inclusive and no symptoms.

9. Women of childbearing potential* must use an acceptable method of contraception** from 30 days prior to vaccination until 60 days after the second of dose of M-001 or placebo.

10. Women of childbearing potential***** must use an acceptable method of contraception****** from 30 days prior to receipt of IIV vaccination, and must plan to use until 28 days after the IIV.

    *****Not sterilized via tubal ligation, bilateral oophorectomy, hysterectomy, or successful Essure(R) placement (permanent, non-surgical, non-hormonal sterilization with history of documented radiological confirmation test achieved or with use of another approved birth control method if confirmation test not confirmed) and still menstruating or < 1 year of the last menses if menopausal).

    ******Includes, but is not limited to, non-male sexual relationships, abstinence from sexual intercourse with a male partner, monogamous relationship with a vasectomized partner, male condoms with the use of applied spermicide, intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables, contraceptive patches or oral contraceptives ("the pill"). Method of contraception will be captured on the appropriate data collection form.

11. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 24 hours prior to study vaccination.

Exclusion Criteria:

1. Have an acute illness*, as determined by the site PI or appropriate sub-investigator, within 72 hours prior to study vaccination.

   • An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the site PI or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety parameters as required by the protocol.

2. Have any medical disease or condition that, in the opinion of the site PI or appropriate sub-investigator, is a contraindication to study participation**.

   **Including acute or chronic medical disease or condition, defined as persisting for at least 90 days, that would place the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or the subject's successful completion of this study.

3. Have immunosuppression as a result of an underlying illness or treatment, or use of anticancer chemotherapy or radiation therapy (cytotoxic) within 3 years prior to study vaccination.
4. Have known active neoplastic disease or a history of any hematologic malignancy. Non-melanoma skin cancers that are not active are permitted.
5. Have known HIV, hepatitis B, or hepatitis C infection.
6. Have known hypersensitivity or allergy to eggs, egg or chicken protein, or other components of the study vaccine.
7. Have a history of severe reactions following previous immunization with licensed or unlicensed influenza vaccines.
8. Have a history of Guillain-Barré Syndrome.
9. Have a history of alcohol or drug abuse within 5 years prior to study vaccination.
10. Have any diagnosis, current or past, of schizophrenia, bipolar disease, or other psychiatric diagnosis that may interfere with subject compliance or safety evaluations.
11. Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others within 10 years prior to study vaccination.
12. Have taken oral or parenteral (including intraarticular) corticosteroids of any dose within 30 days prior to study vaccination.

13. Have taken high-dose*** dose inhaled corticosteroids within 30 days prior to study vaccination****.

    ***High-dose defined as per age as using inhaled high dose per reference chart https://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/quick-reference-html#estimated-comparative-daily-doses.

    ****Topical and nasal steroids are permissible.

14. Received any licensed live vaccine or plan to receive a licensed live vaccine within 30 days prior or 21 days after each M-001 study vaccination.
15. Received a licensed inactivated vaccine within 14 days prior to or 21 days after each M-001 study vaccination.
16. Plans to or received the current 2018-2019 influenza vaccine (inactivated or live prior to ordering the study (the 2018-2019 influenza vaccine will be given during the trial.))
17. Received immunoglobulin or other blood products (with exception of Rho D immunoglobulin) within 90 days prior to study vaccination.

18. Received an experimental agent***** within 30 days prior to the first study vaccination, or expects to receive an experimental agent****** during the 7-month trial-reporting period.

    *****Including vaccine, drug, biologic, device, blood product, or medication.

    ******Other than from participation in this study.

19. Are participating or plan to participate in another clinical trial with an interventional agent******* that will be received during the 7-month trial-reporting period.

    *******Including agent (licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication) during the 9-month study period.

20. Plan to travel outside the U.S. (continental U.S., Hawaii and Alaska) in the time between the first study vaccination and 21 days after the last study vaccination********.

    ********Study vaccination refers to investigational study product vaccination.

21. Female subjects who are breastfeeding or plan to breastfeed at any given time from the first study vaccination until 30 days after the last study vaccination.
22. Blood donation or planned blood donation within 30 days prior to the study vaccination through 30 days after the last blood drawn for this study.

23. Have signs or symptoms that could confound or confuse assessment of study vaccine reactogenicity*********.

    *********The study vaccination should be postponed/deferred until signs or symptoms have resolved and if within the acceptable protocol-specified window for that visit.

24. Have a history of convulsions or encephalomyelitis within 90 days prior to study vaccination.

Contacts and Locations

Locations

United States, Iowa

University of Iowa - Vaccine Research and Education Unit

Iowa City, Iowa, United States, 52242-2600

United States, Ohio

Cincinnati Children's Hospital Medical Center - Infectious Diseases

Cincinnati, Ohio, United States, 45229-3039

United States, Texas

Baylor College of Medicine - Molecular Virology and Microbiology

Houston, Texas, United States, 77030-3411

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):

Statistical Analysis Plan  [PDF] September 9, 2019

Study Protocol  [PDF] December 6, 2018

More Information

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT03058692
• Other Study ID Numbers: 14-0112; HHSN272201300015I
• First Posted: February 23, 2017
• Results First Posted: February 5, 2020
• Last Update Posted: June 18, 2020
• Last Verified: November 27, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Immunogenicity; Influenza Vaccine; M-001 vaccine; Reactogenicity; Safety

Additional relevant MeSH terms:

Influenza, Human; Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Vaccines; Immunologic Factors; Physiological Effects of Drugs