H1N1v Virus Challenge Study in Healthy Subjects

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT04044352
• Collaborator: (none)
• Enrollment: 76
• Locations: 4
• Arm: 1
• Actual Duration (Months): 4.3
• Patients Per Site: 19
• Patients Per Site Per Month: 4.4

Study Details

Study Description

Brief Summary

This is a study of a reverse-engineered, Good Manufacturing Practice (GMP) grade, antiviral-sensitive, influenza A/Bethesda/MM2/H1N1 virus (A/California/04/2009/H1N1-like) infection to assess the effect of pre-existing immunity on clinical and immunological responses. Up to 80 healthy adult subjects will undergo intranasal inoculation with A/Bethesda/MM2/H1N1 virus, and their clinical manifestations, viral shedding and immunological responses will be characterized. The Primary Objective for this study is to evaluate the association of symptomatic Reverse Transcription-Polymerase Chain Reaction (RT-PCR)-positive influenza virus infection post-challenge and pre-existing Hemagglutinin Inhibition Test (HAI) antibody titers.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Biological: Influenza A/Bethesda/MM2/H1N1 Challenge	Phase 1

Detailed Description

This is a study of a reverse-engineered, Good Manufacturing Practice (GMP) grade, antiviral-sensitive, influenza A/Bethesda/MM2/H1N1 virus (A/California/04/2009/H1N1-like) infection to assess the effect of pre-existing immunity on clinical and immunological responses. Up to 80 healthy adult subjects will undergo intranasal inoculation with A/Bethesda/MM2/H1N1 virus, and their clinical manifestations, viral shedding and immunological responses will be characterized. This proposed study will establish a H1N1 influenza virus controlled human infection (CHI) model at the National Institute of Allergy and Infectious Diseases (NIAID) Division of Microbiology and Infectious Diseases (DMID)-sponsored Vaccine and Treatment Evaluation Units (VTEU) clinical study sites. The model has been developed and used by NIAID Division of Intramural Research. The proposed study will expand US research capacity to perform influenza CHI studies to advance the understanding of influenza pathogenesis and novel vaccine research and development. The Primary Objective for this study is to evaluate the association of symptomatic Reverse Transcription-Polymerase Chain Reaction (RT-PCR)-positive influenza virus infection post-challenge and pre-existing Hemagglutinin Inhibition Test (HAI) antibody titers. The Secondary Objectives for this study are: 1) To describe viral recovery by quantitative RT-PCR from study subjects at baseline and post-challenge; 2) To describe serum HAI and MN antibody responses post-challenge in healthy subjects by infection status; 3) To evaluate the association of asymptomatic RT-PCR-positive influenza virus infection (viral shedding) post-challenge and pre-existing HAI antibody titers; 4) To evaluate the association of symptomatic RT-PCR-negative status post-challenge and pre-existing HAI antibody titers; 5) To determine the frequency of serious adverse events (SAE) post-challenge.

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: A Controlled Human Infection Study of Influenza A/Bethesda/MM2/H1N1 Virus (A/California/04/2009/H1N1-like) in Healthy Subjects to Assess the Effect of Pre-Existing Immunity on Symptomatic Influenza Virus Infection
• Actual Study Start Date: Oct 22, 2019
• Actual Primary Completion Date: Mar 2, 2020
• Actual Study Completion Date: Mar 2, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1challenge virus administered intranasally via a sprayer on Day 1. N=80.	Biological: Influenza A/Bethesda/MM2/H1N1 Challenge; Reverse-genetics derived live A/California/04/2009/H1N1-like influenza virus passaged six times in Vero cells.

Outcome Measures

Primary Outcome Measures

1. Percentage of Healthy Participants Reporting Mild-to-Moderate Influenza Disease (MMID) by Baseline A/Bethesda/MM2/H1N1 Hemagglutination Inhibition (HAI) Antibody Seroprotection Status (Titer >/= 1:40 vs. Titer < 1:40) [Day 2 through Day 8]

   Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). MMID is a composite endpoint determined by the presence of viral shedding (detected by any approved positive RT-PCR test from a NP swab), accompanied by at least one the following symptoms occurring any time from Day 2 through Day 8; body aches or pain, chest tightness, chills, conjunctivitis, nasal congestion, sinus congestion, coryza, decreased appetite, diarrhea, dry cough, dyspnea, fatigue, fever, headache, lymphopenia, nausea, a 3% or more decrease in oxygen saturation from baseline, productive cough, rhinorrhea, sore throat, and sweats. The percentage of participants that developed MMID was calculated within each pre-challenge seroprotection status group.

2. Association Between Clinical or Laboratory Manifestation of MMID and A/Bethesda/MM2/H1N1 HAI Antibodies in Serum at Baseline [Day 2 to Day 8]

   Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. MMID is a composite endpoint determined by the presence of viral shedding (detected by any approved positive RT-PCR test from a NP swab), accompanied by at least one the following symptoms occurring any time from Day 2 through Day 8; body aches or pain, chest tightness, chills, conjunctivitis, nasal congestion, sinus congestion, coryza, decreased appetite, diarrhea, dry cough, dyspnea, fatigue, fever, headache, lymphopenia, nausea, a 3% or more decrease in oxygen saturation from baseline, productive cough, rhinorrhea, sore throat, and sweats. The relationship between the level of pre-challenge HAI titer and the likelihood of developing MMID during the study challenge period (Day 2 to Day 8) was assessed via logistic regression.

Secondary Outcome Measures

1. Geometric Mean Titer (GMT) of HAI Antibody in Serum at Baseline by Infection Status [Day -2]

   Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

2. GMT of HAI Antibody in Serum at Day 8 by Infection Status [Day 8]

   Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

3. GMT of HAI Antibody in Serum at Day 29 by Infection Status [Day 29]

   Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

4. GMT of HAI Antibody in Serum at Day 61 by Infection Status [Day 61]

   Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

5. Percentage of Healthy Participants Achieving HAI Seroconversion From Baseline in Serum at Day 8 by Infection Status [Day 8]

   Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. Seroconversion was defined as a pre-challenge titer 1:10 or greater and a minimum 4-fold rise in post-challenge antibody titer. The percentage of participants achieving seroconversion was calculated within each post-challenge study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

6. Percentage of Healthy Participants Achieving HAI Seroconversion in Serum From Baseline at Day 29 by Infection Status [Day 29]

   Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. Seroconversion was defined as a pre-challenge titer 1:10 or greater and a minimum 4-fold rise in post-challenge antibody titer. The percentage of participants achieving seroconversion was calculated within each post-challenge study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

7. Percentage of Healthy Participants Achieving HAI Seroconversion in Serum From Baseline at Day 61 by Infection Status [Day 61]

   Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. Seroconversion was defined as a pre-challenge titer 1:10 or greater and a minimum 4-fold rise in post-challenge antibody titer. The percentage of participants achieving seroconversion was calculated within each post-challenge study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

8. GMT of Microneutralization (MN) Antibody in Serum at Baseline by Infection Status [Day -2]

   Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

9. GMT of MN Antibody in Serum at Day 8 by Infection Status [Day 8]

   Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

10. GMT of MN Antibody in Serum at Day 29 by Infection Status [Day 29]

    Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

11. GMT of MN Antibody in Serum at Day 61 by Infection Status [Day 61]

    Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

12. Percentage of Healthy Participants Achieving MN Seroconversion From Baseline in Serum at Day 8 by Infection Status [Day 8]

    Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. Seroconversion was defined as a pre-challenge titer 1:10 or greater and a minimum 4-fold rise in post-challenge antibody titer. The percentage of participants achieving seroconversion was calculated within each post-challenge study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

13. Percentage of Healthy Participants Achieving MN Seroconversion From Baseline in Serum at Day 29 by Infection Status [Day 29]

    Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. Seroconversion was defined as a pre-challenge titer 1:10 or greater and a minimum 4-fold rise in post-challenge antibody titer. The percentage of participants achieving seroconversion was calculated within each post-challenge study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

14. Percentage of Healthy Participants Achieving MN Seroconversion From Baseline in Serum at Day 61 by Infection Status [Day 61]

    Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. Seroconversion was defined as a pre-challenge titer 1:10 or greater and a minimum 4-fold rise in post-challenge antibody titer. The percentage of participants achieving seroconversion was calculated within each post-challenge study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).

15. Duration of Viral Shedding in Nasopharyngeal (NP) Swab by Baseline HAI Seroprotection Status [Day 2 through Day 15]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). Duration of viral shedding (detected by any approved positive RT-PCR test from NP swab) was calculated from the day of the initial positive PCR result to the day of the last positive PCR result prior to discharge from the challenge unit facility, regardless of intermittent negative PCR results. The mean duration of viral shedding was calculated among participants with detected virus within each pre-challenge HAI seroprotection status group.

16. Duration of Viral Shedding in NP Swab by Baseline MN Seroprotection Status [Day 2 to Day 15]

    Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). Duration of viral shedding (detected by any approved positive RT-PCR test from NP swab) was calculated from the day of the initial positive PCR result to the day of the last positive PCR result prior to discharge from the challenge unit facility, regardless of intermittent negative PCR results. The mean duration of viral shedding was calculated among participants with detected virus within each pre-challenge MN seroprotection status group.

17. Number of Participants With Viral Shedding in NP Swab at Day 2 by Baseline HAI Seroprotection Status [Day 2]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

18. Number of Participants With Viral Shedding in NP Swab at Day 3 by Baseline HAI Seroprotection Status [Day 3]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

19. Number of Participants With Viral Shedding in NP Swab at Day 4 by Baseline HAI Seroprotection Status [Day 4]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

20. Number of Participants With Viral Shedding in NP Swab at Day 5 by Baseline HAI Seroprotection Status [Day 5]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

21. Number of Participants With Viral Shedding in NP Swab at Day 6 by Baseline HAI Seroprotection Status [Day 6]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

22. Number of Participants With Viral Shedding in NP Swab at Day 7 by Baseline HAI Seroprotection Status [Day 7]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

23. Number of Participants With Viral Shedding in NP Swab at Day 8 by Baseline HAI Seroprotection Status [Day 8]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

24. Number of Participants With Viral Shedding in NP Swab Anytime Post-challenge by Baseline HAI Seroprotection Status [Day 2 to Day 8]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

25. Number of Participants With Viral Shedding in NP Swab at Day 2 by Baseline MN Seroprotection Status [Day 2]

    Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

26. Number of Participants With Viral Shedding in NP Swab at Day 3 by Baseline MN Seroprotection Status [Day 3]

    Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

27. Number of Participants With Viral Shedding in NP Swab at Day 4 by Baseline MN Seroprotection Status [Day 4]

    Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

28. Number of Participants With Viral Shedding in NP Swab at Day 5 by Baseline MN Seroprotection Status [Day 5]

    Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

29. Number of Participants With Viral Shedding in NP Swab at Day 6 by Baseline MN Seroprotection Status [Day 6]

    Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

30. Number of Participants With Viral Shedding in NP Swab at Day 7 by Baseline MN Seroprotection Status [Day 7]

    Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

31. Number of Participants With Viral Shedding in NP Swab at Day 8 by Baseline MN Seroprotection Status [Day 8]

    Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

32. Number of Participants With Viral Shedding in NP Swab Anytime Post-challenge by Baseline MN Seroprotection Status [Day 2 through Day 8]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.

33. Time Until Detectable Viral Shedding in NP Swab by Baseline HAI Seroprotection Status [Day 2 through Day 8]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). Time until viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated as the initial day of viral shedding post-challenge for each participant. Median time to viral shedding was calculated within each pre-challenge seroprotection status group via the Kaplan-Meier estimator.

34. Time Until Detectable Viral Shedding in NP Swab by Baseline MN Seroprotection Status [Day 2 through Day 8]

    Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). Time until viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated as the initial day of viral shedding post-challenge for each participant. Median time to viral shedding was calculated within each pre-challenge seroprotection status group via the Kaplan-Meier estimator.

35. Magnitude of Viral Shedding in NP Swab by Baseline HAI Seroprotection Status [Day 2 through Day 15]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The quantity of viral load copies/mL from NP swab was measured via quantitative RT-PCR result for each post-challenge study day. The mean of each sample's quantitative PCR replicate results was calculated from available results. Total viral shedding, as observed until study discharge, was calculated as the area under the curve (AUC), then log-10 transformed. Peak viral shedding was calculated as the maximum viral load copies/mL observed until study discharge, then log-10 transformed. The mean and median of the log-10 AUC and the mean and median of the log-10 peak viral load were both calculated within each pre-challenge seroprotection status group.

36. Magnitude of Viral Shedding in NP Swab by Baseline MN Seroprotection Status [Day 2 through Day 15]

    Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The quantity of viral load copies/mL from NP swab was measured via quantitative RT-PCR result for each post-challenge study day. The mean of each sample's quantitative PCR replicate results was calculated from available results. Total viral shedding, as observed until study discharge, was calculated as the area under the curve (AUC), then log-10 transformed. Peak viral shedding was calculated as the maximum viral load copies/mL observed until study discharge, then log-10 transformed. The mean and median of the log-10 AUC and the mean and median of the log-10 peak viral load were both calculated within each pre-challenge seroprotection status group.

37. Percentage of Participants Reporting Any MMID Symptom During Challenge Period by Viral Shedding Status and Baseline HAI Seroprotection Status From Serum Measured at Baseline - RT-PCR Positive (One or More) [Day 2 through Day 8]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The presence of any of the following symptoms was assessed from Day 2 to Day 8; body aches or pain, chest tightness, chills, conjunctivitis, nasal congestion, sinus congestion, coryza, decreased appetite, diarrhea, dry cough, dyspnea, fatigue, fever, headache, lymphopenia, nausea, a 3% or more decrease in oxygen saturation from baseline, productive cough, rhinorrhea, sore throat, and sweats. The percentage of participants that reported any symptom was calculated within each pre-challenge seroprotection status group and by viral shedding status, as observed anytime from Day 2 to Day 8; RT-PCR Negative (never positive), and at least once RT-PCR Positive.

38. Percentage of Participants Reporting Any MMID Symptom During Challenge Period by Viral Shedding Status and Baseline HAI Seroprotection Status From Serum Measured at Baseline With RT-PCR Negative (None Positive) [Day 2 through Day 8]

    Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The presence of any of the following symptoms was assessed from Day 2 to Day 8; body aches or pain, chest tightness, chills, conjunctivitis, nasal congestion, sinus congestion, coryza, decreased appetite, diarrhea, dry cough, dyspnea, fatigue, fever, headache, lymphopenia, nausea, a 3% or more decrease in oxygen saturation from baseline, productive cough, rhinorrhea, sore throat, and sweats. The percentage of participants that reported any symptom was calculated within each pre-challenge seroprotection status group and by viral shedding status, as observed anytime from Day 2 to Day 8; RT-PCR Negative (never positive), and at least once RT-PCR Positive.

39. Number of Serious Adverse Events (SAE) Post-challenge Through the Inpatient Stay [Day 1 through Day 8]

    SAEs included any untoward medical occurrence that resulted in death or a congenital anomaly/birth defect; was life threatening or a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation of existing hospitalization. All events are included regardless of relationship to the study challenge.

40. Number of Serious Adverse Events (SAE) Post- Inpatient Discharge Through the Duration of the Study [Day 9 through Day 91]

    SAEs included any untoward medical occurrence that resulted in death or a congenital anomaly/birth defect; was life threatening or a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation of existing hospitalization. All events are included regardless of relationship to the study challenge.This table provides the number and percentage of participants who reported SAEs following discharge from the study hospital.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Provide written informed consent prior to initiation of any study procedure.

2. Are able to understand and comply with planned study procedures and be available for all study visits.

3. Agree to remain an inpatient for at least seven days after challenge, and until they have no virus shedding,* determined by qualitative RT-PCR for a minimum of two consecutive days post-challenge.

• For a minimum of seven days post-challenge (Study Day 8).

1. Healthy* males and non-pregnant, non-breastfeeding females**, aged >/= 18 and </=49 years of age, inclusive, at enrollment.

*Good health is defined in inclusion criteria 10.

• Females subjects of childbearing potential must agree to have a serum pregnancy test at screening, a urine pregnancy test before Chest X-Ray (CXR) performed (if more than 7 days have passed between CXR and serum pregnancy test), and a urine pregnancy test upon admission to the inpatient unit prior to CHI, and results must be negative.

1. Women of childbearing potential* must agree to use or have practiced true abstinence** or use at least 1 acceptable primary form of contraception***,****.

These criteria are applicable to females in a heterosexual relationship and child-bearing potential (i.e., the criteria do not apply to subjects in a same sex relationship).

*Not of child bearing potential - post-menopausal females (defined as having a history of amenorrhea for at least one year) or a documented status as being surgically sterile (hysterectomy, bilateral oophorectomy, tubal ligation/salpingectomy, or Essure(R) placement with history of documented radiological confirmation test at least 90 days after the procedure).

**True abstinence is 100% of time no sexual intercourse (male's penis enters the female's vagina). (Periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).

***Acceptable forms of primary contraception include monogamous relationship with a vasectomized partner who has been vasectomized for180 days or more prior to the subject receiving the influenza challenge virus, intrauterine devices, birth control pills, and injectable/implantable/insertable hormonal birth control products.

****Must use at least one acceptable primary form of contraception for at least 30 days prior to admission and at least one acceptable primary form of contraception during the remainder of the study.

1. Non-habitual smoker* of tobacco, e-cigarettes or marijuana.

*Non-habitual smokers are those who smoke no more than four cigarettes, other tobacco products, e-cigarettes or marijuana in a week for more than three months and agree not to smoke cigarettes, other tobacco products, e-cigarettes and/or marijuana products during participation in the study.

1. No self-reported or known history of alcoholism or drug use within the last 30 days and agrees to abstain from alcohol and drugs* for at least one week before admission and throughout the inpatient period.

*Including forms of marijuana not included in criterion 6.

1. Negative drug urine toxicology result on screening (i.e., amphetamines, cocaine, and opiates) and on admission to the challenge unit (i.e., amphetamines, cocaine, opiates, and cannabinoids).

2. Agree not to use the listed* prescription or over-the-counter medications within 7 days prior to inpatient stay and through inpatient stay, unless approved by the investigator.

*Oseltamivir, zanamivir, peramivir, baloxavir marboxil, amantadine (generic) and rimantadine (Flumadine and generic), aspirin, intranasal steroids, decongestants, antihistamines, and other non-steroidal anti-inflammatory drugs (NSAIDs).

1. In good health* and not have clinically significant medical, psychiatric, chronic or intermittent health conditions including those listed in the Subject Exclusion Criteria.

*Good health, as determined by medical history, medication use and physical examination to evaluate ongoing chronic medical or psychiatric diagnoses or conditions, defined as those that have been present for at least 90 days, which would not affect the assessment of the safety of subjects or the immunogenicity of challenge. These medical diagnoses or conditions should be stable for the last 90 days (no hospitalizations, emergency room (ER) or urgent care for condition (excluding musculoskeletal conditions) and not listed in the Subject Exclusion Criteria. Subjects may be on medications only if the condition or disease is stable and not deteriorating, if the medical intervention (such as device or medication) was not available during the maximal inpatient period of time, medications are not listed in the Subject Exclusion Criteria and pose no additional risk to subject safety or assessment of adverse events. This also includes no change in prescription medication, dose or frequency as a result of new symptoms or deterioration of the medical diagnosis or condition in the 90 days prior to enrollment. 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 (e.g., lowering of the dosage or frequency), as determined by the site principal investigator (PI) or designated clinician licensed to make medical diagnoses and listed on Form FDA 1572, will not be considered a deviation of this inclusion criterion.

1. Does not have an ongoing symptomatic condition* for which subject has had or has ongoing medical investigations but has not yet received a diagnosis or treatment plan.

*e.g., ongoing fatigue without a diagnosis for symptom.

1. Vital signs as follows: pulse is 47 to 99 beats per minute, inclusive; systolic blood pressure is 85 to 139 mmHg, inclusive; diastolic blood pressure is 55 to 89 mmHg, inclusive; SpO2 >95%; RR<18; oral temperature is less than 100.0 Degrees Fahrenheit.

2. Eligibility laboratory values (White Blood Cell (WBC), Absolute Lymphocyte Count, Hemoglobin (Hgb), Platelets (PLTs), Alanine Transaminase (ALT) and Creatinine (Cr)) are within acceptable parameters.

3. Body mass index (BMI) >18.5 and <35 kg/m^2 at screening.

4. Other screening tests (ECG and CXR) are within normal reference range or not deemed clinically significant by the PI or appropriate sub-investigator*.

*Designated clinician licensed to make medical diagnoses and listed on the Form FDA 1572.

1. Negative test for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) at screening blood draw.

2. Negative respiratory virus panel by BIOFIRE(R) FILMARRAY(R) respiratory panel by bioMérieux or by Luminex xTAG (R) on Day (-2), and Day (-1).

Exclusion Criteria:

1. Female subject who has a positive pregnancy test on screening or admission, is breastfeeding or planning to become pregnant from 30 days prior to challenge through the end of the study.

2. Presence of self-reported or medically documented significant medical or psychiatric condition(s)*.

*Significant medical or psychiatric conditions include but are not limited to:

• Respiratory disease (e.g., chronic obstructive pulmonary disease (COPD), asthma) requiring daily medications (Asthma medications: inhaled, oral, or intravenous (IV) corticosteroids, leukotriene modifiers, long and short acting beta agonists, theophylline, ipratropium, biologics) currently or any treatment of respiratory disease exacerbations (e.g., asthma exacerbation) in the last 5 years

• Presence of any febrile illness or symptoms suggestive of a respiratory infection within two weeks prior to Controlled Human Infection (CHI).

• Significant cardiovascular disease (e.g., congestive heart failure, cardiomyopathy, ischemic heart disease) or history of myocarditis or pericarditis as an adult.

• Neurological or neurodevelopmental conditions (e.g., epilepsy, stroke, seizures, encephalopathy, focal neurologic deficits, Guillain-Barre syndrome, encephalomyelitis or transverse myelitis).

• Ongoing malignancy or recent diagnosis of malignancy in the last five years excluding basal cell carcinoma of the skin, which is allowed.

• An autoimmune disease.

• An immunodeficiency of any cause.

• A history of diabetes.

1. Presence of immunosuppression or any medications that may be associated with impaired immune responsiveness*.

*Including, but not limited to, corticosteroids exceeding 10 mg/day of prednisone equivalent, allergy injections, immunoglobulin, interferon, immunomodulators, cytotoxic drugs, or systemic corticosteroids or other similar or toxic drugs during the preceding 12-month period prior to screening. Low dose topical and intranasal steroid preparations used for a discrete period of time are permitted.

1. Known allergy or intolerance to treatments for influenza (including but not limited to oseltamivir, baloxavir marboxil, acetaminophen).

2. Known allergy to two or more classes of antibiotics (e.g., penicillins, cephalosporins, fluoroquinolones, or glycopeptides).

3. Known allergy to excipients in the challenge virus inoculum.

4. Receipt or planned receipt of any investigational drug/investigational vaccine/licensed vaccine within 30 days prior to the date of CHI.

5. Prior enrollment in any influenza virus challenge study.

6. Currently enrolled in any investigational study or intends to enroll in such a study within the ensuing study period.

7. Receipt of any influenza vaccine six months prior to challenge or plans to receive influenza vaccine within 60 days post-challenge.

8. History of a previous severe allergic reaction of any kind with generalized urticaria, angioedema, or anaphylaxis.

9. Receipt of blood or blood products during the six months prior to the planned date of challenge.

10. History of blood donation during the two months prior to the planned date of challenge and or plans to donate blood for the duration of the study.

11. Any condition, to include medical and psychiatric conditions, that in the opinion of the Investigator, might interfere with the safety of the subject and/or study objectives.

12. Known close contact with anyone known to have influenza 7 days prior to challenge.

13. Acute medical condition with new prescription medication use in the last 30 days.

14. Significant abnormality altering the anatomy of the nose/nasopharynx* clinically significant nasal deviation, or nasal/sinus surgery within 180 days prior to challenge.

*Including significant nasal polyps.

1. History in the last five years of chronic or frequent intermittent sinusitis.

2. Recent history (180 days) of epistaxis or anatomic or neurologic abnormality impairing the gag reflex or contributing to aspiration.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Maryland Baltimore - School of Medicine - Medicine	Baltimore	Maryland	United States	21201-1509
2	Saint Louis University - Center for Vaccine Development	Saint Louis	Missouri	United States	63104-1015
3	Duke Human Vaccine Institute - Duke Vaccine and Trials Unit	Durham	North Carolina	United States	27704
4	Cincinnati Children's Hospital Medical Center - Infectious Diseases	Cincinnati	Ohio	United States	45229-3039

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Nov 4, 2020
• Statistical Analysis Plan - Dec 16, 2020
• Informed Consent Form - Oct 23, 2019

More Information

Publications

None provided.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT04044352
• Other Study ID Numbers: 18-0010; HHSN272201300015I
• First Posted: Aug 5, 2019
• Last Update Posted: Apr 28, 2021
• Last Verified: Dec 29, 2020

• 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): A/Bethesda/MM2/H1N1 Virus; Challenge; Dose Escalation; Healthy Subjects; Influenza; Live virus
• Additional relevant MeSH terms: Influenza, Human

Study Results

Participant Flow

Recruitment Details	Healthy adults, male and female, between the ages of 18 and 49, who are non-habitual smokers without medical conditions at high risk for severe complications of influenza virus infection were enrolled. Participants were enrolled between 22OCT2019 and 05DEC2019.

Arm/Group Title	Study Group
Arm/Group Description	Participants will receive 2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Period Title: Overall Study
STARTED	76
COMPLETED	65
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	Study Group
Arm/Group Description	Participants will receive 2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1challenge virus administered intranasally via a sprayer on Day 1.
Overall Participants	76
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	76 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.4 (9.2)
Sex: Female, Male (Count of Participants)
Female	30 39.5%
Male	46 60.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 6.6%
Not Hispanic or Latino	71 93.4%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.3%
Asian	1 1.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	35 46.1%
White	34 44.7%
More than one race	3 3.9%
Unknown or Not Reported	2 2.6%
Region of Enrollment (Count of Participants)
United States	76 100%
Region of Enrollment (Count of Participants)
Saint Louis University	17 22.4%
Cincinnati Children's Hospital	24 31.6%
University of Maryland	20 26.3%
Duke University	15 19.7%
Receipt of Prior Seasonal Influenza Vaccination (2018-2019) (Count of Participants)
Yes	9 11.8%
No	67 88.2%
Receipt of Prior Non-Seasonal Influenza Vaccination (2018-2019) (Count of Participants)
Yes	3 3.9%
No	73 96.1%
Baseline Seroprotection (Hemagglutination Inhibition) (Count of Participants)
Low < 1:40	39 51.3%
High >= 1:40	37 48.7%
Baseline Seroprotection (Microneutralization) (Count of Participants)
Low < 1:40	23 30.3%
High >= 1:40	53 69.7%

Outcome Measures

1. Primary Outcome

Title	Percentage of Healthy Participants Reporting Mild-to-Moderate Influenza Disease (MMID) by Baseline A/Bethesda/MM2/H1N1 Hemagglutination Inhibition (HAI) Antibody Seroprotection Status (Titer >/= 1:40 vs. Titer < 1:40)
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). MMID is a composite endpoint determined by the presence of viral shedding (detected by any approved positive RT-PCR test from a NP swab), accompanied by at least one the following symptoms occurring any time from Day 2 through Day 8; body aches or pain, chest tightness, chills, conjunctivitis, nasal congestion, sinus congestion, coryza, decreased appetite, diarrhea, dry cough, dyspnea, fatigue, fever, headache, lymphopenia, nausea, a 3% or more decrease in oxygen saturation from baseline, productive cough, rhinorrhea, sore throat, and sweats. The percentage of participants that developed MMID was calculated within each pre-challenge seroprotection status group.
Time Frame	Day 2 through Day 8

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had a baseline sample for immunogenicity, and were followed for the entire duration of the study challenge period, or at least until MMID was observed.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Baseline Seroprotection Status Low < 1:40 : MMID	77 101.3%
Baseline Seroprotection Status Low < 1:40 : No MMID	23 30.3%
Baseline Seroprotection Status High > = 1:40 : MMID	65 85.5%
Baseline Seroprotection Status High > = 1:40 : No MMID	35 46.1%

2. Primary Outcome

Title	Association Between Clinical or Laboratory Manifestation of MMID and A/Bethesda/MM2/H1N1 HAI Antibodies in Serum at Baseline
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. MMID is a composite endpoint determined by the presence of viral shedding (detected by any approved positive RT-PCR test from a NP swab), accompanied by at least one the following symptoms occurring any time from Day 2 through Day 8; body aches or pain, chest tightness, chills, conjunctivitis, nasal congestion, sinus congestion, coryza, decreased appetite, diarrhea, dry cough, dyspnea, fatigue, fever, headache, lymphopenia, nausea, a 3% or more decrease in oxygen saturation from baseline, productive cough, rhinorrhea, sore throat, and sweats. The relationship between the level of pre-challenge HAI titer and the likelihood of developing MMID during the study challenge period (Day 2 to Day 8) was assessed via logistic regression.
Time Frame	Day 2 to Day 8

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had a baseline sample for immunogenicity, and were followed for the entire duration of the study challenge period, or at least until MMID was observed.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Number [Odds Ratio]	0.81

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Group
	Comments	Pre-challenge (baseline) HAI geometric mean titer was log-2 transformed and treated as a continuous variable in the model.
	Type of Statistical Test	Other
	Comments	Likelihood ratio test was the statistical test.
Statistical Test of Hypothesis	p-Value	0.126
	Comments
	Method	Wald Chi-Square
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.62 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	A two-fold increase in HAI pre-challenge titer (i.e. one unit increase in log-2 titer) corresponds to a 19% decrease in the odds of developing MMID during the study challenge period (Day 2 through Day 8).

3. Secondary Outcome

Title	Geometric Mean Titer (GMT) of HAI Antibody in Serum at Baseline by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day -2

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
RT-PCR Positive Symptomatic	36.8
RT-PCR Positive Asymptomatic	20.0
RT-PCR Negative	117.9

4. Secondary Outcome

Title	GMT of HAI Antibody in Serum at Day 8 by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day 8

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	75
RT-PCR Positive Symptomatic	46.1
RT-PCR Positive Asymptomatic	23.7
RT-PCR Negative	122.5

5. Secondary Outcome

Title	GMT of HAI Antibody in Serum at Day 29 by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	67
RT-PCR Positive Symptomatic	87.4
RT-PCR Positive Asymptomatic	63.9
RT-PCR Negative	126.6

6. Secondary Outcome

Title	GMT of HAI Antibody in Serum at Day 61 by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day 61

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	62
RT-PCR Positive Symptomatic	78.0
RT-PCR Positive Asymptomatic	71.3
RT-PCR Negative	123.1

7. Secondary Outcome

Title	Percentage of Healthy Participants Achieving HAI Seroconversion From Baseline in Serum at Day 8 by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. Seroconversion was defined as a pre-challenge titer 1:10 or greater and a minimum 4-fold rise in post-challenge antibody titer. The percentage of participants achieving seroconversion was calculated within each post-challenge study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day 8

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	75
RT-PCR Positive Symptomatic	3.8 5%
RT-PCR Positive Asymptomatic	0 0%
RT-PCR Negative	0 0%

8. Secondary Outcome

Title	Percentage of Healthy Participants Achieving HAI Seroconversion in Serum From Baseline at Day 29 by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. Seroconversion was defined as a pre-challenge titer 1:10 or greater and a minimum 4-fold rise in post-challenge antibody titer. The percentage of participants achieving seroconversion was calculated within each post-challenge study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	67
RT-PCR Positive Symptomatic	28.3 37.2%
RT-PCR Positive Asymptomatic	28.6 37.6%
RT-PCR Negative	0 0%

9. Secondary Outcome

Title	Percentage of Healthy Participants Achieving HAI Seroconversion in Serum From Baseline at Day 61 by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. Seroconversion was defined as a pre-challenge titer 1:10 or greater and a minimum 4-fold rise in post-challenge antibody titer. The percentage of participants achieving seroconversion was calculated within each post-challenge study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day 61

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	62
RT-PCR Positive Symptomatic	18.6 24.5%
RT-PCR Positive Asymptomatic	33.3 43.8%
RT-PCR Negative	0 0%

10. Secondary Outcome

Title	GMT of Microneutralization (MN) Antibody in Serum at Baseline by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day -2

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
RT-PCR Positive Symptomatic	62.9
RT-PCR Positive Asymptomatic	44.3
RT-PCR Negative	276.7

11. Secondary Outcome

Title	GMT of MN Antibody in Serum at Day 8 by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day 8

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	75
RT-PCR Positive Symptomatic	87.7
RT-PCR Positive Asymptomatic	52.4
RT-PCR Negative	250.6

12. Secondary Outcome

Title	GMT of MN Antibody in Serum at Day 29 by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	67
RT-PCR Positive Symptomatic	159.5
RT-PCR Positive Asymptomatic	103.1
RT-PCR Negative	320.0

13. Secondary Outcome

Title	GMT of MN Antibody in Serum at Day 61 by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results. The geometric mean across samples was calculated within each study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day 61

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	62
RT-PCR Positive Symptomatic (MMID-1)	151.8
RT-PCR Positive Asymptomatic	107.2
RT-PCR Negative	287.6

14. Secondary Outcome

Title	Percentage of Healthy Participants Achieving MN Seroconversion From Baseline in Serum at Day 8 by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. Seroconversion was defined as a pre-challenge titer 1:10 or greater and a minimum 4-fold rise in post-challenge antibody titer. The percentage of participants achieving seroconversion was calculated within each post-challenge study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day 8

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	75
RT-PCR Positive Symptomatic	7.5 9.9%
RT-PCR Positive Asymptomatic	0 0%
RT-PCR Negative	0 0%

15. Secondary Outcome

Title	Percentage of Healthy Participants Achieving MN Seroconversion From Baseline in Serum at Day 29 by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. Seroconversion was defined as a pre-challenge titer 1:10 or greater and a minimum 4-fold rise in post-challenge antibody titer. The percentage of participants achieving seroconversion was calculated within each post-challenge study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day 29

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	67
RT-PCR Positive Symptomatic	26.1 34.3%
RT-PCR Positive Asymptomatic	28.6 37.6%
RT-PCR Negative	0 0%

16. Secondary Outcome

Title	Percentage of Healthy Participants Achieving MN Seroconversion From Baseline in Serum at Day 61 by Infection Status
Description	Blood samples were collected pre-challenge (Day -2) and post-challenge on Days 8, 29 and 61 for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. Seroconversion was defined as a pre-challenge titer 1:10 or greater and a minimum 4-fold rise in post-challenge antibody titer. The percentage of participants achieving seroconversion was calculated within each post-challenge study day and by infection status as observed over the study challenge period (Day 2 to Day 8); RT-PCR Negative (never positive), RT-PCR Positive Asymptomatic (participants with at least one positive PCR result but no symptoms reported), at least once RT-PCR Positive Symptomatic (or MMID).
Time Frame	Day 61

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had an available immunogenicity sample for the given study day, and were followed for the entire duration of the study challenge period, or at least until MMID was observed

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	62
RT-PCR Positive Symptomatic	18.6 24.5%
RT-PCR Positive Asymptomatic	50 65.8%
RT-PCR Negative	0 0%

17. Secondary Outcome

Title	Duration of Viral Shedding in Nasopharyngeal (NP) Swab by Baseline HAI Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). Duration of viral shedding (detected by any approved positive RT-PCR test from NP swab) was calculated from the day of the initial positive PCR result to the day of the last positive PCR result prior to discharge from the challenge unit facility, regardless of intermittent negative PCR results. The mean duration of viral shedding was calculated among participants with detected virus within each pre-challenge HAI seroprotection status group.
Time Frame	Day 2 through Day 15

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had a baseline sample for immunogenicity, and were followed for the entire duration of the study challenge period.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	61
Low < 1:40	3.8
High >= 1:40	2.3

18. Secondary Outcome

Title	Duration of Viral Shedding in NP Swab by Baseline MN Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). Duration of viral shedding (detected by any approved positive RT-PCR test from NP swab) was calculated from the day of the initial positive PCR result to the day of the last positive PCR result prior to discharge from the challenge unit facility, regardless of intermittent negative PCR results. The mean duration of viral shedding was calculated among participants with detected virus within each pre-challenge MN seroprotection status group.
Time Frame	Day 2 to Day 15

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had a baseline sample for immunogenicity, and were followed for the entire duration of the study challenge period.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	75
Low < 1:40	3.9
High >= 1:40	2.7

19. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 2 by Baseline HAI Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 2

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	35 46.1%
High >= 1:40	25 32.9%

20. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 3 by Baseline HAI Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	27 35.5%
High >= 1:40	11 14.5%

21. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 4 by Baseline HAI Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 4

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	18 23.7%
High >= 1:40	7 9.2%

22. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 5 by Baseline HAI Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	15 19.7%
High >= 1:40	0 0%

23. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 6 by Baseline HAI Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 6

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	12 15.8%
High >= 1:40	3 3.9%

24. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 7 by Baseline HAI Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	9 11.8%
High >= 1:40	1 1.3%

25. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 8 by Baseline HAI Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 8

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	75
Low < 1:40	5 6.6%
High >= 1:40	1 1.3%

26. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab Anytime Post-challenge by Baseline HAI Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 2 to Day 8

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	36 47.4%
High >= 1:40	26 34.2%

27. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 2 by Baseline MN Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 2

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	21 27.6%
High >= 1:40	39 51.3%

28. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 3 by Baseline MN Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	16 21.1%
High >= 1:40	22 28.9%

29. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 4 by Baseline MN Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 4

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	10 13.2%
High >= 1:40	15 19.7%

30. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 5 by Baseline MN Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 5

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	9 11.8%
High >= 1:40	6 7.9%

31. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 6 by Baseline MN Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 6

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	8 10.5%
High >= 1:40	7 9.2%

32. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 7 by Baseline MN Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	6 7.9%
High >= 1:40	4 5.3%

33. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab at Day 8 by Baseline MN Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 8

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	75
Low < 1:40	5 6.6%
High >= 1:40	1 1.3%

34. Secondary Outcome

Title	Number of Participants With Viral Shedding in NP Swab Anytime Post-challenge by Baseline MN Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated for available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The number of participants with viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated for each study day post-challenge (Day 2 to Day 8) and at any time during the entire challenge period within each pre-challenge seroprotection status group.
Time Frame	Day 2 through Day 8

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge with available results.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	22 28.9%
High >= 1:40	40 52.6%

35. Secondary Outcome

Title	Time Until Detectable Viral Shedding in NP Swab by Baseline HAI Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). Time until viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated as the initial day of viral shedding post-challenge for each participant. Median time to viral shedding was calculated within each pre-challenge seroprotection status group via the Kaplan-Meier estimator.
Time Frame	Day 2 through Day 8

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had a baseline sample for immunogenicity, and were followed for the entire duration of the study challenge period, or at least until viral shedding was observed.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	2.0
High >= 1:40	2.0
All Subjects	2.0

36. Secondary Outcome

Title	Time Until Detectable Viral Shedding in NP Swab by Baseline MN Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). Time until viral shedding (detected by any approved positive RT-PCR test from a NP swab) was calculated as the initial day of viral shedding post-challenge for each participant. Median time to viral shedding was calculated within each pre-challenge seroprotection status group via the Kaplan-Meier estimator.
Time Frame	Day 2 through Day 8

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had a baseline sample for immunogenicity, and were followed for the entire duration of the study challenge period, or at least until viral shedding was observed.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1 challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Low < 1:40	2.0
High >= 1:40	2.0

37. Secondary Outcome

Title	Magnitude of Viral Shedding in NP Swab by Baseline HAI Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The quantity of viral load copies/mL from NP swab was measured via quantitative RT-PCR result for each post-challenge study day. The mean of each sample's quantitative PCR replicate results was calculated from available results. Total viral shedding, as observed until study discharge, was calculated as the area under the curve (AUC), then log-10 transformed. Peak viral shedding was calculated as the maximum viral load copies/mL observed until study discharge, then log-10 transformed. The mean and median of the log-10 AUC and the mean and median of the log-10 peak viral load were both calculated within each pre-challenge seroprotection status group.
Time Frame	Day 2 through Day 15

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had a baseline sample for immunogenicity, were followed for the entire duration of the study challenge period,.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	75
Peak viral load - Low < 1:40	4.7
Peak viral load - High >= 1:40	2.1
AUC - Low < 1:40	4.7
AUC - High >= 1:40	1.8

38. Secondary Outcome

Title	Magnitude of Viral Shedding in NP Swab by Baseline MN Seroprotection Status
Description	Blood samples were collected pre-challenge (Day -2) for the MN assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The quantity of viral load copies/mL from NP swab was measured via quantitative RT-PCR result for each post-challenge study day. The mean of each sample's quantitative PCR replicate results was calculated from available results. Total viral shedding, as observed until study discharge, was calculated as the area under the curve (AUC), then log-10 transformed. Peak viral shedding was calculated as the maximum viral load copies/mL observed until study discharge, then log-10 transformed. The mean and median of the log-10 AUC and the mean and median of the log-10 peak viral load were both calculated within each pre-challenge seroprotection status group.
Time Frame	Day 2 through Day 15

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge, had a baseline sample for immunogenicity, and were followed for the entire duration of the study challenge period.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	75
Peak viral load - Low < 1:40	4.7
Peak viral load - High >= 1:40	2.9
AUC - Low < 1:40	4.6
AUC - High >= 1:40	2.7

39. Secondary Outcome

Title	Percentage of Participants Reporting Any MMID Symptom During Challenge Period by Viral Shedding Status and Baseline HAI Seroprotection Status From Serum Measured at Baseline - RT-PCR Positive (One or More)
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The presence of any of the following symptoms was assessed from Day 2 to Day 8; body aches or pain, chest tightness, chills, conjunctivitis, nasal congestion, sinus congestion, coryza, decreased appetite, diarrhea, dry cough, dyspnea, fatigue, fever, headache, lymphopenia, nausea, a 3% or more decrease in oxygen saturation from baseline, productive cough, rhinorrhea, sore throat, and sweats. The percentage of participants that reported any symptom was calculated within each pre-challenge seroprotection status group and by viral shedding status, as observed anytime from Day 2 to Day 8; RT-PCR Negative (never positive), and at least once RT-PCR Positive.
Time Frame	Day 2 through Day 8

Outcome Measure Data

Analysis Population Description

All RT-PCR Positive (one or more) participants who received the study challenge, had a baseline sample for immunogenicity, and were followed for the entire duration of the study challenge period.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	62
Any Symptom: Low < 1:40	83.3 109.6%
Any Symptom: High >= 1:40	92.3 121.4%

40. Secondary Outcome

Title	Percentage of Participants Reporting Any MMID Symptom During Challenge Period by Viral Shedding Status and Baseline HAI Seroprotection Status From Serum Measured at Baseline With RT-PCR Negative (None Positive)
Description	Blood samples were collected pre-challenge (Day -2) for the HAI assay conducted with the A/Bethesda/MM2/H1N1 virus as the antigen. The geometric mean of each sample's replicate results was calculated from available results, then grouped by seroprotection status (titer results >= 1:40 vs < 1:40). The presence of any of the following symptoms was assessed from Day 2 to Day 8; body aches or pain, chest tightness, chills, conjunctivitis, nasal congestion, sinus congestion, coryza, decreased appetite, diarrhea, dry cough, dyspnea, fatigue, fever, headache, lymphopenia, nausea, a 3% or more decrease in oxygen saturation from baseline, productive cough, rhinorrhea, sore throat, and sweats. The percentage of participants that reported any symptom was calculated within each pre-challenge seroprotection status group and by viral shedding status, as observed anytime from Day 2 to Day 8; RT-PCR Negative (never positive), and at least once RT-PCR Positive.
Time Frame	Day 2 through Day 8

Outcome Measure Data

Analysis Population Description

All RT-PCR Negative (none positive) participants who received the study challenge, had a baseline sample for immunogenicity, and were followed for the entire duration of the study challenge period.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	14
Any Symptom: Low < 1:40	100 131.6%
Any Symptom: High >= 1:40	100 131.6%

41. Secondary Outcome

Title	Number of Serious Adverse Events (SAE) Post-challenge Through the Inpatient Stay
Description	SAEs included any untoward medical occurrence that resulted in death or a congenital anomaly/birth defect; was life threatening or a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation of existing hospitalization. All events are included regardless of relationship to the study challenge.
Time Frame	Day 1 through Day 8

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge.

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Count of Participants [Participants]	0 0%

42. Secondary Outcome

Title	Number of Serious Adverse Events (SAE) Post- Inpatient Discharge Through the Duration of the Study
Description	SAEs included any untoward medical occurrence that resulted in death or a congenital anomaly/birth defect; was life threatening or a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation of existing hospitalization. All events are included regardless of relationship to the study challenge.This table provides the number and percentage of participants who reported SAEs following discharge from the study hospital.
Time Frame	Day 9 through Day 91

Outcome Measure Data

Analysis Population Description

All participants who received the study challenge

Arm/Group Title	Study Group
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1challenge virus administered intranasally via a sprayer on Day 1.
Measure Participants	76
Count of Participants [Participants]	0 0%

Adverse Events

Time Frame	All adverse events (AEs) that occurred from Receipt of Vaccination (Day 1) through final study visit (Day 91 +/- 7 days) were reported.
Adverse Event Reporting Description	Solicited AEs were assessed using MedDRA 22.0
Arm/Group Title	Group 1
Arm/Group Description	2 mL (approximately 5x10^6/mL tissue culture infective dose (TCID50)) of influenza A/Bethesda/MM2/H1N1challenge virus administered intranasally via a sprayer on Day 1. N=80. Influenza A/Bethesda/MM2/H1N1 Challenge: Reverse-genetics derived live A/California/04/2009/H1N1-like influenza virus passaged six times in Vero cells.
All Cause Mortality
	Group 1
	Affected / at Risk (%)	# Events
Total	0/76 (0%)
Serious Adverse Events
	Group 1
	Affected / at Risk (%)	# Events
Total	0/76 (0%)
Other (Not Including Serious) Adverse Events
	Group 1
	Affected / at Risk (%)	# Events
Total	41/76 (53.9%)
Blood and lymphatic system disorders
Lymphadenopathy	10/76 (13.2%)	10
Cardiac disorders
Tachycardia	8/76 (10.5%)	8
Infections and infestations
Upper Respiratory Tract Infection	5/76 (6.6%)	5
Investigations
Alanine Aminotransferase Increased	7/76 (9.2%)	11
Blood Pressure Diastolic Decreased	5/76 (6.6%)	8
Blood Pressure Increased	4/76 (5.3%)	4
Blood Pressure Systolic Increased	9/76 (11.8%)	15
Platelet Count Increased	7/76 (9.2%)	14
Respiratory Rate Increased	6/76 (7.9%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.