Influenza Challenge Study to Determine the Optimal Infection Dose and Safety of a Recombinant H3N2 (A/Texas/71/2017 (H3N2, Clade 3C3a) Influenza Strain

Recruiting at 3 trial locations

Overseen By Christopher Woods

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Corticosteroids, Immunosuppressants, Allergy injections, others

Disqualifiers: Respiratory disease, Cardiovascular disease, Neurological conditions, Autoimmune disease, Immunodeficiency, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial uses a specially made flu virus to find the safest dose that still makes people sick. Healthy adults are chosen because they are less likely to have other health issues. Researchers give different doses of the virus and watch how the body responds to find the best amount for future studies.

Will I have to stop taking my current medications?

The trial requires participants to stop using certain medications, such as specific antiviral drugs and over-the-counter medications like aspirin and NSAIDs, at least 7 days before and during the confinement period, unless approved by the investigator. If you are on other medications, it is best to discuss with the study team to see if they are allowed.

Is the treatment generally safe for humans?

The treatment, evaluated under different names, has been studied in various contexts, including influenza vaccines. Some studies report that vaccines are generally well tolerated, but allergic reactions like anaphylaxis (a severe allergic reaction) can occur in some individuals. These reactions may not be directly caused by the vaccine's unique components. ^{1 2 3 4 5}

How does the Influenza RG-A/Texas/71/2017 (H3N2) Challenge treatment differ from other influenza treatments?

The Influenza RG-A/Texas/71/2017 (H3N2) Challenge treatment is unique because it involves a specific H3N2 strain that has evolved to escape antibodies elicited by existing vaccines, making it a valuable tool for studying immune responses and vaccine effectiveness against this variant. This strain has specific changes in its hemagglutinin protein that affect how it binds to cells and evades immune detection, which is not typically addressed by standard influenza vaccines. ^{6 7 8 9 10}

What data supports the effectiveness of the drug Influenza RG-A/Texas/71/2017 (H3N2) Challenge?

The research indicates that influenza vaccines, including those targeting H3N2 strains, often face challenges due to the virus's ability to mutate, leading to reduced effectiveness. However, the World Health Organization updates vaccine formulations to improve their match with circulating strains, which suggests ongoing efforts to enhance vaccine effectiveness. ^{11 12 13 14 15}

Are You a Good Fit for This Trial?

Inclusion Criteria

Provide written informed consent prior to initiation of any study procedure

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

Agree to remain an inpatient for at least 7 days after challenge AND until they have no viral shedding*, determined by qualitative Reverse Transcription - Polymerase Chain Reaction (RT-PCR) beginning on Study Day 6

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Challenge

Participants are challenged with a recombinant H3N2 influenza virus to determine the optimal infection dose and safety

1 day

1 visit (in-person)

Post-challenge Monitoring

Participants are monitored for viral shedding, clinical symptoms, and immune responses

8-10 days

Daily monitoring (inpatient)

Follow-up

Participants are monitored for safety and effectiveness after the challenge

57 days

What Are the Treatments Tested in This Trial?

Interventions

• Influenza RG-A/Texas/71/2017 (H3N2) Challenge
• Placebo

How Is the Trial Designed?

Group I: Cohort 3B Experimental Treatment 2 Interventions

10\^6 TCID50 of recombinant H3N2 (A/Texas/71/2017, clade 3C3a) 1.0 mL (0.5 mL per nostril) influenza virus (n=17) and Sham Sucrose phosphate glutamate (SPG) inoculum 1.0 mL (0.5 mL per nostril) (n=1) administered intranasally on Day 1. N = 18

Group II: Cohort 3A Experimental Treatment 2 Interventions

10\^6 TCID50 of recombinant H3N2 (A/Texas/71/2017, clade 3C3a) 1.0 mL (0.5 mL per nostril) influenza virus (n=17) and Sham Sucrose phosphate glutamate (SPG) inoculum 1.0 mL (0.5 mL per nostril) (n=1) administered intranasally on Day 1. If no safety threshold is met (halting conditions) proceed to Cohort 3B. N = 18

Group III: Cohort 2C Experimental Treatment 2 Interventions

10\^5 TCID50 of recombinant H3N2 (A/Texas/71/2017, clade 3C3a) 1.0 mL (0.5 mL per nostril) influenza virus (n=12) and Sham Sucrose phosphate glutamate (SPG) inoculum 1.0 mL (0.5 mL per nostril) (n=1) administered intranasally on Day 1. If 70% or more of the subjects in Cohorts 2A, 2B, and 2C combined meet the case definition for influenza then the optimal dose of 10\^4 TCID50 will be selected. Cumulatively, if fewer than 70% of subjects in Cohorts 2A, 2B, and 2C meet the case definition for influenza the dose will escalate to include Cohort 3A. N = 13

Group IV: Cohort 2B Experimental Treatment 2 Interventions

10\^5 TCID50 of recombinant H3N2 (A/Texas/71/2017, clade 3C3a) 1.0 mL (0.5 mL per nostril) influenza virus (n=12) and Sham Sucrose phosphate glutamate (SPG) inoculum 1.0 mL (0.5 mL per nostril) (n=1) administered intranasally on Day 1.If 70% or more subjects in Cohort 2A and 2B meet the case definition for influenza, proceed to Cohort 2C. Cumulatively, if fewer than 70% of subjects in Cohorts 2A and 2B meet the case definition for influenza, the dose will escalate to include Cohort 3A N = 13

Group V: Cohort 2A Experimental Treatment 2 Interventions

10\^5 TCID50 of recombinant H3N2 (A/Texas/71/2017, clade 3C3a) 1.0 mL (0.5 mL per nostril) influenza virus (n=12) and Sham Sucrose phosphate glutamate (SPG) inoculum 1.0 mL (0.5 mL per nostril) (n=1) administered intranasally on Day 1. If 70% or more subjects in Cohort 2A meet the case definition for influenza, proceed to Cohort 1B. If fewer than 70% of subjects meet the case definition for influenza in Cohort 2A, the dose will escalate to include Cohort 3A. N = 13

Group VI: Cohort 1C Experimental Treatment 2 Interventions

10\^4 TCID50 of recombinant H3N2 (A/Texas/71/2017, clade 3C3a) 1.0 mL (0.5 mL per nostril) influenza virus (n=12) and sham sucrose phosphate glutamate (SPG) inoculum 1.0 mL (0.5 mL per nostril) (n=1) administered intranasally on Day 1. If 80% or more of the subjects in Cohorts 1A, 1B, and 1C combined meet the case definition for influenza then the optimal dose of 104 TCID50 will be selected. Cumulatively, if fewer than 80% of subjects in Cohorts 1A, 1B, and 1C meet the case definition for influenza the dose will escalate to include Cohort 2A. N = 13

Group VII: Cohort 1B Experimental Treatment 2 Interventions

10\^4 TCID50 of recombinant H3N2 (A/Texas/71/2017, clade 3C3a) 1.0 mL (0.5 mL per nostril) influenza virus (n=12) and Sham Sucrose phosphate glutamate (SPG) inoculum 1.0 mL (0.5 mL per nostril) (n=1) administered intranasally on Day 1. If 80% or more subjects in Cohort 1A and 1B meet the case definition for influenza, proceed to Cohort 1C. Cumulatively, if fewer than 80% of subjects in Cohorts 1A and 1B meet the case definition for influenza, the dose will escalate to include Cohort 2A. N = 13

Group VIII: Cohort 1A Experimental Treatment 2 Interventions

10\^4 TCID50of recombinant H3N2 (A/Texas/71/2017, clade 3C3a) 1.0 mL (0.5mL per nostril) influenza virus (n=12) and Sham Sucrose phosphate glutamate (SPG) inoculum 1.0 mL (0.5mL per nostril) (n=1) administered intranasally on Day 1. If 80% or more subjects in Cohort 1A meet the case definition for influenza, proceed to Cohort 1B. If fewer than 80% of subjects meet the case definition for influenza in Cohort 1A, the dose will escalate to include Cohort 2A. N = 13

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

The 2012 trivalent inactivated influenza vaccine did not significantly prevent hospital admissions for confirmed influenza A(H3N2) infection, as shown in a study of 92 patients.

Vaccination status did not influence the length of hospital stay or the final clinical outcomes for patients infected with the H3N2 strain, indicating limited efficacy of the vaccine against this specific influenza virus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of effect of seasonal trivalent influenza vaccine against influenza A(H3N2) infections in hospitalised patients in winter 2012. Buchanan, J., Buckley, C., Jennings, LC., et al.[2014]

In a study monitoring approximately 3.6 million doses of inactivated influenza vaccine (IIV) and 250,000 doses of live attenuated influenza vaccine (LAIV), no increased risk of adverse events such as seizures, Guillain-Barré syndrome, encephalitis, or anaphylaxis was found following vaccination.

The surveillance indicated that the 2012-2013 influenza vaccines were safe, as no elevated risks were identified compared to historical controls or self-matched intervals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absence of associations between influenza vaccines and increased risks of seizures, Guillain-Barré syndrome, encephalitis, or anaphylaxis in the 2012-2013 season. Kawai, AT., Li, L., Kulldorff, M., et al.[2022]

The wild-type influenza A/Bethesda/MM1/H3N2 challenge virus was safely administered to 37 healthy volunteers, resulting in mild to moderate influenza disease in 32% of participants, indicating its potential for studying influenza pathogenesis and immunity.

Compared to the A(H1N1)pdm09 challenge virus, the H3N2 virus caused less severe disease and lower viral shedding, suggesting that preexisting immunity may play a significant role in limiting viral replication and symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Dose-finding Study of a Wild-type Influenza A(H3N2) Virus in a Healthy Volunteer Human Challenge Model. Han, A., Czajkowski, LM., Donaldson, A., et al.[2021]

Citations

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Enhanced Genetic Characterization of Influenza A(H3N2) Viruses and Vaccine Effectiveness by Genetic Group, 2014-2015. [2022]

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Cell-Mediated Immunity Against Antigenically Drifted Influenza A(H3N2) Viruses in Children During a Vaccine Mismatch Season. [2022]

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Identification of Hemagglutinin Residues Responsible for H3N2 Antigenic Drift during the 2014-2015 Influenza Season. [2022]

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Lack of effect of seasonal trivalent influenza vaccine against influenza A(H3N2) infections in hospitalised patients in winter 2012. [2014]

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Nursing home outbreak of influenza A (H3N2): evaluation of vaccine efficacy and influenza case definitions. [2019]

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Accelerating Influenza Research: Vaccines, Antivirals, Immunomodulators and Monoclonal Antibodies. The Manufacture of a New Wild-Type H3N2 Virus for the Human Viral Challenge Model. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Absence of associations between influenza vaccines and increased risks of seizures, Guillain-Barré syndrome, encephalitis, or anaphylaxis in the 2012-2013 season. [2022]

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Postmarketing safety surveillance of trivalent recombinant influenza vaccine: Reports to the Vaccine Adverse Event Reporting System. [2018]

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A Dose-finding Study of a Wild-type Influenza A(H3N2) Virus in a Healthy Volunteer Human Challenge Model. [2021]

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Comparative immunogenicity of recombinant influenza hemagglutinin (rHA) and trivalent inactivated vaccine (TIV) among persons > or =65 years old. [2009]

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Antigenic and virological properties of an H3N2 variant that continues to dominate the 2021-22 Northern Hemisphere influenza season. [2023]

12. United States pubmed.ncbi.nlm.nih.gov

Differential Antibody Recognition of H3N2 Vaccine and Seasonal Influenza Virus Strains Based on Age, Vaccine Status, and Sex in the 2017-2018 Season. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Insights into the antigenic advancement of influenza A(H3N2) viruses, 2011-2018. [2020]

14. England pubmed.ncbi.nlm.nih.gov

H3N2 Mismatch of 2014-15 Northern Hemisphere Influenza Vaccines and Head-to-head Comparison between Human and Ferret Antisera derived Antigenic Maps. [2022]

15. Netherlands pubmed.ncbi.nlm.nih.gov

Generation and characterization of monoclonal antibodies against the hemagglutinin of H3N2 influenza A viruses. [2022]