A Safety and Immunogenicity of Intranasal Nanoemulsion Adjuvanted Recombinant Pandemic Flu Vaccine in Healthy Adults

BlueWillow Biologics40 enrolled

Overview

The purpose of this clinical trial is to evaluate the safety and immunogenicity of BW-1014. BW-1014 is a nanoemulsion (NE) adjuvanted recombinant Hemagglutinin 5 (rH5) that would protect against pandemic flu. The study will be conducted in 40 healthy adults volunteers, age 18 - 45, in one center in the United States. The study will compare 3 different dose levels of rH5 (25µg, 50µg and 100µg rH5 in 20% NE adjuvant using a pipette dropper with rH5 control (100µg without NE adjuvant) and placebo control (saline). The investigational product will be administered in 2 doses intranasally (IN). This will be followed 6 months later with a licensed H5N1 IIV IM vaccine. In addition to safety outcome, homologous and heterologous immunological outcomes will be tested in nasal wash, serum, and blood cells.

This study is a single center, phase 1, first-in-human, single-center, randomized, placebo-controlled, double-blind study to assess the safety, tolerability, and immunogenicity of a primary series of intranasal recombinant H5 influenza vaccine with and without nanoemulsion adjuvant followed by boosting dose of licensed, intramuscular influenza A (H5N1) vaccine. Participants will be randomized in one of the following 5 arms: A. BW-1014: 25 µg / 20% NE; 8 participants. B. BW-1014: 50 µg / 20% NE; 8 participants. C. BW-1014: 100 µg / 20% NE; 8 participants. D. rH5 control: 100µg; 8 participants. E. Saline (Placebo); 8 participants. Because this is a dose escalation trial, our study has four stages with one cohort receiving vaccines at each stage. Up to 40 participants will be randomized to one of the five study groups at an allocation ratio depending on the escalation stage. If all participants proceed to vaccination, the final vaccine allocation ratio will be 1:1:1:1:1. Subjects will receive a primary series of two intranasal vaccinations of study treatment administered on Days 1 and 29. Subject dosing will proceed in a stepwise process. Each dose of adjuvanted study vaccine will be assessed in sentinel participants before the remainder of the study group is vaccinated and before proceeding to vaccination of sentinel participants with the next higher dose of adjuvanted study vaccine. Following receipt of the first vaccine dose, sentinel participants will be followed for 7 days for halting criteria and SMC data review prior to proceeding with vaccination of the remainder of the study group. All participants will subsequently receive a third dose of intramuscular, heterologous influenza A (H5N1) vaccine on Day 197. Participants will be followed for safety and immunology endpoints for one year following their second study treatment vaccination. Participants will be assessed for production of specific mucosal and humoral antibodies in addition to cellular immune response in mononuclear cells collected from peripheral blood and from nasal wash fluid throughout the study. These assessments will be to both homologous H5N1 clade 2.1 and heterologous H5N1 clade 1.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

Interventions

BW-1014: 25 µg rH5 in 20% NE - pipette - INBIOLOGICAL

20% Nanoemulsion and 25 µg recombinant H5 antigen administered intranasally by an electronic pipette (500µL) Two doses administered 4 weeks apart

BW-1014: 50 µg rH5 in 20% NE - pipette - INBIOLOGICAL

20% Nanoemulsion and 50 µg recombinant H5 antigen administered intranasally by an electronic pipette (500µL) Two doses administered 4 weeks apart

BW-1014: 100 µg rH5 in 20% NE - pipette - INBIOLOGICAL

20% Nanoemulsion and 100 µg recombinant H5 antigen administered intranasally by an electronic pipette (500µL) Two doses administered 4 weeks apart

rH5 (100 µg) control - pipette - INBIOLOGICAL

100 µg recombinant H5 antigen (without adjuvant) administered intranasally by an electronic pipette (500µL) Two doses administered 4 weeks apart

Saline (Placebo) - pipette - INBIOLOGICAL

Saline (negative control) administered intranasally by an electronic pipette (500µL) Two doses administered 4 weeks apart

H5N1 IIV - IMBIOLOGICAL

90 µg H5N1 IIV administered intramuscularly (1 mL) One booster dose administered 6 months following last immunization

Eligibility

Sex: ALLMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. Healthy men or women aged 18 through 45 years of age, inclusive. 2. Women must not be pregnant or nursing. If premenopausal, absence of pregnancy must be confirmed by a negative serum pregnancy test conducted at screening and a negative urine pregnancy test conducted at the site within 24 hours preceding receipt of vaccine. 3. Women who are not surgically sterile or at least one year post-menopausal must agree to use acceptable birth control. Acceptable birth control methods include oral, implantable, transdermal or injectable contraceptive; barrier methods such as condoms, cervical caps, or diaphragms with spermicide; abstinence from sexual relationships with a male partner, non-male sexual relationships, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more prior to the subject receiving the first study vaccination, and other reliable forms of contraception approved by the Investigator. Acceptable birth control must be used for a minimum of 30 days prior to vaccination and for 3 months following final study vaccination. 4. Subjects must be in good general health, as determined by medical history and physical examination. Acceptable vital signs and clinical laboratory examinations are within the normal range per study toxicity tables (Appendix B). Vital signs and clinical laboratory examinations meeting Grade 1 criteria may also be acceptable in the opinion of the PI or appropriate Sub-Investigator. For this study, an appropriate Sub-Investigator is a designated clinician licensed to make medical diagnoses and listed on the Form FDA 1572. Exclusionary clinical laboratory examinations may be repeated one time to assess clinical improvement in the event temporary halting criteria (described in Section 8.6.2) are met at the time of the first examination. 5. Subjects must be able to comprehend the study requirements as evidenced by a score of ≥ 70% on the comprehension assessment (two attempts permitted), be available for the required study period, and have the ability to attend scheduled visits. 6. Subjects must be able to provide written informed consent to participate in the study. 7. Subject agrees to future use of left-over specimens and to the collection of additional specimens for potential future use research. 8. Receipt of the CDC-recommended number of doses of an EUA authorized or licensed COVID-19 vaccine product ≥ four weeks prior to first study vaccination. Exclusion Criteria: 1. Presence of significant acute or chronic, uncontrolled medical or psychiatric illness (institution of new medical or surgical treatment, or a significant dose alteration for uncontrolled symptoms or drug toxicity within 3 months). This includes signs or symptoms consistent with upper or lower respiratory tract infections. 2. Participants with symptoms of COVID-19 and/or who are positive for SARS-CoV-2 by molecular testing conducted within 2 days prevaccination. 3. Have known hypersensitivity or allergy to eggs, egg or chicken protein, or other components of the Influenza Virus Vaccine, H5N1 (Sanofi Pasteur). 4. Receipt of licensed or experimental H5N1 influenza vaccine ever. 5. Subjects with a history of chronic cough, frequent sinus infections, sinusitis, allergic rhinitis, nasal polyps or obstruction, including deviated septum significant enough to obstruct the nasal openings or a history of nasal surgery. 6. Body mass index (BMI) BMI ≤ 18.5 or ≥ 40. 7. Positive serology for human immunodeficiency virus (HIV)-1 or HIV-2, hepatitis B, or hepatitis C (HCV). 8. Platelet count less than 100,000/mm prior to randomization during baseline visit. 9. History of drug or chemical abuse within the past year prior to screening. 10. History of aspiration, dysphagia, swallowing disorders, stroke or other neurologic conditions that may predispose the subject to aspiration of test articles into the respiratory tract. 11. History of Bell's palsy. 12. History of Guillain-Barré syndrome within 6 weeks of prior influenza virus vaccine. 13. Cancer or treatment for cancer, within 3 years. Basal cell carcinoma or squamous cell carcinoma are allowed, unless present on or near the nose. 14. Impaired immune responsiveness, including a history of diabetes mellitus. 15. Chronic use of inhaled or intranasal sprays including decongestants and corticosteroids. 16. A current vaper, smoker or tobacco user or a history of smoking or tobacco use within the past year prior to screening. 17. Receipt or history of receiving any medications or treatments that affected the immune system such as immune globulin, interferon, immunomodulators, cytotoxic drugs or drugs known to be frequently associated with significant major organ toxicity, or systemic corticosteroids (oral or injectable) in the past 6 months. 18. Has received or has plans to receive any licensed or authorized vaccines within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) prior to first study vaccination through Day 57. 19. History of allergic and/or anaphylactic type reaction to injected influenza vaccines or to any of the components of BW-1014 \[soybean oil, dehydrated alcohol (anhydrous ethanol), polysorbate (Tween 80), cetylpyridinium chloride (CPC), and tobacco\]. 20. Receipt of any investigational product or nonregistered drug within the 30 days before screening or currently enrolled in any investigational drug study or intends to enroll in such a study within the ensuing 13-month period. 21. Use of nasally administered prescription or over-the-counter medications within 7 days before vaccination. 22. Receipt of blood or blood products 8 weeks before screening or planned administration prior to the Week 8 visit. 23. Donation of blood or blood products within 8 weeks before screening or at any time up to the Week 4 clinic visit. If a subject presents at screening or on a vaccination date with an acute illness, the Investigator will refer to Individual Halting Criteria to assess whether to temporarily delay enrollment or vaccination until the illness is resolved.

Locations (1)

Center for Vaccine Development and Global Health, University of Maryland School of Medicine

Baltimore, Maryland, United States

Outcomes

Primary Outcomes

Safety Outcome: Number of Participants Reporting Local or Systemic Reactions After First Intranasal Vaccination

Local and systemic reactions will be assessed in the clinic within 1 hour of intranasal BW-1014, positive control, and placebo administration, including visual assessment of nasal passages

Time frame: Within one hour of first intranasal vaccination

Safety Outcome: Number of Participants Reporting Solicited Reactions and General AEs After First Intranasal Vaccination

Solicited reactions and general AEs will be assessed in follow up visit/phone call within 7 days of first intranasal vaccination with intranasal BW-1014, positive control and placebo

Time frame: 7 days

Safety Objective: Number of Participants Reporting Unsolicited AEs

Number and proportion of participants reporting unsolicited adverse events within 28 days after each intranasal vaccination with BW-1014, rH5 control, or placebo, assessed at study Days 29 and 57.

Time frame: Day 29 and Day 57 (each summarizing unsolicited adverse events occurring during the preceding 28-day period)

Safety Outcome: Number of Participants Reporting Any Hematological and Biochemical Laboratory Abnormality (Grade 1 of Higher) Within 7 Days of the First Intranasal Vaccination

Hematological and biochemical laboratory abnormalities (Grade 1 or higher) were assessed in follow-up visits within 7 days after the first intranasal vaccination with BW-1014, rH5 control, or placebo using protocol-specified hematology and clinical chemistry laboratory evaluations

Time frame: 7 days

Safety Outcome: Number of Participants Reporting Medically Attended AEs (MAAEs)

MAAEs will be assessed in follow up visits/phone calls within 28 days of primary vaccinations with intranasal BW-1014, positive control, and placebo

Time frame: 57 days

Safety Outcome: Number of Participants Reporting Serious Adverse Events (SAEs)

SAEs will be assessed by study arm. An adverse event is considered "serious" if it results in death, or a life-threatening AE, or in hospitalization, or in a substantial disruption of the ability to conduct normal life functions, or in a congenital anomaly/birth defect.

Time frame: Up to Day 393

Safety Outcome: Number of Participants Reporting Potential Immune-mediated Medical Conditions (PIMMCs)

PIMMCs will be assessed by follow up visits/phone calls following vaccinations with intranasal BW-1014, positive control, and placebo

Time frame: Up to Day 393

Safety Outcome: Number of Participants Reporting New Onset Chronic Medical Conditions (NOCMCs)

NOCMCs will be assessed by follow up visits/phone calls following vaccinations with intranasal BW-1014, positive control, and placebo

Time frame: Up to Day 393

Safety Outcome: Number of Participants Reporting Local or Systemic Reactions After Second Intranasal Vaccination

Local and systemic reactions will be assessed in the clinic within 1 hour of intranasal BW-1014, positive control, and placebo administration, including visual assessment of nasal passages

Time frame: Within one hour of second intranasal vaccination

Safety Outcome: Number of Participants Reporting Solicited Reactions and General AEs After Second Intranasal Vaccination

Solicited reactions and general adverse events were assessed during follow-up visits and telephone contacts within 7 days after the second intranasal vaccination with BW-1014, rH5 control, or placebo

Time frame: Day 36, for the preceding 7-day period

Safety Outcome: Number of Participants Reporting Any Hematological and Biochemical Laboratory Abnormality (Grade 1 of Higher) Within 14 Days of the Second Intranasal Vaccination

Hematological and biochemical laboratory abnormalities (Grade 1 or higher) were assessed during follow-up visits within 14 days after the second intranasal vaccination with BW-1014, rH5 control, or placebo.

Time frame: Day 43, for the preceding 14-day period

Secondary Outcomes

Safety Endpoint: Number of Participants Reporting Local or Systemic Reactions to Intramuscular H5N1 IIV Vaccine

Number and percentage of participants experiencing local or systemic reactions within 1 hour of vaccination with intramuscular H5N1 IIV vaccine

Time frame: Day 197

Safety Endpoint: Number of Participants Reporting Solicited Reactions and General AEs

Solicited reactions and general adverse events were assessed within 7 days after intramuscular H5N1 IIV vaccination

Time frame: Day 204, for the preceding 7-day period

Safety Endpoint: Number of Participants Reporting Unsolicited AEs

Unsolicited adverse events were assessed within 28 days after intramuscular H5N1 IIV vaccination

Time frame: Day 225, for the preceding 28-day period

Safety Endpoint: Number of Participants Reporting Any Hematological and Biochemical Laboratory Abnormality (Grade 1 of Higher)

Hematological and biochemical laboratory abnormalities (Grade 1 or higher) were assessed within 7 days after intramuscular H5N1 IIV vaccination.

Time frame: Day 204, for the preceding 7-day period

Safety Endpoint: Number of Participants Reporting Medically Attended AEs (MAAEs)

Medically attended adverse events (MAAEs) were assessed within 28 days after intramuscular H5N1 IIV vaccination

Time frame: Day 225, for the preceding 28-day period

Primary Humoral Immune Response Outcome: Serum HI Geometrical Mean Titers Levels at Baseline

Serum H5N1 (clade 2.1) hemagglutination inhibition antibody geometric mean titers (GMTs) were measured in specimens collected on the day of, but prior to the first study vaccination (baseline)

Time frame: Baseline

Primary Humoral Immune Response Outcome: Rates of Seroconversion

Data from ClinicalTrials.gov

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Serum H5N1 (clade 2.1) hemagglutination inhibition antibody seroconversion rates were assessed 28 days after the second intranasal vaccination (study Day 57). Seroconversion was defined as a pre-vaccination HI titer \<1:10 with a post-vaccination HI titer ≥1:40, or a pre-vaccination HI titer ≥1:10 with a minimum four-fold rise in post-vaccination HI antibody titer.

Time frame: Day 57 compared to Day 1

Primary Humoral Immune Response Outcome: Serum IgA ELISA Geometric Mean Titer (GMT) at Baseline

Baseline strain-specific serum IgA geometric mean titer (GMT) was measured by ELISA in specimens collected on the day of, but prior to, the first study vaccination

Time frame: Baseline

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific IgA Geometric Mean Titer (GMT) at Baseline

Mucosal vaccine-specific IgA geometric mean titer (GMT) was measured by ELISA in nasal lavage specimens collected on the day of, but prior to, the first study vaccination

Time frame: baseline

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific Activation Marker (CD69), Cytokines/Chemokines

Vaccine-specific activation marker (CD69) expression was assessed by flow cytometry in cells isolated from nasal lavage specimens collected through study Day 197 following intranasal vaccination

Time frame: Up to Day 197

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific Activation Marker (CD154), Cytokines/Chemokines

Vaccine-specific activation marker (CD154) expression was assessed by flow cytometry in cells isolated from nasal lavage specimens collected through study Day 197 following intranasal vaccination

Time frame: Up to Day 197

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific IgG Geometric Mean Titer (GMT) at Baseline

Mucosal vaccine-specific IgG geometric mean titer (GMT) was measured by ELISA in nasal lavage specimens collected on the day of, but prior to, the first study vaccination

Time frame: baseline

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific IFN-gamma

Vaccine-specific TNF-α expression was assessed by flow cytometry in cells isolated from nasal lavage specimens collected through study Day 197 following intranasal vaccination

Time frame: Up to Day 197

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific TNF-α

Vaccine-specific cytokine (TNF-α) expression was assessed by flow cytometry in cells isolated from nasal lavage specimens collected through study Day 197 following intranasal vaccination

Time frame: Up to Day 197

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific IL-4

Vaccine-specific IL-4 expression was assessed by flow cytometry in cells isolated from nasal lavage specimens collected through study Day 197 following intranasal vaccination

Time frame: Up to Day 197

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific IL-2

Vaccine-specific cytokine (IL-2) expression was assessed by flow cytometry in cells isolated from nasal lavage specimens collected through study Day 197 following intranasal vaccination

Time frame: Up to Day 197

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific IL-10

Vaccine-specific IL-10 expression was assessed by flow cytometry in cells isolated from nasal lavage specimens collected through study Day 197 following intranasal vaccination

Time frame: Up to Day 197

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific IL-21

Vaccine-specific IL-21 expression was assessed by flow cytometry in cells isolated from nasal lavage specimens collected through study Day 197 following intranasal vaccination

Time frame: Up to Day 197

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific CD107a

Vaccine-specific degranulation marker (CD107a) expression was assessed by flow cytometry in cells isolated from nasal lavage specimens collected through study Day 197 following intranasal vaccination

Time frame: Up to Day 197

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific Granzyme B

Vaccine-specific degranulation marker (Granzyme B) expression was assessed by flow cytometry in cells isolated from nasal lavage specimens collected through study Day 197 following intranasal vaccination

Time frame: Up to Day 197

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific T-cell Memory Subset (Effector Memory Cell)

Vaccine-specific effector memory T-cell subsets were assessed by flow cytometry in cells isolated from nasal lavage specimens collected through study Day 197 following intranasal vaccination

Time frame: Up to Day 197

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific T-cell Memory Subset (Central Memory Cell)

Vaccine-specific T-cell memory subset (central memory cell) expression was assessed by flow cytometry in cells isolated from nasal lavage specimens collected through study Day 197 following intranasal vaccination

Time frame: Up to Day 197

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific T-cell Memory Subset (Effector Memory CD45RA+ Cell)

Vaccine-specific T-cell memory subset (effector memory CD45RA+ cell) expression was assessed by flow cytometry in cells isolated from nasal lavage specimens collected through study Day 197 following intranasal vaccination

Time frame: Up to Day 197

Primary Humoral Immune Response Outcome: Serum H5N1 (Clade 2.1) Hemagglutination Inhibition Geometric Mean Titer (GMT) at Day 57

Serum H5N1 (clade 2.1) hemagglutination inhibition geometric mean titer (GMT) was assessed in specimens collected 28 days after the second intranasal vaccination (study Day 57)

Time frame: Day 57

Primary Humoral Immune Response Outcome: Serum IgA ELISA Geometric Mean Titer (GMT) After Both Intranasal Vaccinations

Strain-specific serum IgA geometric mean titer (GMT) was measured by ELISA in specimens collected 28 days after the second intranasal vaccination (study Day 57)

Time frame: Day 57

Primary Humoral Immune Response Outcome: Serum IgG ELISA Geometric Mean Titer (GMT) at Baseline

Baseline strain-specific serum IgG geometric mean titer (GMT) was measured by ELISA in specimens collected on the day of, but before, the first study vaccination

Time frame: Baseline

Primary Humoral Immune Response Outcome: Serum IgG ELISA Geometric Mean Titer (GMT) at Day 57

Strain-specific serum IgG geometric mean titer (GMT) was measured by ELISA in specimens collected 28 days after the second intranasal vaccination (study Day 57).

Time frame: Day 57

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific IgG Geometric Mean Titer (GMT) at Day 43

Mucosal vaccine-specific IgG geometric mean titer (GMT) was measured by ELISA in nasal lavage specimens collected 14 days after the second intranasal vaccination (study Day 43)

Time frame: Day 43

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific IgG Geometric Mean Titer (GMT) at Day 57

Mucosal vaccine-specific IgG geometric mean titer (GMT) was measured by ELISA in nasal lavage specimens collected 28 days after the second intranasal vaccination (study Day 57)

Time frame: Day 57

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific IgG Geometric Mean Titer (GMT) at Day 197

Mucosal vaccine-specific IgG geometric mean titer (GMT) was measured by ELISA in nasal lavage specimens collected immediately before intramuscular H5N1 IIV vaccination (study Day 197)

Time frame: Day 197

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific IgA Geometric Mean Titer (GMT) at Day 43

Mucosal vaccine-specific IgA geometric mean titer (GMT) was measured by ELISA in nasal lavage specimens collected 14 days after the second intranasal vaccination (study Day 43)

Time frame: Day 43

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific IgA Geometric Mean Titer (GMT) at Day 57

Mucosal vaccine-specific IgA geometric mean titer (GMT) was measured by ELISA in nasal lavage specimens collected 28 days after the second intranasal vaccination (study Day 57)

Time frame: Day 57

Primary Mucosal Immunogenicity Outcome: Mucosal Vaccine-specific IgA Geometric Mean Titer (GMT) at Day 197

Mucosal vaccine-specific IgA geometric mean titer (GMT) was measured by ELISA in nasal lavage specimens collected immediately before intramuscular H5N1 IIV vaccination (study Day 197)

Time frame: Day 197