Safety and Immunogenicity of BPL-1357, A BPL-Inactivated, Whole-Virus, Universal Influenza Vaccine

Study Description: This is a randomized, double-blinded, placebo-controlled, single-center, phase 1 clinical trial of beta-propiolactone (BPL)- inactivated quadruple influenza virus cocktail vaccine (BPL-1357) administered intramuscularly (IM) or intranasally (IN) in 2 doses 28 days apart. Participants will be randomized to one of three groups for treatment assignment. The primary hypothesis is that IN and IM BPL-1357 will be well tolerated.

Objectives:

Primary Objective:

• To assess the safety of BPL-1357 given IM or IN, compared to placebo.

Secondary Objective:

• To further assess the safety of BPL-1357 given IM or IN, compared to placebo.
• To assess the immunogenicity of BPL-1357 given IM or IN, compared to placebo.

Tertiary Objective:

• To characterize the systemic and mucosal humoral immune responses induced by BPL-1357 given IM or IN, compared to placebo.
• To further characterize the immune response induced by BPL-1357 given IM or IN through variable, diversity, and joining (VDJ) gene repertoire analysis, cytokine analysis, cytometry, transcriptomics, and assessment of T-cell responses.
• To assess the rates of influenza disease among groups given IM or IN BPL-1357 compared to placebo.

Endpoints:

Primary Endpoints:

• Type and severity (by grading) of adverse events (AEs) through vaccine 2 (V2) day 28 (D28) [28 days after vaccine dose 2].
• Type of serious adverse events (SAEs) through V2D28 [28 days after vaccine dose 2].

Secondary Endpoints:

• Safety

• Type and severity (by grading) of AEs through V2D182 [182 days after vaccine dose 2].
• Type of SAEs through V2D182 [182 days after vaccine dose 2].
• Immunogenicity

• Antibodies against H1, H3, H5, and H7 head and stalk as measured by hemagglutination inhibition (HAI) or enzyme-linked immunosorbent assay (ELISA) from blood and mucosal samples at V2D28.
• Antibodies against N1, N3, N8, and N9 as measured by neuraminidase inhibition (NAI) or ELISA from blood and mucosal samples at V2D28.

Tertiary Endpoints:

• Additional antibody titer characterization via:

• Antibodies against H1, H3, H5, and H7 head and stalk as measured by HAI or ELISA from blood and mucosal samples at V1D7, V1D14, V1D28, V2D7, V2D14, V2D56, and V2D182.
• Antibodies against N1, N3, N8, and N9 as measured by NAI or ELISA from blood and mucosal samples at V1D7, V1D14, V1D28, V2D7, V2D14, V2D56, and V2D182.
• Additional immune response characterization via:

• VDJ gene repertoire analysis.
• Cytokine analysis.
• Flow cytometric phenotyping of lymphocytes.
• Transcriptomic gene expression.
• T-cell responses.
• Influenza disease

• INCLUSION CRITERIA:

Individuals must meet all of the following criteria to be eligible for study participation:

• 18 and <= 55 years of age.

• Non-smoker (tobacco and cannabis) and does not use vape or e-cigarette products.
• Has not received influenza vaccination of any type in the 8 weeks prior to enrollment and willing to not receive influenza vaccination of any type until after the V2D56 visit. Participants who enroll in our study will be informed of the Centers for Disease Control and Prevention (CDC) recommendation to receive seasonal influenza vaccination annually.
• Has not received Coronavirus Disease 19 (COVID-19) vaccination of any type in the 4 weeks prior to enrollment and willing to not receive COVID-19 vaccination of any type until after the V2D28 visit. Participants who enroll in our study who are interested in getting a COVID-19 vaccination will be counselled to receive it prior to enrolling into our study.
• A female participant is eligible for this study if she is not pregnant or breastfeeding and meets one of the following criteria, beginning at least 4 weeks prior to enrollment through the end of the study period (V2D182):

• Is infertile, including postmenopausal status (as defined by no menses for >= 1 year) or history of hysterectomy or bilateral oophorectomy.
• Agrees to practice abstinence.
• Agrees that, with heterosexual intercourse with a fertile male partner, she will use an acceptable form of contraception and her male partner will use a condom with spermicide. Acceptable effective methods of female contraception include the following: bilateral tubal ligation, implant of levonorgestrel, injectable progestogen, intrauterine device, oral contraceptive pills, and diaphragm with spermicide.
• Able to provide informed consent.
• Able to speak English.
• Human immunodeficiency virus (HIV) uninfected with a negative test within 60 days of enrollment.
• Does not use IN medications (including but not limited to nasal sprays, sinus rinses), over-the-counter medications (including but not limited to aspirin, decongestants, antihistamines, and other nonsteroidal anti-inflammatory drugs), and herbal medications (including but not limited to herbal tea or St. John s Wort) within 14 days prior to study enrollment, and agrees not to use these mediations through the final study visit, unless approved by the investigator.
• Agrees not to donate blood or blood products from 3 months prior to enrollment through the final study visit.

Exclusion criteria

Individuals meeting any of the following criteria will be excluded from study participation:

• Presence of self-reported or medically documented significant medical condition including but not limited to:

• Chronic pulmonary disease (e.g., asthma, emphysema).
• Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart failure, cardiac surgery, ischemic heart disease, known anatomic defects).
• Chronic medical conditions requiring close medical follow-up or hospitalization during the past 5 years (e.g., insulin-dependent diabetes mellitus, renal dysfunction, hemoglobinopathies).
• Immunosuppression, immune deficiency, or ongoing malignancy.
• Neurological and neurodevelopmental conditions (e.g., Bell s palsy, cerebral palsy, epilepsy, stroke, seizures).
• Postinfectious or postvaccine neurological sequelae including GBS.
• Body mass index (BMI) <= 18 and >= 35.
• Acute illness within 7 days prior to enrollment.
• Individuals who have grade 2 or above clinically significant laboratory values outside the limits thus specified by normal laboratory parameters.
• Known allergy to influenza vaccination or excipients contained in the influenza vaccine used.
• Known allergy to lidocaine or phenylephrine.
• Receipt of blood or blood products (including immunoglobulins) within 3 months prior to enrollment.
• Receipt of any unlicensed drug within 3 months or 5.5 half-lives (whichever is greater) prior to enrollment.
• Receipt of any unlicensed vaccine within 6 months prior to enrollment, not including COVID-19 vaccines under Emergency Use Authorization.
• Self-reported or known history of alcoholism or drug abuse within 6 months prior to enrollment, or positive urine test for drugs of abuse (i.e., amphetamines, cocaine metabolites, benzodiazepines, opiates, or tetrahydrocannabinol) prior to vaccination on V1D0.
• Self-reported or known history of psychiatric or psychological issues that require treatment and are deemed by the principal investigator (PI) to be a contraindication to protocol participation.
• History of angioedema or anaphylaxis.
• History of SARS-COV-2 infection with residual or ongoing symptoms.
• Any condition or event that, in the judgment of the PI, is a contraindication to protocol participation or impairs the participant s ability to give informed consent.