BPL-1357 Against H1N1 Influenza Virus Challenge

Study Description:

This is a randomized, double-blinded, placebo-controlled, multicenter, phase 2 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. The study has 2 phases: a vaccination phase (Phase A) and a challenge phase (Phase B). In phase A participants will be randomized to 1 of 3 groups for treatment assignment: group A IM BPL-1357 plus IN placebo, group B IM placebo plus IN BPL-1357, or group C IM placebo and IN placebo. In phase B, participants will undergo influenza challenge as inpatients. The primary hypothesis is that IN and IM BPL-1357 will be safe and offer protection against mild-moderate influenza disease (MMID) caused by H1N1 influenza challenge compared to placebo.

Objectives:

Primary Objective:

• To measure the efficacy of BPL-1357, given IM or IN, in preventing MMID compared to placebo.
• To assess the safety of BPL-1357, given IM or IN as 2 doses 28 days apart, including after H1N1 influenza challenge.

Secondary Objective:

• To measure the efficacy of BPL-1357, given IM or IN, in reducing total InFLUenza Patient Reported Outcome (FLUPRO) scores compared to placebo.
• To measure the efficacy of BPL-1357, given IM or IN, in preventing shedding measured by quantitative real-time polymerase chain reaction (rtPCR) compared to placebo.
• To measure the efficacy of BPL-1357, given IM or IN, in reducing shedding duration measured by rtPCR compared to placebo.
• To assess the immunogenicity of BPL-1357 given IM or IN.

Tertiary Objective:

• To assess the correlates of protection associated with BPL-1357 against H1N1 influenza challenge.
• To characterize the systemic and mucosal humoral immune responses induced by BPL-1357 at multiple timepoints before and after influenza challenge.
• To further characterize the immune response induced by BPL-1357 and subsequent influenza challenge through variable, diversity, and joining (VDJ) gene repertoire analysis, cytokine analysis, cytometry, transcriptomics, and further assessment of B- and T-cell responses.
• To examine whether clinical outcomes and immune responses vary according to time elapsed since vaccination to clinical outcome.
• To characterize how specific HLA types influence the magnitude and type of immune response.
• To assess BPL-1357 vaccine efficacy against any community-acquired influenza during the study.

Endpoints:

Primary Endpoints:

• Efficacy: Rate of MMID, defined as a positive US Food and Drug Administration (FDA) - approved clinical test for influenza plus 1 or more influenza symptoms, in the 7 days after challenge.
• Safety:

• Solicited adverse events (AEs) occurring within 7 days of each vaccination dose recorded through questionnaires.
• Unsolicited AEs occurring within 28 days of each vaccination dose.
• Serious adverse events (SAEs) occurring through study completion or withdrawal from study.

Secondary Endpoints:

• Total FLU-PRO questionnaire scores after influenza challenge.
• Proportion of patients who shed virus after influenza challenge as measured by rtPCR.
• Mean duration (days) of shedding as measured by rtPCR.
• Immunogenicity at 28 days after vaccine dose 2 (PAD56):

• 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 PAD56.
• Antibodies against N1, N3, N8, and N9 as measured by neuraminidase inhibition (NAI) or ELISA from blood and mucosal samples at PAD56.
• Neutralizing antibodies in blood at PAD56.
• Mucosal response and seroresponse rate after vaccination, defined to be the proportion of patients having a 2.5-fold increase from baseline (PAD0) in ELISA titer and a 4-fold increase from baseline in neutralizing, HAI, or NAI titer.

Tertiary Endpoints:

• Association between pre-challenge immune markers and the occurrence of MMID.
• 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 all timepoints.
• Antibodies against N1, N3, N8, and N9 as measured by NAI or ELISA from blood and mucosal samples at all timepoints.
• Neutralizing antibodies in blood at all timepoints.
• Mucosal response and seroresponse rate after vaccination.
• Additional immune response characterization through:

• VDJ gene repertoire analysis.
• Cytokine analysis.
• Flow cytometric phenotyping of lymphocytes.
• Transcriptomic gene expression.
• B- and T-cell responses.
• Associations between time-from-vaccination to clinical outcome and immune responses.
• Associations between HLA types and immune response.
• Association of clinical endpoints such as MMID and community acquired influenza diagnosed while on study.

• INCLUSION CRITERIA:

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

• Adults >=18 and <= 55 years of age at the time of consent.
• Able to provide written informed consent.
• Non-smoker (i.e., tobacco and cannabis) and does not use vape or e-cigarette products currently. Also, must not have used any of these products extensively in the past (regular use more than 5 times per week, more than 6 months lifetime total).
• Has not received influenza vaccination of any type within 6 months prior to enrollment and consents to not receive influenza vaccination of any type until after the end of study participation (PBD63).
• Has not received any other vaccination of any type within 4 weeks prior to enrollment and consents to not receive any unlicensed vaccine until after the end of the study (PBD63).
• Has not received any broadly protective influenza vaccine in the past.
• Participants of childbearing potential must meet one of the following criteria through the end of study participation (PBD63):

• Is infertile, including postmenopausal status (as defined by age >=45 years plus no menses for >= 1 year without an alternative medical cause) or history of hysterectomy or bilateral oophorectomy.
• Agrees that, when engaging in intercourse that can result in pregnancy, they will use an acceptable or highly effective form of contraception, and their male partner will use a condom with spermicide. Acceptable methods of female contraception include

the following:

• Bilateral tubal ligation
• Implant of levonorgestrel
• Injectable progestogen
• Oral contraceptive pills
• Diaphragm with spermicide
• Intrauterine device (IUD)
• Sexual abstinence
• Vasectomized partner
• Able to speak and understand English.
• A negative HIV test within 6 months before enrollment.
• Has not used IN medications (including but not limited to nasal sprays, sinus rinses), and has not routinely used 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 (about 2 weeks) prior to study enrollment and agrees not to use these medications until after the end of study participation (PBD63), unless approved by the investigator.
• Agrees not to donate blood or blood products from enrollment through the final study visit (PBD63).
• Not planning on cohabitating with any high-risk individuals (e.g., infants, elderly, those with high-risk conditions (e.g., pregnancy, medical conditions such as those outlined in exclusion criterion 1) for at least 2 weeks after discharge from the inpatient portion of this study.
• Participant is willing and able to comply with all trial procedures.

Exclusion criteria

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

• Current medical conditions (self-reported or medically documented) 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 (e.g., insulin-dependent diabetes mellitus, renal dysfunction, hemoglobinopathies).
• Immunosuppression, immune deficiency, or ongoing malignancy.
• Neurological and neurodevelopmental condition (e.g., Bell s palsy, cerebral palsy, epilepsy, seizures).
• Body mass index (BMI) <18 and >35.
• Pregnant or breastfeeding.
• History of postinfectious or postvaccine neurological sequelae including GBS.
• History of stroke within the past 5 years.
• Acute illness within 7 days prior to enrollment (PAD0).
• Known allergy to influenza vaccination or components contained in the influenza vaccine being used.
• Known allergy to influenza treatments (including oseltamivir or nonsteroidal anti-inflammatory medications).
• Known allergy to 2 or more classes of antibiotics (e.g., penicillins, cephalosporins, fluoroquinolones, or glycopeptides).
• Receipt of blood or blood products (including immunoglobulins) within 3 months prior to enrollment.
• Receipt of any unlicensed drug or investigational agent within 3 months or 5.5 half-life (whichever is greater) prior to enrollment.
• Receipt of any unlicensed vaccine within 6 months prior to enrollment.
• Self-reported or known history of alcoholism or drug abuse or use within 6 months prior to enrollment, or positive urine test for illicit drugs (i.e., amphetamines, cocaine metabolites, benzodiazepines, opiates, but not tetrahydrocannabinol) prior to vaccination on PAD0.
• Self-reported or known history of psychiatric or psychological issues that require treatment and are deemed by the PI to be a contraindication to protocol participation.
• History of angioedema or anaphylaxis.
• Study site staff who directly report to the study or site PI are excluded from participation.
• Any condition, event or lab value that, in the judgment of the investigator, is a contraindication to protocol participation or would place the participant at increased risk for participation.
• Any condition or event that, in the judgment of the investigator, impairs the participant's ability to give informed consent.

Individuals meeting any of the following criteria will be excluded from participation in Phase B:

• Positive urine test for illicit drugs (i.e., amphetamines, cocaine metabolites, benzodiazepines, opiates, but not tetrahydrocannabinol) prior to inoculation (PBD0).
• Acute illness within 7 days prior to inoculation with the human challenge virus (PBD0).
• Grade 3 or greater sign, symptom, or lab abnormality that is clinically significant and (in the opinion of the site PI) puts the participant at higher risk of adverse effects with influenza challenge.
• Pregnant or breastfeeding.
• Positive test for influenza within 8 weeks prior to challenge.