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:
1. To measure the efficacy of BPL-1357, given IM or IN, in preventing MMID compared to placebo.
2. To assess the safety of BPL-1357, given IM or IN as 2 doses 28 days apart, including after H1N1 influenza challenge.
Secondary Objective:
1. To assess the correlates of protection associated with BPL- 1357 against H1N1 influenza challenge.
2. To measure the efficacy of BPL-1357, given IM or IN, in reducing total InFLUenza Patient Reported Outcome (FLUPRO) scores compared to placebo.
3. 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.
4. To measure the efficacy of BPL-1357, given IM or IN, in reducing shedding duration measured by rtPCR compared to placebo.
5. To assess the immunogenicity of BPL-1357 given IM or IN.
Tertiary Objective:
1. To characterize the systemic and mucosal humoral immune responses induced by BPL-1357 at multiple timepoints before and after influenza challenge.
2. 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.
3. To assess time-from-vaccination with clinical outcomes.
4. To assess HLA types with immune responses.
5. To assess BPL-1357 vaccine efficacy against any community-acquired influenza during the study.
Endpoints:
Primary Endpoints:
1. 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.
2. Safety:
1. Solicited adverse events (AEs) occurring within 7 days of each vaccination dose recorded through questionnaires.
2. Unsolicited AEs occurring within 28 days of each vaccination dose.
3. Serious adverse events (SAEs) occurring through study completion or withdrawal from study.
Secondary Endpoints:
1. Correlations and relationships between clinical outcomes and immune responses.
2. Total FLU-PRO questionnaire scores after influenza challenge.
3. Proportion of patients who shed virus after influenza challenge as measured by rtPCR.
4. Mean duration (days) of shedding as measured by rtPCR.
5. Immunogenicity at 28 days after vaccine dose 2 (PAD56):
1. 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.
2. Antibodies against N1, N3, N8, and N9 as measured by neuraminidase inhibition (NAI) or ELISA from blood and mucosal samples at PAD56.
Tertiary Endpoints:
1. Additional antibody titer characterization via:
1. Antibodies against H1, H3, H5, and H7 head and stalk as measured by HAI or ELISA from blood and mucosal samples at all timepoints.
2. Antibodies against N1, N3, N8, and N9 as measured by NAI or ELISA from blood and mucosal samples at all timepoints.
2. Additional immune response characterization through:
1. VDJ gene repertoire analysis.
2. Cytokine analysis.
3. Flow cytometric phenotyping of lymphocytes.
4. Transcriptomic gene expression.
5. B- and T-cell responses.
3. Correlations and relationships between time-from-vaccination and clinical outcomes and immune responses.
4. Relationship between HLA types and immune responses.
5. Integrated challenge endpoints (e.g., MMID, infection) with any community acquired influenza diagnosed while on study.
