Safety and Immunogenicity of Artificial Invaplex (Shigella Flexneri 2a InvaplexAR)

Study Overview
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Brief Summary
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This study is an open-label, dose-escalating Phase 1 investigation of S. flexneri 2a InvaplexAR vaccine. A total of up to 40 subjects will receive one of four S. flexneri 2a InvaplexAR vaccine doses. The vaccine will be administered intranasally (without adjuvant).

Detailed Description
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The vaccine will be administered on Days 0,14, and 28. Volunteers (10 per group [8 minimum]) will receive the same dose at each vaccination dependent upon group assignment. Groups will be divided according to the table below. An interval no less than 1 week will separate the third dose of a group from the first dose of the next group (receiving an increased InvaplexAR dose). Blood, stool, and saliva specimens will be collected at pre-specified intervals to examine systemic and mucosal vaccine antigen-specific immune responses. Ocular tear samples will be collected in groups C and D. Vaccine safety will be actively monitored during vaccination and for 28 days following the third vaccine dose. The decision to advance to the next dose level is based on the safety assessment (not immunogenicity). A dose level with no occurrence of stopping criteria in the 7 days following the last vaccine dose will prompt moving to the next higher level. All safety data will be summarized and reviewed with the research monitor prior to dose escalation. In addition, a report of all safety data will be provided to the sponsor's safety office for informational purposes.

Official Title
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A Phase 1 Open-label, Dose Escalating Study of Artificial Shigella Flexneri 2a InvaplexAR Administered Intranasally to Healthy, Adult Volunteers to Evaluate Safety and Immunogenicity

Conditions
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Shigellosis, Bacillary Dysentery

Intervention / Treatment
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* Biological: Shigella flexneri 2a InvaplexAR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, adult, male or female, age 18 to 45 years (inclusive) at the time of enrollment. Completion and review of comprehension test (achieved > 70% accuracy). Signed informed consent document. Available for the required follow-up period and scheduled clinic visits. Women: Negative pregnancy test with understanding (through informed consent process) to not become pregnant nor to breastfeed during the study or within 3 months following last vaccination Exclusion Criteria: Health problems (for example, chronic medical conditions such as psychiatric conditions, diabetes mellitus, hypertension, or any other conditions that might place the subjects at increased risk of adverse events)- study clinicians, in consultation with the PI, will use clinical judgment on a case-by-case basis to assess safety risks under this criterion. The PI will consult with the Research Monitor as appropriate. Clinically significant abnormalities on physical examination (chronic sinusitis or seasonal rhinitis) which compromise identification and interpretation of potential vaccine associated adverse effects. Use of immunosuppressive and/or immunomodulative drugs such as corticosteroids or chemotherapeutics that may influence antibody development. Immunosuppressive illnesses (including IgA deficiency defined by serum IgA below level of detection or <7mg/dL). Participation in research involving another investigational product (defined as receipt of an investigational product or exposure to an invasive investigational device) 30 days before planned date of first vaccination or anytime throughout the duration of the study until the last study safety visit. Positive blood test for HBsAG, HCV, HIV-1/HIV-2. Clinically significant abnormalities on basic laboratory screening. Presence of significant unexplained laboratory abnormalities that in the opinion of the PI may potentially confound the analysis of the study results. Current smoker or smoker in past 1 year ('smoker' defined as daily cigarette, cigar, or pipe use for a period of at least 1 month). Research specific Structural abnormalities on sinus/nasal cavity examination. Rhinoplasty. Nasal polyps. Nasal ulcers. Deviated nasal septum. This question is being used to determine whether the volunteer has a clinically significant deviated septum that causes nasal obstruction (thereby causing difficulty breathing), interferes with normal sinus drainage, or obscures visualization of the posterior nasal cavity complicating examination and safety monitoring.. Chronic sinusitis/rhinitis. Current or planned use of nasal topical corticosteroids and/or nasal spray medications in the 4 weeks prior to dosing or during the study vaccination period. Current or recent history (in the past 5 years) of reactive airway disease (asthma), chronic obstructive pulmonary disease, or chronic bronchitis. History of Bell's palsy. Chronic use (weekly or more often) of anti-diarrheal, anti-constipation, or antacid therapy (excluding use associated with spicy meals). Abnormal stool pattern (fewer than 3 stools per week or more than 3 stools per day) on a regular basis; loose or liquid stools on other than an occasional basis. Personal or family history of inflammatory arthritis. Positive blood test for HLA-B27. History of allergy to any vaccine. Prior Exposure to Shigella Serum IgG titer ≥ 2500 to Shigella flexneri 2a LPS. History of microbiologically confirmed Shigella infection in the past 3 years. Received previous experimental Shigella vaccine or live Shigella challenge. Travel to countries with symptoms of travelers' diarrhea where Shigella or other enteric infections are endemic (most of the developing world) within the past 6 months prior to dosing. Occupation involving handling of Shigella bacteria currently, or in the past 3 years.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 10 μg S. flexneri 2a Invaplex<br>10 subjects vaccinated on days 0, 14, 28 | Biological: Shigella flexneri 2a InvaplexAR<br>* The investigational product is S. flexneri 2a InvaplexAR. The product is composed of three individual components IpaB, IpaC, and LPS. The components were assembled into the high molecular weight S. flexneri 2a InvaplexAR complex and subsequently purified by ion-exchange chromatography yielding a bulk lot.<br>|
| Active Comparator: 50 μg S. flexneri 2a Invaplex<br>10 subjects vaccinated on days 0, 14, 28 | Biological: Shigella flexneri 2a InvaplexAR<br>* The investigational product is S. flexneri 2a InvaplexAR. The product is composed of three individual components IpaB, IpaC, and LPS. The components were assembled into the high molecular weight S. flexneri 2a InvaplexAR complex and subsequently purified by ion-exchange chromatography yielding a bulk lot.<br>|
| Active Comparator: 250 μg S. flexneri 2a Invaplex<br>10 subjects vaccinated on days 0, 14, 28 | Biological: Shigella flexneri 2a InvaplexAR<br>* The investigational product is S. flexneri 2a InvaplexAR. The product is composed of three individual components IpaB, IpaC, and LPS. The components were assembled into the high molecular weight S. flexneri 2a InvaplexAR complex and subsequently purified by ion-exchange chromatography yielding a bulk lot.<br>|
| Active Comparator: 500 μg S. flexneri 2a Invaplex<br>10 subjects vaccinated on days 0, 14, 28 | Biological: Shigella flexneri 2a InvaplexAR<br>* The investigational product is S. flexneri 2a InvaplexAR. The product is composed of three individual components IpaB, IpaC, and LPS. The components were assembled into the high molecular weight S. flexneri 2a InvaplexAR complex and subsequently purified by ion-exchange chromatography yielding a bulk lot.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment Related Adverse Events | Number of adverse events related to the vaccine for each arm | 166 days | 
| Antibody Titers Against IgG and IgA Immunizing Antigens | Serum samples will be assayed for antibody titers against the immunizing antigens LPS, IpaB, IpaC, and S. flexneri 2a Invaplex at screening, and Days 0, 14, 28, 35, 42, and 56 for 36 subjects. Previously established high-titer specimens will be included on each plate to track day to day interassay variation. For each antigen, pre- and post-vaccination serum samples will be assayed side-by-side. The antibody titer assigned to each sample will represent the geometric mean of duplicate tests performed on 2 different days. Reciprocal endpoint titers < 5 will be assigned a value of 2.5 for computational purposes. Seroconversion will be defined as a > 4-fold increase in endpoint titer between pre-and post-vaccination samples AND a post-vaccination reciprocal titer >10. | At screening and Days 0, 14, 28, 35, 42, and 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IgG and IgA Antigen-Specific Antibody Secreting Cell (ASC) Mucosal Responses | ASC responses were assessed using isolated peripheral blood mononuclear cells (PBMCs). For each antigen, pre- and post-vaccination samples were tested on the same plates for total and vaccine-specific numbers. The ASC responses indirectly reflect intestinal immune responses through measurement of antigen-specific B-lymphocytes in systemic circulation before homing to gut effector sites. An ASC response was defined as > 10 ASCs above baseline. | 56 Days | 
| IgG and IgA Antigen-Specific Antibody Lymphocyte Supernatant (ALS) Mucosal Responses | ALS responses were assessed using isolated peripheral blood mononuclear cells (PBMCs). For each antigen, pre- and post-vaccination samples were tested on the same plates for total and vaccine-specific numbers. The ALS responses indirectly reflect intestinal immune responses through measurement of antigen-specific B-lymphocytes in systemic circulation before homing to gut effector sites. An ALS response was defined as a ≥ 4-fold increase over baseline ALS titers. | 56 Days |