Safety, Tolerability, and Immunogenicity of One Dose of NDV 3A Vaccine in People With STAT3-Mutated Hyper-IgE Syndrome

Study Overview
=================
Brief Summary
-----------------
Background: AD-HIES is a disease that weakens the immune system. It puts people at risk for infections, particularly Staph and Candida infections. Researchers want to test a vaccine that may help keep people from getting these infections, which would help people with AD-HIES. Objective: To test the new vaccine NDV-3A for protection against infection from the yeast Candida and the bacterium Staphylococcus aureus (Staph). Eligibility: Adults ages 18-55 who have AD-HIES Healthy volunteers ages 18-55 Design: Participants will have 6-7 study visits over 6-7 months. They will also be contacted by phone in between some visits. Participants will be screened with a medical history, physical exam, and blood and urine tests. Participants will have 2 baseline visits. They will have repeat the screening tests. They will have samples of saliva, stool, skin, mucus (oral, nasal, and/or vaginal) collected. Vaginal and stool samples are optional. Any eczema on their skin will be looked at. Participants will fill out symptom diary cards to record how they feel. Participants will have the NDV-3A vaccine injected into a muscle in the arm. Participants will return the next 2 days. They will have a physical exam. Blood will be collected. Participants will have 2 more follow-up visits at the NIH. They will have a physical exam. They will have blood, saliva, stool, skin, vaginal fluid, and/or mucus samples collected. Vaginal and stool samples are optional. Participants will be called once a month for 5 months after the vaccination. There is an optional visit about 6 weeks after the vaccination. Participants will provide a blood sample at this visit.

Detailed Description
-----------------
Autosomal-dominant hyper-IgE syndrome (AD-HIES) is characterized by recurrent Staphylococcus aureus and Candida epithelial infections, which is thought to be due, in part, to a lack of Th17 cell differentiation, thus impairing epithelial immunity. Treatment of AD-HIES is primarily supportive with prophylactic antibiotics; however, this is limited by microbial resistance and intolerance of medications, and infections do still occur. Immunological intervention with a vaccine could improve quality of life by preventing these infections altogether. The NDV-3A vaccine consists of a recombinant protein derived from the Candida Als3 adhesion protein. This protein is homologous to surface proteins on S aureus and has been shown in preclinical studies to protect against both intravascular and subcutaneous challenge with S aureus. Therefore, NDV-3A represents not only the first antifungal vaccine, but also the first vaccine to provide cross-kingdom protection. In Phase 1 and Phase 2 studies in healthy volunteers (150 receiving vaccine), the safety profile of this vaccine is very reassuring as the vaccine elicits a strong antibody response after a single dose in all vaccinees as well as a Th1 and/or Th17 response in the majority of vaccinees. We will enroll 20 healthy adult volunteers and 20 adults with AD-HIES in an open-label, single-dose study to assess the immunological response to and the safety/tolerability of the NDV-3A vaccine. We anticipate an increase in baseline anti-Als3 IgG within 2 weeks post-vaccination.

Official Title
-----------------
A Phase 2a Study to Evaluate the Safety, Tolerability, and Immunogenicity of One Dose of NDV-3A Vaccine in Patients With STAT3-Mutated Hyper-IgE Syndrome

Conditions
-----------------
Autosomal-dominant Hyper-IgE Syndrome

Intervention / Treatment
-----------------
* Drug: NDV-3A


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: Age 18-55 years. For healthy volunteers: in general good health, without significant medical illness, physical exam findings, or significant laboratory abnormalities as determined by the investigator. For participants with AD-HIES: confirmation of diagnosis with a STAT3 mutation. Participants who can get pregnant must be willing to use an acceptable form of contraception for the duration of participation and have a negative pregnancy test at screening. Agree to allow storage of biological samples for future research. EXCLUSION CRITERIA: Has a history of allergic response or other serious reaction to aluminum and/or yeast products. Has a history of clinically significant allergy including anaphylaxis or other serious reaction to food, vaccines, or other drugs, that in the opinion of the investigator, might put the participant at undue risk. Has an active infection (such as S aureus abscess, pneumonia, acute Candida mucocutaneous infection). Baseline state of chronic infections will be considered by the PI (eg, chronic Pseudomonas infection in lung). Has an active infection with hepatitis B, hepatitis C, or HIV. Has received or is planning to receive any investigational drug, investigational vaccine, or investigational device within four weeks prior to vaccination, or at any other time during their participation in the study. Has received or is planning to receive any other live vaccine within three weeks before vaccination or for three weeks after vaccination. Self-reported current alcohol abuse or addiction. Self-reported current illicit drug abuse or addiction, or drug screen positive for illicit drugs. Current or planned use, within 3 weeks before vaccination, of any medications or treatments that may alter immune responses to the study vaccine (eg, immunosuppressive medications including systemic corticosteroids, cyclosporine, tacrolimus, cytotoxic drugs, Bacillus Calmette-Guerin, monoclonal antibodies, or radiation therapy). Topical, intranasal, or inhaled immunosuppressants such as corticosteroids will be allowed. Current or planned use within 2 weeks before vaccination of immune globulin replacement. Has any of the following laboratory abnormalities at the screening visit: Alanine transaminase (ALT), aspartate transaminase (AST), and/or alkaline phosphatase (ALP) > 1.5 times the upper limit of normal (ULN). Total bilirubin level > 1.5 times the ULN Serum creatinine level > 1.5 times the ULN Absolute neutrophil count < 750 cells/microliter Hemoglobin < 9 mg/dL Platelet count < 100,000 Refusal or inability to comply with study procedures to the extent that it is potentially harmful to the participant or to the integrity of the study data. Has donated blood/plasma within four weeks before vaccination. Is pregnant or breastfeeding, or intends to become pregnant over the course of the study. Is unable to commit to the follow-up visits and or has unreliable access to a telephone for follow-up contacts, either by self-admission (self-reporting) or in the opinion of the investigator. Any other condition the investigator believes would interfere with the participant s ability to provide informed consent, comply with study instructions, or that might confound the interpretation of the study results or put the participant at undue risk.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NDV 3A vaccine<br>Participants will receive a single dose of 0.5 mL (300 micrograms of rAls3) administered via IM injection. | Drug: NDV-3A<br>* A vaccine containing recombinant Candida albicans agglutinin-like sequence 3 (rAls3) protein as the antigen, formulated with AlOH adjuvant in phosphate buffered saline. Participants will receive a single 0.5 mL dose containing 300 micrograms of rAls3 and 0.5 mg of aluminum as AlOH, delivered via intramuscular injection.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Each Group With at Least a Four-fold Increase in Anti rAls3 Antibody Titer. | Antibody titer | 2 weeks after vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious Adverse Events That Led to Study Termination. |  | Up to 6 months | 
| Anti-Als3 Antibody Titers at 6 Months After Vaccination in Patients With AD HIES and Healthy Volunteers. |  | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AD-HIES, Anti-rAls3 Antibody, Staphylococcus Aureus, Candida Albicans, RNA Transcriptome