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

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT02996448
• Collaborator: (none)
• Enrollment: 3
• Location: 1
• Arm: 1
• Duration (Months): 22.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Autosomal-dominant Hyper-IgE Syndrome	Drug: NDV-3A	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• 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
• Study Start Date: Nov 17, 2016
• Actual Primary Completion Date: Jul 22, 2018
• Actual Study Completion Date: Oct 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NDV 3A vaccine Participants will receive a single dose of 0.5 mL (300 micrograms of rAls3) administered via IM injection.	Drug: NDV-3A; 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.

Outcome Measures

Primary Outcome Measures

1. Percent of Each Group With at Least a Four-fold Increase in Anti rAls3 Antibody Titer. [2 weeks after vaccination]

   Antibody titer

Secondary Outcome Measures

1. Number of Participants With Serious Adverse Events That Led to Study Termination. [Up to 6 months]

2. Anti-Als3 Antibody Titers at 6 Months After Vaccination in Patients With AD HIES and Healthy Volunteers. [6 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

• INCLUSION CRITERIA:

1. Age 18-55 years.

2. For healthy volunteers: in general good health, without significant medical illness, physical exam findings, or significant laboratory abnormalities as determined by the investigator.

3. For participants with AD-HIES: confirmation of diagnosis with a STAT3 mutation.

4. 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.

5. Agree to allow storage of biological samples for future research.

EXCLUSION CRITERIA:

1. Has a history of allergic response or other serious reaction to aluminum and/or yeast products.

2. 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.

3. 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).

4. Has an active infection with hepatitis B, hepatitis C, or HIV.

5. 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.

6. Has received or is planning to receive any other live vaccine within three weeks before vaccination or for three weeks after vaccination.

7. Self-reported current alcohol abuse or addiction.

8. Self-reported current illicit drug abuse or addiction, or drug screen positive for illicit drugs.

9. 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.

10. Current or planned use within 2 weeks before vaccination of immune globulin replacement.

11. Has any of the following laboratory abnormalities at the screening visit:

12. Alanine transaminase (ALT), aspartate transaminase (AST), and/or alkaline

phosphatase (ALP) > 1.5 times the upper limit of normal (ULN).

1. Total bilirubin level > 1.5 times the ULN

2. Serum creatinine level > 1.5 times the ULN

3. Absolute neutrophil count < 750 cells/microliter

4. Hemoglobin < 9 mg/dL

5. Platelet count < 100,000

6. 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.

7. Has donated blood/plasma within four weeks before vaccination.

8. Is pregnant or breastfeeding, or intends to become pregnant over the course of the study.

9. 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.

10. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Alexandra Freeman, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 13, 2018

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Liu Y, Filler SG. Candida albicans Als3, a multifunctional adhesin and invasin. Eukaryot Cell. 2011 Feb;10(2):168-73. doi: 10.1128/EC.00279-10. Epub 2010 Nov 29. Review.
• Sowerwine KJ, Holland SM, Freeman AF. Hyper-IgE syndrome update. Ann N Y Acad Sci. 2012 Feb;1250:25-32. doi: 10.1111/j.1749-6632.2011.06387.x. Epub 2012 Jan 23. Review.
• Spellberg BJ, Ibrahim AS, Avanesian V, Fu Y, Myers C, Phan QT, Filler SG, Yeaman MR, Edwards JE Jr. Efficacy of the anti-Candida rAls3p-N or rAls1p-N vaccines against disseminated and mucosal candidiasis. J Infect Dis. 2006 Jul 15;194(2):256-60. Epub 2006 Jun 6.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02996448
• Other Study ID Numbers: 170017; 17-I-0017
• First Posted: Dec 19, 2016
• Last Update Posted: Jun 30, 2020
• Last Verified: Oct 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): AD-HIES; Anti-rAls3 Antibody; Staphylococcus Aureus; Candida Albicans; RNA Transcriptome
• Additional relevant MeSH terms: Job Syndrome; Syndrome

Study Results

Participant Flow

Pre-assignment Detail	Healthy volunteers were not enrolled to the study due to the early termination. The three subjects enrolled were those with AD-HIES.

Arm/Group Title	Vaccination Group, Single Arm Study
Arm/Group Description	Participants will receive a single dose of 0.5 mL (300 micrograms of rAls3) administered via IM injection. NDV-3A: 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.
Period Title: Overall Study
STARTED	3
COMPLETED	0
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Vaccination Group- Single Arm Study
Arm/Group Description	Participants will receive a single dose of 0.5 mL (300 micrograms of rAls3) administered via IM injection. NDV-3A: 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.
Overall Participants	3
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	20
Sex: Female, Male (Count of Participants)
Female	1 33.3%
Male	2 66.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	2 66.7%
More than one race	1 33.3%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	3 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

As study was stopped prematurely due to safety concerns, the data was not obtained.

Arm/Group Title	Vaccine Recipients
Arm/Group Description	Participants will receive a single dose of 0.5 mL (300 micrograms of rAls3) administered via IM injection. NDV-3A: 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.
Measure Participants	0

2. Secondary Outcome

Title	Number of Participants With Serious Adverse Events That Led to Study Termination.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vaccination Group- Single Arm Study
Arm/Group Description	Participants will receive a single dose of 0.5 mL (300 micrograms of rAls3) administered via IM injection. NDV-3A: 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.
Measure Participants	3
Count of Participants [Participants]	1 33.3%

3. Secondary Outcome

Title	Anti-Als3 Antibody Titers at 6 Months After Vaccination in Patients With AD HIES and Healthy Volunteers.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Data were not collected due to premature termination of study.

Arm/Group Title	Vaccination Group- Single Arm Study
Arm/Group Description	Participants will receive a single dose of 0.5 mL (300 micrograms of rAls3) administered via IM injection. NDV-3A: 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.
Measure Participants	0

Adverse Events

Time Frame	Up to 6 months
Arm/Group Title	Vaccination Group- Single Arm Study
Arm/Group Description	Participants will receive a single dose of 0.5 mL (300 micrograms of rAls3) administered via IM injection. NDV-3A: 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.
All Cause Mortality
	Vaccination Group- Single Arm Study
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Serious Adverse Events
	Vaccination Group- Single Arm Study
	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)
Immune system disorders
Anaphylaxis	1/3 (33.3%)
Other (Not Including Serious) Adverse Events
	Vaccination Group- Single Arm Study
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Gastrointestinal disorders
Nausea	1/3 (33.3%)
Musculoskeletal and connective tissue disorders
Injection site pain	1/3 (33.3%)	1
Nervous system disorders
Dizziness	1/3 (33.3%)
fatigue	1/3 (33.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/3 (33.3%)
Upper respiratory tract infection	1/3 (33.3%)
Skin and subcutaneous tissue disorders
Eczema exacerbation	2/3 (66.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.