Evaluation of Safety, Immunogenicity, and Prevention of TB With AERAS-404 and BCG Revaccination in Healthy Adolescents

• Sponsor: Aeras (Other)
• Overall Status: Completed
• CT.gov ID: NCT02075203
• Collaborator: Sanofi Pasteur, a Sanofi Company (Industry)
• Enrollment: 989
• Locations: 2
• Arms: 3
• Duration (Months): 44.1
• Patients Per Site: 494.5
• Patients Per Site Per Month: 11.2

Study Details

Study Description

Brief Summary

Randomized, Placebo Controlled, Partially Blinded Phase II Study to Evaluate Safety, Immunogenicity, and Prevention of Infection with Mycobacterium tuberculosis of AERAS-404 and BCG Revaccination in Healthy Adolescents

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Biological: AERAS-404; Drug: Placebo; Biological: Bacillus Calmette-Guérin (BCG)	Phase 2

Detailed Description

This Phase II, randomized, 3-arm, placebo controlled, partially blinded, clinical trial will be conducted in 990 healthy, HIV-uninfected, QFT-GIT negative, previously BCG vaccinated adolescents. The trial will be conducted at the South African Tuberculosis Vaccine Initiative (SATVI) site in the Western Cape region of South Africa, where epidemiological studies involving thousands of adolescents have been conducted over the last decade to characterize rates of Mtb infection and active TB disease in this age group. Subjects will be enrolled in two sequential cohorts and within each cohort subjects will be randomized in a 1:1:1 ratio to receive either AERAS-404 or saline placebo on Days 0 and 56, or BCG Vaccine SSI on Day 0. The first 90 subjects (30 from each arm) will form the Safety & Immunogenicity Cohort and will be subject to more intensive collection of safety data, with data reviewed by the Data Monitoring Committee (DMC), principal investigator and local medical monitor. Selected immunogenicity assays, including whole blood intracellular cytokine staining (ICS), will also be performed in this cohort. The remaining 900 subjects will be enrolled into the Correlates Cohort. All 990 subjects in the study will be evaluated for safety and biomarker outcomes, and for prevention of Mtb infection.

The primary Mtb infection endpoint will be QFT-GIT conversion from a negative to positive test, using the manufacturer's recommended threshold of 0.35 IU/mL, at any time-point after Day 84 and through end of follow-up for the primary endpoint. The 84-day 'wash-out' period is stipulated in order to exclude subjects who may have already been Mtb infected, but not yet converted their QFT-GIT test at screening, thus subjects who convert their QFT-GIT at Day 84 will not be included in the analyses of prevention of Mtb infection.

Study Design

• Study Type: Interventional
• Actual Enrollment: 989 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Randomized, Placebo Controlled, Partially Blinded Phase II Study to Evaluate Safety, Immunogenicity, and Prevention of Infection With Mycobacterium Tuberculosis of AERAS-404 and BCG Revaccination in Healthy Adolescents
• Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Aug 28, 2017
• Actual Study Completion Date: Oct 6, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AERAS-404 (15 mcgH4/500 nmol IC31) 2 doses on Study Days 0 and 56	Biological: AERAS-404; The H4 antigen is a fusion protein created from two Mtb antigens: antigen Ag85B and TB10.4. Ag85B is also referred to as α-antigen and is a 30-kDa mycolyl transferase protein. TB10.4 is one of three members of the very similar ESAT-6 group of proteins found in Mtb culture supernatants. TB10.4 induces broad immune responses in T cells isolated from TB subjects compared to BCG-vaccinated donors and unvaccinated donors. IC31 is a combination of a leucine-rich peptide named KLK & a synthetic oligonucleotide named ODN1a. The optimal molar ratio of KLK to ODN1a in mice is 25:1. AERAS-404 & saline placebo trial arms will be double-blinded since BCG causes a recognizable local injection site reaction, the BCG revaccination trial arm will be unblinded.; Other Names: H4 H4:IC31
Active Comparator: Bacillus Calmette-Guérin (BCG) 1 Dose on Study Day 0	Biological: Bacillus Calmette-Guérin (BCG); BCG SSI Vaccine is registered in South Africa for prevention of TB in children and adults. BCG, an attenuated, live culture of the Bacillus Calmette-Guérin, was originally attenuated between 1906 and 1919 by serial passage of an M. bovis strain. The manufacturer Statens Serum Institut (SSI) in Copenhagen, Denmark derives this vaccine from the Danish BCG strain 1331. BCG SSI is supplied by the manufacturer in amber 10-dose vials containing 0.75 mg lyophilized SSI BCG. The BCG revaccination trial arm will be unblinded (open label).; Other Names: BCG BCG SSI
Placebo Comparator: Placebo 2 Doses on Study Days 0 and 56	Drug: Placebo; Saline; Other Names: 0.9% Saline

Outcome Measures

Primary Outcome Measures

1. Safety Profile of H4:IC31 and BCG Revaccination in HIV-uninfected, Remotely BCG Vaccinated Adolescents. [Study day 7 thru 6 months after last vaccination]

   Number of unsolicited and solicited adverse events recorded post vaccination. Unsolicited adverse events: 28 days post each vaccination Solicited adverse events: 7 days post each vaccination (with diary cards used for 7 days after each vaccination for Safety and Immunogenicity Cohort only) Solicited and unsolicited injection site reaction adverse events: BCG Group - 84 days post vaccination; H4:IC31/Placebo Groups - 28 days post each vaccination Serious adverse events, adverse events of special interest, and SUSARs: Entire study period, with a minimum of 6 months following the last dose of study vaccine

2. Number of Participants Testing Positive for Mtb at Day 84 [Study day 84 through 6 months post-conversion]

   Rates of conversion to Mtb-positive measured by QuantiFERON-TB Gold In-tube (QFT-GIT) assay. The primary evaluation of Mtb infection was QFT-GIT conversion from a negative to positive test, using the manufacturer's recommended threshold of ≥0.35 IU/mL, at any time point after Day 84 and through end of follow-up for the primary endpoint. All participants with primary QFT-GIT conversion were followed for an additional 6 months post-conversion to ascertain the sustained QFT-GIT conversion and QFT-GIT reversion endpoints. Participants with an initial QFT-GIT conversion at Month 6 or 12 were asked to return for a final QFT-GIT evaluation and assessment for TB signs and symptoms at least 24 months after their initial vaccination. H4:IC31 compared to placebo BCG revaccination compared to placebo

Secondary Outcome Measures

1. Rates of Sustained Conversion to Mtb-positive [6 months after initial conversion]

   Rates of sustained conversion to Mtb-positive as measured by QFT-GIT assay. H4:IC31 compared to placebo BCG revaccination compared to placebo

2. Percentage of Participants With Immune Response to Vaccine in HIV-uninfected, Remotely BCG-vaccinated Adolescents: o H4:IC31 o BCG Revaccination [Study day 70]

   A 13 color intracellular cytokine staining assay (ICS) was performed on peripheral blood mononuclear cells (PBMC) to assess CD4+ T cells that expressed IFN-γ, TNF, IL-2, IL-17, IL-22, CD107a, and/or CD154 alone or in combination in response to stimulation with peptide pools representing the entire amino acid sequence of the TB mycobacterial antigens Ag85B and TB10.4, and BCG antigens. Responders were IFN-gamma and/or IL-2 positive. An intracellular cytokine assay was performed on whole blood (WB) to measure the frequencies and patterns of CD4+ T cells expressing Th1 and Th17 cytokines following stimulation of whole blood with peptide pools representing the entire amino acid sequence of the TB mycobacterial antigens Ag85B and TB10.4, as well as viable BCG from the vaccine vial. Responders were IFN-gamma, IL-2, TNF, IL-17, and/or IL-22 positive.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Has completed the written informed consent and assent process

2. Is age ≥ 12 years and ≤ 17 years on Study Day 0

3. Agrees to stay in contact with the study site for the duration of the study, provide updated contact information

4. For female subjects: agrees to avoid pregnancy from 28 days prior to Study Day 0 and for the full duration of the study.

5. Has general good health, confirmed by medical history and physical examination

6. Had BCG vaccination at least 5 years ago documented through medical history or by presence of healed BCG scar

7. Tests QFT-GIT negative at screening, using the manufacturer's recommended threshold of 0.35 IU/mL

Exclusion Criteria:

1. Acute illness on Study Day 0

2. Oral temperature ≥37.5°C on Study Day 0

3. Clinically significant (and no more than Grade 1 on the Toxicity Scale) abnormal laboratory values from blood collected within 21 days

4. Evidence of clinically significant (and no more than Grade 1 on the Toxicity Scale) systemic or local disease on urinalysis

5. History or evidence of any clinically significant systemic disease, or any acute or chronic illness that might affect the safety, immunogenicity, or efficacy of study vaccine in the opinion of the investigator

6. History of treatment for active TB disease or latent Mtb infection

7. History or evidence, including chest X-ray, of active TB disease

8. Shared residence with an individual receiving anti-TB treatment, or known incompletely treated culture or smear positive TB

9. History of autoimmune disease or immunosuppression

10. Used immunosuppressive medication within 42 days before Study Day 0

11. Received immunoglobulin or blood products within 42 days before Study Day 0

12. Received any investigational drug therapy or investigational vaccine within 182 days before Study Day 0

13. Received investigational TB vaccine, other than BCG

14. Planned administration/administration of a licensed vaccine in the period starting 28 days before and ending 28 days after each dose of study vaccine

15. History or laboratory evidence of any past or present possible immunodeficiency state not limited to any lab indication of HIV-1 infection

16. History of allergic disease likely to be exacerbated by any component of the study vaccine

17. History of alcohol or drug abuse

18. All female subjects: currently pregnant or lactating/nursing; or positive urine pregnancy test during screening

19. Received a (TST) within 3 months (90 days) prior to Study Day 0.

20. Any current medical, psychiatric, occupational, substance abuse problems problems that in opinion of investigator will make unlikely for the subject to comply with the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	South African Tuberculosis Vaccine Initiative , Project Office, Brewelskloof Hospital , Harlem Street, Worcester	Cape Town	Western Cape	South Africa	6850
2	Desmond Tutu HIV Foundation (DTHF)	Nyanga		South Africa

Sponsors and Collaborators

• Aeras
• Sanofi Pasteur, a Sanofi Company

Investigators

• Principal Investigator: Mark Hatherill, MD, The South African Tuberculosis Vaccine Initiative(SATVI)

Study Documents (Full-Text)

• Study Protocol - Jul 25, 2016
• Statistical Analysis Plan - Sep 29, 2017
• Informed Consent Form - Jan 10, 2014

More Information

Publications

None provided.

• Responsible Party: Aeras
• ClinicalTrials.gov Identifier: NCT02075203
• Other Study ID Numbers: C-040-404
• First Posted: Mar 3, 2014
• Last Update Posted: Sep 4, 2019
• Last Verified: May 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Aeras: BCG Vaccinated
• Additional relevant MeSH terms: Tuberculosis; BCG Vaccine

Study Results

Participant Flow

Arm/Group Title	AERAS-404 (15 mcgH4/500 Nmol IC31)	Bacillus Calmette-Guérin (BCG)	Placebo
Arm/Group Description	2 doses on Study Days 0 and 56 AERAS-404: The H4 antigen is a fusion protein created from two Mtb antigens: antigen Ag85B and TB10.4. Ag85B is also referred to as α-antigen and is a 30-kDa mycolyl transferase protein. TB10.4 is one of three members of the very similar ESAT-6 group of proteins found in Mtb culture supernatants. TB10.4 induces broad immune responses in T cells isolated from TB subjects compared to BCG-vaccinated donors and unvaccinated donors. IC31 is a combination of a leucine-rich peptide named KLK & a synthetic oligonucleotide named ODN1a. The optimal molar ratio of KLK to ODN1a in mice is 25:1. AERAS-404 & saline placebo trial arms will be double-blinded since BCG causes a recognizable local injection site reaction, the BCG revaccination trial arm will be unblinded.	1 Dose on Study Day 0 Bacillus Calmette-Guérin (BCG): BCG SSI Vaccine is registered in South Africa for prevention of TB in children and adults. BCG, an attenuated, live culture of the Bacillus Calmette-Guérin, was originally attenuated between 1906 and 1919 by serial passage of an M. bovis strain. The manufacturer Statens Serum Institut (SSI) in Copenhagen, Denmark derives this vaccine from the Danish BCG strain 1331. BCG SSI is supplied by the manufacturer in amber 10-dose vials containing 0.75 mg lyophilized SSI BCG. The BCG revaccination trial arm will be unblinded (open label).	2 Doses on Study Days 0 and 56 Placebo: Saline
Period Title: Overall Study
STARTED	330	330	329
COMPLETED	327	330	328
NOT COMPLETED	3	0	1

Baseline Characteristics

Arm/Group Title	AERAS-404 (15 mcgH4/500 Nmol IC31)	Bacillus Calmette-Guérin (BCG)	Placebo	Total
Arm/Group Description	2 doses on Study Days 0 and 56 AERAS-404: The H4 antigen is a fusion protein created from two Mtb antigens: antigen Ag85B and TB10.4. Ag85B is also referred to as α-antigen and is a 30-kDa mycolyl transferase protein. TB10.4 is one of three members of the very similar ESAT-6 group of proteins found in Mtb culture supernatants. TB10.4 induces broad immune responses in T cells isolated from TB subjects compared to BCG-vaccinated donors and unvaccinated donors. IC31 is a combination of a leucine-rich peptide named KLK & a synthetic oligonucleotide named ODN1a. The optimal molar ratio of KLK to ODN1a in mice is 25:1. AERAS-404 & saline placebo trial arms will be double-blinded since BCG causes a recognizable local injection site reaction, the BCG revaccination trial arm will be unblinded.	1 Dose on Study Day 0 Bacillus Calmette-Guérin (BCG): BCG SSI Vaccine is registered in South Africa for prevention of TB in children and adults. BCG, an attenuated, live culture of the Bacillus Calmette-Guérin, was originally attenuated between 1906 and 1919 by serial passage of an M. bovis strain. The manufacturer Statens Serum Institut (SSI) in Copenhagen, Denmark derives this vaccine from the Danish BCG strain 1331. BCG SSI is supplied by the manufacturer in amber 10-dose vials containing 0.75 mg lyophilized SSI BCG. The BCG revaccination trial arm will be unblinded (open label).	2 Doses on Study Days 0 and 56 Placebo: Saline	Total of all reporting groups
Overall Participants	330	330	329	989
Age (Count of Participants)
<=18 years	330 100%	330 100%	329 100%	989 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.1 (1.47)	14.2 (1.49)	14.3 (1.54)	14.2 (1.50)
Sex: Female, Male (Count of Participants)
Female	189 57.3%	162 49.1%	169 51.4%	520 52.6%
Male	141 42.7%	168 50.9%	160 48.6%	469 47.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	330 100%	330 100%	329 100%	989 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 0.3%	1 0.3%	1 0.3%	3 0.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	120 36.4%	126 38.2%	120 36.5%	366 37%
White	1 0.3%	3 0.9%	1 0.3%	5 0.5%
More than one race	208 63%	200 60.6%	207 62.9%	615 62.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
South Africa	330 100%	330 100%	329 100%	989 100%

Outcome Measures

1. Primary Outcome

Title	Safety Profile of H4:IC31 and BCG Revaccination in HIV-uninfected, Remotely BCG Vaccinated Adolescents.
Description	Number of unsolicited and solicited adverse events recorded post vaccination. Unsolicited adverse events: 28 days post each vaccination Solicited adverse events: 7 days post each vaccination (with diary cards used for 7 days after each vaccination for Safety and Immunogenicity Cohort only) Solicited and unsolicited injection site reaction adverse events: BCG Group - 84 days post vaccination; H4:IC31/Placebo Groups - 28 days post each vaccination Serious adverse events, adverse events of special interest, and SUSARs: Entire study period, with a minimum of 6 months following the last dose of study vaccine
Time Frame	Study day 7 thru 6 months after last vaccination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AERAS-404 (15 mcgH4/500 Nmol IC31)	Bacillus Calmette-Guérin (BCG)	Placebo
Arm/Group Description	2 doses on Study Days 0 and 56 AERAS-404: The H4 antigen is a fusion protein created from two Mtb antigens: antigen Ag85B and TB10.4. Ag85B is also referred to as α-antigen and is a 30-kDa mycolyl transferase protein. TB10.4 is one of three members of the very similar ESAT-6 group of proteins found in Mtb culture supernatants. TB10.4 induces broad immune responses in T cells isolated from TB subjects compared to BCG-vaccinated donors and unvaccinated donors. IC31 is a combination of a leucine-rich peptide named KLK & a synthetic oligonucleotide named ODN1a. The optimal molar ratio of KLK to ODN1a in mice is 25:1. AERAS-404 & saline placebo trial arms will be double-blinded since BCG causes a recognizable local injection site reaction, the BCG revaccination trial arm will be unblinded.	1 Dose on Study Day 0 Bacillus Calmette-Guérin (BCG): BCG SSI Vaccine is registered in South Africa for prevention of TB in children and adults. BCG, an attenuated, live culture of the Bacillus Calmette-Guérin, was originally attenuated between 1906 and 1919 by serial passage of an M. bovis strain. The manufacturer Statens Serum Institut (SSI) in Copenhagen, Denmark derives this vaccine from the Danish BCG strain 1331. BCG SSI is supplied by the manufacturer in amber 10-dose vials containing 0.75 mg lyophilized SSI BCG. The BCG revaccination trial arm will be unblinded (open label).	2 Doses on Study Days 0 and 56 Placebo: Saline
Measure Participants	330	330	329
Number [number of AEs]	286	1257	272

2. Primary Outcome

Title	Number of Participants Testing Positive for Mtb at Day 84
Description	Rates of conversion to Mtb-positive measured by QuantiFERON-TB Gold In-tube (QFT-GIT) assay. The primary evaluation of Mtb infection was QFT-GIT conversion from a negative to positive test, using the manufacturer's recommended threshold of ≥0.35 IU/mL, at any time point after Day 84 and through end of follow-up for the primary endpoint. All participants with primary QFT-GIT conversion were followed for an additional 6 months post-conversion to ascertain the sustained QFT-GIT conversion and QFT-GIT reversion endpoints. Participants with an initial QFT-GIT conversion at Month 6 or 12 were asked to return for a final QFT-GIT evaluation and assessment for TB signs and symptoms at least 24 months after their initial vaccination. H4:IC31 compared to placebo BCG revaccination compared to placebo
Time Frame	Study day 84 through 6 months post-conversion

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	AERAS-404 (15 mcgH4/500 Nmol IC31)	Bacillus Calmette-Guérin (BCG)	Placebo
Arm/Group Description	2 doses on Study Days 0 and 56 AERAS-404: The H4 antigen is a fusion protein created from two Mtb antigens: antigen Ag85B and TB10.4. Ag85B is also referred to as α-antigen and is a 30-kDa mycolyl transferase protein. TB10.4 is one of three members of the very similar ESAT-6 group of proteins found in Mtb culture supernatants. TB10.4 induces broad immune responses in T cells isolated from TB subjects compared to BCG-vaccinated donors and unvaccinated donors. IC31 is a combination of a leucine-rich peptide named KLK & a synthetic oligonucleotide named ODN1a. The optimal molar ratio of KLK to ODN1a in mice is 25:1. AERAS-404 & saline placebo trial arms will be double-blinded since BCG causes a recognizable local injection site reaction, the BCG revaccination trial arm will be unblinded.	1 Dose on Study Day 0 Bacillus Calmette-Guérin (BCG): BCG SSI Vaccine is registered in South Africa for prevention of TB in children and adults. BCG, an attenuated, live culture of the Bacillus Calmette-Guérin, was originally attenuated between 1906 and 1919 by serial passage of an M. bovis strain. The manufacturer Statens Serum Institut (SSI) in Copenhagen, Denmark derives this vaccine from the Danish BCG strain 1331. BCG SSI is supplied by the manufacturer in amber 10-dose vials containing 0.75 mg lyophilized SSI BCG. The BCG revaccination trial arm will be unblinded (open label).	2 Doses on Study Days 0 and 56 Placebo: Saline
Measure Participants	308	312	310
Number [participants]	44 13.3%	41 12.4%	49 14.9%

3. Secondary Outcome

Title	Rates of Sustained Conversion to Mtb-positive
Description	Rates of sustained conversion to Mtb-positive as measured by QFT-GIT assay. H4:IC31 compared to placebo BCG revaccination compared to placebo
Time Frame	6 months after initial conversion

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat

Arm/Group Title	AERAS-404 (15 mcgH4/500 Nmol IC31)	Bacillus Calmette-Guérin (BCG)	Placebo
Arm/Group Description	2 doses on Study Days 0 and 56 AERAS-404: The H4 antigen is a fusion protein created from two Mtb antigens: antigen Ag85B and TB10.4. Ag85B is also referred to as α-antigen and is a 30-kDa mycolyl transferase protein. TB10.4 is one of three members of the very similar ESAT-6 group of proteins found in Mtb culture supernatants. TB10.4 induces broad immune responses in T cells isolated from TB subjects compared to BCG-vaccinated donors and unvaccinated donors. IC31 is a combination of a leucine-rich peptide named KLK & a synthetic oligonucleotide named ODN1a. The optimal molar ratio of KLK to ODN1a in mice is 25:1. AERAS-404 & saline placebo trial arms will be double-blinded since BCG causes a recognizable local injection site reaction, the BCG revaccination trial arm will be unblinded.	1 Dose on Study Day 0 Bacillus Calmette-Guérin (BCG): BCG SSI Vaccine is registered in South Africa for prevention of TB in children and adults. BCG, an attenuated, live culture of the Bacillus Calmette-Guérin, was originally attenuated between 1906 and 1919 by serial passage of an M. bovis strain. The manufacturer Statens Serum Institut (SSI) in Copenhagen, Denmark derives this vaccine from the Danish BCG strain 1331. BCG SSI is supplied by the manufacturer in amber 10-dose vials containing 0.75 mg lyophilized SSI BCG. The BCG revaccination trial arm will be unblinded (open label).	2 Doses on Study Days 0 and 56 Placebo: Saline
Measure Participants	308	312	310
Number [participants]	25 7.6%	21 6.4%	36 10.9%

4. Secondary Outcome

Title	Percentage of Participants With Immune Response to Vaccine in HIV-uninfected, Remotely BCG-vaccinated Adolescents: o H4:IC31 o BCG Revaccination
Description	A 13 color intracellular cytokine staining assay (ICS) was performed on peripheral blood mononuclear cells (PBMC) to assess CD4+ T cells that expressed IFN-γ, TNF, IL-2, IL-17, IL-22, CD107a, and/or CD154 alone or in combination in response to stimulation with peptide pools representing the entire amino acid sequence of the TB mycobacterial antigens Ag85B and TB10.4, and BCG antigens. Responders were IFN-gamma and/or IL-2 positive. An intracellular cytokine assay was performed on whole blood (WB) to measure the frequencies and patterns of CD4+ T cells expressing Th1 and Th17 cytokines following stimulation of whole blood with peptide pools representing the entire amino acid sequence of the TB mycobacterial antigens Ag85B and TB10.4, as well as viable BCG from the vaccine vial. Responders were IFN-gamma, IL-2, TNF, IL-17, and/or IL-22 positive.
Time Frame	Study day 70

Outcome Measure Data

Analysis Population Description

Modified ITT analysis set: Safety and immunogenicity cohort

Arm/Group Title	AERAS-404 (15 mcgH4/500 Nmol IC31)	Bacillus Calmette-Guérin (BCG)	Placebo
Arm/Group Description	2 doses on Study Days 0 and 56 AERAS-404: The H4 antigen is a fusion protein created from two Mtb antigens: antigen Ag85B and TB10.4. Ag85B is also referred to as α-antigen and is a 30-kDa mycolyl transferase protein. TB10.4 is one of three members of the very similar ESAT-6 group of proteins found in Mtb culture supernatants. TB10.4 induces broad immune responses in T cells isolated from TB subjects compared to BCG-vaccinated donors and unvaccinated donors. IC31 is a combination of a leucine-rich peptide named KLK & a synthetic oligonucleotide named ODN1a. The optimal molar ratio of KLK to ODN1a in mice is 25:1. AERAS-404 & saline placebo trial arms will be double-blinded since BCG causes a recognizable local injection site reaction, the BCG revaccination trial arm will be unblinded.	1 Dose on Study Day 0 Bacillus Calmette-Guérin (BCG): BCG SSI Vaccine is registered in South Africa for prevention of TB in children and adults. BCG, an attenuated, live culture of the Bacillus Calmette-Guérin, was originally attenuated between 1906 and 1919 by serial passage of an M. bovis strain. The manufacturer Statens Serum Institut (SSI) in Copenhagen, Denmark derives this vaccine from the Danish BCG strain 1331. BCG SSI is supplied by the manufacturer in amber 10-dose vials containing 0.75 mg lyophilized SSI BCG. The BCG revaccination trial arm will be unblinded (open label).	2 Doses on Study Days 0 and 56 Placebo: Saline
Measure Participants	28	28	27
PBMC ICS: Percent of responders on day 70	81.8 24.8%	16.0 4.8%	12.0 3.6%
WB ICS: Percent responders on day 70	12.5 3.8%	8.0 2.4%	8.3 2.5%

Adverse Events

Time Frame	Unsolicited AEs: 28 days post each vaccination Solicited AEs: 7 days post each vaccination (with diary cards used for 7 days after each vaccination for Safety and Immunogenicity Cohort only) Solicited and unsolicited injection site reaction AEs: BCG Group - 84 days post vaccination; H4:IC31/Placebo Groups - 28 days post vaccination Serious adverse events, adverse events of special interest, and SUSARs: Entire study period (minimum of 6 months following last dose of study vaccine)
Arm/Group Title	AERAS-404 (15 mcgH4/500 Nmol IC31)		Bacillus Calmette-Guerin (BCG)		Placebo
Arm/Group Description	2 doses on Study Days 0 and 56 AERAS-404: The H4 antigen is a fusion protein created from two Mtb antigens: antigen Ag85B and TB10.4. Ag85B is also referred to as α-antigen and is a 30-kDa mycolyl transferase protein. TB10.4 is one of three members of the very similar ESAT-6 group of proteins found in Mtb culture supernatants. TB10.4 induces broad immune responses in T cells isolated from TB subjects compared to BCG-vaccinated donors and unvaccinated donors. IC31 is a combination of a leucine-rich peptide named KLK & a synthetic oligonucleotide named ODN1a. The optimal molar ratio of KLK to ODN1a in mice is 25:1. AERAS-404 & saline placebo trial arms will be double-blinded since BCG causes a recognizable local injection site reaction, the BCG revaccination trial arm will be unblinded.		1 Dose on Study Day 0 Bacillus Calmette-Guérin (BCG): BCG SSI Vaccine is registered in South Africa for prevention of TB in children and adults. BCG, an attenuated, live culture of the Bacillus Calmette-Guérin, was originally attenuated between 1906 and 1919 by serial passage of an M. bovis strain. The manufacturer Statens Serum Institut (SSI) in Copenhagen, Denmark derives this vaccine from the Danish BCG strain 1331. BCG SSI is supplied by the manufacturer in amber 10-dose vials containing 0.75 mg lyophilized SSI BCG. The BCG revaccination trial arm will be unblinded (open label).		2 Doses on Study Days 0 and 56 Placebo: Saline
All Cause Mortality
	AERAS-404 (15 mcgH4/500 Nmol IC31)		Bacillus Calmette-Guerin (BCG)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/330 (0%)		0/330 (0%)		1/329 (0.3%)
Serious Adverse Events
	AERAS-404 (15 mcgH4/500 Nmol IC31)		Bacillus Calmette-Guerin (BCG)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/330 (1.5%)		7/330 (2.1%)		7/329 (2.1%)
Gastrointestinal disorders
Small intestinal obstruction	0/330 (0%)	0	1/330 (0.3%)	1	0/329 (0%)	0
Infections and infestations
Breast abscess	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Cellulitis	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Gastroenteritis	0/330 (0%)	0	2/330 (0.6%)	2	0/329 (0%)	0
Meningitis viral	1/330 (0.3%)	1	0/330 (0%)	0	0/329 (0%)	0
Pyelonephritis	2/330 (0.6%)	2	0/330 (0%)	0	0/329 (0%)	0
Subcutaneous abscess	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Injury, poisoning and procedural complications
Chest injury	0/330 (0%)	0	1/330 (0.3%)	1	0/329 (0%)	0
Near drowning	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Road traffic accident	1/330 (0.3%)	1	0/330 (0%)	0	0/329 (0%)	0
Thermal burn	0/330 (0%)	0	1/330 (0.3%)	1	0/329 (0%)	0
Pregnancy, puerperium and perinatal conditions
Eclampsia	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Premature rupture of membranes	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Psychiatric disorders
Completed suicide	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Intentional self-injury	1/330 (0.3%)	1	1/330 (0.3%)	1	0/329 (0%)	0
Suicide attempt	0/330 (0%)	0	1/330 (0.3%)	1	0/329 (0%)	0
Other (Not Including Serious) Adverse Events
	AERAS-404 (15 mcgH4/500 Nmol IC31)		Bacillus Calmette-Guerin (BCG)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	118/330 (35.8%)		329/330 (99.7%)		104/329 (31.6%)
Blood and lymphatic system disorders
Lymphadenopathy	2/330 (0.6%)	2	2/330 (0.6%)	2	0/329 (0%)	0
Cardiac disorders
Tachycardia	1/330 (0.3%)	1	0/330 (0%)	0	0/329 (0%)	0
Eye disorders
Conjunctivitis	2/330 (0.6%)	2	0/330 (0%)	0	1/329 (0.3%)	1
Gastrointestinal disorders
Abdominal pain	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Diarrhoea	3/330 (0.9%)	5	6/330 (1.8%)	7	5/329 (1.5%)	5
Gastritis	2/330 (0.6%)	2	0/330 (0%)	0	1/329 (0.3%)	1
Lip dry	1/330 (0.3%)	1	0/330 (0%)	0	0/329 (0%)	0
Nausea	12/330 (3.6%)	15	10/330 (3%)	12	3/329 (0.9%)	5
Vomiting	2/330 (0.6%)	2	0/330 (0%)	0	0/329 (0%)	0
General disorders
Chills	6/330 (1.8%)	6	3/330 (0.9%)	5	5/329 (1.5%)	7
Fatigue	16/330 (4.8%)	23	10/330 (3%)	15	18/329 (5.5%)	26
Injection site erythema	8/330 (2.4%)	9	0/330 (0%)	0	6/329 (1.8%)	7
Injection site induration	1/330 (0.3%)	1	0/330 (0%)	0	1/329 (0.3%)	1
Injection site pain	34/330 (10.3%)	46	0/330 (0%)	0	20/329 (6.1%)	27
Injection site pruritus	1/330 (0.3%)	1	0/330 (0%)	0	2/329 (0.6%)	2
Injection site swelling	15/330 (4.5%)	17	0/330 (0%)	0	8/329 (2.4%)	11
Injection site warmth	8/330 (2.4%)	12	0/330 (0%)	0	6/329 (1.8%)	10
Malaise	1/330 (0.3%)	1	0/330 (0%)	0	0/329 (0%)	0
Pyrexia	3/330 (0.9%)	4	2/330 (0.6%)	2	1/329 (0.3%)	1
Vaccination site discharge	0/330 (0%)	0	163/330 (49.4%)	169	0/329 (0%)	0
Vaccination site discolouration	0/330 (0%)	0	22/330 (6.7%)	22	0/329 (0%)	0
Vaccination site erythema	0/330 (0%)	0	147/330 (44.5%)	150	0/329 (0%)	0
Vaccination site exfoliation	0/330 (0%)	0	90/330 (27.3%)	92	0/329 (0%)	0
Vaccination site induration	0/330 (0%)	0	171/330 (51.8%)	171	0/329 (0%)	0
Vaccination site pain	0/330 (0%)	0	45/330 (13.6%)	47	0/329 (0%)	0
Vaccination site pallor	0/330 (0%)	0	8/330 (2.4%)	8	0/329 (0%)	0
Vaccination site papule	0/330 (0%)	0	10/330 (3%)	10	0/329 (0%)	0
Vaccination site pruritus	0/330 (0%)	0	3/330 (0.9%)	3	0/329 (0%)	0
Vaccination site scab	0/330 (0%)	0	145/330 (43.9%)	147	0/329 (0%)	0
Vaccination site scar	0/330 (0%)	0	255/330 (77.3%)	255	0/329 (0%)	0
Vaccination site swelling	0/330 (0%)	0	172/330 (52.1%)	179	0/329 (0%)	0
Vaccination site ulcer	0/330 (0%)	0	104/330 (31.5%)	104	0/329 (0%)	0
Vaccination site warmth	0/330 (0%)	0	20/330 (6.1%)	22	0/329 (0%)	0
Immune system disorders
Seasonal allergy	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Infections and infestations
Acarodermatitis	0/330 (0%)	0	1/330 (0.3%)	1	0/329 (0%)	0
Body tinea	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Cellulitis	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Folliculitis	1/330 (0.3%)	1	0/330 (0%)	0	0/329 (0%)	0
Gastroenteritis	1/330 (0.3%)	1	0/330 (0%)	0	0/329 (0%)	0
Herpes simplex	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Hordeolum	1/330 (0.3%)	1	0/330 (0%)	0	0/329 (0%)	0
Lower respiratory tract infection	0/330 (0%)	0	1/330 (0.3%)	1	1/329 (0.3%)	1
Oral herpes	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Otitis externa	1/330 (0.3%)	1	0/330 (0%)	0	0/329 (0%)	0
Pharyngitis	3/330 (0.9%)	3	0/330 (0%)	0	2/329 (0.6%)	2
Pharyngotonsillitis	0/330 (0%)	0	1/330 (0.3%)	1	0/329 (0%)	0
Respiratory tract infection	1/330 (0.3%)	1	0/330 (0%)	0	0/329 (0%)	0
Rhinitis	0/330 (0%)	0	0/330 (0%)	0	5/329 (1.5%)	5
Rubella	1/330 (0.3%)	1	0/330 (0%)	0	1/329 (0.3%)	1
Sinusitis	0/330 (0%)	0	1/330 (0.3%)	1	2/329 (0.6%)	2
Tonsillitis	0/330 (0%)	0	1/330 (0.3%)	1	0/329 (0%)	0
Upper respiratory tract infection	31/330 (9.4%)	31	7/330 (2.1%)	7	26/329 (7.9%)	26
Urinary tract infection	0/330 (0%)	0	1/330 (0.3%)	1	2/329 (0.6%)	2
Vaccination site pustule	0/330 (0%)	0	29/330 (8.8%)	29	0/329 (0%)	0
Varicella	2/330 (0.6%)	2	0/330 (0%)	0	1/329 (0.3%)	1
Injury, poisoning and procedural complications
Arthropod bite	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Arthropod sting	0/330 (0%)	0	1/330 (0.3%)	1	0/329 (0%)	0
Back injury	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Concussion	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Contusion	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Excoriation	0/330 (0%)	0	0/330 (0%)	0	2/329 (0.6%)	2
Head injury	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Joint injury	0/330 (0%)	0	1/330 (0.3%)	1	1/329 (0.3%)	1
Ligament injury	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Limb injury	0/330 (0%)	0	0/330 (0%)	0	3/329 (0.9%)	3
Skin wound	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Thermal burn	1/330 (0.3%)	1	1/330 (0.3%)	1	0/329 (0%)	0
Wound	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	2
Investigations
Alanine aminotransferase increased	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Aspartate aminotransferase increased	0/330 (0%)	0	0/330 (0%)	0	2/329 (0.6%)	2
Blood alkaline phosphatase increased	0/330 (0%)	0	0/330 (0%)	0	3/329 (0.9%)	3
Blood bilirubin increased	1/330 (0.3%)	1	0/330 (0%)	0	0/329 (0%)	0
Blood pressure diastolic increased	0/330 (0%)	0	2/330 (0.6%)	2	4/329 (1.2%)	4
Blood pressure increased	2/330 (0.6%)	2	0/330 (0%)	0	3/329 (0.9%)	3
Blood pressure systolic increased	6/330 (1.8%)	6	1/330 (0.3%)	1	0/329 (0%)	0
Blood urine present	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Haemoglobin decreased	2/330 (0.6%)	2	0/330 (0%)	0	3/329 (0.9%)	3
Heart rate increased	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Neutrophil count decreased	1/330 (0.3%)	1	2/330 (0.6%)	2	3/329 (0.9%)	3
Neutrophil count increased	2/330 (0.6%)	2	2/330 (0.6%)	2	0/329 (0%)	0
Platelet count increased	3/330 (0.9%)	3	2/330 (0.6%)	2	2/329 (0.6%)	2
Weight decreased	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
White blood cell count increased	5/330 (1.5%)	5	2/330 (0.6%)	2	0/329 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	1/330 (0.3%)	1	0/330 (0%)	0	1/329 (0.3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	5/330 (1.5%)	6	5/330 (1.5%)	5	7/329 (2.1%)	9
Back pain	0/330 (0%)	0	1/330 (0.3%)	1	0/329 (0%)	0
Muscle spasms	0/330 (0%)	0	1/330 (0.3%)	1	1/329 (0.3%)	1
Musculoskeletal stiffness	0/330 (0%)	0	1/330 (0.3%)	1	0/329 (0%)	0
Myalgia	17/330 (5.2%)	22	7/330 (2.1%)	8	11/329 (3.3%)	14
Pain in extremity	1/330 (0.3%)	1	0/330 (0%)	0	0/329 (0%)	0
Nervous system disorders
Dizziness	0/330 (0%)	0	1/330 (0.3%)	2	1/329 (0.3%)	1
Headache	25/330 (7.6%)	27	27/330 (8.2%)	32	31/329 (9.4%)	42
Presyncope	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Renal and urinary disorders
Haematuria	3/330 (0.9%)	3	0/330 (0%)	0	2/329 (0.6%)	2
Proteinuria	2/330 (0.6%)	2	2/330 (0.6%)	2	4/329 (1.2%)	4
Reproductive system and breast disorders
Dysmenorrhoea	3/330 (0.9%)	3	2/330 (0.6%)	2	3/329 (0.9%)	4
Gynaecomastia	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Ovarian cyst	0/330 (0%)	0	1/330 (0.3%)	1	0/329 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Oropharyngeal pain	0/330 (0%)	0	1/330 (0.3%)	1	0/329 (0%)	0
Rhinitis allergic	1/330 (0.3%)	1	0/330 (0%)	0	0/329 (0%)	0
Rhinorrhoea	1/330 (0.3%)	1	1/330 (0.3%)	1	0/329 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis	0/330 (0%)	0	1/330 (0.3%)	1	1/329 (0.3%)	1
Pityriasis rosea	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Pruritus	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Rash	2/330 (0.6%)	2	0/330 (0%)	0	2/329 (0.6%)	2
Skin ulcer	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1
Vascular disorders
Haematoma	0/330 (0%)	0	0/330 (0%)	0	1/329 (0.3%)	1

Limitations/Caveats

[Not Specified]

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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.