Aeras Provides Update on Phase 2 Trial (C-040-404/TUB09)                  of H4:IC31

Rockville, MD, June 16, 2016 – The Sanofi Pasteur-Aeras Joint Steering Committee for the Phase 2 trial (C-040-404/TUB09) convened on 14 June 2016 to review and discuss the recommendations of the study’s independent Data Monitoring Committee (DMC).

The DMC, which met on 02 June 2016, reviewed unblinded safety and efficacy data and concluded that the trial had been well conducted to date and that the data was of good quality. There were no safety concerns of note. The DMC recommends that follow-up be continued as per protocol with a further DMC review close to the end of follow-up. The DMC also recommended that, based on QuantiFERON-TB Gold-in-Tube (QFT) data, all subjects have a QFT assay performed at 24 months, rather than testing only those who have remained QFT negative. The Joint Steering Committee agreed to follow the DMC recommendations.  

Study Overview

This Prevention of (sustained) Infection, pre-Proof of Concept study was designed to evaluate BCG and a novel tuberculosis (TB) vaccine candidate, H4:IC31, for the prevention of Mycobacterium tuberculosis (Mtb) infection.

This novel trial design establishes a potential new paradigm in TB vaccine development. Clinical development of TB vaccines is hampered by the lack of biologic correlates of protection and lack of validated preclinical models, which could provide evidence of likely efficacy in early stages of development. The Prevention of Infection trial design enables a smaller, faster pre-proof of concept to help in deciding on advancement into large-scale disease-prevention trials. While a TB vaccine would not need to prevent infection with Mtb to prevent TB disease, prevention of infection with Mtb would be an important marker of biological effect.

Studies that measure the prevention of TB disease typically are larger, longer and more expensive than this study of 990 healthy adolescents, which will provide quicker results with fewer subjects. If a vaccine demonstrates the ability to prevent sustained Mtb infection, it indicates a high probability of success that it will be able to prevent disease and ultimately break the cycle of transmission. This Prevention of Infection study design can be an important tool for identifying highly promising TB vaccine candidates.

Study Design

The study was designed to see if H4:IC31 or BCG could prevent infection by Mtb.  If the study shows that H4:IC31 prevented infection by Mtb, then it would give us more confidence in proceeding to longer and more costly studies to see if the vaccine could prevent TB disease.

With Aeras as the regulatory sponsor and conducted by the South African Tuberculosis Vaccine Initiative (SATVI), this is the first study to evaluate whether Sanofi Pasteur’s H4:IC31 vaccine candidate has important biological activity in humans and has the ability to prevent sustained infection by Mtb. Sanofi Pasteur worked with Aeras on the development of the study design and protocol, and supplied the vaccine candidate, H4:IC31.

The study randomly assigned adolescents, ages 12 – 17, who received BCG as infants and who were not infected with Mtb – the bacterium that causes TB – to get either H4:IC31 or a placebo or BCG re-vaccination, and is following them for at least two years. 

The randomized, placebo-controlled, partially blinded trial enrolled 990 adolescents in the Western Cape Province of South Africa. One-third of the participants received a revaccination with BCG; one-third received vaccination with H4:IC31, and one-third received a placebo. Mtb infection is determined with the use of commercially available interferon gamma release assays (QuantiFERON-TB Gold In-Tube assay from Qiagen). 

The study was launched in March 2014 and is expected to be completed by the end of 2017. The trial is approved by the Medicines Control Council of South Africa and the relevant local independent ethics committees.

Primary Endpoints

It’s very difficult to truly know if someone is infected with Mtb, but a common method is to see if a person’s immune system responds to Mtb components (antigens).  An assay called QuantiFERON®- TB Gold In-Tube, or just QuantiFERON (QFT), was used in this study to identify people whose immune systems recognized Mtb.

The pre-defined criteria were based on the primary study endpoint, i.e., occurrence of Mtb infection as defined by conversion of the QFT assay. This endpoint is considered a reasonable surrogate of the risk of future Mtb disease.

The primary analysis was to be conducted when at least 64 endpoints were accrued and after a median follow-up time of at least 15 months. Follow-up of the volunteers in the ongoing study continues, with data collection to support the final analysis of the study, which incorporates results for secondary and exploratory endpoints.


H4:IC31is a novel vaccine candidate being developed jointly by Aeras and Sanofi Pasteur (in collaboration with SSI). It has already been tested in four Phase 1 studies in adults—including one in South Africa, which showed an acceptable safety profile and immunogenicity. It is also being evaluated in three current studies:

  • C-040-404/TUB09
    • A Prevention of (sustained) Infection, Proof of Concept, Phase 2a study designed to evaluate BCG or H4:IC31 for the prevention of Mtb infection in healthy adolescents in South Africa. Clinical trial sites include SATVI and Emavundleni.
  • C-015-404
    • A Safety and Immunogenicity Phase 1/2 study in infants being conducted in several sites in Africa, to evaluate H4:IC31 in infants who have previously been vaccinated with BCG (with IMPAACT, NIAID, Sanofi Pasteur, Aeras). Clinical trial sites include Soweto, Stellenbosch, Kidcru, and SATVI).
  • A-042/HVTN602
    • A Phase 1 immunogenicity, experimental medicine study being conducted in adolescents in South Africa to evaluate immune assays that can be used in efficacy trials to identify potential correlates of risk of or protection against TB (with HVTN, NIAID, Sanofi, Pasteur, Aeras, SSI and Valneva). This clinical trial is being conducted at Emavundleni.

H4:IC31 is comprised of the H4 antigen (a fusion protein of Mtb antigens 85B and TB10.4 originally developed by Statens Serum Institut; (SSI) ), combined with the biotech company Valneva's IC31® adjuvant to stimulate T cell-mediated immunity. The vaccine candidate has been shown to be immunogenic and protective before and after Mtb exposure in preclinical animal models.

This vaccine candidate is intended to be used in adolescents and young adults who have received BCG immunization in the past (most likely as infants).


Bacille Calmette-Guerin (BCG), the only currently licensed TB vaccine, is one of the most widely administered vaccines globally. It is moderately effective in preventing severe TB in infants and young children. It does not effectively protect against pulmonary TB, which is developed and spread mostly by adolescents and adults, and its widespread use in infants has failed to control the global epidemic.

BCG was included in this study based upon meta-analysis performed on prior studies that suggests that BCG immunization may possess the capacity to provide a level of protection against Mtb infection.  This study provided an opportunity to test prospectively whether BCG revaccination could prevent Mtb infection.

Urgent Need for a New TB Vaccine

The world urgently needs a new TB vaccine because the existing vaccine, BCG, while moderately effective in preventing severe TB in infants and young children, doesn’t adequately protect teens and adults, who are most at risk for developing and spreading TB. According to the World Health Organization, a new vaccine is critically needed to halt the TB epidemic, just as vaccines have prevented other diseases that previously threatened millions, such as polio, measles, and whooping cough. Additionally, a new vaccine would protect against multidrug-resistant strains of TB, as drug resistance does not equal vaccine resistance.

Tuberculosis Quick Facts

  • TB is an infectious disease caused by the bacterium Mycobacterium tuberculosis (Mtb)
  • TB kills more people than any other single infectious disease agent in the world, causing 9.6 million illnesses and 1.5 million deaths in 2014
  • Approximately 1/3 of the world’s population is infected with Mtb as a latent infection, which presents no symptoms and is not contagious, and about 10% of them will develop active TB during their lifetime
  • People with active TB typically infect 10 – 15 others before they are treated and no longer contagious
  • Symptoms of pulmonary TB can include a bad cough that lasts three weeks or longer, chest pain, coughing up blood and sputum, fatigue, weight loss, lack of appetite, chills, fever, and night sweats
  • The world desperately needs new tools to bring an end to the TB epidemic, including better drugs, diagnostics, and vaccines
    • The World Health Organization and other key stakeholders agree that treatment alone will not end the TB epidemic
    • Vaccines have been crucial in combating other deadly infectious diseases, such as polio, smallpox, measles, and tetanus
    • A new effective TB vaccine would be the ultimate game changer that could help end this epidemic
  • Building on the End TB Strategy adopted by the World Health Assembly in 2014, the United Nations endorsed a set of development goals in 2015 to guide international efforts to fight poverty, known as the Sustainable Development Goals. A core component of these goals is a target to end the TB epidemic by 2030, yet without new approaches we have no clear path to achieve this target
    • SDG 3.3: “By 2030, end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases”