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 Full Title
Phase II Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Safety and Immunogenicity of H1/IC31®, an Adjuvanted TB Subunit Vaccine, in HIV-Infected Adults with CD4+ Lymphocyte Counts Greater than 350 CELLS/MM3.
 Short Title TB H1 Vaccine
 Project Leader Klaus Reither
 Description Despite more than a half-century of widespread vaccination, tuberculosis (TB) remains one of the world’s most serious infectious diseases, claiming nearly 2 million lives every year.  TB is typically passed from an infected person to a new host by inhalation of bacteria in sputum exhaled by an infected person. The characteristic symptom of TB is a prolonged cough, which is induced by tissue destruction in the lung by the pathogen. Unfortunately, cough and fever are relatively non-specific symptoms, and the period of time between infection and appearance of symptoms can be anywhere from a few months to several decades. In addition to improved public health control measures, such as 
intensified case finding, an effective TB vaccination programme is required to meet the Millennium Development Goals and Stop TB partnership’s target for TB elimination by 2050.  

The majority of TB is now restricted to the world’s poorest countries, and ongoing studies suggest that in these countries as many as 30-40% of adolescents are already latently infected and thus at risk of disease. In addition to TB-related mortality, the resources used to combat TB and the productive years lost to TB morbidity inflict a punishing toll on the economies of TB-endemic countries, helping mire them in poverty. The last factor worsening the epidemic is the observation that HIV positivity is a significant risk factor for the development of TB and the prognosis for those with HIV/TB co-infection is particularly poor. 
BCG (Mycobacterium bovis Calmette Guerin) is an attenuated strain 
of  ycobacterium bovis derived through more than 13 years of continuous in vitro passage. It remains the only approved vaccine against TB and more than 3 billion people have received BCG to date.  

However, while studies have repeatedly demonstrated that vaccination with BCG in infancy is highly effective against TB in children, the major burden of TB is associated with pulmonary disease in later life, against which the vaccine has proven less effective. There is thus a huge need for a new, effective boost or therapeutic TB vaccine in adults that can be made available to low income settings. In addition, it needs to be safe in those who are HIVinfected.  BCG fails both of these requirements, and so a new vaccine is the only way forward. Testing new TB vaccines in Africa is thus of the highest priority. Several new 
TB vaccines are being developed, including recombinant BCG vaccines, 
attenuated Mycobacterium tuberculosis vaccines, DNA-based vaccines and subunit vaccines (3). Living mycobacterial vaccines pose significant health risks in HIV-infected individuals, and although this can be addressed by auxotrophic mutants, significant regulatory barriers imposed on genetically modified organisms have impeded efficient development of living mycobacterial vaccines. DNA vaccines have so far been disappointing with regard to immunogenicity and protection in model studies. Not surprisingly, then, three of the most advanced 
vaccines are all subunit vaccines, and two of these comprise ecombinant 
proteins. 

The subunit vaccine approach builds on the concept of stimulating the immune response to a number of selected antigens delivered in the form of recombinant antigens. The Statens Serum Institut has cloned and screened 250 antigens from Mycobacterium tuberculosis and selected a small number of the most antigenic candidates. Among these are the early secretory antigenic target (ESAT-6) and antigen 85 (Ag85B). Both are strongly recognized T-cell antigens in the first phase of infection, that have demonstrated protective efficacy in animal models, and both contain numerous well recognized epitopes, recognized in TB patients.
 Collaborators Prof. Gavin Churchyard      Aurum Institute

Lynn Katsoulis                 Aurum Institute

Lesego Khantsi                Aurum Institute

Fred Lwilla                      Ifakara Health Institute 

Humphrey Shao               Ifakara Health Institute 

Khadija Said                   Ifakara Health Institute 

Claudia Daubenberger      Swiss Tropical & Public Health Institute

Prof. Mark Doherty          Statens Serum Institut

Suzanne Verver              KNCV Tuberculosis Foundation

Ellen Michell                   KNCV Tuberculosis Foundation

Peter Bang                    Statens Serum Institut

 Source of funding European & Developing Countries Clinical Trials Partnership (EDCTP)
 Start Date October 2010                                     End Date     September 2012
     

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