Introduction and Background of the Project

Tuberculosis (TB) is spread via aerosol infection, entering the body through the lungs, usually establishing a pulmonary infection that can act as human reservoir for further infections. A TB patient with active cavitary disease can infect up to 15 people simply by coughing, sneezing or talking.  TB remains a major global health concern. The currently available TB vaccine used today, BCG, is almost 90 years old and although it provides some protection against severe TB disease in infants, it is ineffective against adolescent and adult pulmonary TB, which accounts for most of the worldwide disease burden. Every year nearly 9 million new cases occur (22 high burden countries account for over 80% of the world’s TB cases) and nearly 1.5 million people die from TB. The spread of multi-drug resistant TB and TB-HIV co-infection are making the epidemic even more complex to address. Totally drug resistant TB has been found in only a few instances, but heralds a new and increasing risk for public health. Without improved TB vaccines, elimination of this deadly disease will not be possible. Despite intensive research and vaccine discovery programs worldwide there is as yet no clear lead vaccine that has demonstrated clinical efficacy. Given the state of the TB epidemic and the spread of drug resistance TB, there is an urgent need to bring forward promising new vaccine candidates to protect people from this infectious disease.

How can your partnership (project) address global health challenges?

According to the WHO, the incidence of TB is falling globally, however, the decline is so slow that at current transmission rates and with the current tools available to us, it will take a millennium to end TB if at all.  Moreover, in some high burden countries, TB incidence has actually increased. In South Africa, for example, TB incidence has increased 400% over the past 15 years. The increased incidence of co-infection with HIV and an increase in drug-resistant strains of TB are making the epidemic even more severe and complicated to address. To address this complex, multifaceted global epidemic, we need better tools that incorporate the latest scientific breakthroughs in diagnostics and vaccine development.

Prof. Yasutomi, Director of Tsukuba Primate Center, NIBIO, has found that recombinant human parainfluenza type2 virus (rhPIV2) vector vaccine candidate expressing TB antigen Ag85B is more potent than BCG in reducing TB disease in the mouse model of TB. This rhPIV2 vector is a promising new vaccine candidate for prevention of pulmonary TB in adolescents and adults and is anticipated to be safe in children. A goal of our partnership is development and commercialization of this vaccine candidate. This will realize a dramatic improvement of Global Health, especially in developing countries and will contribute to the economic well-being of developing countries.

What sort of innovation are you bringing in your project?

A significant global effort is currently underway to develop new and effective TB vaccines. At present there are about a dozen candidates in clinical trials around the world. In addition there are many early stage discovery leads and preclinical vaccine candidates. Today’s global TB vaccine portfolio includes recombinant BCG, attenuated M. tuberculosis, viral-vectored platforms such as vaccinia virus or adenovirus and adjuvanted, recombinant purified proteins. However, there are no clinical candidates based on induction of a robust mucosal immune response. Responding to this gap, we propose to undertake the clinical development of just such a candidate in this project.

The candidate rhPIV2 virus vector vaccine has been shown to induce mucosal immunity after intranasal administration and is also a potent inducer of systemic immunity. Moreover there is evidence that the presence of preexisting antibody to this virus has no influence on the efficacy of this platform in prevention of infection when used via the intranasal route. Furthermore, though this virus can infect humans it has limited virulence and the safety profile of this platform has been significantly enhanced by eliminating a gene required for viral replication. It is anticipated that this vaccine candidate would be very effective for pulmonary TB because it induces appropriate and targeted mucosal immune responses. The rhPIV2 vector vaccine would be tested as the first candidate of mucosal TB vaccine concept.

Final Report

1. Project objective 

The objective of this project is to undertake a clinical development plan with rhPIV2 vector vaccine in order to prevent adolescents and adults from developing TB disease. It is also promising that this candidate can potentially be used for infants, including those who are HIV positive.

2. Project design 

This vaccine candidate has been shown to induce mucosal immunity after intranasal administration and is also a potent inducer of systemic immunity. It is anticipated that this rhPIV2 platform will work as a booster for BCG vaccine. In addition host anti-vector immunity does not appear to affect vaccine efficacy. We will therefore, establish a proof of concept in preclinical animal studies to optimize the candidate rhPIV2 TB vaccine.

3. Results, lessons learned 

An enhanced protective effect was confirmed in BCG-primed and wild type hPIV2 with TB antigen boosted mice in comparison with those immunized with BCG alone. Interferon-gamma ELISPOT assays showed that immunogenicity of wild type hPIV2 with TB antigen in mice was not affected with a prior infection with wild type hPIV2. HPIV2 is replication-incompetent in mouse cells. This virus can replicate in human and macaque cells. Since rhPIV2 platform is aimed at development of replication-incompetent viral vector, this function could not be confirmed in mouse system. So, we have a plan to proceed to macaque study to evaluate effect of gene deficient PIV2 with multiple TB antigens. Current gene deficient rhPIV2 viral productivity (yield) was not at a sufficient level to prepare virus stocks for the scheduled macaque studies, therefore virus growth optimization is undergoing.