T5-TBVAC

The challenge

More than 10 million people develop tuberculosis each year, and over a million people die of the disease. The only licensed vaccine, BCG, does not prevent the development of TB disease in adolescents and adults with Mycobacterium tuberculosis (Mtb) infection, which is a critical gap in TB control. The TB vaccine pipeline is not well-stocked, particularly at early stages of clinical development, and new candidates are urgently needed.

TB vaccine development is highly challenging. Although various types of immune response are known to be associated with protection, protective immunity remains incompletely understood. In addition, the efficacy of vaccines in animal models is poorly predictive of clinical benefits in humans. More effective ways to assess the performance of candidate vaccines and to prioritise candidates for large-scale field evaluation are therefore critically needed.

The project

The T5-TBVAC project is gathering data on a promising new tuberculosis vaccine candidate while also building capacity to run controlled human BCG-based challenge studies to evaluate TB vaccines in sub-Saharan Africa.

Because animal models are poorly predictive, data are more reliable when obtained directly from humans. Human challenge studies, in which volunteers are deliberately infected with pathogens under highly controlled conditions, enable the collection of rich data without the need for lengthy and expensive field trials. 

Deliberate infection with virulent strains of Mtb itself is generally considered inappropriate. However, there is an alternative – challenge with BCG, an attenuated form of Mycobacterium bovis that still replicates and is very closely related to Mtb. (In challenge studies, BCG is not being used as a vaccine but as a ‘weakened’ pathogen.)

The T5-TBVAC project team has already successfully established a BCG-based human challenge model in the UK. In this model, BCG is administered to the skin, and skin biopsies are used to assess the effect of prior vaccination on BCG replication.

The efficacy of TB vaccination varies markedly across countries, likely reflecting the degree of prior exposure to mycobacterial and other pathogens. Therefore, to provide a reliable indication of likely vaccine performance, studies need to be carried out in high-burden countries where the vaccine will be used. The T5-TBVAC project will address this crucial issue by establishing the BCG challenge model in sub-Saharan Africa.

The T5-TBVAC project team has developed a candidate vaccine based on a well-established viral vector platform. While a candidate vaccine containing a single Mtb antigen stimulated strong immune responses and protected mice, such a vaccine is unlikely to protect diverse populations worldwide. The team has therefore developed a refined vaccine with five immunogenic Mtb antigens (Ag85A, PPE15, PE8, ESXJ, ESXI), which should provide protection across a broader proportion of the population.

Furthermore, T5-TBVAC has been designed to be delivered by aerosol, stimulating immune responses at the site of Mtb infection in the lungs. Aerosol delivery has another potential advantage: recipients are likely to prefer a nasal spray to an injection, thereby increasing the likelihood of vaccine uptake.

The project first assesses the safety of the multi-antigen candidate in the existing UK human challenge model. The model will then be introduced in Uganda, where studies will compare the impact of both aerosol and intramuscular delivery of T5-TBVAC on BCG replication. In addition, conventional Phase 2a studies in Senegal, West Africa, will provide safety and immunogenicity data on the vaccine in a very different African setting. 

A wide range of cellular and antibody-based immune responses will be monitored to assess the vaccine's immunogenicity across different settings. This may also provide new insights into key correlates of protection – immune mechanisms that show a strong association with the vaccine's protective effects.

Impact

The T5-TBVAC project will provide a major impetus to tuberculosis vaccine development. It will:

• Generate key safety and immunogenicity data on a novel multivalent vaccine.
• Provide initial efficacy data from a human challenge model in both the UK and sub-Saharan Africa.
• Create a platform for further TB vaccine evaluation in human participants in East Africa.

Results from the T5-TBVAC project should provide a clear indication of T5-TBVAC's likely efficacy, paving the way for field trials to assess its clinical efficacy. In addition, the human challenge platform will be a critical tool for evaluating and comparing candidate vaccines in an endemic setting, with the potential to significantly de-risk TB vaccine development.