The race to eliminate tuberculosis

What is carried by a third of the world’s population. kills someone every 18 seconds somewhere on the planet and develops a new case almost every second? The answer may surprise you - it’s tuberculosis (TB), a disease which many in Europe assumed had been wiped out in the post-war era. That assumption has contributed to TB becoming a forgotten disease – and one for which there is no fully effective vaccine.

The TuBerculosis Vaccine Initiative (TBVI) is an independent foundation on an urgent mission: to develop safe, effective, globally accessible vaccines to protect the future of the world’s population from this deadly disease.

The BCG vaccine was naturally hailed as a breakthrough in TB prevention when it was developed in the early 1900s. Together with improved public health, it almost helped eliminate the disease in post-war Europe. But TB never left the developing world, killing millions, causing poverty and costing ill-equipped governments millions of dollars in lost economic output and in treating the disease. And recently it’s made an ominous comeback in Europe too – with 6,000-10,000 deaths a year, and the emergence of drug-resistant strains. Far from a disease in decline, there are now more cases of TB in the world than ever.

Curiously, the near-elimination of TB in Europe became a victim of its own success. As cases of TB fell, research into the disease, and awareness of it even within the medical profession, nearly disappeared. BCG remained the only vaccine available and yet it has little or no effect on the most common and infectious form of the disease, pulmonary TB. Moreover, it is also unsafe to give to newborns with HIV. In short, there was little to stop the resurgence of the disease that went almost unnoticed in Europe, arguably until the World Health Organisation declared it a global emergency in 1993.

Following on from EC-funded vaccine research projects begun in 2000, TBVI was set up in 2008. It’s aim was simple – to develop a range of safe, effective and affordable vaccines against this contagious disease that moves with steady, remorseless efficiency through whole populations and is fatal if left untreated.

“We have not only built up a wealth of knowledge but also translated it into very promising vaccines that are now evaluated in clinical trials,” says TBVI’s Director, Dr Jelle Thole. “It is possible that the first new vaccines will become available by 2020.” It is interesting to note that today’s most advanced vaccine candidates worldwide are the results of European research efforts.

With the involvement of approximately 40 research teams across Europe, and others in Africa and Asia, such a large-scale clinical evaluation project takes a huge collaborative effort. And in these more austere economic times, Dr Thole and the team must monitor and co-ordinate the research effectively to ensure efforts and resources are focused as efficiently as possible to make best use of limited funding.

To bring two vaccines on to the market by 2020, the total investment needed from the TBVI portfolio is €560 million over 10 years. Raising that kind of funding at a time of world recession is a considerable challenge. Dr Thole’s colleague, Dr Joris Vandeputte, is Senior Vice President Advocacy and Resource Mobilisation, responsible, as his job title suggests, for mobilising the necessary resources and advocating the solution for TB vaccines, in Europe. “The traditional funding model is of course a grant but that is extremely difficult to secure at the moment,” says Dr Vandeputte.

“So in addition we came up with an innovative funding model. We went to political decision makers and said ‘this is the project, but instead of asking you for cash, we’d like to have your financial backing in the form of a guarantee, to convince financial institutions to lend us the money. We will then pay back the investment with royalties, levied on the sales of the vaccines, so that you are freed of that guarantee.’ So financial institutions such as the European Investment Bank (EIB) will now be contacted to lend the money under these conditions. This is a paradigm shift – instead of grants, we are going for an investment case for those vaccine candidates which are ready to be translated into innovative vaccines.”

While no funding has been secured yet, reactions to the investment plan have been positive.

“If the funding approach proves successful, the research partners will be able to receive money on a project-by-project basis, after agreement by an independent review committee,” says Dr Vandeputte. “The partners must achieve pre-set milestones at each stage of their research or they will not receive funding for the next one – it’s the only way to ensure the project can be resourced effectively.”

This novel way of using government guarantees to raise money for research appears highly responsible. The rewards for society from such investment will be high, leading to a significant contribution to the elimination of tuberculosis and the reduction of poverty in the world; greater added value from research already done, here and in less developed countries and job creation and much more efficient North-South and South-South collaborations.

TBVI is also advocating a strong economic case for the vaccine programme, alongside a moral duty to save lives. “The world’s Gross National Income (GNI) is over $62,000,000 million – and the World Bank has calculated that TB costs the world 0.52 per cent of that each year in lost output – it’s a huge amount,” says Dr Vandeputte. “In sub-Saharan Africa, one of the poorest regions of the world, it amounts to $52 billion, while the European region spends around €2 billion on treatment alone. So the saying ‘health is wealth’ is very apt in this case.”

Pharmaceutical companies now see the business case, too. “We must make the vaccines affordable to all,” says Dr Thole. “Different techniques, such as tiered pricing, exist to make vaccines low priced and affordable for the least developed countries. However the urgency now is to translate knowledge into these effective, innovative vaccines.” While the need to get things done as quickly as possible in such a hugely challenging project may seem daunting, the TBVI team is already thinking on a global scale.

“Because of different target profiles , we will probably need to develop several different vaccines,” says Dr Thole. “We need ones that can replace BCG at birth but also booster vaccines that can be given in later age groups. In addition we need vaccines that are effective against latent TB. We will also need these vaccines to be effective in different geographical regions and safe in HIV-infected individuals,” Dr Thole continues.

“The challenge for the field is to create an innovative pipeline with safe vaccines that address these different target groups while at the same time ensuring sufficient resources are in place for the clinical development of the most promising candidates. TBVI’s latest collaborative project, NEWTBVAC, focuses on new vaccines that would protect the 2 billion people that are latently infected with the bacterium and at risk of developing the disease later in life.

Furthermore, the project investigates whether vaccines with different targets can be combined into one strategy. We realise that not all the vaccines we are working on will make it through the clinical trials but if we can develop a sufficient number, that will be a great achievement.”

On the research side, Dr Thole highlights two significant achievements to date. “We have brought three vaccines to the clinical trial stage and have also progressed biomarkers, biological indicators which can predict the success of a vaccine before TB has even developed in the cells. TB is a relatively slowly developing disease so the availability of a correlate of protection would speed up the research process enormously.”

On the advocacy side, Dr Vandeputte highlights a landmark development in the European Parliament recently. “On February 3, 2011, the parliament passed a resolution supporting the work of TBVI. We’ve gone from zero political interest to a watershed resolution in 10 years, which is something to be proud of, I think. It is strong encouragement for decision makers to find the right balance between the need to restrain government budgets and the commitment all governments made in the EU 2020 programme to invest three per cent of their GNI in innovation. Financial backing of TBVI’s innovative funding proposal would be a good step towards EU 2020.”

Such progress has come from a determination to build on the success of the previous decade of research and bring the issue of TB back on the political radar. “Ten years ago we had nothing except the BCG vaccine and almost no awareness of TB, even within the medical profession,” says Dr Thole.

“We are now in a position where we hope to have some vaccines available for the market, perhaps within five to seven years or at least by 2020. If we have then achieved our goal of safe, effective, affordable vaccines for all then we will have done our job. If so, I hope that TBVI can be used as a model for other research projects in the future.”

Published: Wednesday, 7th December 2011