Maryland foundation takes on TB giant

Known as a disease of the past and the poor, tuberculosis still plagues many developing countries and is the number one killer for people living with HIV. Why is there only one vaccine, nearly a century old, and unsafe in many cases?

While Americans tend to think of tuberculosis as a disease of an era past, it still kills around 2 million people a year, largely in Asia and Africa. The only vaccine for TB is one developed nearly a century ago, and it’s too risky to give to those born infected with the AIDS virus.

Aeras Global TB Vaccine Foundation in Rockville, Md., is trying to change that. Partnering with industry, academia other foundations and governments, Aeras develops vaccines and will work with its partners to produce and distribute them. Currently, the foundation has four vaccine candidates in clinical trials. With positive results, a new TB vaccine could be ready by 2020.

Last month, I had the rare opportunity to tour Aeras’ BioSafety Level 2 manufacturing facility, which was in stand-down (a time during which laboratory work stops and machines are calibrated). On the tour, I donned a gown and saw labs where the vaccine strains are grown. After the tour, Dr. Lew Barker, Aeras’ senior medical advisor for regulatory affairs and quality assurance, answered some questions about the foundation’s work.

Out of the roughly 2 million deaths per year from TB, how many occur in the U.S., versus developing countries?

TB is well controlled in the United States, where there were fewer than 900 deaths from TB in 2008. It is a disease of poverty that is driven by poor living conditions, crowding, malnutrition and the HIV/AIDS epidemic. In fact, TB is the leading cause of death among people living with HIV. According to the World Health Organization (WHO), the vast majority of new TB cases occur in the developing world, with over half occurring in Asia. Eighty percent of new cases in 2007 were in only 22 countries, and of these, nine are in Africa and eight in central and Southeast Asia.

Vials are filled with individual doses of TB vaccine product.

Why is it so hard to get funding for TB research, when it is still killing so many people?

I must first point out that Aeras has been fortunate to garner significant support for TB vaccine research from a number of generous donors, especially the Bill & Melinda Gates Foundation, and also the governments of the United Kingdom, the Netherlands, Norway and others. However, vaccine research is complex and expensive, and more support is needed.

There is a gap in TB research funding between private investment from industry and public funding for research. This is the role that a product development partnership such as Aeras plays. Why a gap? Industry is driven by profit. There is not a large market to provide a substantial return on investment for tuberculosis interventions in wealthy nations where TB is well-controlled by good public health programs and access to antibiotic treatment. Most of those in need have very limited resources and live in poor countries. Because of this, many pharmaceutical companies are not attracted to invest in a market without a substantial profit potential.

Also, there is competition for research dollars, especially now at such a difficult global economic period. The worst thing we can do is pit one serious disease against another. The reality though, is that approximately 40 percent of all disease research funding currently supports HIV/AIDS programs. We need research to address both TB and TB/HIV co-infection with new drugs, vaccines and diagnostics.

Five-liter process development fermenters are used to determine the best way to manufacturing TB vaccines at a large-scale.

From a biological perspective, what makes TB such a complicated disease?

The bacterium that causes TB has been around for tens of thousands of years – it can survive through adaptation and change. The mycobacterium that causes TB disease hides within the human body’s cells and grows slowly. Treatment currently requires at least a six-month course of antibiotics. Ninety or more percent of those infected with the TB bug do not show symptoms of the disease. However, we don’t have a good understanding of why the other 10 percent develop active TB disease.

Essentially all of the currently available vaccines like polio, measles, hepatitis and pneumococcus cause our bodies to develop antibodies, which can successfully protect us against the disease if or when we are exposed. Unfortunately, this mechanism does not appear to work well against TB. The current strategy pursued by most in the TB vaccine field is to use a vaccine that will encourage our bodies to increase our immune response through T Cells or cellular immune responses.

To make things even more complicated, there’s no simple way of measuring whether or not a vaccine candidate is working based on animal testing or measuring levels of immune response. Instead, the most reliable measure of efficacy is by measuring whether or not vaccinated participants in clinical trials are protected better against TB disease than those who are unvaccinated. This can require very large and lengthy clinical trials.

You are trying to develop a different form of the Bacille Calmette-Guerin (BCG) vaccine, which has been used for nearly a century. What’s changed between the 1920s, when it was introduced, and today, that makes BCG less effective?

BCG is considered to be effective at preventing severe forms of non-pulmonary pediatric tuberculosis. But when given to newborns, as recommended by WHO, its protective ability for adolescents and adults is not so good. Developed before the breakthroughs of modern biotechnology, BCG’s ability to prevent TB is limited and unreliable. We have also learned that BCG is not so safe for infants with HIV.

With modern techniques, scientists can now identify components of the TB bug (antigens) that may be important to develop a more effective vaccine. Scientists at Aeras and elsewhere are applying this knowledge to develop new versions of BCG incorporating a variety of antigens that will help protect against the bacterium at all stages of TB.

Aeras’ quality control team tests and analyzes cells to ensure they are safe and have maintained the qualities need to protect against TB.

You currently have four vaccine candidates in clinical trials. What are some of the things that could go wrong to deem the trial a failure?

These candidates, all designed to be booster vaccines, are currently undergoing clinical testing in North America, Europe and Africa. Two of these have reached the Phase IIb, proof of concept, stage. We expect to have a fifth vaccine enter the clinic later this year.

TB vaccine development is a long and complex process. We do not know what kind of immune response is needed for a TB vaccine to work, and if a vaccine does not work by protecting against TB in people, it does not work. That is why we have several candidates undergoing testing simultaneously. We want to find at least one that will work.

What is a 501c3 doing in the pharmaceutical industry?

As a product development partnership, we are positioned to identify and move forward the best ideas coming out of bench research, through clinical development and ultimately to those who need them most.
Many for-profit vaccine makers won’t risk investing a lot of their funds in the very risky business of developing a product for an anticipated low-margin like a TB vaccine, despite the global need. We use the funding we receive from foundations and governments to leverage the best ideas and move them forward as quickly and cost-effectively as possible. Of course we do place great value on our pharmaceutical industry partners, and we always have our eyes on our bottom line--lives saved.

Your lab can make enough bulk vaccine for the entire world. Say you got the green light on a vaccine tomorrow. How long would it take until all those doses would be ready to ship to distributors?

Actually we have the capacity to scale up production fairly rapidly. However, our plan over time is to provide either bulk vaccine for filling and distribution in countries where TB is endemic or to transfer the manufacturing technology to companies in those countries, as that is ultimately likely to be a good way to ensure vaccine access where it is needed.

Images: Aeras Global TB Vaccine Foundation

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