As many as 2 billion people – almost a third of the world population -- are estimated to be infected with the tuberculosis bacterium and are at risk of developing the disease.

One in every 10 to 20 of those people can be expected to become sick with active TB in his or her lifetime. If not treated, each of these persons with active TB can infect 10 to 15 people in their lifetimes.

TB is a leading killer of people living with HIV, as they have much weakened immune systems. According to the latest data, 8.8 million new cases of TB appeared in 2010, killing a staggering 1.4 million people. Many more struggle with the disease, which apart from causing human suffering, slows economic growth. The annual economic loss is estimated to be 0.52 percent of the world’s gross national income. Although poverty driven, TB is present in all continents. It is said that “the situation is serious in Europe, alarming in Africa and worrisome in parts of Asia.”

The Bacille Calmette-Guerin (BCG) Vaccine, which was discovered at the Lille Pasteur Institut in 1908 by a bacteriologist and a veterinarian, currently available against TB, provides some protection against severe forms of TB in children but is not effective against adult pulmonary TB, the most common and infectious form of the disease, and is not safe in children affected with HIV.

It thus has variable efficacy and no proven control over global TB. So, new TB vaccines, that elicit more protection than the natural immune response, are urgently needed.

Dr Ann Ginsberg, currently the vice president of Scientific Affairs at Aeras, has earlier worked with the Global Alliance for TB Drug Development (TB Alliance) and thus has the double distinction of being involved with development of new drugs as well as vaccines for TB. She concedes that, “Although I worked for almost a decade on new drug regimens for TB, vaccines have really been my passion from the beginning—primarily TB vaccines.”

In her words, “To really eliminate TB as a public health problem, we need both drugs and vaccines. Due to a huge pool of latent TB, there are going to be TB patients for a long time and they need to be treated with better and shorter regimens than what are currently available. But, ultimately to get to the root of the TB problem and to break the cycle of transmission, we need to have effective vaccines.

“I say vaccines because just one is not likely to be effective in all the different populations,” Ginsberg says. “Of course the ideal situation would be to have a single vaccine that could work for all—from infants to grandparents, in HIV infected and HIV non infected populations, and in latently infected and non infected people. But this is a very tall order. So more likely we are going to need different vaccines.”

However, she says, the TB vaccine pipeline looks more promising than ever.

“When I was last involved with TB vaccines, almost a decade ago, there was only one candidate [in clinical trials], but as of now we have a very robust pipeline. Globally there are 12 vaccines in the clinical stages, and many more in the discovery/preclinical stages with different organizations. “

Scientists are trying many different approaches, which is important, since little is known about the protective host immune response.

“So we have to experiment with many different approaches and find out what works and what does not work. Not understanding the fundamental biology is one of the major impediments in TB vaccine development.”

In fact, 90 percent of the human beings who become infected with M Tuberculosis Bacillus never develop TB. The human body has its own mechanism to protect against TB. But scientists still do not understand the immunology well enough to be smart enough to design model vaccines. So developing better models and better understanding of the whole immune response will go a long way to helping to improve the vaccine candidates.

Currently many human trials are going on. Aeras with its partners has two vaccines that are in the late Phase IIb proof of concept trial stage, and there are others in phases I and IIa stages. Phase IIb stage trials are very large with thousands of participants. And after Phase IIb we have the even bigger phase III trials, involving sometimes whole communities that ultimately prove both efficacy and safety of the vaccine tested.

Aeras has conducted a small phase I trial in India but would like to get more engaged with the Indian government and other potential Indian partners as India is a high burden country, and also because now India has a Vaccine Grand Challenge Program that includes TB.

Aeras, with its partners, has two vaccines that are in the late Phase IIb proof of concept trial stage, and there are others in phases I and IIa stages. It is currently sponsoring five booster vaccines and one priming vaccine in different clinical phases of development. MVA85A is the most clinically advanced TB Vaccine candidate. It is a booster vaccine designed for infants and adolescents and uses a recombinant viral vector. It is in the Phase IIb trials on infants (with 2797 participants who had already been vaccinated with BCG at birth), and in HIV infected adult population (1400 adults aged 18-50 years). This marks the first large scale clinical trial of a new TB vaccine in infants in over 80 years. Developing a safe and effective vaccine for immune compromised individuals living with HIV has the potential to save millions of lives. Another candidate, the AERAS-402/Crucell Ad35 booster uses an adenoviral vector. It has undergone testing in multiple Phases I and II Trials among healthy adults, adults with

previous exposure to TB, and adults living with HIV. The proof of concept Phase IIb infant clinical trial of this vaccine is already underway.

Dr Ginsberg conceded that there are several long-term impediments for TB vaccine development, the biggest challenge being insufficient funding. Phase IIb stage trials are very large with thousands of participants. The phase III trials are even bigger, involving sometimes whole communities that ultimately prove both efficacy and safety of the vaccine tested. Thus late phase trials involve many participants and take a long time to complete.

“As TB vaccine development is relatively new, a huge amount of work goes in conducting trials—building capacities at sites and among investigators; strengthening lab capacities,” Ginsberg said – “working with the communities so that they really understand why these vaccines are being tested, etc. So the whole process requires people and resources and is a big challenge, but it is doable. As the clinical trials progress it also becomes more important to find the right assays to predict the protection rate of a vaccine candidate.”

“Until we get a vaccine or better drugs, we need to make maximum use of the tools available. There are still many people who are either not getting diagnosed at all or are diagnosed at later stages of the disease, thus transmitting it unknowingly to other people. So, better and faster diagnosis is crucial. Then patients should be tested for their drug sensitivity as rapidly as possible in order to get the right drugs which will kill the bug in their body. This is crucial and we have tools to do it, but we need to expand their implementation. We also have to ensure that patients complete the treatment.

“Ideally, there should be a follow up after treatment is completed, as a small percentage of them may relapse and these have to be caught early before they can infect other people. We have to keep pushing with the tools we have right now, but the reality is that existing tools are insufficient to tackle the problem. So we need better drugs, better vaccines, better point of care diagnostics, and better community participation. DOTS approach is important, but sometimes in big countries like India, a perfect follow up becomes difficult. So we need new and better vaccines, drugs and diagnostics, so that we are not trying in vain to push the boulder up the hill that we cannot get all the way up.”

So new vaccines seem to be in sight. The challenge is to find the capacity and build the resources to execute the clinical trials and to make the new vaccines available for those who need them, which is estimated could happen within the next ten years. (CNS)

(Shobha Shukla is Managing Editor of Citizen News Service (CNS). She can be reached at shobha@citizen-news.org, website: http://www.citizen-news.org)