TB vaccinesSouth African Minister of Health, Aaron Motsoaledi. Photo: David Harrison

TB vaccines

TB Vaccines
Photo by Shyam Goswami

The search for an effective TB vaccine has so far failed to produce a silver bullet against the disease and recent trial results have been disappointing. However, a number of vaccine trials are underway and the South African TB Vaccine Initiative is playing an important part in this work.

Little progress in 90 years

The only tuberculosis (TB) vaccine in use is the Bacillus Calmette-Guérin (BCG) vaccine. It was developed in 1921 in France using a strain of bovine TB. The World Health Organization recommends giving the BCG vaccine to infants in countries with high TB rates. The vaccine is effective in preventing severe TB disease in children (especially TB meningitis – the inflammation of the lining of the brain), but unfortunately it provides little or no protection to adults.

TB vaccine research has been slow and little has been produced since the development of the BCG vaccine more than 90 years ago. However, in the last decade research activity has intensified and a number of new vaccines are now being investigated. The South African TB Vaccine Initiative is playing an important part in these efforts.

Recent findings, however, have been disappointing. A clinical trial conducted by SATVI on a vaccine called MVA85A showed no efficacy in infants, after having produced promising results in four different animal models.

This trial tested the efficacy of MVA85A in infants who had already received the BCG vaccine. According to Principal Investigator Dr. Michele Tameris of SATVI, infants were chosen because they are a ‘captive audience’ and this means it is easier to monitor them. MVA85A is presently being tested in HIV-positive adults in Senegal.

Dr Willem Hanekom, Director of SATVI, believes there could still be hope for MVA85A. Speaking about the infant trial, he says, “This trial was one dose, in one age group, in one setting, and at one time frame. If we [were to] do it in China we don’t know if [the results] would be different.” BCG has proven to be more effective in certain populations. It was found to have little efficacy in trials in India, but was 60% to 80% effective in British trials.“If we give a double dose, it’s unknown if it will work,” Hanekom notes.

High risk research

Given setbacks like those in the MVA85A infant trial some might be doubtful about the prospect of an effective vaccine. But, it could be argued that the benefits of an effective vaccine would be so great that trials are worthwhile even if the chances of success appear slim.

“Until we know more about [the origin and development of] TB, any vaccine trial is a high-risk undertaking. But in my view, we have no choice,” says  Hanekom. “If you look at the epidemic in South Africa, 500,000 develop TB each year. Worldwide, 1.4 million die [of TB each year]. Until we have a cure, we need high-risk research.”

Clinical trials involving human participants, like those testing MVA85A, are very expensive and time consuming. It can take years before you know whether a vaccine works or not. For this reason, SATVI has taken a two-pronged approach to vaccine research. One focus is on conducting clinical trials of new vaccines and the other is on researching biomarkers.

Biomarkers are measurements of specific blood levels, cells or other physical processes that can indicate the progression of a disease. Finding biomarkers that accurately indicate whether a vaccine is working or not could potentially cut down on the length of trials. It could also help to eliminate vaccines that are ineffective more quickly.

Currently we do not know what to look for in patients who have received a TB vaccine to know if the vaccine is working. “Right now, we’re in the dark,” says Dr. Hennie Geldenhuys, Clinical Researcher and Medical Officer at SATVI. “We need to know what gives protection. Now, it’s a bit of a lottery.”

In the early phases of testing a vaccine, researchers look for an immune response, which is evidence that the vaccine can cause the kind of immunity that is thought to be important for protection against TB. We know that a type of immune cell called CD4 T-cells are critical in protection from TB, and after administering a test vaccine, researchers look to see if the vaccine is stimulating these cells. This technique however is not specific enough. What researchers lack is a more specific indicator (biomarker) showing whether the vaccine is working as intended. Such a biomarker would most likely be something that could be detected in a blood test.

TB biomarkers can be divided into two groups: those that are linked to a person’s risk of infection and those that are indicators of protection against TB. Enrolling people who have a higher genetic risk of developing TB would reduce the size of trials by thousands of participants. This would in turn lower the cost of the studies. Identifying biomarkers that are linked to protection would drastically decrease the time it takes to determine if a vaccine works.

Other vaccine options

MVA85A is only one of a number of TB vaccines being tested. SATVI is also involved in testing a vaccine called M72. This is currently entering Phase IIB trials. In phase IIB, a vaccine is studied for its efficacy. M72 will be tested in 7,000 young adults who are HIV-negative. Trials of the same vaccine are also being conducted among infants in Ghana.

The vaccines we listed above were all proposed as boosters to the BCG vaccine (i.e. they were given to people who had already received the BCG vaccination). One limitation of BCG is that it is not safe for people with HIV. For this reason, MVA85A will also be tested in infants who have not received the BCG vaccine.

Given our current knowledge of TB, it is very difficult to know whether a vaccine will prove effective in blocking the disease. Vaccines that contain only one or two antigens – substances capable of inducing an antibody response from the immune system –  are less promising, because researchers do not know if the body will ‘take’ the vaccine. “We do not know what little bits will work,” says Dr Hanekom.

For this reason, a live vaccine could be more promising because all the parts of the bacteria are present. Phase I trials of MTBVAC – a whole-organism vaccine developed by the Spanish pharmaceutical company Biofabri – are beginning very soon.

Safety can be of greater concern with live vaccines, such as MTBVAC and BCG. There was a disaster in Lübeck, Germany in 1929, when 72 infants died of TB because of an improperly prepared BCG vaccine. Today, vaccines are heavily regulated.

Research is now mostly focused on finding a vaccine to boost the effectiveness of BCG. “We either need to boost BCG or find a new or replacement [vaccine] that protects everyone forever,” says Principal Investigator Dr. Tameris of SATVI. Until that vaccine arrives, people will continue to struggle with TB.
By Shyam Goswami
Shyam Goswami is a freelance journalist. He formerly worked as an engineer for Médecins Sans Frontières.