A TB vaccine reduced the incidence of laboratory-confirmed TB in HIV-positive people by 37% in a large placebo-controlled randomised clinical trial in Tanzania, researchers from the United States and Tanzania reported on Monday at the World Lung Health conference in Paris.
The reduction was statistically significant, and if it were possible to vaccinate 50% of people diagnosed with HIV in Tanzania, the number of new TB cases in the country could fall by around 3300 per year, said lead investigator Dr Ford von Reyn.
However questions remain about the true degree of efficacy of the vaccine, and how it might be made available, making its availability in the field a long-term prospect.
Tuberculosis is one of the most common opportunistic infections in people with HIV, and can develop long before other opportunistic infections, when the immune system is relatively intact. Immune responses to mycobacteria, of which tuberculosis is one, begin to decline as the immune system deteriorates as a result of HIV infection or malnutrition, and the BCG TB vaccine given in childhood in many countries ceases to be effective.
Developing a vaccine against TB that provides protection for people with HIV is an important research priority. The only treatment that can prevent TB in people with HIV is isoniazid preventive therapy, which is given to people who have latent TB – a TB infection which has been walled off by the immune system and is not causing active disease. Isoniazid preventive therapy is still not offered widely to people with HIV in resource-limited settings, despite a recommendation to do so by the World Health Organization.
The DarDar study (so called because it was a collaboration between Dartmouth School of Medicine and Muhimbili University in Dar es Salaam) was a phase III study designed to test the safety and efficacy of a TB vaccine in a large population of HIV-positive people, with the intention that if successful, the study results could be used in licensing the vaccine for widespread use.
The study used a whole inactivated mycobacterium called M. vaccae, which had been tested for safety and immunogenicity in a variety of previous human studies in Europe, North America and Africa.
The DarDar study began recruitment in 2001, and recruited 2000 people with HIV, 70% women, with CD4 counts in the range 200 – 500 cells/mm3. The investigators chose this CD4 range because immune responses to mycobacteria decline substantially when the CD4 count falls below 200 cells/mm3, increasing the risk that study participants would have little or no immunological response to the vaccine, and therefore fail to develop protection as a result of vaccination.
The average CD4 cell count of participants was around 400 cells/mm3.
The study only recruited participants who had an identifiable BCG vaccination scar, which indicated that they been immunised against TB during childhood. The study was thus examining the boosting effect of the M. vaccae vaccine in people who had previously received the BCG vaccine.
The study’s primary endpoint was the incidence of disseminated tuberculosis, measured by bacterial culture.
The secondary study endpoints were reductions in cases of TB that were confirmed by positive sputum culture or blood culture – defined as `definite` TB – and reductions in cases of `probable TB` - cases which met two of the following criteria: two smear-positive sputum samples, or a chest X-ray plus symptoms, or chest X-ray plus a response to TB treatment.
Two thousand participants were randomised in equal proportions to receive five intradermal immunisations with the active vaccine or a placebo over a 12-month period; 85% received all doses of the vaccine. The vaccine was well tolerated, with only 12 discontinuations due to injection site reactions or other vaccine-related adverse events; in most patients who experienced them, injection site reactions were mild.
After an average follow-up period of three years, the investigators observed 207 cases of active TB in the study, but only 20 cases of disseminated TB had been identified, making it impossible to prove that there was a significant effect of the vaccine on the incidence primary study endpoint.
Dr von Reyn said that the low incidence of disseminated TB was probably due to the aggressive attempts of trial physicians to identify symptomatic cases of pulmonary TB before they progressed to disseminated TB, and because of loss-to-follow-up among very sick patients (16% of participants were lost to follow-up).
The trial found a significant reduction in cases of definite TB (p = 0.027); 33 occurred in the vaccine recipients compared with 52 in the placebo group, indicating a vaccine efficacy of 37%. The protective effect of the vaccine was evident within a year of vaccination when the event rate was plotted in a Kaplan-Meier graph. There was no association with age, sex, prior TB history, isoniazid preventive therapy or antiretroviral therapy (ART) status (by the end of the study 29% of participants were taking ART).
However there was no significant reduction in `probable TB` (p = 0.23).
The study investigators concluded that the vaccine provides significant protection against `definite` TB, and commenting on the 37% reduction in risk observed, Dr Ford von Reyn said, “anything more than 20% is very favourable in the context of a very common complication of AIDS”.
To illustrate the protective effect further Dr von Reyn showed data modelling the potential effect of the vaccine on the TB case load among people with diagnosed HIV infection in Tanzania.
In order to prevent one case of definite TB per year, 40 to 66 immunisations would have to take place. 100% coverage in the HIV-positive population could prevent 6600 cases of definite TB, and 50% coverage could prevent 3300 cases. Fifty per cent coverage would reflect the proportion of the HIV-diagnosed population with a CD4 count above 200 cells/mm3 – those in whom the vaccine is proven to be effective – claimed Dr von Reyn. He envisaged that people would receive the vaccine as part of the initial package of care following HIV diagnosis, and after they had received a CD4 cell count.
Dr von Reyn acknowledged the fact that a major limitation of the findings is the lack of data on the effect of vaccination in HIV-positive people with CD4 cell counts below 200 cells/mm3. He said a small trial would be needed to test the immune response to the vaccine in this group, but he acknowledged that the correlates of protection against TB in vaccinated individuals are still unknown, making it difficult to design such a study at present.
The M. vaccae vaccine has been in development for more than 15 years, and was originally developed by SR Pharmaceuticals. Its future development remains unclear, although discussions are already underway with the Aeras Global TB Vaccine Foundation, a public-private partnership that is organising studies of TB vaccine candidates in partnership with industry and academia. A second TB vaccine, developed by Crucell and Aeras, is due to enter a phase II trial in South Africa within the next few weeks.
Dr von Reyn said that the Tanzanian ministry of health is interested in implementing a vaccination programme, but a manufacturer must be identified to make sufficient batches for a large-scale programme (Tanzania has more than 1 million people already diagnosed with HIV infection), and the vaccine must clear licensing hurdles first. Since the vaccine’s efficacy is only proven in a specific CD4 stratum, there will also be questions to resolve about how it can be made available in settings where CD4 counts are not available.
Dr von Reyn told a press conference that the lack of CD4 testing should not be an obstacle to making the vaccine available to people with HIV, noting that the vaccine would be safe at any CD4 count.
Professor Tony Harries, an adviser to the International Union Against TB and Lung Disease and to the Malawian government’s HIV programme, said that from a Malawian perspective – where CD4 counts are not available – almost three-quarters of people diagnosed with HIV are not yet eligible for treatment because they do not have symptoms caused by HIV. Almost 100,000 people have been diagnosed with HIV in Malawi in the past year as a result of a government HIV testing campaign that included a national HIV testing week.
“Because there’s a big drive across Africa to 'know your HIV status', there’s been a big ratcheting up of HIV testing,” Prof. Harries told the press conference.
It was important to be able to offer these patients something in order to reduce the high rates of loss to follow-up among those diagnosed with HIV who are not yet eligible for HIV treatment.
“We’re thinking in terms of pre-ART care – what would the package of care look like? We could offer cotrimoxazole prophylaxis and a one-year course of five vaccinations to prevent tuberculosis,” he said.
Von Reyn CF et al. The DarDar prime-boost TB vaccine trial in HIV infection: final results. 39th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease, Paris, abstract PS-81689-20, 2008 (published in the International Journal of Tuberculosis and Lung Disease 12 (11): supplement 2, 2008)