Mycobacterium vaccae Vaccine Prevents Tuberculosis in HIV Positive People with Prior BCG Vaccination

		SUMMARY: A large trial in Tanzania found that a multiple-dose vaccination series using Mycobacterium vaccae was safe and partially effective -- a 39% risk reduction -- in preventing tuberculosis (TB) in HIV positive adults who had received the minimally effective BCG vaccine as children, researchers reported in the January 28, 2010 advance online edition of AIDS.

By Liz Highleyman

HIV positive individuals, especially those with advance immune suppression, are at elevated risk for TB, which is a leading cause of death for people with HIV/AIDS worldwide.

Colonies of the bacterium Mycobacterium vaccae grown in a petri dish in the lab

Charles Ford von Reyn from Dartmouth Medical School and fellow investigators with the DarDar Study Group assess the safety and efficacy of a multiple-dose vaccine containing whole inactivated Mycobacterium vaccae, non-pathogenic bacteria related to Mycobacterium tuberculosis (the cause of TB) in people with HIV. Prior vaccine studies in HIV negative populations have produced mixed results.

The researchers hypothesized that the M. vaccae vaccine might strengthen pre-existing immune response triggered by the Bacille Calmette-Guerin (BCG) vaccine. BCG is a routine childhood vaccination in many countries (not including the U.S.). It provides only modest (and typically temporary) protection at best, and has demonstrated lower efficacy in resource-limited regions closer to the equator.

The Phase 3 DarDar (Dartmouth/Dar es Salaam) trial -- sponsored by the U.S. National Institute of Allergy and Infectious Diseases -- included 2013 HIV positive patients seen at an outpatient facility in Dar es Salaam, Tanzania. Participants had a CD4 cell count of at least 200 cells/mm3 and had a scar indicating prior BCG vaccinations. They were randomly assigned (1:1) to received 5 intradermal injections of the M. vaccae vaccine or placebo over the course of a year.

Participants were followed every 3 months for a median of 3.3 years. They received regular tuberculin skin tests, and those with reactions of 5 mm or larger (indicating TB infection) received isoniazid for 6 months.

The primary study end-point was disseminated (spread outside the lungs) tuberculosis. Definite and probable TB were secondary end-points.

Results

	The trial was stopped ahead of scheduled due to slow accrual of cases of disseminated tuberculosis and significant protection against definite tuberculosis.
	7 people in the M. vaccae vaccine group developed disseminated TB compared with 13 in the placebo group, yielding a hazard ratio (HR) of 0.52, indicating the risk was reduced by about half; due to small numbers, however, the difference did not reach statistical significance (P = 0.16).
	33 people in the vaccine group and 52 people in the placebo group were diagnosed with definite TB, a hazard ratio of 0.61, or a 39% decrease, which was significant (P = 0.03).
	48 people in the vaccine group and 40 in the placebo group were considered to have probable TB -- a slightly increased risk (HR 1.17), though the difference again was not statistically significant (P = 0.46).
	M. vaccae immunization was well tolerated, with no adverse effect on CD4 cell count or HIV viral load and serious adverse event rates similar to those of the placebo group.

Based on these findings, the researchers concluded, "Administration of a multiple-dose series of M. vaccae to HIV-infected adults with childhood Bacille Calmette-Guerin immunization is safe and is associated with significant protection against definite tuberculosis."

"These results provide evidence that immunization with a whole cell mycobacterial vaccine is a viable strategy for the prevention of HIV-associated tuberculosis," they added.

"Since development of a new vaccine against tuberculosis is a major international health priority, especially for patients with HIV infection, we and our Tanzanian collaborators are very encouraged by the results of the DarDar Study," von Reyn said in a press release issued by Dartmouth.

Dartmouth Medical School, Hanover, NH; Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania; Tufts University School of Medicine, Boston, MA; University of Vermont, Burlington, VT; Boston University School of Public Health, Boston, MA; National Public Health Institute, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Finland.

2/5/10

Reference

C von Reyn, L Mtei, RD Arbeit, and others (DarDar Study Group). Prevention of tuberculosis in Bacille Calmette-Guerin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine. AIDS (Abstract). January 28, 2010 (Epub ahead of print).

Other Sources

Dartmouth College. New vaccine effective in preventing TB in African patients with HIV infection. News release. January 29, 2010.

Kaiser Family Foundation. Experimental Vaccine Reduced TB Rate Among HIV-Positive People In Tanzania, Study Finds. Kaiser Daily Global Health Policy Report. February 1, 2010.