Results from the Phase 2 trial of the DAR-901 tuberculosis (TB) vaccine have been announced by investigators at Dartmouth University's Geisel School of Medicine. The three-year trial was conducted among 650 adolescents in Tanzania, a nation with high rates of TB infection, and showed that the vaccine was safe and induced immune responses against the disease.
Tuberculosis is most common infectious disease cause of death in the world (1.5m deaths per year compared to 1m to date from COVID-19) and a new preventive vaccine is a major global health priority. Dr Ford von Reyn, professor of medicine at the Geisel School of Medicine and lead for the vaccine development program, explained that the trial moves the Dartmouth TB vaccine one step closer to a full Phase 3 efficacy trial against TB disease. "Our collaborators in Tanzania deserve credit for their excellent work in conducting a clinical trial to rigorous international standards and moving DAR-901 forward to Phase 3," said Von Reyn.
The vaccine trial was a collaboration between Geisel, the Muhimibili University of Health and Allied Sciences (MUHAS) in Tanzania, the Tokyo Medical and Dental University in Japan, Tufts University School of Medicine, and the Boston University School of Public Health.
Tanzanian students age 13-15 with no evidence of prior TB infection were recruited from schools in Dar es Salaam to receive three injections of the DAR-901 vaccine or placebo in the double-blind trial. All participants had already received the current TB vaccine (BCG) at birth and DAR-901 was administered as a booster. After immunisation all participants were followed for safety and re-tested for TB infection annually for three years.
Senior Tanzanian collaborator Dr Kisali Pallangyo, professor of internal medicine at MUHAS said, "The three dose schedule of DAR-901 was very well tolerated by the students with minimal local reactions and no serious side effects, a very positive result."
The study was conducted as a Prevention of Infection (POI) trial, a new design for TB vaccine trials. TB infection is the first phase of the human response to TB exposure. Because TB infection is not associated with symptoms it can only be detected by a skin test or an IGRA blood test. Development of TB infection is favourable in most people because it provides immunity against progression to TB disease. Among 100 people who acquire TB infection, 90-95% never develop TB disease; only 5-10% will progress to actual TB disease over a lifetime. Although it has been reasoned that if a vaccine can prevent TB infection it will also prevent TB disease, the Dartmouth trial raises questions about this assumption.
DAR-901 was manufactured from SRL172, an inactivated whole cell vaccine which had already been shown to reduce the risk of TB disease in a 2,000 subject Phase 3 trial among subjects with HIV. In the new Phase 2 trial DAR-901 did not reduce the risk of new TB infection, a finding that was not anticipated.
Participants who received DAR-901 and did develop new TB infection had greater immune responses to TB than participants who received placebo. The investigators believe this finding suggests DAR-901 may prevent TB disease by inducing the favourable immune response that protects 90-95% of persons with TB infection from ever developing TB disease. This hypothesis will be tested in a large Phase 3 Prevention of Disease (POD) trial that would be required for licensure.
Background: SRL172 prevented disease due to Mycobacterium tuberculosis in a Phase 3 trial. DAR-901 represents a scalable manufacturing process for SRL172. We sought to determine if DAR-901 would prevent infection with M. tuberculosis among BCG-primed adolescents age 13–15 years in Tanzania.
Methods: Adolescents with a negative T- SPOT.TBR interferon gamma release assay (IGRA) were randomized 1:1 to three intradermal injections of DAR-901 or saline placebo at 0, 2 and 4 months. Repeat IGRAs were performed at 2 months, and at 1, 2, and 3 years. The primary efficacy outcome was time to new TB infection (IGRA conversion to positive); the secondary outcome was time to persistent TB infection (IGRA conversion with repeat positive IGRA).
Results: Among 936 participants screened 667 were eligible and randomized to their first dose of vaccine or placebo (safety cohort). At 2 months, 625 participants remained IGRA-negative and were scheduled for the additional two doses (efficacy cohort). DAR-901 was safe and well-tolerated. One DAR-901 recipient developed a vaccine site abscess. Neither the primary nor secondary endpoints differed between the two treatment arms (p = 0.90 and p = 0.20, respectively). DAR-901 IGRA converters had median responses to ESAT-6 of 50.1 spot-forming cells (SFCs) vs. 19.6 SFCs in placebo IGRA converters (p = 0.03).
Conclusions: A three-dose series of 1 mg DAR-901 was safe and well-tolerated but did not prevent initial or persistent IGRA conversion. DAR-901 recipients with IGRA conversion demonstrated enhanced immune responses to ESAT-6. Since protection against disease may require different immunologic responses than protection against infection a trial of DAR-901 to prevent TB disease is warranted.
Patricia Munseri, Jamila Said, Maryam Amour, Albert Magohe, Mecky Matee, Christiaan A Rees, Todd Mackenzie, Susan Tvaroha, Chris Bailey-Kellogg, Isaac Maro, Wendy Wieland-Alter, Lisa V Adams, C Robert Horsburgh, Keiko Nakamura, Robert D Arbeit, Kisali Pallangyo, Fordham von Reyn
The Geisel School of Medicine at Dartmouth