Tuberculosis (TB) is a major cause of death worldwide, and the number one cause of death in persons with HIV infection. Drug-resistant TB, an increasingly global epidemic, requires prolonged treatment with toxic, expensive drugs. BCG, the only vaccine currently in use for prevention of TB, is very effective for the first few years of life, but loses efficacy after 10-15 years. Booster immunization of adolescents or adults with a repeat dose of live BCG does not increase protection (presumably because the immunity induced by a priming dose of BCG reduces replication of a booster dose). Therefore, development of an effective booster TB vaccine for the world is a major international health priority. Modeling indicates that an effective booster for adolescents and adults will have a greater impact on disease than an improved BCG for infants and is the only strategy that can be expected to meet the global target of tuberculosis elimination by 2035. New rBCG vaccines being developed for infant immunization may benefit from a strategy that includes an inactivated booster vaccine (i.e., a vaccine that does not require replication) for adolescents and adults.
More than 30 new TB vaccines have entered development over the past twenty years. Several have failed; others are have not reached the clinic; a few are in early stages of development. The only new TB vaccine to have shown efficacy in humans in a fully-powered Phase 3 trial (NTC00052195) is the booster vaccine being developed by investigators at Dartmouth College. The DarDar Trial, a 7-year, 2,000-subject rigorously designed trial conducted in Tanzania and sponsored by the National Institutes of Health showed that SRL172, a inactivated, whole cell vaccine prepared from an environmental mycobacteria, was safe and effective in persons with HIV infection (von Reyn et al AIDS 2010; 24: 675-685).
In 2013, Dartmouth College obtained from Immodulon (London) an exclusive, transferable, worldwide license for the seed strain of SRL 172 for TB prevention. A new, scalable method of manufacture was developed by Aeras (Rockville, MD) and an initial batch of GMP vaccine prepared. The vaccine product, now designated DAR-901, is the most advanced and promising candidate in the global portfolio. Pre-clinical studies completed include tuberculosis challenge study indicating DAR-901 is superior to BCG booster (Lahey et al, PLoS One, 2016).
The DarDar Tuberculosis Vaccine Trial was sponsored by the National Institutes of Health and conducted from 2001-2008 among 2,013 HIV-infected volunteers in Dar es Salaam, Tanzania. Subjects were adults with CD4 counts >200 and childhood BCG immunization and were randomized 1:1 to receive 5 intradermal doses of inactivated SRL-172 (an environmental non-tuberculous mycobacterium) or identical placebo. In the process of screening asymptomatic subjects for active tuberculosis the study team identified the new clinical entity of subclinical tuberculosis.
The trial was stopped by the Data and Safety Monitoring Board when the vaccine was judged to have shown efficacy based on a trend in protection against the primary endpoint of disseminated tuberculosis and a statistically significant reduction in the secondary endpoint of definite culture-confirmed tuberculosis. The main effects manuscript was published in AIDS in 2010 and the immunogenicity manuscript in Vaccine in 2010.
The trial supports the concept of a polyantigenic vaccine as an effective approach to the prevention of tuberculosis in HIV-infected adults. A broth manufacturing process for SRL-172 has been developed by Aeras for the vaccine now known as DAR-901. DAR-901 has been added to the Aeras TB vaccine portfolio and is in a Phase I trial in the United States.
Kisali Pallangyo MD. Professor of Medicine, MUHAS, emeritus Vice-Chancellor was the site PI for the DarDar SRL172 trial.
The DarDar Pediatric Program (DPP) was established in 2006 – structured as a collaborative clinical program for the care of HIV-infected and exposed children in greater Dar es Salaam. DPP supports large-scale HIV care and treatment, Prevention of Mother to Child Transmission of HIV (PMTCT), HIV early infant diagnosis (HEID), broad educational opportunities, and a growing portfolio of research activities. Founded as a collaborative program between Dartmouth Medical School (DMS) and Muhimbili University of Health and Allied Sciences (MUHAS), DPP was the recipient of construction and operational funding from the Foundation for the Treatment of Children with AIDS (FTCA – see associated article). Additional operational support continues through the PEPFAR program (President’s Emergency Program for AIDS Relief) and from numerous research grants. Following the initial occupation of a temporary clinic facility in April 2006, DPP moved into its new clinic located at the Infectious Disease Center (IDC) in central Dar es Salaam, built with FTCA funding, in June 2007.
DPP is a unique clinic in Tanzania in that it primarily features HIV prevention and care for the pediatric population. Engagement of pediatric HIV care globally has generally lagged behind care for adults in the large treatment roll-out programs to date. DPP’s dedicated HIV clinic for children with its pediatric-trained staff has attracted considerable interest in Tanzania as a model and an effective strategy to help address pediatric implementation deficits.
DPP provides HIV and TB diagnostic evaluation and treatment for children from the newborn period through 14 years of age. Over 1,300 children have received care at DPP since opening in 2006. Of these, 550 receive ongoing care for HIV infection with 400 eligible for and receiving specific HIV medication (by Tanzanian national guidelines). In addition, DPP also offers care and treatment for HIV-infected parents of children in its program – now totaling 226 adults (primarily mothers) who receive comprehensive HIV/ AIDS care and treatment. This has resulted in a family-centered care option featuring pediatric index cases.
DPP is the only pediatric-specific clinic for HIV care in Dar es Salaam, serving as a model and educational resource for other programs and their clinical staff. DPP is also a popular destination for student and training internships supporting a wide range of scholars including undergraduates, graduates, medical students, and faculty from both Tanzania and the Dartmouth community. In addition, DPP is the site of numerous research activities.
DPP has a professional, experienced, pediatric-focused staff which provides comprehensive care. Leadership is provided in Dar es Salaam by Dr. Helga Naburi (Medical Director) and Dr. Goodluck Lyatuu (Clinic Medical Director) and from Dartmouth by Dr. Lisa Adams (Director) and Dr. Paul Palumbo (Executive Director). DPP staff is comprised of physicians, nurses, pharmacists, and data managers and other support staff. This leadership and staff are committed to high quality pediatric care and the associated goals of education and research.
Study ran 2010-2015
Several studies have shown that HIV+ individuals develop hearing problems at a high rate. But how frequently this occurs, and the reasons for it, are not known.
The National Institute for Deafness and Communications Disorders is sponsoring the DarDar hearing study to determine how frequently hearing problems develop in HIV+ adults and children. Also, this study is examining the relationship of hearing loss to drugs, infections, and the duration of HIV treatment. Both adults and children with HIV, and with HIV and tuberculosis, are enrolled in the study and followed over time at the Infectious Disease Center in Dar es Salaam.
At the clinic, the study participants complete a battery of auditory tests using a laptop-based, hearing assessment system that includes standard audiometry, distortion product otoacoustic emission testing, a gap detection test, and tympanometry. Participants also complete a questionnaire asking about their exposure to other factors that might affect their hearing (e.g. noise, other drugs, chemicals). Individuals with significant hearing loss requiring amplification are fitted with hearing aids from Solar Ear equipped with a solar battery charger.
Study ran 2009-2013
The DarDar Nutrition Study was sponsored by the National Institutes of Health and is designed to test the hypothesis that administration of a protein calorie supplement (PCS) to HIV-infected women at risk of malnutrition will improve their health outcomes. Two groups of women in Dar es Salaam were enrolled to receive a PCS or control multivitamin in the randomized studies : 1) 96 pregnant women in their third trimester who planned to exclusively breast feed for 6 months [Study 2-B, NCT01461863] and 2) 180 women with newly diagnosed tuberculosis [Study 2-C, NTC01635153]. Results of the two trials have been submitted for publication.
The trials were preceded by studies in Tanzania which documented nutritional deficiencies in both HIV-infected children and HIV-infected lactating women.
In the first three 5-year NIH training grants with Tanzania faculty from Dartmouth and Boston University School of Public Health provided degree training, short term training, and research conferences on HIV and TB to hundreds of Tanzanian researchers and health care workers. A total of 15 Tanzanian physicians have completed MPH degrees at The Dartmouth Institute, 2 have completed Masters Degrees in Epidemiology at Boston University and 4 Fogarty Fellows have completed doctoral programs at Dartmouth or BU in basic science or biostatistics.
The many Tanzanian alumni of the DBU Fogarty training programs have provided key personnel for the numerous collaborative epidemiologic studies and clinical trials conducted as part of the DarDar collaboration. In the most recent 5 year cycle the training grant led to the development of a Tuberculosis Research Institute at MUHAS (TRIM-TB). This institute became the foundation for the broader vision of an overall Infectious Disease Institute (IDI) at MUHAS which will be the focus of the next 5 year training cycle.
Further details is available here.
The Ford von Reyn Research Elective in Global Health is available to 4th-year Geisel medical students seeking to develop their research skills in resource-limited settings. One student is selected annually to conduct clinical research at the DarDar site in Dar es Salaam, Tanzania for 4-8 weeks between September and May. Fellows are awarded a research grant supported by Dartmouth’s Section of Infectious Disease and International Health and the Global Health Initiative at Dartmouth’s Dickey Center for International Understanding. Student research may involve study design, data collection and data analysis in association with one of our ongoing clinical studies of HIV-associated tuberculosis involving either adults enrolled at the DarDar site or children enrolled at the DarDar Pediatric Program. In addition to becoming familiar with the portfolio of collaborative HIV and TB research being conducted by Dartmouth and our international partners, students will learn how a Good Clinical Practices (GCP) trial is conducted, and how data are collected and validated.
The James Strickler Clinical Elective in Global Health is available to 4th-year Geisel medical students interested in applying clinical skills in resource-limited settings. Up to two students are selected annually to assist with the diagnostic evaluation of and provision of care to patients at Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania during a 6-8 week elective between September and May. This fellowship is conducted in association with Muhimbili University of Health and Allied Sciences and is supported by Dartmouth’s Global Health Initiative of the Dickey Center for International Understanding. During their elective, fellows become familiar with the spectrum of disease in a tropical setting and advance their skills in recognizing acute complications of HIV and subsequent management of care. In addition, fellows will gain an understanding of the socio-cultural issues concerning HIV care and treatment. Prior to their departure from Tanzania Strickler Fellows will present a case-based lecture on an Internal Medicine subject to MNH students, residents and faculty, and do a case presentation to Geisel Infectious Disease and International Health faculty and students upon their return to Dartmouth.