DarDar Health Programs

Hanover, NH • Dar Es Salaam, Tanzania

The DarDar Program was established in 2001 as a research collaboration between Geisel School of Medicine at Dartmouth and the Muhimbili University of Health and Allied Sciences (MUHAS) in Dar es Salaam, Tanzania and has subsequently grown to include training programs (Dartmouth-Boston University Fogarty) and clinical care programs (DarDar Pediatric Program). DarDar mimics the Kiswahili word for sister, “dada”, and connotes the strong bond between the two institutions.
TB Vaccine Development

TB Vaccine DevelopmentTuberculosis (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.

DAR-901

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 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 complete include tuberculosis challenge study indicating DAR-901 is superior to BCG booster (Lahey et al, PLoS One, 2016).

Who are the members of the development team?
  • Ford von Reyn MD, Principal Investigator, is Professor of Medicine at Geisel School of Medicine and the 2013 recipient of the Lifetime Achievement Award from the International Union against Tuberculosis
  • Tim Lahey MD, MMSc, Investigator, is Associate Professor of Medicine at Geisel and one of two 2004 national recipients of the Infectious Disease Society of America Young Investigator AwardM
  • Robert D Arbeit MD, is former Associate Chief of Staff for Research at the Boston VA and has 15 years of experience in industry drug development
  • C. Robert Horsburgh MD, Professor, Department of Epidemiology, Boston University School of Public Health and a leader of numerous national and international TB treatment trials
  • Ajit Lalvani MA, DM, FRCP, Professor, Director, Tuberculosis Research Centre, National Heart and Lung Institute Imperial College London
Why is DAR-901 the most promising new TB vaccine?
  • SRL 172 is the only new TB vaccine to have progressed to Phase 3 showing efficacy in humans
  • DAR-901 represents a new scalable manufacturing method for SRL 172 developed by Aeras to permit manufacture in commercial quantities at reasonable cost.
  • DAR-901 represents an entire bacterial organism and includes thousands of different antigens to stimulate a broad immune response.
Recent studies with DAR-901
  • An animal challenge study published in late 2016 showed that a DAR-901 booster provided greater protection against TB than a BCG booster.
  • A human Phase 1 dose escalation trial demonstrated that a 3-injection series of DAR-901 was safe and well tolerated in humans and induced immune responses similar to those seen with the effective SRL172 vaccine.
Current 2b clinical trial with DAR-901
  • DAR-901 is currently being evaluated in the DAR-901-PIAT randomized, controlled Phase 2b study in Tanzania.
  • DAR-901-PIAT is a Prevention of Infection (POI) trial among 650 adolescents aged 13-15 in Dar es Salaam
  • All subjects completed 3 injections of vaccine or placebo by March 2017 confirming the safety and tolerability of immunization.
  • The trial will end in Q4 2018
  • DAR-PIA is supported by a grant from the Global Health innovative Technology Fund (GHIT, Japan)
Tanzania Tuberculosis Vaccine Trial: SRL-172

vaccine development teamThe 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.

Published Studies
Dartmouth Pediatric Program

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.

Hearing Study

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.

Nutrition Study

Study ran 2009-2013

The DarDar Nutrition Study is 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 will receive a PCS or control multivitamin in the randomized studies : 1) 96 pregnant women in their third trimester who plan to exclusively breast feed for 6 months [Study 2-B] and 2) 180 women with newly diagnosed tuberculosis [Study 2-C].

A pilot study [Study 2-A] was completed in 2011.

Forgarty TRIM-TB

Dartmouth-Boston University D43 Fogarty Research Training Program Tuberculosis Research Institute at MUHAS (TRIM-TB)

Duration: 2013-2018

Tuberculosis is the leading cause of death among persons with HIV infection in Tanzania. Clinical and operational research to improve prevention and treatment of both adult and pediatric HIV-TB is a defined national priority but there is no specifically designated and staffed institute to plan, coordinate and conduct such research.

The objective of the Dartmouth-Boston University (DBU) application is to provide the training to develop a premier HIV-TB clinical and operational research institute: the Tuberculosis Research Institute at Muhimibili University of Health and Allied Sciences (MUHAS) (TRIM- TB).

MUHAS leadership, the Tanzanian National Tuberculosis and Leprosy Program (NTLP) and former Fogarty trainees have all contributed to planning the new institute.

The program will consolidate the expertise of past Fogarty trainees with a new focused plan to train the requisite professionals to fully staff TRIM-TB.

The institute will be based a new office complex at MUHAS with additional staffing located at the NTLP. An initial faculty core at MUHAS (Director, Associate Director) will be augmented by the addition of trainees who will complete the following degrees determined to be necessary for providing the necessary research expertise for the institute: 3 MPH degrees at Dartmouth, 3 MPH degrees at MUHAS, 1 master’s degree at BU (pharmacology) and 2 doctoral degrees at BU (epidemiology, public health).

Additional short and medium term training in ethics, good clinical practice and HIV-TB research methods will be provided for investigators.

Advanced TB microbiology and TB immunology training will be provided for research microbiologists who will staff the TRIM-TB core laboratory.

Pilot grant funding will be available for HIV-TB research projects and investigators will coordinate efforts thru monthly research seminars at MUHAS linked by teleconference to Dartmouth and BU. Defined performance measures focused on development of independent HIV-TB research capacity have been developed and will be monitored. An extensive candidate pool will be recruited from health science students at MUHAS, prior DBU AITRP trainees, Fogarty alumni, public presentations and focused advertising.

Performance sites for research will include adult and pediatric DarDar Programs, NTLP clinical sites, and the Fogarty African Consortium on Tuberculosis (FACT, developed by the DBU AITRP). Faculty for the program have extensive experience in HIV-TB research, actively funded research projects, and wide experience training and mentoring junior colleagues.

An expert Training Advisory Committee will oversee the program. After 5 years TRIM-TB will have set HIV-TB research priorities for Tanzania and have secured independent funding for research on these priorities.Further details and application information is available here.

Further details and application information is available here.

Geisel Clinical Electives

Ford von Reyn Research Elective in Global Health

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.

James Strickler Clinical Elective in Global Health

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.