News

15 December, 2022 A global health equity leader and early advisor to the Center for Health Equity, Dr. Ford von Reyn ‘67, Geisel ‘69, Professor of Medicine at Geisel, recently received an honorary D.Sc. Degree from our longstanding partner Muhimbili University of Health and Allied Sciences (MUHAS) in Dar es Salaam, Tanzania. This was only the third honorary degree ever conferred by MUHAS. Tanzanian Vice President Philip Mpango, of Tanzania bestowed the degree upon Dr. von Reyn for his work to establish the DarDar International Programs, a TB and HIV research collaboration he started in 2001 between Geisel and MUHAS. Under his leadership, the DarDar collaboration has expanded to include bilateral exchanges in which students and faculty from both schools participate in capacity building to improve health and healthcare delivery.

Read the full story from the Geisel School of Medicine here.

TB Vaccine Development

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.

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 (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).

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 Award
• Lisa V. Adams MD, is the Associate Dean for Global Health and an Associate Professor of Medicine in the Section of Infectious Disease and International Health at Dartmouth’s Geisel School of Medicine
• 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. (NCT02063555)

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. (NCT01451863)
• DAR-901-PIAT is a Prevention of Infection (POI) trial among 650 adolescents aged 13-15 in Dar es Salaam. (NCT02712424)
• All subjects completed 3 injections of vaccine or placebo by March 2017 confirming the safety and tolerability of immunization.
• The successful Phase 2 Trial ended in December of 2019
• DAR-PIAT is supported by a grant from the Global Health innovative Technology Fund (GHIT, Japan)

Tanzania Tuberculosis Vaccine Trial: SRL-172

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.

Published Studies

• Prevention of tuberculosis in Bacille Calmette–Guerin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine (AIDS, 2010)
• Immunogenicity of an inactivated mycobacterial vaccine for the prevention of HIV-associated tuberculosis: a randomized, controlled trial (AIDS, 2003)
• Interferon γ Responses to Mycobacterial Antigens Protect against Subsequent HIV-Associated Tuberculosis (JID, Oct. 2010)
• Immunogenicity of a protective whole cell mycobacterial vaccine in HIV-infected adults: A phase III study in Tanzania (Vaccine, 2010)
• Immunogenicity and Protective Efficacy of the DAR-901 Booster Vaccine in a Murine Model of Tuberculosis; T. Lahey et al. / PLoS ONE 11(12): e0168521. doi:10.1371/journal.pone.0168521
• von Reyn CF. Correcting the record on BCG before we license new vaccines against tuberculosis. J Royal Soc Med 2017; 110: 428-433

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.

Neurocognitive Effects of HIV Infection

Individuals infected with HIV can develop problems with thinking, solving problems, and maintaining attention—a group of symptoms called HIV-associated neurocognitive disorder. This can occur despite effective treatment for the HIV virus. This is one of the most devastating side effects of long standing HIV infection, and new ways to diagnose and follow this problem are needed. Previous work at the DarDar health program has shown that the hearing system in the brain – the pathways in the brain that work to understand words and interpret speech – is affected in people with HIV infection. This suggests that simple tests of the ability of the brain to process sound may offer a new and novel way to assess brain function in people with HIV.

The National Institute for Deafness and Communication Disorders is supporting a study in Dar to assess how the central hearing system can be used to monitor changes in brain function. A cohort of HIV+ adults and children in Dar have been followed regularly at the DarDar Health Center, where they have assessments of their brain function using cognitive tests, along with a battery of central (brain) tests of the ability of the brain to process and understand sound. These central auditory tests may offer a simpler, easier to perform way to assess brain function than current techniques. Ultimately, this could alter clinical practice if central auditory tests can be shown to be useful for screening for or tracking central nervous system effects in HIV+ adults and children.

• Ndeserua Moshi, M.D., Site Principal Investigator, Muhimbili University for Health and Allied Sciences
• Enica Richard Massawe, M.D., Co-Investigator, Muhimbili University for Health and Allied Sciences
• Albert Magohe, M.D., Clinical Investigator, Dar Dar Health Programs
• Abigail M. Fellows, M.A., Research Coordinator, Geisel School of Medicine at Dartmouth
• Jay C. Buckey, MD, Principal Investigator. Professor of Medicine at Geisel School of Medicine at Dartmouth

Understanding an unexplained syndrome of hearing loss, visual loss, and limb numbness in young Tanzanian adults

Since 1991, otolaryngologists in Dar es Salaam, Tanzania have been evaluating young people with unexplained hearing loss. Often, these same people have been referred to ophthalmology or neurology clinics because of visual problems, or symptoms of leg numbness and tingling. These symptoms seem comprise a syndrome that affects some young people in the Dar es Salaam area.

The Hitchcock Foundation at Dartmouth-Hitchcock is funding an investigation into the nature of this syndrome, and what factors might contribute to it. People with the syndrome have been studied at the DarDar Health Center, where they have had a comprehensive assessment of their hearing along with measurements of vision and sensation in the legs. The study also collects information from a questionnaire along with blood tests for inflammation and tests for heavy metal levels. The goal is to determine whether this syndrome might be linked to an environmental factor or perhaps an undetected infection.

• Enica Richard Massawe, M.D., Site Principal Investigator, Muhimbili University for Health and Allied Sciences
• Ndeserua Moshi, M.D., Co-Investigator, Muhimbili University for Health and Allied Sciences
• Albert Magohe, M.D., Clinical Investigator, Dar Dar Health Programs
• Abigail M. Fellows, M.A., Research Coordinator, Geisel School of Medicine at Dartmouth
• Jay C. Buckey, MD, Principal Investigator, Professor of Medicine at Geisel School of Medicine at Dartmouth

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.