DAR-901 vaccine for the prevention of infection with Mycobacterium tuberculosis among BCG-immunized adolescents in Tanzania: A randomized controlled, double-blind phase 2b trial
Introduction
Tuberculosis (TB) is the leading infectious disease cause of death in the world [1]. The World Health Organization (WHO) has targeted elimination of tuberculosis by 2030, an objective that will require development of a more effective preventive vaccine strategy. The only licensed vaccine against tuberculosis, Bacille Calmette-Guerin (BCG), is effective when given as a priming vaccine at birth, but activity wanes after 15–20 years [2]. Both improved priming vaccines and new booster vaccines are in development but modelling indicates that an adolescent and adult booster would have a greater impact on the epidemic than an improved priming vaccine over the initial several decades [3], [4], [5], [6]. Preferred Product Characteristics (PPCs) defined by WHO for a new vaccine include efficacy of at least 50%, as well as safety and efficacy in all of the following groups: persons with and without prior infection with Mycobacterium tuberculosis, and persons with HIV infection [7].
SRL172, an inactivated whole cell non-tuberculous mycobacterial vaccine, was shown to be safe and immunogenic in HIV-uninfected and HIV-infected participants [8]. In a subsequent Phase 3 trial, SRL172 was administered as a 5- dose booster to BCG-primed, HIV-infected patients in Tanzania and showed protection against TB disease in those with and without prior infection with M. tuberculosis [9]. DAR-901 is the product of a new, scalable manufacturing method for SRL172. It has been shown to be effective as a BCG booster in preventing TB disease in pre-clinical studies [10]. A Phase 1 trial in the United States showed that a three-dose series of DAR-901 was safe and immunogenic in BCG-primed adults with and without prior infection with M. tuberculosis and safe in patients with HIV infection [11], [12].
In the present Phase 2b study, we sought to determine whether DAR-901 was safe and effective in preventing initial or persistent infection with M. tuberculosis among BCG-primed adolescents in Tanzania.
Section snippets
Study design and participants
In this randomized, double-blind, placebo-controlled study we recruited and screened healthy adolescents aged 13–15 years from 16 secondary schools in Dar es Salaam, Tanzania between April and October 2016 and administered study treatment (DAR-901 or saline placebo) from April 2016 to March 2017. Follow-up was continued for up to three years through December 2019. We obtained written informed assent from all participants and informed consent from their parents or guardians. Eligibility
Trial participants
Of the 936 adolescents screened from 16 schools in Dar es Salaam, 667 were randomized and all received at least one dose of study treatment. Among the volunteers ineligible at screening, 164 were not IGRA negative at baseline (146 positive, 17 border line, one invalid). All participants were African; baseline characteristics of study participants did not differ between the two treatment groups (Table 1). IGRA testing prior to the second dose of study treatment scheduled at two months identified
Discussion
A three-dose series of 1 mg DAR-901 was safe and well-tolerated in IGRA-negative, BCG-immunized adolescents in Tanzania. Adolescents are a priority target group for booster immunization since the efficacy of BCG begins to wane at 15–20 years [2]. Thus, the safety demonstrated in this age group adds to the accumulating evidence supporting the potential for this inactivated whole cell non-tuberculous mycobacterial vaccine to serve as a BCG booster: superior protection to BCG in an animal model
Contributors
CFvR, RDA, KP, PM, TM, KN and MA, designed the study. KP, MM, PM, CFvR, MA, JD, IM, AM, ST, WWA and RC conducted the study. CR, CB-K, TM, WW-A, LVA, and CRH assisted with data analysis. CFvR, RDA and PM wrote the manuscript and all authors contributed to review and approval of the manuscript.
Data sharing
De-identified individual participant data that underlie the results reported in this Article will be available upon request on the FigShare platform after publication. The full study protocol and statistical analysis plan are available on FigShare.
Funding
Global Health Innovative Technology Fund (Japan), Jack and Dorothy Byrne Foundation (US), Oxford Immunotec (UK).
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
The authors wish to thank our adolescent volunteers for participating in the trial, the many secondary school teachers who assisted and our study staff for their contributions: Suleiman Chum, Mary Ngatoluwa, Asha Swaleh, Tumaini Massawa, Deus Buma, Alphonce Marealle, Betty Mchaki, Colman Mchau, Modestus Choka, Chijano Makunenge, Pilly Mwakalobo, and Safina Baleche. We thank Sabina Mugusi for serving as a Medical Monitor, the volunteer members of our Community Advisory Board and the members of
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