9th July 2021.- On July 18, 1921, at the Hospital de Charité, Paris, the first newborn baby whose mother had died of tuberculosis was successfully vaccinated with Mycobacterium bovis Bacille Calmette-Guérin (BCG). 2021 marks the 100th anniversary of the first administration of the tuberculosis vaccine BCG. In honour of this event, the scientific journal «Vaccine» of the Elsevier group, publishes a special issue of tribute to BCG, including the scientific review entitled “MTBVAC, a live TB vaccine poised to initiate efficacy trials 100 years after BCG”.
BCG has been (and continues being) an inspiration for the construction and development of hundreds of new TB vaccine candidates in the last two and a half decades. There are a total of 14 candidates in clinical development within the global TB vaccine pipeline today, and MTBVAC is one of these candidates. Based on a live-attenuated Mycobacterium tuberculosis clinical isolate rationally attenuated by genetic engineering, MTBVAC’s 25 years of vaccine discovery, construction and characterisation have followed Pasteur principles, and in the process, BCG has served as its reference gold standard for establishing its safety and protective efficacy in countless preclinical animal studies and now in human clinical trials. MTBVAC, which contains the antigen repertoire of M. tuberculosis, absent in BCG, is expected to safely confer more specific and longer-lasting protection in humans. After almost a decade in clinical evaluation, in 2022 MTBVAC will initiate Phase 3 efficacy trials in newborns in TB-endemic regions of Sub-Saharan Africa.
MTBVAC clinical trajectory to date supporting progress to efficacy trials
Prior to reaching efficacy evaluation phase, any given vaccine has to undergo various clinical trials separated into two phases for determining the safety and immunogenicity of the vaccine. In this regard, first Phase 1 trials (usually involving less than 100 volunteers) are conducted to establish the safety (and minimum immunogenicity) of the vaccine when administered for the first time in a given population. Successful Phase 1 studies are followed by medium-size Phase 2 trials (including 100 or more volunteers in total) conducted to confirm safety, expand on immunogenicity and define the dose of the vaccine necessary for efficacy evaluation in Phase 3 trials.
In the particular case of MTBVAC, following successful completion of its first-in-human Phase 1a trial in adults in Switzerland (2012-2014), MTBVAC was successfully evaluated in a dose-escalation Phase 1b study in South Africa in healthy HIV-unexposed newborn babies by the South African Tuberculosis Vaccine Initiative (SATVI). The trial in newborns confirmed vaccine safety and greater immunogenicity as compared to BCG, suggestive of MTBVAC’s broader antigenic content. MTBVAC is now completing two dose-defining Phase 2 trials in South Africa at SATVI, using BCG as reference comparator: one in BCG-vaccinated adolescents and adults with and without prior M. tuberculosis infection (NCT02933281) and another in newborns (NCT03536117). The Phase 2 trial in newborns, funded by the European Union through The European & Developing Countries Clinical Trials Partnership (EDCTP), includes capacity building studies in Senegal and Madagascar . Successful dose definition of MTBVAC in newborns will allow its entry into already planned Phase 3 efficacy studies in high-burden TB-endemic regions of Sub-Saharan Africa. To this end, MTBVAC project was recently awarded partial EDCTP funding supporting multi-centre Phase 3 efficacy evaluation in newborn babies in South Africa (at different clinical sites), Madagascar and Senegal . The Phase 3 is now estimated to initiate second quarter of 2022, taking into account delays in the Phase 2 trials caused by the COVID-19 pandemic in 2020.
MTBVAC has been designed and constructed by researchers from the University of Zaragoza in collaboration with the Pasteur Institute. The Spanish biopharmaceutical and vaccine manufacturer Biofabri is the exclusive licensee and industrial and clinical developer of MTBVAC, also Sponsor of the clinical trials. The success of MTBVAC to date is mainly due to the close partnership that Biofabri has kept (since 2008) with the European non-profit Tuberculosis Vaccine Initiative (TBVI) and the MTBVAC intellectual owner, University of Zaragoza.
Since its early beginning as vaccine candidate, MTBVAC development has faithfully followed Regulatory (national, European, and international) and WHO requirements for safety, immunogenicity, and protective efficacy. If MTBVAC is able to demonstrate significantly greater efficacy than BCG or improved safety in newborns in Phase 3 efficacy trials in high-burden TB-endemic settings, MTBVAC could eventually replace BCG.
About the journal “Vaccine”
Vaccine is the pre-eminent journal for those interested in vaccines and vaccination. It is the official journal of The Edward Jenner Society and The Japanese Society for Vaccinology and is published by Elsevier
MTBVAC is the only vaccine against tuberculosis in clinical trials based on a genetically modified form of the pathogen isolated from humans Mycobacterium tuberculosis which, unlike BCG, contains all the antigens present in strains that infect humans. This vaccine was constructed in the laboratory of the University of Zaragoza, which forms part of CIBERES since the beginning of the project, in collaboration with Dr. Brigitte Gicquel of the Pasteur Institute in Paris. Currently, the University of Zaragoza has as an industrial partner the Spanish biotechnology company BIOFABRI, responsible for the industrial and clinical development of MTBVAC, studying its immunity and safety in two Phase IIa trials in newborn babies and adults in South Africa. Vaccine efficacy studies are expected to begin next year. For the Clinical Development of MTBVAC, the tuberculosis vaccine project counts with the advice and support of the European TBVI since 2008 and since 2016 with IAVI for the clinical development in adults.
About the University of Zaragoza
The University of Zaragoza is the main centre for technological innovation in the Ebro valley and has great prestige among Spanish and European universities. The University of Zaragoza participates in various exchange programs, collaborating with universities and research centres in Europe, Latin America and the United States, thus strengthening its international position. Microbiologists from our university belonging to CIBERES lead the research and discovery of MTBVAC. Within the TBVI consortium, the MTBVAC discovery phase has included rigorous preclinical characterization by independent laboratories and research groups. Biofabri is the industrial partner of the University of Zaragoza, responsible for the industrial and clinical development of MTBVAC.
BIOFABRI is a Spanish biopharmaceutical company created in 2008 with the vision of researching, developing and manufacturing vaccines for humans. BIOFABRI focuses on human health, with strong technical, development and manufacturing capabilities and a proven track record. Biofabri belongs to Zendal Group, a Spanish biopharmaceutical business group that specializes in the development, manufacture and commercialization of biotechnology and pharmacy products, both for humans and animals. Biofabri is also the manufacturer and exclusive licensee of MTBVAC.
EDCTP is an EU-funded partnership between institutions mandated by the governments of 14 European and 16 African countries. Launched in 2003 and renewed in 2014 with funding through to 2024, EDCTP has been the focal point for EU support for global health research in Africa, and a visible sign of the EU’s commitment to the Millennium Development Goals and more recently the Sustainable Development Goals. Through its evolution, EDCTP has been driven by the infectious disease priorities of sub-Saharan Africa and the need to develop African countries’ capacity to collectively address these priorities into the future. The European & Developing Countries Clinical Trials Partnership (EDCTP) is a public-public partnership between countries in Europe and sub-Saharan Africa, supported by the European Union. EDCTP’s vision is to reduce the individual, social and economic burden of poverty-related infectious diseases in sub-Saharan Africa, by supporting collaborative research to develop accessible, suitable and affordable medical interventions. EDCTP’s mission is to enhance research capacity and accelerate the development of new or improved medical interventions for the identification, treatment and prevention of poverty-related infectious diseases, including emerging and re-emerging diseases in sub-Saharan Africa, through all phases of clinical trials, with emphasis on phase II and III trials.
The Tuberculosis Vaccine Initiative (TBVI) is a non-profit foundation that facilitates the discovery and development of new tuberculosis vaccines that are safe and effective, accessible and affordable for all people. TBVI integrates, translates, and prioritizes research and development efforts to discover and develop new tuberculosis vaccines and biomarkers for global use. TBVI provides essential services that support the R&D efforts of its 50-partner consortia from academia, research institutes and private industry in the TB vaccine field. These services include the identification, design and development of projects; Projects management; resource mobilization; Knowledge development, exchange and networking. Technical advice and support for clinical and product development.
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