Diarrheal diseases are the world's second leading cause of death in children aged under 5 years, and of these, bacillary dysentery or shigellosis remains a major public health issue. This disease is most prevalent in African and South-East Asian countries, where it is endemic despite significant improvements in terms of access to drinking water and management of contaminated water. Consequently, vaccination remains the preferred method of prevention although there are no vaccines currently approved. Scientists at the Institut Pasteur have developed an innovative conjugate vaccine prototype using a synthetic sugar component mimicking the bacterial polysaccharide antigen, which induces protective antibodies. A phase 1 trial was conducted in Israel. Its results, recently published in The Lancet Infectious Diseases, establish proof of concept of the safety and immunogenicity of this candidate based on a unique design approach.
Shigellosis, caused by the enteric pathogenic bacterium Shigella, remains a major burden with over 250 million cases every year occurring mainly in low- to middle-income countries. Mortality is estimated at approximately 212,000 deaths per year, 63,000 of which occur in children aged under 5 years. Shigellosis-related morbidities in this age group include stunting and cognitive delay, requiring the implementation of measures to limit the long-term impact of this infection (see the Institut Pasteur fact sheet on shigellosis). Moreover, the emergence of Shigella strains with multiple resistances to first- and second-generation antibiotics limits the use of antibiotic therapy. Given these circumstances, an effective vaccine is needed to prevent this disease in addition to the numerous yet insufficient measures taken to improve hygiene levels in the affected countries. Various vaccine approaches have been under development for decades but have not yet come to fruition, complicated by the fact that there are different types of the Shigella bacterium (serotypes) which contribute to the global burden of disease and thus need to be covered by the vaccine.
A unique vaccine candidate design based on glycochemistry
A unique vaccine candidate has been developed by Laurence Mulard, Head of the Chemistry of Biomolecules Unit§, in collaboration with Armelle Phalipon¥, former Group Leader in the Molecular Microbial Pathogenesis Unit.
This vaccine candidate originated from the molecular-level understanding of the distinctive properties of the polysaccharide exposed at the surface of the Shigella flexneri 2a bacterium (a Shigella serotype that is prevalent throughout the world) and its role as a major target of the protective antibody response against reinfection. “It comprises a well-defined carbohydrate – an oligosaccharide – designed to mimic the natural polysaccharide. This fine-tuned oligosaccharide produced by chemical synthesis has been optimized through a multidisciplinary approach combining synthesis and structure-activity relationship studies”, explains Laurence Mulard. Conjugated to a protein carrier, this synthetic carbohydrate led to a vaccine candidate, which induced a protective antibody response in mice against this bacterium.
"These promising preclinical data paved the way to a phase 1 clinical trial sponsored by the Institut Pasteur aimed at assessing the safety and immunogenicity of this vaccine candidate in healthy adults," adds Armelle Phalipon. The study financed by the European Stopenterics consortium led by Philippe Sansonetti, former Head of the Molecular Microbial Pathogenesis Unit, was conducted at the Clinical Research Center at Sourasky Medical Center, Tel Aviv, Israel, and coordinated by Cécile Artaud, Clinical Project Manager at the Center for Translational Science (CRT). The results published in The Lancet Infectious Diseases show that the vaccine candidate is very well tolerated and induces high levels of functional antibodies against Shigella flexneri 2a.
New studies to further evaluate this promising vaccine candidate
Based on the success of the Phase I trial, the GlycoShig team (Laurence Mulard, Armelle Phalipon, Cécile Artaud and Christiane Gerke) has been organized to continue the development of this unique approach towards a vaccine for implementation in endemic countries following three objectives:
- The first is to assess the protective efficacy of this monovalent vaccine candidate in humans. A Phase 2b clinical study including a controlled human infection has therefore been initiated in partnership with the Center for Vaccine Development at the University of Maryland at Baltimore, MD, USA, coordinated by Christiane Gerke from the Innovation Development Office, and Cécile Artaud, with funding from the Bill and Melinda Gates Foundation (BMGF).
- The second objective is to assess the tolerability and immunogenicity of this vaccine candidate in the target population of very young children in endemic areas. A phase 2a study sponsored by the Institut Pasteur and coordinated by Armelle Phalipon and Cécile Artaud has recently been initiated at the Kericho Clinical Research Center (HJFMRI-KEMRI) in Kenya, with funding from the BMGF and Wellcome Trust.
- The third objective is the transfer of this attractive molecular strategy to other Shigella serotypes. The respective upstream research, coordinated by Laurence Mulard and Armelle Phalipon, aims at the proof of concept in mice, with funding from the Stopenterics consortium, the Institut Pasteur, and the BMGF.
These objectives and the Phase 1 results support ongoing developments, coordinated by Laurence Mulard and Christiane Gerke, which aim to achieve a multivalent vaccine candidate based on fine-tuned synthetic oligosaccharide conjugates providing broad protection against the main circulating strains of Shigella. To reach this ultimate goal, the Institut Pasteur and Gates Medical Research Institute (Gates MRI) have signed a license and collaboration agreement. If successful in the preclinical setting, the Gates MRI will sponsor clinical studies to assess clinical proof of concept of the multivalent vaccine candidate and spearhead the further development.
§ Contribution of the Chem-GlycoShig team
¥ Present address: Innovation Laboratory: Vaccines
Safety and immunogenicity of a synthetic carbohydrate conjugate vaccine against Shigella flexneri 2a in healthy adult volunteers: a phase 1, dose escalating, single-blind, randomised, placebo-controlled study. Lancet Infectious Diseases, November, 10, 2020
Dani Cohen, PhD1*, Jacob Atsmon, MD1,2, Cécile Artaud, MSc3, Shiri Meron-Sudai, PhD1, Marie-Lise Gougeon, PhD4, Anya Bialik, MSc1, Sophy Goren, BSc1, Valeria Asato, MSc1, Ortal Ariel-Cohen, PhD1, Arava Reizis, PhD1, Alexandra Dorman MSc1, Carla W.G. Hoitink, PhD5 Janny Westdijk, BSc5, Shai Ashkenazi, MD6, Philippe J. Sansonetti, MD7, Laurence A. Mulard, PhD8, #, Armelle Phalipon, PhD7,#
1. School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel. 2. Clinical Research Center, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 6423906, Israel.
3. Centre de Recherche Translationnelle - Coordination Clinique Institut Pasteur, 28 rue du Dr Roux, Paris, France
4. Unité Immunité Innée et Virus, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris, France.
5. Intravacc, Bilthoven, The Netherlands.
6. Adelson School of Medicine, Ariel University and Schneider Children's Hospital Petah Tikva 49202, Israel.
7. Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, INSERM U1202, 28 rue du Dr Roux, 75724 Paris, France.
8. Unité de Chimie des Biomolécules, Institut Pasteur, UMR3523 CNRS, 28 rue du Dr Roux, 75724 Paris, France.
* Corresponding author, # Co-senior authors