Philippe Sansonetti's team, from the Molecular Microbial Pathogenicity Unit, Institut Pasteur (Inserm U389), has developped a live, attenuated oral vaccine candidate against shigellosis. Shigellosis causes bloody diarrhoea and dysentery, killing between 600,000 and 1 million people a year, mostly young children in the developing world. A series of clinical trial conducted by the US army have just demonstrated efficacy of this vaccine among volunteers. The results have been published in Infection and Immunity*. Availibility of a Shigella vaccine would represent a significant advance in the control of the disease.
Shigellosis, or bacillary dysentery, is an enteric infection caused by the bacterium Shigella. Shigellosis is endemic throughout the world, but more than 99% of the cases occur in the developing world, particularly in tropical zones. Dramatic outbreaks may also occur, particularly in the context of humanitarian disasters (wars, refugee camps). Shigellosis is not the most frequent cause of diarrhoeal disease, but its dysenteric form is the most severe: each year, it kills between 600,000 and 1 million people, mostly children in developing countries. Shigella is transmitted through the faeco-oral route. The bacteria are highly infectious and virulent, as inocula of only 10 to 100 bacteria are required to cause the disease.
In contrast to other forms of diarrhoea, oral rehydration is not sufficient in the treatment of shigellosis. Shigella attack the mucosa of the human colon and cause a strong inflammatory reaction leading to severe tissue destruction in the invaded zone. Antibiotics are generally efficient at curing the disease. However, emergence of multiresistant strains hampers the antibiotic approach and emphazises the urgent need for a vaccine. WHO has made Shigella vaccine development a priority among the vaccines that need to be developed against diarrhoeal diseases.
Researchers of the Molecular Microbial Pathogenicity Unit at Institut Pasteur have identified several bacterial genes that are essential for Shigella virulence. These genes give the bacterium its capacity to penetrate intestinal epithelial cells, to spread from cell to cell and to survive and grow in mucosal tissues. All properties explaining the severity of the disease. This work has allowed to develop a strategy based on a rational attenuation of Shigella virulence by eliminating selected virulence genes in order to obtain mutants expressing weaker pathogenic properties. The difficulty was to find the right balance between attenuation to avoid causing intestinal symptoms in vaccinees receiving one oral vaccine dose and preservation of a sufficient degree of invasiveness to ensure proper recognition by the intestinal immune system in order to generate a protective response.
Reaserchers have constructed a candidate vaccine strain of Shigella
flexneri serotype 2a (the most prevalent serotype of the species
responsible for endemic forms of the disease) carrying two mutations : one
on the virulence plasmid, to block cell-to-cell dissemination and prevent
colonisation of the epithelium; the other is located on the bacterial chromosome
to restrict bacterial survival in intestinal tissues. This vaccine candidate,
SC602, was first succesfully tested in monkeys¤.
Clinical trials of SC602 were initiated in 1996 in adult american volunteers at Fort Detrick, Maryland, under the supervision of Dr T. Coster (United States Army Medical Research Institute for Infectious Diseases) and Dr T.L. Hale (Walter Reed Army Institute of Research).
First, tolerance trials (phase 1) were carried out to determine a vaccine dose that was both well tolerated and immunogenic. Protective efficacy was then tested in 7 vaccinated individuals that were exposed to a virulent strain; none of them developed symptoms of dysentery, unlike non immunized control individuals who developed dysentery and required immediate antibiotic treatment. Further genetic modifications may be introduced in the future, based on ongoing progress in the understanding of Shigella pathogenesis. However, these results appear sufficiently promising for moving the project to its next step : performing clinical trials in endemic zones. This is currently being organized in Bangladesh.
Other Shigella species cause shigellosis : Shigella dysenteriae type 1 causes dramatic epidemics in tropical regions and Shigella sonnei is present both in industrialized and developing countries. Vaccine trials with attenuated Shigella dysenteriae 1 and Shigella sonnei strains constructed on similar bases are due to start next year. The ultimate aim is to obtain a trivalent vaccine which may be effective against most cases of shigellosis.
This type of live oral vaccine, based on attenuated virulence, is relatively simple and cheap to produce. It may ultimately be possible to standardise its preparation for local production in endemic regions. Furthermore, if efficacy of a single oral dose is confirmed by larger field trials in endemic areas, it would represent a substantial advantage for introduction in the already busy schedule of vaccination in children.
If this encouraging results are confirmed, this vaccine strategy is likely to prove to be a valuable public health tool for controlling shigellosis in high-risk-areas.
*/ "Vaccination against shigellosis with attenuated Shigella
flexneri 2A strain SC602"
Infection and Immunity, Juillet 1999
T.S. Coster1, C.W. Hoge2, L.L. Van De Verg2, A.B. Hartman2, E.V. Oaks2, M.M. Venkatesan2, D. Cohen3, G. Robin3, A. Fontaine-Thompson4, P.J. Sansonetti4, T. Hale2.
1- Medical Division, United States Army Medical Research Institute for
2- Division of Communicable Diseases and Immunology, Walter Reed Army Institute of Research
3- Israel Defence Force Medical Corps
4- Unité de Pathogénie Microbienne Moléculaire, unité mixte Institut Pasteur / INSERM
¤/ "Omp B (osmo-regulation) and ics A (cell to celle spread)
mutants of Shigella flexneri. Evaluation as vaccine candidates. Probe to
study the pathogenesis of shigellosis."
Vaccine, 9 : 416-422 - 1991
P.J. Sansonetti, J. Arondel, A. Fontaine, H. d'Hauteville, M.L. Bernardini.
Philippe Sansonetti, tel : 33 1 45 68 83 42