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Shigellosis is endemic throughout the world where it is held responsible for some 165 million cases of severe dysentery with blood and mucus in the stools, the overwhelming majority of which occur in developing countries and involve children less than five years of age. More than one million people are estimated to die from Shigella infection each year. In addition, some 580 000 cases of shigellosis are reported among travellers and military personnel from industrialized countries. Since the late 1960s, pandemic waves of Shigella dysentery have hit sub-Saharan Africa, Central America and South and South-East Asia, often striking areas of political upheaval and natural disaster. During the 1994 genocide in Rwanda, approximately 20 000 Rwandan refugees who had fled into the North Kivu region of Zaire died in the first month alone from dysentery caused by a strain of Shigella that was resistant to all commonly used antibiotics. The combination of Shigella and HIV infections has deleterious consequences, due to compromised immunity in HIV-positive persons.
Three major species of Shigella are responsible for bacillary dysentery: S. sonnei, S. flexneri and S. dysenteriae. S. sonnei is the causative agent of most shigellosis in industrialized countries where it accounts for 77% of cases (compared to 15% in developing countries), but it also seems to have become predominant in Thailand in recent years, a phenomenon possibly linked to the level of development of the country. S. flexneri is endemic in developing countries (60%) and is the most frequently isolated species worldwide. S. dysenteriae (Sd1) is the cause of epidemic dysentery and can cause vicious outbreaks in confined populations, especially refugee camps. A major obstacle to the control of Sd1 is its resistance to antimicrobial drugs.
Shigella species are transmitted by ingestion of contaminated food or water, or by person-to-person contact, a most common source of transmission. The bacteria invade the colonic epithelium through M cells and then spread laterally from cell-to-cell. This invasive ability is due to several virulence factors encoded by a high molecular weight virulence plasmid. In addition, S. dysenteriae secretes the Shiga toxin, which inhibits protein synthesis in eukaryotic cells via inactivation of ribosomal RNA, leading to cell death.
Candidate shigellosis vaccines currently in advanced development include both killed and live vaccines. The killed, subunit vaccine approach includes the following.
- Parenteral conjugate vaccines consisting of purified S. dysenteriae type one lipopolysaccharide (LPS) conjugated to tetanus toxoid, and S. flexneri and S. sonnei LPS conjugated to recombinant Pseudomonas aeruginosa exotoxin A. These vaccines, which are developed at the NIH, were shown to be 74% efficacious against disease when tested in field trials with Israeli military volunteers and demonstrated safety and immunogenicity in 4–7 year-old children.
- A parenteral nuclear protein/ribosomal vaccine approach, developed by the International Vaccine Institute (IVI) and the Walter Reed Army Institute of Research (WRAIR), still at a preclinical stage;
- A nasally administered proteosome vaccine consisting of Shigella LPS linked to micelles of the outer membrane protein of group B Neisseria meningitidis.
- In addition, Antex (USA) is developing both a Shigella inactivated whole cell vaccine and an oral traveller's diarrhoea vaccine (Activax) containing antigens from Campylobacter, Shigella and ETEC. These candidate vaccines should presently enter clinical testing.
Definite progress has been made with candidate live oral shigellosis vaccines, but the main problem remains the small margin that exists between under-attenuation responsible for excessive reactogenicity of the strains and over-attenuation leading to poor immunogenicity in human subjects. These approaches include the following.
International Vaccine Institute [new window]
- A live bivalent S. flexneri 2a and S. sonnei vaccine (FS) that was developed at the Lanzhou Institute of Biological Products. Large field studies in China have demonstrated 61–65% protection against S. flexneri 2a, 57–72% protection against S. sonnei, and 48–52% protective efficacy against heterologous Shigella species. However, the use of a 3-dose regimen with high doses of vaccine strain (>2x10E10 cfu) remains problematic. Further field studies of the FS vaccine in toddlers and infants may help define the public health application of this vaccine in China.
- A live, attenuated S. flexneri 2a strain (SC602), and an S. dysenteriae type 1 strain (SC599) carrying mutations in their icsA, iuc, int and toxA genes, that were developed at the Pasteur Institute, Paris. SC602 was tested in adult volunteers in the USA and in adults and children in Bangladesh in collaboration with WRAIR and IVI. A remarkable efficacy against challenge was observed in USA volunteers, but results of immunogenicity were disappointing in young infants in the field, due to lack of colonization of the gut, perhaps as a consequence of the presence of maternal antibodies from breastfeeding, or due to over-attenuation of the vaccine candidate for this population.
- Live attenuated Shigella vaccine candidates targeting S. flexneri types 2a, 3a and 6, S. sonnei, and S. dysenteriae type 1, which are in development at CVD, each carrying additional fimbriae genes from ETEC. A series of strains with progressive deletions of virulence genes (CVD1203, CVD 1204) was engineered, culminating in strain CVD1208S, which should presently enter Phase I clinical trials.
- An S. sonnei vaccine candidate (WRSS1) that has been developed with a single deletion mutation of the VirG gene and tested in a Phase I study conducted at CVD, where the vaccine was found to be midly reactogenic at higher titres and elicited a significant immune response in the volunteers. Further development is planned.
- Streptomycin-dependent (SmD) vaccines have been developed and shown to be safe for S. flexneri 1, 2a, and 3a and S. sonnei. Large studies in the former Yugoslavia showed that the vaccines were protective in 82–100% of cases. However, side effects were observed and the development of the vaccine was not continued.
Insitute Pasteur [new window]
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