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Appendix D-15
The Prospects for Immunizing Against Shigella spp.

DISEASE DESCRIPTION

Shigella species cause an acute, usually febrile, gastrointestinal disease manifested by watery diarrhea, which may progress to a bloody diarrhea or dysentery (Keusch, 1982). The latter is a clinical syndrome composed of a classic triad of signs and symptoms including abdominal cramps, tenesmus (painful and ineffectual straining at stool), and the passage of frequent (up to 40) small volume bloody-mucoid stools per day. Constant straining at stool can result in rectal prolapse, especially in young children. In many patients, the initial presentation is watery diarrhea, which becomes bloody or dysenteric in a matter of hours to a day or two. The severity of the disease is determined in part by the infecting species; Shigella sonnei generally causes a self-limited watery diarrhea, whereas Shigella dysenteriae 1 usually progresses rapidly to bloody diarrhea or dysentery. Clinical manifestations thus depend, in part, on the prevalence of the different shigella species.

In the United States, where S. sonnei predominates, watery diarrhea is most common. In Bangladesh, where S. dysenteriae and S. flexneri are common, bloody diarrhea and dysentery are most frequent (Stoll et al., 1982). Watery shigella diarrhea may be voluminous and result in clinical dehydration, especially in young infants, but this is usually not as profound as that caused by cholera, enterotoxigenic E. coli, or rotavirus infection. S. flexneri and S. dysenteriae 1 often result in a chronic infection characterized by significant protein-losing enteropathy, especially in malnourished infants and children. This can lead to the development of kwashiorkor with its attendant high mortality rate from secondary infections.

Shigellosis has a number of extraintestinal manifestations (Keusch, 1982). The rapid rise in temperature is often associated with seizures, which may be the initial manifestation of illness. These behave very

The advice and assistance of R.E.Black, C.C.J.Carpenter, and R.B.Sack are gratefully acknowledged. The committee assumes full responsibility for all judgments and assumptions.



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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Appendix D-15 The Prospects for Immunizing Against Shigella spp. DISEASE DESCRIPTION Shigella species cause an acute, usually febrile, gastrointestinal disease manifested by watery diarrhea, which may progress to a bloody diarrhea or dysentery (Keusch, 1982). The latter is a clinical syndrome composed of a classic triad of signs and symptoms including abdominal cramps, tenesmus (painful and ineffectual straining at stool), and the passage of frequent (up to 40) small volume bloody-mucoid stools per day. Constant straining at stool can result in rectal prolapse, especially in young children. In many patients, the initial presentation is watery diarrhea, which becomes bloody or dysenteric in a matter of hours to a day or two. The severity of the disease is determined in part by the infecting species; Shigella sonnei generally causes a self-limited watery diarrhea, whereas Shigella dysenteriae 1 usually progresses rapidly to bloody diarrhea or dysentery. Clinical manifestations thus depend, in part, on the prevalence of the different shigella species. In the United States, where S. sonnei predominates, watery diarrhea is most common. In Bangladesh, where S. dysenteriae and S. flexneri are common, bloody diarrhea and dysentery are most frequent (Stoll et al., 1982). Watery shigella diarrhea may be voluminous and result in clinical dehydration, especially in young infants, but this is usually not as profound as that caused by cholera, enterotoxigenic E. coli, or rotavirus infection. S. flexneri and S. dysenteriae 1 often result in a chronic infection characterized by significant protein-losing enteropathy, especially in malnourished infants and children. This can lead to the development of kwashiorkor with its attendant high mortality rate from secondary infections. Shigellosis has a number of extraintestinal manifestations (Keusch, 1982). The rapid rise in temperature is often associated with seizures, which may be the initial manifestation of illness. These behave very The advice and assistance of R.E.Black, C.C.J.Carpenter, and R.B.Sack are gratefully acknowledged. The committee assumes full responsibility for all judgments and assumptions.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries much like febrile seizures, except that they may occur in children with no or only low-grade fever and are prominent in children beyond the usual age of susceptibility to febrile seizures (2 to 3 years of age). Shigella bacteremia is more common than previously believed (especially with infection due to S. dysenteriae 1), has been detected in about 4 percent of patients with shigellosis admitted to the International Centre for Diarrhoeal Disease Research hospital in Bangladesh (ICDDR,B); and is associated with increased mortality (Struelens et al., 1985). Denudation of the intestinal epithelium increases the likelihood of gram-negative sepsis with other Enterobacteriaceae, especially in malnourished children, and has been documented in another 4 percent of hospitalized patients in Dhaka, Bangladesh. Denudation also dramatically increases the mortality rate. Infection due to S. dysenteriae 1, and to a lesser extent S. flexneri, is associated with the development of a leukemoid reaction in 4 percent of hospitalized patients with shigellosis. Of these, one-third have evidence of hemolysis, one-third develop a hemolytic-uremic syndrome, and a few have transient uremia alone (Butler et al., 1984). The mortality rate for those with uncomplicated or complicated leukemoid reactions is about 20 percent. Bacteremia, leukemoid reactions, and hemolytic-uremic syndrome occur most often in poorly nourished children infected with S. dysenteriae 1, and are therefore more common in developing countries. Reactive arthritis with or without other classical manifestations of Reiter’s syndrome occurs more frequently with some types of shigella (e.g., S. flexneri) and is often seen in individuals positive for HLA-B27 histocompatibility antigen (Keusch, 1982). PATHOGEN DESCRIPTION Shigellas are classified in the family Enterobacteriaceae, tribe Escherichieae, and are closely related to E. coli. They are nonmotile, rod shaped, gram-negative bacteria that ferment glucose but do not produce gas. They are usually recognized first by their inability to ferment lactose, although S. sonnei is capable of late lactose fermentation. Selective media are employed for this purpose; these media contain bile salts to inhibit the growth of other fecal organisms and a dye indicator to demonstrate lactose fermentation. Although many media have been devised, some are highly inhibitory to shigellas, especially to S. dysenteriae 1. The genus is subdivided into four species, dysenteriae, flexneri, boydii, and sonnei. These have antigenically distinct lipopolysaccharides and may be recognized through the use of grouping antisera, as well as by biochemical reactions. There are multiple subtypes of S. dysenteriae, flexneri, and boydii and multiple colicin types of S. sonnei. Generally, however, a limited number of subtypes prevail in any given geographic area. Two major virulence attributes are involved in pathogenesis: the ability to invade epithelial cells, which is under polygenic control, and toxin production, the genetics of which are still uncertain.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries HOST IMMUNE RESPONSE Epidemiological evidence suggests that there is acquired immunity to shigellosis; however, it is species- and subtype-specific. Endemic shigellosis is primarily a childhood disease, although introduction of a new strain into a population results in disease in all age groups (Keusch, 1982). The best evidence for type-specific immunity comes from trials using live streptomycin-dependent shigella vaccine strains in a large community field study in Yugoslavia (Mel et al., 1968). In this study, two groups of subjects received different vaccine strains. The overall rate of shigellosis did not differ between the groups, but each group was protected only against the strains included in the vaccine it received. This finding is supported by experimental vaccine studies in volunteers, which demonstrate serotype-specific protection when challenged with the same strain (Dupont et al., 1972). These findings indicate that antibacterial immunity is involved. Although patients develop antibodies to the homologous somatic O antigens of the infecting strain, primarily of the IgM isotype, there is no evidence that this serum antibody is protective. Patients with shigellosis also develop IgM-neutralizing serum antibody to the shigella toxin. Current evidence indicates, however, that serum-neutralizing antibody is not protective against oral challenge with the organism (Keusch, 1982). Indeed, parenteral immunization of Rhesus monkeys with toxoid resulting in high serum antitoxin titers does not protect against clinical shigellosis following oral bacterial challenge (McIver et al., 1977). DISTRIBUTION OF DISEASE Geographic Distribution Shigellas are worldwide in distribution, but the prevalence of different species varies from country to country. For unexplained epidemiological reasons, S. dysenteriae 1, which was the predominant worldwide isolate for the first 30 years after its discovery in 1898, was replaced by S. flexneri in the years before World War II. For the past 2 decades, S. sonnei has become the dominant organism in the industrialized nations, while S. flexneri has persisted in the developing countries, punctuated by outbreaks of epidemic dysentery due to S. dysenteriae 1 (Keusch, 1982). Because the more virulent species are more prevalent in developing countries, where malnutrition, poor hygiene, and lack of medical care are also widespread, morbidity and mortality are considerably more severe. Disease Burden Estimates The disease burden estimates for shigella are shown in Table D-15.1. The derivation of the number of acute cases is described in Appendix C.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-15.1 Disease Burden: Shigella       Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Condition Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity Mild diarrhea 125,690,000 5 56,977,000 5 42,393,000 5 7,190,000 5 B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work Moderately severe diarrhea 11,172,000 7 460,000 7 342,000 7 303,000 7 C Severe pain, severe short-term impairment, or hospitalization Severe diarrea 5,237,000 11 230,000 10 171,000 10 126,000 10 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)     n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work)   52,370 n.a.   n.a.   n.a.   n.a. F Total impairment     n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility     n.a.   n.a.   n.a.   n.a. H Death   576,000 n.a. 46,000 n.a. 26,000 n.a. 6,000 n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries The number of acute cases suggested by the calculations in Appendix C has been modified in light of knowledge about chronic diarrhea and wasting associated with Shigella (Keusch, 1982; Rahaman and Wahed, 1983). Such conditions can last from weeks to months, often leading to protein-energy malnutrition. Two percent of severe cases in children under 5 years of age (morbidity category C, hospitalization indicated) are assumed to incur such illness, with about half progressing through morbidity category E to death. These deaths are added to those from acute illness (see Appendix C). The extended illness (assumed to be of about 3 months duration) experienced by the survivors in this subgroup of morbidity category C cases raises the average duration for all cases from 10 days for uncomplicated cases to about 11 days. PROBABLE VACCINE TARGET POPULATION Shigellosis is primarily a pediatric disease. In the developing countries it becomes a problem by the second half of the first year of life, although the highest incidence is in the 2 to 4 years age group. Immunization of infants during the first 6 months of life would allow administration of a shigella vaccine through the World Health Organization Expanded Program on Immunization (WHO-EPI); however, immunization at 12 or even 24 months of age would substantially reduce the rate of shigellosis. With epidemic spread of newly introduced strains, such as observed with S. dysenteriae 1 in Central America, India, and Bangladesh, and in central Africa during the past 15 years, all age groups should be immunized because all are susceptible (Keusch, 1982). Vaccine Preventable Illness* A vaccine incorporating protective antigens from the most common infecting strains in a given geographic area should prevent 80 to 90 percent of the shigella infections, depending on the prevalence of these strains and assuming total coverage of the target population with a “perfect” vaccine delivered at the earliest feasible age. Observed or apparent vaccine efficacy will depend, therefore, on knowledge of appropriate antigens from the different strains infecting the population in the regions where vaccine is used. *   Vaccine preventable illness is defined as that portion of the disease burden that could be prevented by immunization of the entire target population (at the anticipated age of administration) with a hypothetical vaccine that is 100 percent effective (see Chapter 7).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries SUITABILITY FOR VACCINE CONTROL Shigellosis accounts for 12 percent of the etiologically diagnosed diarrhea among patients presenting to the Dhaka Diarrhoeal Disease Centre Hospital, and, because dehydration is not the major manifestation, oral rehydration is less successful in averting death than it is for cholera and other watery diarrheas (Stoll et al., 1982). In prospective field studies, Mata (1978) has shown that children in the highlands of Guatemala suffer two infections per child per year with shigella species, from age 6 months to 3 years. Because these infections are often chronic (Mata, 1978), and are associated with a significant protein-losing enteropathy (Rahaman and Wahed, 1983), they are important causes of secondary malnutrition and thus increase both the short-term and long-term mortality of shigellosis. Alternative measures for control of shigellosis are not likely to have an important impact in the developing world for the foreseeable future (see below), which means that vaccines must be the major strategy for intervention. Because shigellas are highly host-adapted to humans, there is no animal reservoir to cause concern. Alternative Control Measures and Treatments One of the hallmarks of shigellosis is the small infectious inoculum needed to cause disease. In otherwise healthy adult volunteers, the ID10 is in the range of 10 to 100 organisms, while the ID50 is only 1,000 organisms (Dupont et al., 1969; Levine et al., 1973). In young infants and children, especially those compromised by marginal or poor nutritional state, the infectious dose is probably even smaller. For these reasons, direct person-to-person contact is the common transmission route, and contaminated food and water sources are much less important than for other enteric pathogens. There is little doubt that sanitary fecal waste disposal, environmental hygiene, and the availability of sufficient water for personal hygiene can reduce the incidence of shigellosis (Keusch, 1982). Handwashing with soap and water has been shown to reduce the secondary infection rate in the childhood target group in Bangladesh households from approximately 40 percent to around 10 percent (Khan, 1982). However, there is little likelihood that such measures will become generally available in the rural areas of developing countries over the next few decades. Transferable antibiotic resistance, first documented in the genus Shigella 30 years ago, has increased in prevalence, and the proportion of isolates with multiple resistance is becoming alarming. Epidemic S. dysenteriae 1 infection caused by multiply resistant organisms is now occurring in India, Bangladesh, and Central Africa. In some instances, the only usable drugs are expensive third generation penicillins or cephalosporins (Kabir et al., 1984), which are economically unfeasible for developing countries. The rate of acquisition of antimicrobial resistance suggests that new antibiotics are at best a temporizing measure. Vaccines, therefore, are imperative if shigellosis is to be controlled.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries PROSPECTS FOR VACCINE DEVELOPMENT In both humans and experimental animals, parenteral administration of killed whole cell vaccines is ineffective in stimulating protection against orally administered shigellas (Levine et al., 1983). Similarly, parenteral administration of toxoid prepared with formalin from the shigella toxin is without effect in the Rhesus monkey model of shigellosis. In contrast, oral immunization using live attenuated shigella strains or mutants to induce local immunity has been effective. While none of the attenuated candidate vaccine strains developed thus far (including colonial mutants, streptomycin-dependent mutants, and hybrids prepared by insertion of E. coli genes into Shigella strains, or vice versa) have been sufficiently safe from the danger of reversion to be used clinically, studies of these vaccine strains have established the importance of local immunity in protecting against this infection and have contributed to our understanding of the protective antigens (Levine et al., 1983). Recent work of particular importance has established the role of certain outer membrane proteins (OMPs) in S. sonnei and S. flexneri in the initial invasive step in shigella pathogenesis (Kopecko et al., 1980; Sansonetti et al., 1982). The genes controlling these OMPs are contained on large plasmids in these species, and they can be transferred to other organisms, rendering them invasive. If the plasmid is cured from the shigella strain, it is rendered noninvasive and avirulent. These OMPs are therefore primary candidates for the development of a new generation of shigella vaccine. A very promising approach involves the use of the well-defined and safe oral typhoid vaccine strain, Salmonella typhi Ty21a, as a vehicle to carry the plasmid containing the OMP genes (Formal et al., 1981). The transconjugant expresses both typhoid and shigella somatic antigens and is protective against intraperitoneal challenge in mice. The initial studies of orally administered transconjugant vaccine in humans have been very promising (Levine et al., 1983). The vaccine strain multiplies, invades the tissues, and expresses antigens, inducing an immune response. Because of its metabolic defect (the absence of the enzyme galactose epimerase), the organism dies off without causing systemic illness. It is uncertain at this time how many plasmids can be stably inserted into the carrier organism and still be expressed in an immunologically useful fashion; this question appears to be the major limiting factor. The lack of a representative animal model for shigellosis other than the Rhesus monkey, and the lack of any suitable animal model for S. typhi infection (because the host range for this organism is entirely restricted to humans), means that vaccine testing must be conducted in humans. Initial studies can be performed in medical centers in the United States or overseas. However, human field trials must be an important early step in vaccine evaluation because of the absence of animal models. Such studies could be conducted in a number of places in the world, notably the ICDDR,B.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries At the time of publication of this report, a vaccine candidate based on Salmonella typhi Ty21a was scheduled for a safety and antigenicity trial in children and a field trial for efficacy in children and adults. Another recombinant approach, an E. coli strain carrying the protective S. flexneri type 2A gene, also awaited human trials. In addition, attempts were under way to obtain, for testing in the United States, an apparently protective attenuated strain of S. flexneri developed as an oral vaccine in Rumania (National Institute of Allergy and Infectious Diseases, 1985). REFERENCES Butler, T., M.R.Islam, and P.K.Bardhan. 1984. The leukemoid reaction in shigellosis. Am. J. Dis. Child. 138:162–165. Dupont, H.L., R.B.Hornick, A.T.Dawkins, M.J.Snyder, and S.B. Formal. 1969. The response of man to virulent Shigella flexneri 2a. J. Infect. Dis. 119:296–299. Dupont, H.L., R.B.Hornick, M.J.Snyder, J.P.Libonatti, S.B.Formal, and E.H.Gangarosa. 1972. Immunity in shigellosis. II. Protection induced by oral live vaccine or primary infection. J. Infect. Dis. 125:12–16. Formal, S.B., L.S.Baron, D.J.Kopecko, O.Washington, C.Powell, and C.A. Life. 1981. Construction of a potential bivalent vaccine strain: Introduction of Shigella sonnei form I antigen genes into the ga1E Salmonella typhi Ty 21a typhoid vaccine strain. Infect. Immun. 34:746–750. Kabir, I., M.M.Rahaman, S.M.Ahmed, S.Q.Akhter, and T.Butler. 1984, Comparative efficacies of pivmecillinam and ampicillin in acute shigellosis. Antimicrob. Agents Chemother. 25:643–645. Keusch, G.T. 1982. Shigellosis. Pp. 487–509 in Bacterial Infections of Humans, A.S.Evans and H.A.Feldman, eds. New York: Plenum. Khan, M.U. 1982. Interruption of shigellosis by hand washing. Trans. Roy. Soc. Trop. Med. Hyg. 76:164–168. Kopecko, D.J., O.Washington, and S.B.Formal. 1980. Genetic and physical evidence for plasmid control of Shigella sonnei form I cell surface antigen. Infect. Immun. 29:207–214. Levine, M.M., H.L.Dupont, S.B.Formal, R.B.Hornick, A.Takeuchi, E.H.Gangarosa, M.J.Snyder, and J.P.Libonatti. 1973. Pathogenesis of Shigella dysenteriae 1 (Shiga) dysentery. J. Infect. Dis. 127:261–270. Levine, M.M., Kaper, J.B., R.E.Black, and M.L.Clements. 1983. New knowledge on pathogenesis of bacterial enteric infections as applied to vaccine development. Microbiol. Rev. 47:510–550. Mata, L.J. 1978. The children of Santa Maria Cauque. Cambridge, Mass.: MIT University Press. McIver, J., G.F.Grady, and S.B.Formal. 1977. Immunization with Shigella dysenteriae type 1: Evaluation of antitoxic immunity in prevention of experimental disease in rhesus monkeys (Macaca mulatta). J. Infect. Dis. 136:416–421.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Mel, D.M., B.L.Arsic, B.D.Nikolic, and M.L.Radovanovic. 1968. Studies on vaccination against bacillary dysentery. IV. Oral immunization with live monotypic and combined vaccines. Bull. WHO 39:375–380. National Institute of Allergy and Infectious Diseases. 1985. Program of Accelerated Development of New Vaccines. Progress Report. Bethesda, Md.: National Institutes of Health. Rahaman, M.M., and M.A.Wahed. 1983. Direct nutrient loss and diarrhoea. Pp. 155–160 in Diarrhoea and Malnutrition, L.C.Chen and N.S.Scrimshaw, eds. New York: Plenum. Sansonetti, P.J., D.J.Kopecko, and S.B.Formal. 1982. Involvement of a plasmid in the invasive ability of Shigella flexneri. Infect. Immun. 35:852–860. Stoll, B.J., R.I.Glass, M.I.Huq, M.U.Kahn, H.Banu, and J.Holt. 1982. Epidemiologic and clinical features of patients infected with Shigella who attended a diarrhoeal disease hospital in Bangladesh. J. Infect. Dis. 146:177–183. Struelens, M.J., M.L.Bennish, D.Patte, G.Mondal, M.Rahaman, and H.Coignau. 1985. The importance of bacteremia as a complication of diarrhoeal illness in Bangladesh. P. 100 in Abstracts of the 25th Interscience Conference on Anti-Microbial Agents and Chemotherapy, Minneapolis, Minn., Sept. 29–Oct. 2, 1985.