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Appendix D-14
The Prospects for Immunizing Against Salmonella typhi

DISEASE DESCRIPTION

Typhoid fever is an enteric fever caused by the bacterium Salmonella typhi. The disease is characterized by systemic symptoms of fever, malaise, and abdominal discomfort. A transient rash, splenomegaly, and leukopenia often occur. The major complications of the disease are intestinal hemorrhage, occurring in 2 to 8 percent of cases, and intestinal perforation, occurring in 3 to 4 percent of cases. The rate of mortality with the uncomplicated disease is generally low (less than 1 percent), especially if appropriate antibiotic treatment is provided; however, cases with severe illness and complications have a higher mortality rate (3 to 30 percent; Hornick, 1982).

Protection from disease by vaccination was first attempted at the end of the nineteenth century, and for the next 70 years efforts focused primarily on killed-parenteral vaccines. The history of these efforts has been comprehensively reviewed by Germanier (1984). Several varieties of killed, whole-cell parenteral S. typhi vaccines have been studied in field trials to determine safety and efficacy. These parenteral, whole-cell vaccines caused significant adverse reactions, including fever, malaise, and severe local pain and swelling. Because of the frequency of such reactions to parenteral typhoid vaccines, these vaccines have not been considered useful public health tools. Thus, the major thrust in the development of new immunizing agents against typhoid fever has been to identify agents that are at least equal in efficacy to the whole-cell parenteral vaccine, but that cause no adverse reactions (Germanier, 1984).

A candidate live attenuated vaccine based on S. typhi Ty21a is in an advanced stage of development.

The committee gratefully acknowledges the efforts of R.E.Black, who prepared major portions of this appendix, and the advice and assistance of P.A.Blake. 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-14 The Prospects for Immunizing Against Salmonella typhi DISEASE DESCRIPTION Typhoid fever is an enteric fever caused by the bacterium Salmonella typhi. The disease is characterized by systemic symptoms of fever, malaise, and abdominal discomfort. A transient rash, splenomegaly, and leukopenia often occur. The major complications of the disease are intestinal hemorrhage, occurring in 2 to 8 percent of cases, and intestinal perforation, occurring in 3 to 4 percent of cases. The rate of mortality with the uncomplicated disease is generally low (less than 1 percent), especially if appropriate antibiotic treatment is provided; however, cases with severe illness and complications have a higher mortality rate (3 to 30 percent; Hornick, 1982). Protection from disease by vaccination was first attempted at the end of the nineteenth century, and for the next 70 years efforts focused primarily on killed-parenteral vaccines. The history of these efforts has been comprehensively reviewed by Germanier (1984). Several varieties of killed, whole-cell parenteral S. typhi vaccines have been studied in field trials to determine safety and efficacy. These parenteral, whole-cell vaccines caused significant adverse reactions, including fever, malaise, and severe local pain and swelling. Because of the frequency of such reactions to parenteral typhoid vaccines, these vaccines have not been considered useful public health tools. Thus, the major thrust in the development of new immunizing agents against typhoid fever has been to identify agents that are at least equal in efficacy to the whole-cell parenteral vaccine, but that cause no adverse reactions (Germanier, 1984). A candidate live attenuated vaccine based on S. typhi Ty21a is in an advanced stage of development. The committee gratefully acknowledges the efforts of R.E.Black, who prepared major portions of this appendix, and the advice and assistance of P.A.Blake. 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 PATHOGEN DESCRIPTION Salmonella typhi, an obligate intracellular pathogen, is the cause of typhoid fever. The organism is a gram-negative, nonsporing bacillus, actively motile with numerous long peritrichous flagellae. Other salmonellae, S.paratyphi A and B, cause paratyphoid fever, which is similar to typhoid fever but usually a milder disease clinically. These organisms can be differentiated based on their cultural characteristics. S. typhi and S. paratyphi have a strong host specificity for man and do not naturally infect animals. In most countries in which these diseases have been studied, the ratio of disease caused by S. typhi to that caused by S. paratyphi is about 10 to 1. (For further information on S.typhi, see Hornick, 1982, 1985.) HOST IMMUNE RESPONSE Infection with S. typhi confers some immunity, but second illnesses can occur following reexposure. It appears that immunity can be overwhelmed by the ingestion of a large number of S. typhi, as was suggested by studies in which volunteers with previously documented typhoid fever ingested 105 S. typhi and had a clinical attack rate similar to that of a control group. Several specific antibody responses have been demonstrated after typhoid fever. However, there is no evidence that these responses to O, H, and Vi antigens are protective against infection or illness. It is likely that secretory IgA is also produced in the small intestine, but this has not been well documented. Animal models indicate that the cellular immune response probably is of primary importance in the protection against typhoid fever. Host defense relies on macrophage microbicidal mechanisms to kill phagocytosed bacteria. Enhancement of macrophage function is directed by specifically committed activated T-lymphocytes and controlled by a family of effector and regulatory T-cells. Current knowledge about immunity to S. typhi in humans does not permit more than general speculation about the way in which cell-mediated immunity is stimulated by either prior disease or a vaccine to prevent acute typhoid fever and its complications, or the development of the chronic carrier state (Germanier, 1984; Hornick, 1982, 1985; Levine et al., 1983). DISTRIBUTION OF DISEASE Geographic Distribution Typhoid fever has worldwide distribution, but is especially prevalent in less-developed countries. Areas with environmental conditions conducive to the spread of the disease or with populations with a high prevalence of biliary tract disease and chronic carriage of S. typhi have higher rates of the disease (Germanier, 1984).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Disease Burden Estimates Table D-14.1 shows the estimated incidence by age of typhoid fever cases in Africa, Asia, Latin America, and Oceania. Febrile, unrecognized cases of typhoid are assigned to morbidity category A; recognized moderate cases are assigned to category B; and recognized severe cases are assigned to category C. It is estimated that the number of mild cases of typhoid fever (probably undiagnosed) equals the number of recognized cases. It should be noted that the fatality rates in different regions vary: Table D-14.2 presents reported typhoid case-fatality rates in selected countries from 1951 to the present. Figures from Table D-14.1 were used as a basis for the disease burden estimates in Table D-14.3. PROBABLE VACCINE TARGET POPULATION The incidence of clinically recognized typhoid fever appears to be highest in school-age children and young adults in endemic areas (Punjabi, 1984). Relatively few cases of typhoid fever are reported in children younger than 2 years of age in the same populations. There is some evidence that when these young children are exposed to S. typhi, they develop a bacteremic but clinically milder illness. Prospective studies of the age-specific incidence of the disease are needed to determine the best strategy for controlling endemic typhoid fever by vaccination. Additional information also is needed on the duration of protection afforded by such vaccines as Ty21a S. typhi and their efficacy when administered to young children. It will be impossible to incorporate a typhoid fever vaccine into the existing World Health Organization Expanded Program on Immunization (WHO-EPI) if the primary target population is restricted to school-age children and young adults. However, if a candidate vaccine proves to be effective when given to small children and to have a long duration of protection (20 to 30 years), this situation could change. Development of a vaccine formulation other than enteric-coated capsules (which cannot be swallowed by infants and young children) will be necessary for this to happen. The calculation of vaccine benefits is based on the assumption that efforts in this direction will be successful. Vaccine Preventable Illness* Crude estimates indicate that at least 75 percent of the disease burden falls upon school-age children and young adults up to 34 years *   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 TABLE D-14.1 Estimated Typhoid Fever Cases in the Developing World by Region and Age Group Region Total Population (millions) Incidence of Recognized Typhoid Fever per 100,000 (all ages) Total Number of Moderate and Severe Cases Number of Moderate Cases (0.67) Number of Severe Cases (0.33) Fatality Ratec (percent of severe cases) Number of Deaths Number of Mild Cases (febrile-unrecognized) Africa 531 500a 2,655,000 1,778,850 876,150 15 131,422 2,655,000 Asia 2,662 500a 13,310,000 8,917,700 4,392,300 10 439,230 13,310,000 Latin America 397 150b 595,500 398,985 196,515 5 9,826 595,500 Oceania 5 150b 7,500 5,025 2,475 5 124 7,500 Total     16,568,000 11,100,560 5,467,440   580,602 16,568,000 NOTE: Percentage of cases by age group: under 5 is 6 percent; 5–14 is 37 percent; 15–59 is 55 percent; 60 and over is 2 percent. aBased on India (540, 543, and 634) and Indonesia (450). bBased on Chile (110). cPunjabi (1984)

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-14.2 Typhoid Incidence and Case-Fatality Rates (CFR) Location Year Patient Population Number of Cases of Typhoid Fever Deaths CFR (percent) South Korea 1951 U.S. and United Nations soldiers 81,575 14,051 17 Indonesia 1950 Hospitalized Indonesians 17 1 6 Egypt 1950 Hospitalized Egyptians 200 13 7 South Africa 1951 Hospitalized South Africans 139 17 12 India 1953 Hospitalized Indians 1,064 180 17 Iran 1954–1967 Hospitalized Iranian children 35 3 8 India 1959–1965 Hospitalized Indians 340 19 6 South Africa 1959–1967 Hospitalized South African children 298 21 7 Nigeria 1959–1970 Hospitalized Nigerians 959 172 18 Iran 1961 Hospitalized Iranians 530 19 4 Indonesia 1961 Hospitalized Indonesian children 68 4 6 India 1967 Hospitalized Indians 98 13 13 India 1969–1970 Hospitalized Indians 100 7 7 Ethiopia 1975–1980 Hospitalized Ethiopians 50 6 12 Nigeria 1972–1978 Hospitalized Nigerian children 101 32 32 Indonesia 1971–1972 Hospitalized Indonesians 188 28 15 South Vietnam 1971–1974 Hospitalized Vietnamese 101 8 8 Indonesia 1977–1978 Hospitalized Indonesians 60 7 12 Indonesia 1976–1979 Hospitalized Indonesians 542 46 9 India 1977–1982 Hospitalized Indians 410 73 18 Indonesia 1980 Hospitalized Indonesians 33 6 18   SOURCE: Punjabi (1984).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-14.3 Disease Burden: Salmonella typhi       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 Malaise, mild fever 994,080 3 6,130,160 3 9,112,400 3 331,360 3 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 Moderate fever, abdominal pain 666,034 6 4,107,207 6 6,105,308 6 222,011 6 C Severe pain, severe short term impairment, or hospitalization Fever, intestinal hemorrhage 328,046 12 2,022,953 12 3,007,092 12 109,349 12 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)     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   34,836 n.a. 214,823 n.a. 319,331 n.a. 11,612 n.a.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries of age. However, if all preschool children could be vaccinated with a vaccine that provided 100 percent protection over a long period, it would be possible to eliminate 100 percent of the disease. This assumption, adopted for calculations, assumes that a formulation acceptable and effective in infants and young children can be developed. SUITABILITY FOR VACCINE CONTROL Typhoid fever appears to be quite suitable for vaccine control, especially given the possibility of vaccines developed from oral, nonreactogenic strains of S. typhi, such as Ty21a. Such a vaccine probably could be delivered before the youngest age at which disease occurs. If the new vaccine prevents people from becoming carriers, benefits would be extended to unvaccinated individuals because of reduced exposure. Alternative Control Measures and Treatments There is no animal host or environmental reservoir of S. typhi. Patients with typhoid fever, asymptomatic transient carriers, and chronic carriers are the only sources of infection. S. typhi can be spread by either food or water. Alternative strategies to prevent disease would be to reduce the number of infected persons, including carriers, and to ensure that food and water are not contaminated by them or are not consumed by susceptible persons. In many areas of the world, these strategies are not feasible at this time. Effective antibiotic treatment with chloramphenicol, co-trimoxazole, or other drugs can shorten the duration of disease and reduce the mortality rate. However, in some areas the mortality rate remains high despite effective antibiotic treatment. It recently has been demonstrated that the death of some severely ill patients can be prevented by the use of high-dose corticosteroids in combination with antibiotics. In addition, management of hospitalized patients requires attention to nutrition, fluid and electrolyte balance, and prompt treatment of complications, such as intestinal perforation or bleeding. PROSPECTS FOR VACCINE DEVELOPMENT Two comprehensive reviews have recently dealt with vaccines directed against S. typhi. Germanier (1984) has described the history of efforts to date to develop effective vaccines against S. typhi and provides a detailed account of trials on the live attenuated strain Ty21a. Levine et al. (1983) dealt with this and other vaccine candidates under development. Therefore, this section is a brief overview of these vaccines; further details on specific candidates can be found in these two publications.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Of the killed whole-cell parenteral S. typhi vaccines, the acetone-killed typhoid vaccine is perhaps the best. In field trials in Guyana, two subcutaneous doses of the vaccine provided about 88 percent efficacy for at least 7 years (Germanier, 1984). Because of the frequency of adverse reactions, such as fever, malaise, and abdominal pain, this vaccine has not been widely used. One relatively new approach for a typhoid vaccine has involved the use of purified Vi antigen as a parenteral vaccine. In initial safety testing, it appeared that this vaccine did not elicit severe adverse reactions and that it stimulated high titers of circulating IgG Vi antibody (Levin et al., 1975; Wong et al., 1974). It was postulated that such antibody would prevent the primary bacteremia, during which the reticuloendothelial system becomes seeded with S. typhi after penetration of the intestine. However, in further studies with the purified Vi vaccine, nearly half of the vaccinees had a moderate or severe systemic reaction, and 8 percent had fever. The reaction rate was similar to that of the whole-cell parenteral typhoid fever vaccine. Furthermore, sera from volunteers given the purified Vi vaccine showed rises in antibody to S. typhi lipopolysaccharide, indicating that the vaccine was contaminated with small amounts of this antigen. Another approach has been the development of live attenuated strains of S. typhi. One such vaccine candidate that showed initial promise was the streptomycin-dependent mutant of S. typhi. In volunteer studies, this oral attenuated vaccine was well tolerated and highly protective against experimental challenge. However, when lyophilized vaccine was given, no protection was conferred. Because a lyophilized vaccine formulation is required for field studies and eventual use, further studies with this strain were abandoned (Germanier, 1984). An important advance was the development of the attenuated ga1E mutant S. typhi strain Ty21a, developed by Dr. Rene Germanier (Germanier and Furer, 1975). This mutant is devoid of the enzyme UDP-galactose-4-epimerase and shows reduced activity of two other enzymes. Grown in the presence of galactose, smooth lipopolysaccharide O antigen is produced. However, because of its lack of epimerase, strain Ty21a accumulates intermediate products of metabolism, which results in bacterial lysis. Studies in North American volunteers and field trials in Egypt and Chile have demonstrated that this vaccine is safe and easily administered orally (Germanier, 1984). Recent results from field trials in Santiago, Chile, showed that three doses of the vaccine contained within enteric-coated capsules provided about 75 percent protection for at least 1 year (National Institute of Allergy and Infectious Diseases, 1985). Another method of attenuation that has been used for Salmonella typhimurium and that could perhaps be applied to S. typhi is to derive aromatic amino acid-dependent strains of bacteria (Hoiseth and Stocker, 1981; Stocker et al., 1983). Some auxotrophic mutants that require a metabolite not available in vertebrate tissue would be unable to grow in such tissues and thus would be nonvirulent. Such strains of S. typhimurium have been examined in calves. The vaccine was given

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries orally or parenterally, and 3 weeks later the vaccinated and control calves were challenged orally with pathogenic S. typhimurium (Robertsson et al., 1983). The oral attenuated vaccine protected significantly better than the parenteral killed vaccine. These results are sufficiently promising to evoke interest in analogous aromatic-dependent S. typhi oral vaccine strains for human use. New vaccines to protect against typhoid fever, particularly the live oral vaccines, provide an opportunity for the disease control in endemic areas. However, further vaccine studies are impeded by the lack of understanding of the immunological basis of protection and the lack of suitable animal models for typhoid fever. At this point, the only way to assess the efficacy of a vaccine is through large-scale field trials in endemic areas. REFERENCES Germanier, R. 1984. Typhoid fever. Pp. 137–165 in Bacterial Vaccines, R.Germanier, ed. New York: Academic Press. Germanier, R., and E.Furer. 1975. Isolation and characterization of S. typhi gal E mutant Ty21a: A candidate strain for a live oral typhoid vaccine. J. Infect. Dis. 131:553–558. Hoiseth, S.K., and B.A.D.Stocker. 1981. Aromatic dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature 291:238. Hornick, R.B. 1982. Typhoid fever. Pp. 659–676 in Bacterial Infections of Humans, A.S.Evans and H.A.Feldman, eds. New York: Plenum. Hornick, R.B. 1985. Selective primary health care: strategies for the control of diseases in the developing world. XX. Typhoid fever. Rev. Infect. Dis. 7:536–546. Levin, D.M., K.H.Wong, H.V.Reynolds, A.Sutton, and R.S.Northrup. 1975. Vi antigen from Salmonella typhosa and immunity against typhoid fever. II. Safety and immunogenicity in humans. Infect. Immun. 12:1290–1294. Levine, M.M., J.B.Kaper, 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. National Institute of Allergy and Infectious Diseases. 1985. Program on Accelerated Development of New Vaccines. Progress Report. Bethesda, Md.: National Institutes of Health. Punjabi, N.H. 1984. Paper presented at the International Workshop on Typhoid Fever, Pan American Health Organization, Washington, D.C., November 29–30, 1984. Robertsson, J.A., A.A.Lindberg, S.Hoiseth, and B.A.D.Stocker. 1983. Salmonella typhimurium infection in calves: Protection and survival of virulent challenge bacteria after immunization with live or inactivated vaccines. Infect. Immun. 41:742–750.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Stocker, B.A.D., S.K.Hoiseth, and B.D.Smith. 1983. Aromatic dependent “salmonella sp” as live vaccine in mice and calves. Dev. Biol. Stand. 53:47–54. Wong, K.H., J.C.Feeley, R.S.Northrup, and M.K.Forlines. 1974. Viantigen from Salmonella typhosa and immunity to typhoid fever. I. Isolation and immunologic properties in animals. Infect. Immun. 9:348–353.