341
parenteral preparation was also evaluated; this vaccine gave a consistently higher level of protection in field trials (66-94%) but was associated with considerably more frequent and severe adverse effects and was much more expensive to prepare.2--5 The improved protection was attributed to retention of the Vi-antigen, which was lost in the heat-killed vaccine. Adults living in endemic areas have a degree of naturally acquired immunity through repeated
EDITORIALS
Typhoid vaccination: weighing
the
options Typhoid fever is perceived as a sufficiently serious travel-related infection for there to be three vaccines currently available. However, in reality typhoid is a rare disease in travellers. Between 1982 and 1984 the mean incidence rate of typhoid fever in persons normally resident in the USA who undertook foreign travel was only 6-1 cases per million travellers,l the highest incidence being associated with travel to specific countries in the Indian subcontinent (105-118 cases/million travellers) and to parts of tropical South America (Peru, 174 cases/million). In other regions that are widely regarded as high risk, the rates were much lower-eg, sub-Saharan Africa and Southeast Asia had respective incidence rates of only 7-2 and 48 cases/million travellers, figures that compare favourably with southern and eastern Europe (2.1and 3-5 cases/million). Despite this marginal risk of infection, millions of travellers continue to be vaccinated. For nearly 100 years, the mainstay typhoid vaccine has been the parenterally administered heat-killed whole organism vaccine, although there have been previous unsuccessful attempts to replace it. A live attenuated orally administered vaccine with the vaccine strain Salmonella typhi Ty2la (Vivotif, Swiss Serum Vaccine Institute, Berne, Switzerland), and a parenterally administered purified Vi-antigen vaccine (Typhim Vi, Institut Merieux, Lyon, France) have now been introduced and are beginning to compete with the older heat-killed formulation. The new typhoid vaccines have far fewer side-effects than the heat-killed vaccine, but their ability to protect the recipient from typhoid fever is not entirely clear. The parenterally administered heat-killed vaccine was extensively evaluated in field trials sponsored by the World Health Organisation; these trials were conducted in regions endemic for typhoid fever throughout the 1950s and 1960s. The vaccine was shown to be essentially safe, although there were frequent local adverse effects and the occasional systemic reaction such as fever. Effectiveness in preventing typhoid was documented, with protection rates of 51-81 %,2--5varying by region; two doses were more effective than one.6 An acetone-inactivated
subclinical or clinical exposure to the infectious agent in their environment; attack rates for typhoid fever are much greater in children.3Consequently, the immune responses and protection rates of an introduced vaccine represent an example of boosting a lifetime’s acquisition of natural immunity rather than a true indication of vaccine potential. Apart from very young children, these populations cannot in any way be deemed similar to vaccine target groups in countries where the disease is not endemic. Although this difference is thought to be more relevant to orally administered vaccines, parenteral vaccines can likewise boost local intestinal immunity.There is still a disturbing tendency to equate protection rates in endemic populations with likely protection in immunologically naive previously unexposed travellers from developed countries. Of the three widely available typhoid vaccines, only two have been evaluated for their ability to confer protection against typhoid fever on previously
unexposed subjects, a population equivalent to travellers. The parenterally administered heat-killed vaccine conferred 67% protection against disease in North American subjects with a three-dose schedule.8 However, the protection was only against lowchallenge doses similar to those encountered in waterborne transmission. Such protection is of doubtful value since most travellers who acquire typhoid do so after exposure to the larger inoculum associated with foodborne transmission, against which this vaccine will not protect. In contrast to the field trials, no additional protection was associated with the use of the acetone-inactivated vaccine. Despite the live orally administered vaccine S typhi Ty21a giving protection rates of 43-96 % in field trials in endemic areas, with a three-dose alternate-day schedule of 109 live organisms,9-11 the protective efficacy of this schedule in persons not from or residing in such areas has never been assessed. In the only study of protection conducted in previously unexposed subjects, with a multiple-dose schedule (5-8 doses) of 0-3-1-0 x 1011 live organisms, S typhi Ty21a conferred 87% protection against clinical disease.12 Vaccine doses of only 101 live S typhi Ty21a organisms have not induced immune responses in subjects without a history of disease or vaccination 13 or in children under 2 years residing in an endemic region.14 A report from Nepal suggests that 109 live S typhi Ty21a may not protect travellers who are visiting an endemic area. 15 S typhi Ty21a has the potential to be an effective
342
vaccine, but the evidence suggests that it needs 50-100-fold more viable organisms to be of value to travellers. It has the obvious advantages of being easily taken by mouth, with no adverse effects of any consequence, and could potentially stimulate local intestinal immunity, which is generally held to be important in protecting against infection. However, travellers are responsible for their own vaccination through the long schedule of three (worldwide) or four (USA) alternate-day doses and the necessity of maintaining the vaccine at 4°C. This requirement has been associated with compliance difficulties in the USA, where the vaccine was licensed in December, 1989.16 The purified Vi-antigen vaccine has a protective efficacy of 60-72% against disease in field trials conducted in populations in endemic regions of Nepal and South Africa. 17,18 This preparation is immunogenic in healthy North American subjects, but has never been evaluated for its likely protective efficacy in this proposed target group. The Vi-antigen vaccine has all the disadvantages of a parenterally administered vaccine: apart from the unpleasantness of an injection, there are frequent local and rare systemic reactions (albeit condsiderably milder than those associated with the heat-killed vaccine), and no stimulation of local intestinal immunity. The vaccine is convenient; with a single injection, the health-care provider can be confident that the traveller has been vaccinated. Despite many misgivings about the existing heatkilled typhoid vaccine and the doubts concerning the efficacy of this and the newer preparations, many hundreds of thousands of vaccine doses will be sold to travellers from developed countries during the coming year. Before deciding to embark on the travel vaccination ritual, travellers and their health-care providers should consider carefully the necessity of these vaccinations. Many vaccines are associated with adverse effects, especially the parenterally administered formulations. It is worth recalling that the abolition of cholera vaccination, even for travellers visiting endemic areas, has not been associated with a noticeable increase in travel-related cholera. Travellers should be provided with the opportunity to be vaccinated should they so choose, but they should be made aware (a) of the low risk of acquiring typhoid fever through travel; (b) that of the three available typhoid vaccines, none has proven any ability to confer protection against typhoid in healthy previously unexposed adults with the doses or schedules approved by licensing authorities; and (c) that the only differences between the vaccines are routes of administration, dose schedules, and adverse effects. 1.
Ryan CA, Hagrett-Bean NT, Blake PA. Salmonella typhi infections in the United States, 1975-1984: increasing role of foreign travel. Rev Infect Dis 1989; 11: 1-8.
2. Yugoslav Typhoid Commission. A controlled field trial of the effectiveness of phenol and alcohol typhoid vaccines: final report. Bull WHO 1962; 26: 357-69.
Commission. A controlled field trial of the effectiveness of acetone-dried and inactivated and heat-phenolinactivated typhoid vaccines in Yugoslavia. Bull WHO 1964; 30: 623-30. 4. Ashcroft MT, Singh B, Nicholson CC, Ritchie JM, Sobryan E, Williams F. A seven-year field trial of two typhoid vaccines in Guyana. Lancet 1967; ii: 1056-59. 5. Hejfec LB. Results of the study of typhoid vaccines in four controlled field trials in the USSR. Bull WHO 1965; 32: 1-14. 6. Hejfec LB, Levina LA, Kuz’minova ML, Salmin LV, Slavina AM, Vasil’eva AV. Controlled field trials of paratyphoid B vaccine and evaluation of the effectiveness of a single administration of typhoid vaccine. Bull WHO 1968; 38: 907-15. 7. Forrest BD, LaBrooy JT, Dearlove CE, Shearman DJC. Effect of parenteral immunisation on the intestinal immune response to Salmonella typhi Ty21a in humans. Infect Immun 1992; 60: 465-71. 8. Hornick RB, Greisman SE, Woodward TE, DuPont HL, Dawkins AT, Snyder MJ. Typhoid fever: pathogenesis and immunologic control, part 2. N Engl J Med 1970; 283: 739-46. 9. Wahdan MH, Serie C, Cerisier Y, Sallam S, Germanier R. A controlled field trial of live Salmonella typhi strain Ty21a oral vaccine against typhoid: three-year results. J Infect Dis 1982; 145: 292-95. 10. Levine MM, Ferreccio C, Black RE, Germanier R, Chilean Typhoid Committee. Large-scale field trial of Ty21a live oral typhoid vaccine in enteric-coated capsule formulation. Lancet 1987; i: 1049-52. 11. Simanjuntak CH, Paleologo FP, Punjabi NH, et al. Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine. Lancet 1991; 338: 1055-59. 12. Gilman RH, Hornick RB, Woodward WE, DuPont HL, Levine MM, Libonati JP. Evaluation of a UDP-glucose-4-epimeraseless mutant of Salmonella typhi as a live oral typhoid vaccine. J Infect Dis 1977; 136: 716-23. 13. Forrest BD, LaBrooy JT, Beyer L, Dearlove CE, Shearman DJC. The human humoral immune response to Salmonella typhi Ty21a. J Infect Dis 1991; 163: 336-45. 14. Murphy JR, Grez L, Schlesinger L, et al. Immunogenicity of Salmonella typhi Ty21a for young children. Infect Immun 1991; 59: 4291-93. 15. Schwartz E, Shlim DR, Eaton M, Jenks N, Houston R. The effect of oral and parenteral typhoid vaccination on the rate of infection with Salmonella typhi and Salmonella paratyphi A among foreigners in Nepal. Arch Intern Med 1990; 150: 349-51. 16. Kaplan DT, Hill DR. Compliance with live, oral Ty21a typhoid vaccine. JAMA 1992; 267: 1074. 17. Klugman KP, Gilbertson IT, Koornhof HJ, et al. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever. Lancet 1987; ii: 165-69. 18. Acharya IL, Lowe CU, Thapa R, et al. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi: a preliminary report. N Engl J Med 1987; 317: 1101-04.
3. Yugoslav Typhoid
Tumour
pH
As reported in The Lancet nearly sixty years ago,1 a Nobel prize was awarded to Otto Warburg in recognition of work2 that included the discovery of "the remarkable extent to which living tumour cells are able to convert carbohydrate into lactic acid". For many years afterwards it was assumed that tumours relied largely on the glycolytic pathway, produced large amounts of lactic acid, and consequently had an acidic intracellular pH (pHi). In the intervening years, microelectrode measurements of tumour pH seemed to confirm this assumption. However, we now know that these measurements largely reflect pHe, the interstitial (or extracellular) fluid pH (range 5.5-7.3).3-5 With the advent of magnetic resonance spectroscopy (MRS), a non-invasive in-vivo measure of tissue pH became available, and in 1983 the pH of a human tumour was measured for the first time.6 The pHMRS measurement is based on the pH-dependent chemical shift difference between the 31 PI (inorganic phosphate) signal and an endogenous reference signal. At physiological pH, the Pi signal reflects the
parenteral preparation was also evaluated; this vaccine gave a consistently higher level of protection in field trials (66-94%) but was associated with considerably more frequent and severe adverse effects and was much more expensive to prepare.2--5 The improved protection was attributed to retention of the Vi-antigen, which was lost in the heat-killed vaccine. Adults living in endemic areas have a degree of naturally acquired immunity through repeated
EDITORIALS
Typhoid vaccination: weighing
the
options Typhoid fever is perceived as a sufficiently serious travel-related infection for there to be three vaccines currently available. However, in reality typhoid is a rare disease in travellers. Between 1982 and 1984 the mean incidence rate of typhoid fever in persons normally resident in the USA who undertook foreign travel was only 6-1 cases per million travellers,l the highest incidence being associated with travel to specific countries in the Indian subcontinent (105-118 cases/million travellers) and to parts of tropical South America (Peru, 174 cases/million). In other regions that are widely regarded as high risk, the rates were much lower-eg, sub-Saharan Africa and Southeast Asia had respective incidence rates of only 7-2 and 48 cases/million travellers, figures that compare favourably with southern and eastern Europe (2.1and 3-5 cases/million). Despite this marginal risk of infection, millions of travellers continue to be vaccinated. For nearly 100 years, the mainstay typhoid vaccine has been the parenterally administered heat-killed whole organism vaccine, although there have been previous unsuccessful attempts to replace it. A live attenuated orally administered vaccine with the vaccine strain Salmonella typhi Ty2la (Vivotif, Swiss Serum Vaccine Institute, Berne, Switzerland), and a parenterally administered purified Vi-antigen vaccine (Typhim Vi, Institut Merieux, Lyon, France) have now been introduced and are beginning to compete with the older heat-killed formulation. The new typhoid vaccines have far fewer side-effects than the heat-killed vaccine, but their ability to protect the recipient from typhoid fever is not entirely clear. The parenterally administered heat-killed vaccine was extensively evaluated in field trials sponsored by the World Health Organisation; these trials were conducted in regions endemic for typhoid fever throughout the 1950s and 1960s. The vaccine was shown to be essentially safe, although there were frequent local adverse effects and the occasional systemic reaction such as fever. Effectiveness in preventing typhoid was documented, with protection rates of 51-81 %,2--5varying by region; two doses were more effective than one.6 An acetone-inactivated
subclinical or clinical exposure to the infectious agent in their environment; attack rates for typhoid fever are much greater in children.3Consequently, the immune responses and protection rates of an introduced vaccine represent an example of boosting a lifetime’s acquisition of natural immunity rather than a true indication of vaccine potential. Apart from very young children, these populations cannot in any way be deemed similar to vaccine target groups in countries where the disease is not endemic. Although this difference is thought to be more relevant to orally administered vaccines, parenteral vaccines can likewise boost local intestinal immunity.There is still a disturbing tendency to equate protection rates in endemic populations with likely protection in immunologically naive previously unexposed travellers from developed countries. Of the three widely available typhoid vaccines, only two have been evaluated for their ability to confer protection against typhoid fever on previously
unexposed subjects, a population equivalent to travellers. The parenterally administered heat-killed vaccine conferred 67% protection against disease in North American subjects with a three-dose schedule.8 However, the protection was only against lowchallenge doses similar to those encountered in waterborne transmission. Such protection is of doubtful value since most travellers who acquire typhoid do so after exposure to the larger inoculum associated with foodborne transmission, against which this vaccine will not protect. In contrast to the field trials, no additional protection was associated with the use of the acetone-inactivated vaccine. Despite the live orally administered vaccine S typhi Ty21a giving protection rates of 43-96 % in field trials in endemic areas, with a three-dose alternate-day schedule of 109 live organisms,9-11 the protective efficacy of this schedule in persons not from or residing in such areas has never been assessed. In the only study of protection conducted in previously unexposed subjects, with a multiple-dose schedule (5-8 doses) of 0-3-1-0 x 1011 live organisms, S typhi Ty21a conferred 87% protection against clinical disease.12 Vaccine doses of only 101 live S typhi Ty21a organisms have not induced immune responses in subjects without a history of disease or vaccination 13 or in children under 2 years residing in an endemic region.14 A report from Nepal suggests that 109 live S typhi Ty21a may not protect travellers who are visiting an endemic area. 15 S typhi Ty21a has the potential to be an effective
342
vaccine, but the evidence suggests that it needs 50-100-fold more viable organisms to be of value to travellers. It has the obvious advantages of being easily taken by mouth, with no adverse effects of any consequence, and could potentially stimulate local intestinal immunity, which is generally held to be important in protecting against infection. However, travellers are responsible for their own vaccination through the long schedule of three (worldwide) or four (USA) alternate-day doses and the necessity of maintaining the vaccine at 4°C. This requirement has been associated with compliance difficulties in the USA, where the vaccine was licensed in December, 1989.16 The purified Vi-antigen vaccine has a protective efficacy of 60-72% against disease in field trials conducted in populations in endemic regions of Nepal and South Africa. 17,18 This preparation is immunogenic in healthy North American subjects, but has never been evaluated for its likely protective efficacy in this proposed target group. The Vi-antigen vaccine has all the disadvantages of a parenterally administered vaccine: apart from the unpleasantness of an injection, there are frequent local and rare systemic reactions (albeit condsiderably milder than those associated with the heat-killed vaccine), and no stimulation of local intestinal immunity. The vaccine is convenient; with a single injection, the health-care provider can be confident that the traveller has been vaccinated. Despite many misgivings about the existing heatkilled typhoid vaccine and the doubts concerning the efficacy of this and the newer preparations, many hundreds of thousands of vaccine doses will be sold to travellers from developed countries during the coming year. Before deciding to embark on the travel vaccination ritual, travellers and their health-care providers should consider carefully the necessity of these vaccinations. Many vaccines are associated with adverse effects, especially the parenterally administered formulations. It is worth recalling that the abolition of cholera vaccination, even for travellers visiting endemic areas, has not been associated with a noticeable increase in travel-related cholera. Travellers should be provided with the opportunity to be vaccinated should they so choose, but they should be made aware (a) of the low risk of acquiring typhoid fever through travel; (b) that of the three available typhoid vaccines, none has proven any ability to confer protection against typhoid in healthy previously unexposed adults with the doses or schedules approved by licensing authorities; and (c) that the only differences between the vaccines are routes of administration, dose schedules, and adverse effects. 1.
Ryan CA, Hagrett-Bean NT, Blake PA. Salmonella typhi infections in the United States, 1975-1984: increasing role of foreign travel. Rev Infect Dis 1989; 11: 1-8.
2. Yugoslav Typhoid Commission. A controlled field trial of the effectiveness of phenol and alcohol typhoid vaccines: final report. Bull WHO 1962; 26: 357-69.
Commission. A controlled field trial of the effectiveness of acetone-dried and inactivated and heat-phenolinactivated typhoid vaccines in Yugoslavia. Bull WHO 1964; 30: 623-30. 4. Ashcroft MT, Singh B, Nicholson CC, Ritchie JM, Sobryan E, Williams F. A seven-year field trial of two typhoid vaccines in Guyana. Lancet 1967; ii: 1056-59. 5. Hejfec LB. Results of the study of typhoid vaccines in four controlled field trials in the USSR. Bull WHO 1965; 32: 1-14. 6. Hejfec LB, Levina LA, Kuz’minova ML, Salmin LV, Slavina AM, Vasil’eva AV. Controlled field trials of paratyphoid B vaccine and evaluation of the effectiveness of a single administration of typhoid vaccine. Bull WHO 1968; 38: 907-15. 7. Forrest BD, LaBrooy JT, Dearlove CE, Shearman DJC. Effect of parenteral immunisation on the intestinal immune response to Salmonella typhi Ty21a in humans. Infect Immun 1992; 60: 465-71. 8. Hornick RB, Greisman SE, Woodward TE, DuPont HL, Dawkins AT, Snyder MJ. Typhoid fever: pathogenesis and immunologic control, part 2. N Engl J Med 1970; 283: 739-46. 9. Wahdan MH, Serie C, Cerisier Y, Sallam S, Germanier R. A controlled field trial of live Salmonella typhi strain Ty21a oral vaccine against typhoid: three-year results. J Infect Dis 1982; 145: 292-95. 10. Levine MM, Ferreccio C, Black RE, Germanier R, Chilean Typhoid Committee. Large-scale field trial of Ty21a live oral typhoid vaccine in enteric-coated capsule formulation. Lancet 1987; i: 1049-52. 11. Simanjuntak CH, Paleologo FP, Punjabi NH, et al. Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine. Lancet 1991; 338: 1055-59. 12. Gilman RH, Hornick RB, Woodward WE, DuPont HL, Levine MM, Libonati JP. Evaluation of a UDP-glucose-4-epimeraseless mutant of Salmonella typhi as a live oral typhoid vaccine. J Infect Dis 1977; 136: 716-23. 13. Forrest BD, LaBrooy JT, Beyer L, Dearlove CE, Shearman DJC. The human humoral immune response to Salmonella typhi Ty21a. J Infect Dis 1991; 163: 336-45. 14. Murphy JR, Grez L, Schlesinger L, et al. Immunogenicity of Salmonella typhi Ty21a for young children. Infect Immun 1991; 59: 4291-93. 15. Schwartz E, Shlim DR, Eaton M, Jenks N, Houston R. The effect of oral and parenteral typhoid vaccination on the rate of infection with Salmonella typhi and Salmonella paratyphi A among foreigners in Nepal. Arch Intern Med 1990; 150: 349-51. 16. Kaplan DT, Hill DR. Compliance with live, oral Ty21a typhoid vaccine. JAMA 1992; 267: 1074. 17. Klugman KP, Gilbertson IT, Koornhof HJ, et al. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever. Lancet 1987; ii: 165-69. 18. Acharya IL, Lowe CU, Thapa R, et al. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi: a preliminary report. N Engl J Med 1987; 317: 1101-04.
3. Yugoslav Typhoid
Tumour
pH
As reported in The Lancet nearly sixty years ago,1 a Nobel prize was awarded to Otto Warburg in recognition of work2 that included the discovery of "the remarkable extent to which living tumour cells are able to convert carbohydrate into lactic acid". For many years afterwards it was assumed that tumours relied largely on the glycolytic pathway, produced large amounts of lactic acid, and consequently had an acidic intracellular pH (pHi). In the intervening years, microelectrode measurements of tumour pH seemed to confirm this assumption. However, we now know that these measurements largely reflect pHe, the interstitial (or extracellular) fluid pH (range 5.5-7.3).3-5 With the advent of magnetic resonance spectroscopy (MRS), a non-invasive in-vivo measure of tissue pH became available, and in 1983 the pH of a human tumour was measured for the first time.6 The pHMRS measurement is based on the pH-dependent chemical shift difference between the 31 PI (inorganic phosphate) signal and an endogenous reference signal. At physiological pH, the Pi signal reflects the
