- Email: [email protected]
Oral cholera vaccine—for whom, when, and why?
Travel Medicine and Infectious Disease (2006) 4, 38–42
www.elsevierhealth.com/journals/tmid
REVIEW
Oral cholera vaccine—for whom, when, and why? Maureen H. Topps* Department of Family Medicine, University of Calgary, 1707, 1632-14 Avenue NW, Calgary, Alta., Canada T2N 1M7 Received 16 September 2004; received in revised form 30 November 2004; accepted 1 December 2004 Available online 5 February 2005
KEYWORDS Cholera endemic and epidemic; Vaccine; Enterotoxigenic E. coli; Travelers diarrhoea
Summary The search for a safe, effective, well tolerated, low cost vaccine against the ancient cholera enemy has been ongoing since the 19th century and has been revitalized in the past two decades since the advent of recombinant technology. Large-scale field trials have readily demonstrated the tolerability and safety of oral cholera vaccine in various forms. Variable levels of protection have been shown and one challenge has been to demonstrate whether this is a cost effective treatment in differing environments including its use in endemic and epidemic areas as well as for travelers. A review of recent literature was undertaken to assess the effectiveness and uses of currently available oral cholera vaccine. While the evidence does not support the creation of formal guidelines, some clear recommendations can be made. There is undoubtedly the potential to reduce the burden of illness both in endemic and epidemic situations. For travelers, certain higher risk groups may benefit from protection against cholera. More significantly, the short term crossprotection afforded by whole cell, B subunit (WC BS) oral cholera vaccine formulations against enterotoxigenic E. coli, (ETEC), the commonest causative agent of traveler’s diarrhoea, may prove to be the most important raison d’e ˆtre. q 2005 Elsevier Ltd. All rights reserved.
Introduction Cholera can be a devastating illness, which, not only is endemic in many parts of the world, but also regularly appears in epidemic form. Often seen in the wake of disaster situations both manmade and natural, it adds to the misery of those unfortunate enough to be caught in the wrong place at the wrong time. Periodically, pandemics sweep the world and the microbes confound scientists by changing from previously recognized but benign serotypes into highly virulent organisms that * Tel.: C1 4032109237. E-mail address: [email protected]
challenge the current prophylactic regimes. Access to safe water and appropriate sanitation is the foremost means of preventing this scourge but this remains a significant challenge in large areas of the world. While treatment of cholera is in many ways very straightforward, the sheer numbers of afflicted individuals, and the rapid prostration of those affected, can quickly overwhelm even sophisticated treatment centers. This has resulted in the search for an effective, alternative means of prevention in the form of a safe, inexpensive and well tolerated vaccine. A review of recent literature on the effectiveness and uses of currently available oral cholera vaccine is presented followed by a discussion of the subject.
1477-8939/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tmaid.2004.12.002
Oral cholera vaccine—for whom, when, and why?
Background The disease known as cholera is not caused by the Vibrio cholerae organism itself but by the toxin it produces. This toxin consists of two subunits identified as A and B. Both are critical in the development of the disease process resulting in the characteristic profuse watery diarrhoea, which in turn causes significant morbidity and mortality if left untreated. Cholera toxin is produced when the organisms, which are normally found in salt-water environments, arrive in the small intestine and ‘switch on’ their virulence genes by detecting the change in their environment, particularly the reduction in free iron available. Once produced, toxin subunit B attaches to the mucosal surface of the small intestine and allows subunit A to enter the host cell. On entry to the cell, toxin subunit A is activated by a proteolytic enzyme, normally found within the cell. Following activation, the toxin acts to cause disruption of the normal production of cyclic AMP within the cell. This loss of regulation of cAMP production results in massive movements of electrolytes and fluid across the cell membrane into the lumen of the gut producing the profound osmotic diarrhoea, which is the hallmark of this disease. Infections can range from completely asymptomatic through to rapidly life-threatening. Upon recovery, a long lasting, type specific immunity develops. The severity of the infection is modulated by several factors including inoculum size (generally large, in the order of 108–1011 organisms,1 less in conditions of hypo/achlorhydria), patient’s blood group, infecting organism and prior exposure. There are many different serogroups of V. cholerae but until 1992, only serogroup 01 was considered to be responsible for endemic cholera and epidemic outbreaks. Serogroup 01 is further broken down into Classic and El Tor biotypes with Inaba and Ogawa as the causative serotypes. Since 1992, a new serogroup, 0139 also known as Bengal, has been responsible for epidemic cholera in Bangladesh and has spread to 11 countries in the Asian subcontinent.1 All commercial vaccines developed and field tested to date have used the 01 serogroup; currently there are field trials ongoing but no commercial vaccines for serogroup 0139.2 Of the commercially available oral cholera vaccines, two types are available. The first is a whole cell (WC) formulation of both Classic and El Tor biotypes including both Inaba and Ogawa serotypes; the second type is also a WC formulation encompassing the same bio and serotypes, but with the addition of subunit B (BS). This type of vaccine
39 (WC BS) makes use of the microbiology of the organism by retaining the ‘attachment’ B subunit while removing the ‘active’ subunit A. Thus it causes infection, with subsequent development of immunity, but without illness. Newer versions of this type of vaccine make use of recombinant technology and are referred to as WC rBS. All are ‘killed’ vaccine preparations. More recently, live attenuated vaccines have been produced in oral formulations (CVD 103-HgR).9 There is some recent controversy in the literature as to the merits of oral vaccine formulations versus the original parenteral killed vaccine. The parenteral vaccine had fallen out of favor because it was considered to provide only short term (3 to 6 months) benefit to only 30– 50% of those immunized and to have the further disadvantage of a significant side-effect profile. However, a recent meta-analysis conducted by the Cochrane Database review team3 casts doubt on some earlier claims and raises the profile of the parenteral vaccine again.
Review and discussion Many important questions need to be answered when considering for whom a cholera vaccine should be recommended. Currently, the World Health Organization (WHO) does not recommend the use of a vaccine for cholera in travelers or its use in refugee or disaster-relief type situations. A review of currently available oral vaccine preparations and the work done in evaluating vaccine efficacy demonstrates that the oral vaccines are safe, well tolerated and, in the first 3 years after administration, provide significant, although declining,4 protection for the populations studied. Expanding on this, large-scale trials have been held in Bangladesh,5,6 Peru7 and Vietnam.8 All looked at outcome measures comparing oral vaccine with placebo in terms of numbers of cholera cases observed. The epidemiology of cholera is quite different in endemic situations compared to epidemic situations. Endemicity vastly reduces the numbers of serious cases to less than 10% with a low case fatality rate. Higher attack rates occur in children. Epidemics may result in early case fatality rates of 20–50%, only reducing when facilities for rehydration are made available. Young adults have the highest attack rates. In endemic areas, WC and WC BS vaccines have been demonstrated to provide protection over 3 years. This reduces from around 76% protection against Classic in year one, 64% against El Tor, to
40 58 and 48%, respectively.6 Similar figures have been obtained in other large-scale studies and are reflected in a meta-analysis conducted by the Cochrane group.3 Addition of the BS component reduces the proportion of clinically severe infections.5 Both WC and WC BS types of vaccine reduce the asymptomatic excretion of cholera bacteria, but they have been found to provide better protection against symptomatic illness. Immunity has been shown to develop within three weeks of the start of a two-dose course of WC/WC BS vaccine and within 8 days of a single dose of live attenuated vaccine CVD 103HgR in North American volunteers.9 However, a large study in Indonesia has failed to demonstrate adequate development of immunity with this latest vaccine. 10 Unfortunately, the results demonstrated with the use of WC and WC BS are applicable only to those over the age of five. In one study, in Bangladesh, children between ages 2 and 5 demonstrated evanescent protection against El Tor lasting only four to 6 months, but more sustained protection of 40–56% for 2 years against Classical cholera.6 No reduction was noted in asymptomatic infections in children under age 5 in this study. The majority of cholera infections worldwide are caused by the El Tor biotype. This biotype also tends to cause a milder form of illness compared to Classical cholera, which is now endemic in only a small area of India. Since 1992, 0139 biotype Bengal has spread from Bangladesh to 11 countries in Asia. To date there is no commercial vaccine available for this organism although field tests are underway.11 There is no cross-immunity between serotype 01 and serotype 0139. In endemic situations, the purpose of vaccination is to prevent transmission by interrupting the excretion of V. cholerae organisms. An additional benefit is to modify the clinical course from moderate–severe to mild, allowing easier rehydration using oral solutions and avoiding the need for hospitalization. From the studies conducted to date, the vaccines available at present can provide a 50% three year cumulative protective effect in those over the age of 5. The addition of the BS component provides better protection in the first year and changes the spectrum of illness from moderate-severe to mild. To maintain this protection, booster doses would be needed every 2 to 3 years. For under age 5, protection is more limited and boosters would be required every 6 months. While the vaccine is safe, easy to administer and with minimal side effects, it remains relatively expensive to administer and the logistics of follow up for revaccination present a significant barrier.
M.H. Topps Studies in Vietnam12,13 have demonstrated that WC vaccine can be produced locally at low cost and is as effective as commercially produced vaccines. However, a cost benefit analysis16 demonstrates that ensuring the provision of a safe, clean water supply, with appropriate disposal of human waste and education of the population as to the importance of these factors, is far more critical in the endemic situation. When cholera arises in an epidemic situation, as has happened with explosive speed in disaster situations like Goma,14 arguments have been made for the provision of oral cholera vaccine as pre-emptive treatment.7 Considering that time to immunity is three weeks15,16 with the currently studied two dose vaccines, use of the vaccine may only be worthwhile if the epidemic is long lived. This is extremely difficult to predict. The majority of point-source outbreaks rapidly peak and return to baseline levels once potable water is made available and latrines are provided. The timing of the provision of these necessities, along with oral and intravenous rehydration facilities, is unlikely to be very different from the time taken to provide and administer the vaccine. A benefit to the vaccine is that it would provide ongoing protection for up to 3 years and so if people are displaced, and remain in an environment, which is likely to foster ongoing, or re-emergent cholera, then the vaccine would be protective. Unfortunately, the vaccine is less useful for children and in particular those under age 2 who are frequently at higher risk in disaster/displacement situations. When an analysis is done of the cost effectiveness of provision of oral cholera vaccine in epidemic situations,17 it is seen to be as cost effective as provision of safe water and latrine facilities; these facilities obviously must be attended to in every situation regardless, to avert the development of other food and waterborne illnesses. If the average cost of vaccine production can be kept below US$ 0.38 per dose (1998 costs), it is more cost effective to provide vaccine plus clean water and latrines than to provide clean water and treatment of illness in the form of rehydration facilities. The traveling public fear cholera and are the most frequent recipients of the vaccine. However, the risk to travelers is very small: 0.001–0.01% per month of stay in a developing country. Attention to simple food and water precautions can drastically reduce not only the risk of cholera but also many other food and water borne pathogens.18,19 Nonetheless, adhering to the most straightforward of recommendations (the traveler’s mantra of ‘boil it, peel it, cook it or forget it’) to reduce the potential
Oral cholera vaccine—for whom, when, and why? of exposure from food and water sources, for even a short period, has been shown to be hard to achieve.20,21 Additionally, a lack of understanding of the variety of organisms which have the potential to cause harm, as well as the mistaken belief that having the vaccine will, for sure, protect against illness is disturbing. Product advertising suggests extensive protection but review of the literature shows otherwise. A decision analysis reviewing the effect of case-attack rates on the cost-per-case prevented by vaccination for North American travelers clearly outlines why routine vaccination is not recommended.22 One additional benefit of the WC BS vaccine is the protection it affords against enterotoxigenic E. coli (ETEC). This toxin producing organism is the commonest causative agent of traveler’s diarrhoea and use of the WC BS vaccine can confer short lived protection of between 3 and 6 months. Interestingly, the Cochrane meta-analysis 3 suggests that the parenteral cholera vaccine is not as ineffective or as unpleasant as previously stated. Efficacy is estimated at 57% for the first year (similar to some oral cholera vaccine studies) and protection appears to extend into the second year, where previously it had been thought to be much more short lived. Additionally, protection for children under 5 is similar at 51% for the first year. These levels of immunity are found to be present with only a single dose and side effects were generally mild. This vaccine would not provide any protection against ETEC.
Conclusions Final recommendations on the use of cholera vaccine remain vague. There is clearly the potential to reduce the burden of illness both in endemic and epidemic situations, but this has to be weighed against the costs and logistics of vaccine provision. It has been readily demonstrated that the vaccine is safe and well tolerated. For travelers, decisions should be made on an individual basis. Not all countries have licensed formulations of the various vaccines available. Oral cholera vaccine is not available in the United States but it is available in Canada, Europe, Australia and New Zealand. Those planning a lengthy trip to an endemic area or those whose work takes them into disasterrelief-type situations should consider the vaccine. In particular, anyone with blood group O, an identified risk factor for infection and increased severity of the disease, and/or conditions leading
41 to achlorhydria (including acid suppression drugs), resulting in ease of passage of this acid sensitive organism into the small bowel should think about having the vaccine. Consideration should also be given to the protective effect against ETEC provided by WC BS vaccine. For recreational travelers, health care workers and others, this may turn out to be the most useful aspect of this vaccine. Cost of vaccine in developed nations is significant at present. Given that it has been demonstrated that locally produced vaccine in developing nations is much less expensive, there is hope that costs will decrease to manageable levels for all who wish to utilize this as a preventive measure.
References 1. Ryan ET, Calderwood SB. Cholera vaccines. Clin Infect Dis 2000;31:561–5. 2. Trach DD, Cam PD, Ke NT, et al. Investigations into the safety and immunogenicity of a killed oral cholera vaccine developed in Vietnam. Bull World Health Organ 2002;80: 2–8. 3. Graves P, Deeks J, Demicheli V, Pratt M, Jefferson T. Vaccines for preventing cholera. Cochrane Database Syst Rev 2000; 4:(1)000974. 4. Durham LK, Longini Jr IM, Halloran ME, Clemens JD, Nizam A, Rao M. Estimation of vaccine efficacy in the presence of waning: application to cholera vaccines. Am J Epidemiol 1998;147:948–59. 5. Clemens JD, Sack DA, Rao MR, et al. Evidence that inactivated oral cholera vaccines both prevent and mitigate Vibrio cholerae O1 infections in a cholera-endemic area. J Infect Dis 1992;166:1029–34. 6. van Loon FP, Clemens JD, Chakraborty J, et al. Field trial of inactivated oral cholera vaccines in Bangladesh: results from 5 years of follow-up. Vaccine 1996;14:162–6. 7. Sanchez JL, Vasquez B, Begue RE, et al. Protective efficacy of oral whole-cell/recombinant-B-subunit cholera vaccine in Peruvian military recruits. Lancet 1994;344: 1273–6. 8. Levine MM. Oral vaccines against cholera: lessons from Vietnam and elsewhere. Lancet 1997;349:220–1. 9. Tacket CO, Cohen MB, Wasserman SS, et al. Randomized, double-blind, placebo-controlled, multicentered trial of the efficacy of a single dose of live oral cholera vaccine CVD 103HgR in preventing cholera following challenge with Vibrio cholerae O1 El Tor Inaba three months after vaccination. Infect Immun 1999;67:6341–5. 10. Butler T. New developments in the understanding of cholera. Curr Gastroenterol Rep 2001;3:315–21. 11. Coster TS, Killeen KP, Waldor MK, et al. Immunogenicity, and efficacy of live attenuated Vibrio cholerae O139 vaccine prototype. Lancet 1995;345:949–52. 12. Trach DD, Clemens JD, Ke NT, et al. Field trial of a locally produced, killed, oral cholera vaccine in Vietnam. Lancet 1997;349:231–5. 13. Vu DT, Hossain MM, Nguyen DS, et al. Coverage and costs of mass immunization of an oral cholera vaccine in Vietnam. J Health Popul Nutr 2003;21:304–8.
42 14. Steffen R. New cholera vaccines—for whom? Lancet 1994; 344:1241–2. 15. Sack DA. Cholera vaccine in refugee settings. JAMA 1998; 280:600–2. 16. Naficy A, Rao MR, Paquet C, Antona D, Sorkin A, Clemens JD. Treatment and vaccination strategies to control cholera in sub-Saharan refugee settings: a cost-effectiveness analysis. JAMA 1998;279:521–5. 17. Murray J, McFarland DA, Waldman RJ. Cost-effectiveness of oral cholera vaccine in a stable refugee population at risk for epidemic cholera and in a population with endemic cholera. Bull World Health Organ 1998;76:343–52.
M.H. Topps 18. Krym VF, MacDonald RD. Safe water for travellers. CMAJ 2003;169:317–8. 19. Tellier R, Keystone JS. Prevention of traveler’s diarrhea. Infect Dis Clin North Am 1992;6:333–54. 20. Kozicki M, Steffen R, Schar M. ‘Boil it, cook it, peel it or forget it’: does this rule prevent travellers’ diarrhoea? Int J Epidemiol 1985;14:169–72. 21. Mattila L, Siitonen A, Kyronseppa H, Simula II, Peltola H. Risk behavior for travelers’ diarrhea among finnish travelers. J Travel Med 1995;2:77–84. 22. MacPherson DW, Tonkin M. Cholera vaccination: a decision analysis. CMAJ 1992;146:1947–52.
www.elsevierhealth.com/journals/tmid
REVIEW
Oral cholera vaccine—for whom, when, and why? Maureen H. Topps* Department of Family Medicine, University of Calgary, 1707, 1632-14 Avenue NW, Calgary, Alta., Canada T2N 1M7 Received 16 September 2004; received in revised form 30 November 2004; accepted 1 December 2004 Available online 5 February 2005
KEYWORDS Cholera endemic and epidemic; Vaccine; Enterotoxigenic E. coli; Travelers diarrhoea
Summary The search for a safe, effective, well tolerated, low cost vaccine against the ancient cholera enemy has been ongoing since the 19th century and has been revitalized in the past two decades since the advent of recombinant technology. Large-scale field trials have readily demonstrated the tolerability and safety of oral cholera vaccine in various forms. Variable levels of protection have been shown and one challenge has been to demonstrate whether this is a cost effective treatment in differing environments including its use in endemic and epidemic areas as well as for travelers. A review of recent literature was undertaken to assess the effectiveness and uses of currently available oral cholera vaccine. While the evidence does not support the creation of formal guidelines, some clear recommendations can be made. There is undoubtedly the potential to reduce the burden of illness both in endemic and epidemic situations. For travelers, certain higher risk groups may benefit from protection against cholera. More significantly, the short term crossprotection afforded by whole cell, B subunit (WC BS) oral cholera vaccine formulations against enterotoxigenic E. coli, (ETEC), the commonest causative agent of traveler’s diarrhoea, may prove to be the most important raison d’e ˆtre. q 2005 Elsevier Ltd. All rights reserved.
Introduction Cholera can be a devastating illness, which, not only is endemic in many parts of the world, but also regularly appears in epidemic form. Often seen in the wake of disaster situations both manmade and natural, it adds to the misery of those unfortunate enough to be caught in the wrong place at the wrong time. Periodically, pandemics sweep the world and the microbes confound scientists by changing from previously recognized but benign serotypes into highly virulent organisms that * Tel.: C1 4032109237. E-mail address: [email protected]
challenge the current prophylactic regimes. Access to safe water and appropriate sanitation is the foremost means of preventing this scourge but this remains a significant challenge in large areas of the world. While treatment of cholera is in many ways very straightforward, the sheer numbers of afflicted individuals, and the rapid prostration of those affected, can quickly overwhelm even sophisticated treatment centers. This has resulted in the search for an effective, alternative means of prevention in the form of a safe, inexpensive and well tolerated vaccine. A review of recent literature on the effectiveness and uses of currently available oral cholera vaccine is presented followed by a discussion of the subject.
1477-8939/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tmaid.2004.12.002
Oral cholera vaccine—for whom, when, and why?
Background The disease known as cholera is not caused by the Vibrio cholerae organism itself but by the toxin it produces. This toxin consists of two subunits identified as A and B. Both are critical in the development of the disease process resulting in the characteristic profuse watery diarrhoea, which in turn causes significant morbidity and mortality if left untreated. Cholera toxin is produced when the organisms, which are normally found in salt-water environments, arrive in the small intestine and ‘switch on’ their virulence genes by detecting the change in their environment, particularly the reduction in free iron available. Once produced, toxin subunit B attaches to the mucosal surface of the small intestine and allows subunit A to enter the host cell. On entry to the cell, toxin subunit A is activated by a proteolytic enzyme, normally found within the cell. Following activation, the toxin acts to cause disruption of the normal production of cyclic AMP within the cell. This loss of regulation of cAMP production results in massive movements of electrolytes and fluid across the cell membrane into the lumen of the gut producing the profound osmotic diarrhoea, which is the hallmark of this disease. Infections can range from completely asymptomatic through to rapidly life-threatening. Upon recovery, a long lasting, type specific immunity develops. The severity of the infection is modulated by several factors including inoculum size (generally large, in the order of 108–1011 organisms,1 less in conditions of hypo/achlorhydria), patient’s blood group, infecting organism and prior exposure. There are many different serogroups of V. cholerae but until 1992, only serogroup 01 was considered to be responsible for endemic cholera and epidemic outbreaks. Serogroup 01 is further broken down into Classic and El Tor biotypes with Inaba and Ogawa as the causative serotypes. Since 1992, a new serogroup, 0139 also known as Bengal, has been responsible for epidemic cholera in Bangladesh and has spread to 11 countries in the Asian subcontinent.1 All commercial vaccines developed and field tested to date have used the 01 serogroup; currently there are field trials ongoing but no commercial vaccines for serogroup 0139.2 Of the commercially available oral cholera vaccines, two types are available. The first is a whole cell (WC) formulation of both Classic and El Tor biotypes including both Inaba and Ogawa serotypes; the second type is also a WC formulation encompassing the same bio and serotypes, but with the addition of subunit B (BS). This type of vaccine
39 (WC BS) makes use of the microbiology of the organism by retaining the ‘attachment’ B subunit while removing the ‘active’ subunit A. Thus it causes infection, with subsequent development of immunity, but without illness. Newer versions of this type of vaccine make use of recombinant technology and are referred to as WC rBS. All are ‘killed’ vaccine preparations. More recently, live attenuated vaccines have been produced in oral formulations (CVD 103-HgR).9 There is some recent controversy in the literature as to the merits of oral vaccine formulations versus the original parenteral killed vaccine. The parenteral vaccine had fallen out of favor because it was considered to provide only short term (3 to 6 months) benefit to only 30– 50% of those immunized and to have the further disadvantage of a significant side-effect profile. However, a recent meta-analysis conducted by the Cochrane Database review team3 casts doubt on some earlier claims and raises the profile of the parenteral vaccine again.
Review and discussion Many important questions need to be answered when considering for whom a cholera vaccine should be recommended. Currently, the World Health Organization (WHO) does not recommend the use of a vaccine for cholera in travelers or its use in refugee or disaster-relief type situations. A review of currently available oral vaccine preparations and the work done in evaluating vaccine efficacy demonstrates that the oral vaccines are safe, well tolerated and, in the first 3 years after administration, provide significant, although declining,4 protection for the populations studied. Expanding on this, large-scale trials have been held in Bangladesh,5,6 Peru7 and Vietnam.8 All looked at outcome measures comparing oral vaccine with placebo in terms of numbers of cholera cases observed. The epidemiology of cholera is quite different in endemic situations compared to epidemic situations. Endemicity vastly reduces the numbers of serious cases to less than 10% with a low case fatality rate. Higher attack rates occur in children. Epidemics may result in early case fatality rates of 20–50%, only reducing when facilities for rehydration are made available. Young adults have the highest attack rates. In endemic areas, WC and WC BS vaccines have been demonstrated to provide protection over 3 years. This reduces from around 76% protection against Classic in year one, 64% against El Tor, to
40 58 and 48%, respectively.6 Similar figures have been obtained in other large-scale studies and are reflected in a meta-analysis conducted by the Cochrane group.3 Addition of the BS component reduces the proportion of clinically severe infections.5 Both WC and WC BS types of vaccine reduce the asymptomatic excretion of cholera bacteria, but they have been found to provide better protection against symptomatic illness. Immunity has been shown to develop within three weeks of the start of a two-dose course of WC/WC BS vaccine and within 8 days of a single dose of live attenuated vaccine CVD 103HgR in North American volunteers.9 However, a large study in Indonesia has failed to demonstrate adequate development of immunity with this latest vaccine. 10 Unfortunately, the results demonstrated with the use of WC and WC BS are applicable only to those over the age of five. In one study, in Bangladesh, children between ages 2 and 5 demonstrated evanescent protection against El Tor lasting only four to 6 months, but more sustained protection of 40–56% for 2 years against Classical cholera.6 No reduction was noted in asymptomatic infections in children under age 5 in this study. The majority of cholera infections worldwide are caused by the El Tor biotype. This biotype also tends to cause a milder form of illness compared to Classical cholera, which is now endemic in only a small area of India. Since 1992, 0139 biotype Bengal has spread from Bangladesh to 11 countries in Asia. To date there is no commercial vaccine available for this organism although field tests are underway.11 There is no cross-immunity between serotype 01 and serotype 0139. In endemic situations, the purpose of vaccination is to prevent transmission by interrupting the excretion of V. cholerae organisms. An additional benefit is to modify the clinical course from moderate–severe to mild, allowing easier rehydration using oral solutions and avoiding the need for hospitalization. From the studies conducted to date, the vaccines available at present can provide a 50% three year cumulative protective effect in those over the age of 5. The addition of the BS component provides better protection in the first year and changes the spectrum of illness from moderate-severe to mild. To maintain this protection, booster doses would be needed every 2 to 3 years. For under age 5, protection is more limited and boosters would be required every 6 months. While the vaccine is safe, easy to administer and with minimal side effects, it remains relatively expensive to administer and the logistics of follow up for revaccination present a significant barrier.
M.H. Topps Studies in Vietnam12,13 have demonstrated that WC vaccine can be produced locally at low cost and is as effective as commercially produced vaccines. However, a cost benefit analysis16 demonstrates that ensuring the provision of a safe, clean water supply, with appropriate disposal of human waste and education of the population as to the importance of these factors, is far more critical in the endemic situation. When cholera arises in an epidemic situation, as has happened with explosive speed in disaster situations like Goma,14 arguments have been made for the provision of oral cholera vaccine as pre-emptive treatment.7 Considering that time to immunity is three weeks15,16 with the currently studied two dose vaccines, use of the vaccine may only be worthwhile if the epidemic is long lived. This is extremely difficult to predict. The majority of point-source outbreaks rapidly peak and return to baseline levels once potable water is made available and latrines are provided. The timing of the provision of these necessities, along with oral and intravenous rehydration facilities, is unlikely to be very different from the time taken to provide and administer the vaccine. A benefit to the vaccine is that it would provide ongoing protection for up to 3 years and so if people are displaced, and remain in an environment, which is likely to foster ongoing, or re-emergent cholera, then the vaccine would be protective. Unfortunately, the vaccine is less useful for children and in particular those under age 2 who are frequently at higher risk in disaster/displacement situations. When an analysis is done of the cost effectiveness of provision of oral cholera vaccine in epidemic situations,17 it is seen to be as cost effective as provision of safe water and latrine facilities; these facilities obviously must be attended to in every situation regardless, to avert the development of other food and waterborne illnesses. If the average cost of vaccine production can be kept below US$ 0.38 per dose (1998 costs), it is more cost effective to provide vaccine plus clean water and latrines than to provide clean water and treatment of illness in the form of rehydration facilities. The traveling public fear cholera and are the most frequent recipients of the vaccine. However, the risk to travelers is very small: 0.001–0.01% per month of stay in a developing country. Attention to simple food and water precautions can drastically reduce not only the risk of cholera but also many other food and water borne pathogens.18,19 Nonetheless, adhering to the most straightforward of recommendations (the traveler’s mantra of ‘boil it, peel it, cook it or forget it’) to reduce the potential
Oral cholera vaccine—for whom, when, and why? of exposure from food and water sources, for even a short period, has been shown to be hard to achieve.20,21 Additionally, a lack of understanding of the variety of organisms which have the potential to cause harm, as well as the mistaken belief that having the vaccine will, for sure, protect against illness is disturbing. Product advertising suggests extensive protection but review of the literature shows otherwise. A decision analysis reviewing the effect of case-attack rates on the cost-per-case prevented by vaccination for North American travelers clearly outlines why routine vaccination is not recommended.22 One additional benefit of the WC BS vaccine is the protection it affords against enterotoxigenic E. coli (ETEC). This toxin producing organism is the commonest causative agent of traveler’s diarrhoea and use of the WC BS vaccine can confer short lived protection of between 3 and 6 months. Interestingly, the Cochrane meta-analysis 3 suggests that the parenteral cholera vaccine is not as ineffective or as unpleasant as previously stated. Efficacy is estimated at 57% for the first year (similar to some oral cholera vaccine studies) and protection appears to extend into the second year, where previously it had been thought to be much more short lived. Additionally, protection for children under 5 is similar at 51% for the first year. These levels of immunity are found to be present with only a single dose and side effects were generally mild. This vaccine would not provide any protection against ETEC.
Conclusions Final recommendations on the use of cholera vaccine remain vague. There is clearly the potential to reduce the burden of illness both in endemic and epidemic situations, but this has to be weighed against the costs and logistics of vaccine provision. It has been readily demonstrated that the vaccine is safe and well tolerated. For travelers, decisions should be made on an individual basis. Not all countries have licensed formulations of the various vaccines available. Oral cholera vaccine is not available in the United States but it is available in Canada, Europe, Australia and New Zealand. Those planning a lengthy trip to an endemic area or those whose work takes them into disasterrelief-type situations should consider the vaccine. In particular, anyone with blood group O, an identified risk factor for infection and increased severity of the disease, and/or conditions leading
41 to achlorhydria (including acid suppression drugs), resulting in ease of passage of this acid sensitive organism into the small bowel should think about having the vaccine. Consideration should also be given to the protective effect against ETEC provided by WC BS vaccine. For recreational travelers, health care workers and others, this may turn out to be the most useful aspect of this vaccine. Cost of vaccine in developed nations is significant at present. Given that it has been demonstrated that locally produced vaccine in developing nations is much less expensive, there is hope that costs will decrease to manageable levels for all who wish to utilize this as a preventive measure.
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