Enteric diseases remain a major global health problem, especially among young children in resource-limited countries such as Africa and South Asia. In these nations, diarrheal diseases account for 2 million deaths annually, with most cases occurring in children aged younger than 5 years.1 The effect of repeated childhood enteric infections extends beyond direct morbidity and mortality and includes nutritional and cognitive deficits. Accurate surveillance is complicated by the diversity of bacterial, viral, and parasitic enteropathogens and limited access to modern laboratory diagnostics to identify these agents.
Key interventions aimed at reducing incidence, duration, and severity of childhood diarrhea include oral rehydration solution (ORS), breast-feeding, and supplementation with vitamin A and zinc.2 However, simple and effective treatment with ORS is still often delayed in many resource-limited areas. Access to clean water, improved hygiene, and sanitation would provide the greatest long-term preventive benefits, but immunization offers a valuable short- to mid-term adjunct to these interventions.
Proportional distribution of diarrheal cases among children aged younger than 5 years, by region, 2004: Africa and South Asia account for more than half the cases of childhood diarrhea. Adapted from: World Health Organization, Global Burden of Disease Estimates, 2004. The proportional distribution for UNICEF regions was calculated by applying the WHO cause of death estimates to the most recent estimates for the total number of deaths for children aged younger than 5 years, 2007.
Because most enteropathogens are transmitted by the fecal-oral route, oral vaccines that elicit mucosal antibodies and produce immunological memory in the gut are favored. The benefits of oral vaccination include needle-free immunization, reduced risk of needleborne infections, and suitability for mass vaccination campaigns.
This review focuses on available and future vaccines for the five enteric diseases that have been designated as a priority by the World Health Organization (WHO): rotavirus (RV); cholera; typhoid fever; enterotoxigenic Escherichia coli and Shigella.3
Each year, more than 500,000 children aged younger than 5 years die of RV diarrhea, the most common cause of severe dehydrating diarrhea worldwide, and the responsible agent for 40% of diarrheal hospitalizations.4 Rotavirus spreads through fecal-oral contamination, and almost all children have been infected at least once by the age of 2 years. Although improvements in sanitation and hygiene have resulted in great reductions in deaths secondary to bacterial and parasitic agents, these improvements have had a lesser role on RV infection because of the resilient and contagious nature of the virus. Natural infection has been demonstrated to provide protection against moderate to severe disease, and re-infection broadens and boosts this natural immunity.5 This may imply that multiple doses of an attenuated RV vaccine that mimics natural infection could confer optimal protection.
Currently, three oral live-attenuated vaccines have been licensed for infants: RV5 (Rotateq, Merck), a three-dose pentavalent human bovine reassortant vaccine; RV1 (Rotarix, GlaxoSmithKline), a two-dose monovalent human vaccine; and a singledose, lamb-derived monovalent strain, Lanzhou Lamb Rotavirus (LLR) vaccine, used only in China.
Adding to current WHO guidelines of 2006, the WHO Strategic Advisory Group of Experts reviewed additional efficacy data from African and Asian trials in October 2009, which resulted in a recommendation for worldwide RV vaccination.6 In 2006, large randomized controlled trials (RCTs) conducted primarily in the US and Finland evaluated the use of RV5. The researchers found that with its use, visits to the emergency department (ED) and hospitalizations were reduced by 95%.7 In the same year, RV1 demonstrated 85% efficacy against severe RV gastroenteritis (RVGE) in Latin America.8
When evaluated in three African sites (Kenya, Ghana and Mali), a three-dose regimen of RV5 was 64% efficacious against severe RVGE 1 year after vaccination.9 Similar trials in Asia (Bangladesh and Vietnam) showed 51% efficacy against severe RVGE.10 In South Africa, two- and three- dose regimens of RV1 provided 72% and 82% efficacy against severe RVGE, whereas efficacy rates in Malawi were 49% and 50%, respectively.11 Post-licensure trials in Latin America revealed sustained reductions in morbidity, severe RVGE and mortality.6
These vaccines, however, have the greatest potential for a large-scale effect on RV disease in resource-limited parts of the world. For example, according to the African RV1 data, despite a lower measured efficacy, the vaccine was able to prevent 3.9 severe episodes per 100 vaccinated children in Malawi, compared with 2.5 severe episodes in South Africa per 100 vaccinated children.11 Still, additional studies to improve the performance of RV vaccines in resource-limited countries are necessary. Reasons for lower efficacy in resourcelimited nations are likely multifaceted, but include the presence of tropical enteropathy; malnutrition; and maternally transferred antibodies. Data suggest the vaccines are safe with regard to intussusception and severe adverse events.
The Presence of a Pandemic
We are currently in the midst of a cholera pandemic, which involves nearly all resource-limited areas of the world. This rapidly dehydrating diarrheal disease, caused by O1 and O139 serogroups of Vibrio cholerae, is transmitted primarily by contaminated water or food and can spread quickly. Casefatality rates can exceed 20% without appropriate treatment but are reduced to less than 1% with proper rehydration. Annual incidence estimates of about 3 million cases and 120,000 deaths are likely conservative.12 Cholera infection requires colonization of the small intestine by V. cholerae, and pathogenicity is mediated primarily by a twosubunit cholera toxin. The B subunit of toxin binds the bacteria to the epithelial cell surface, stimulating an immune response, but having no toxic effect. When the A subunit of toxin is released, it stimulates a cellular biochemical cascade causing active secretion of water and electrolytes and leading to watery diarrhea, which can result in severe dehydration and death.
Proportional distribution of deaths due to diarrheal diseases among children aged younger than 5 years, by region, 2004: More than 80% of child deaths due to diarrhea occur in Africa and South Asia. Adapted from: World Health Organization, Global Burden of Disease Estimates, 2004 with additional analyses to calculate UNICEF regions.
Currently, three oral cholera vaccines (OCVs) are licensed for use: WC-rBS (Dukoral, Sanofi Pasteur); modified WC (Shanchol, Shantha Biotechnics); and CVD 103-HgR (Berna). Dukoral consists of a mixture of killed whole cells of V. cholerae, along with the recombinant B subunit of the cholera toxin. The vaccine is licensed for patients aged 2 years and older and is co-administered with a buffer to protect the B subunit from being altered by gastric acid. A large RCT in Bangladesh conducted in approximately 90,000 adults and children aged 2 years and older revealed 85% efficacy at 6 months and maintained 50% protection after 3 years for older children and adults. However, the vaccine failed to offer any protection to young children at 3 years follow-up.13 Although Dukoral has been pre-qualified by WHO, it has mainly been used as a travelers’ vaccine because of its cost.
Using technology transfer from Sweden, a low-cost killed whole-cell vaccine has been developed for use in Vietnam’s national cholera program. A modified version of this vaccine has conferred approximately 70% protection in the third year of a phase 3 RCT among more than 67,000 children and adults in Kolkata, India.14 Because this vaccine (Shanchol) does not contain the B subunit toxin, it does not require a buffer, and is therefore simple to administer and cheaper to produce. It is licensed for patients aged 1 year and older and given in two doses of a 1.5 mL suspension, which makes it convenient for use in resource-limited countries. The manufacturer of Shanchol is seeking WHO prequalification, and if accepted, this vaccine may be used around the world.
A significant limitation of killed OCVs is the need for two doses. Efforts are under way to develop a single-dose, live-attenuated OCV. CVD 103-HgR is licensed for a single-dose schedule for children aged 2 years and older, but this product is not being manufactured after failing to demonstrate protection in a large field trial in Indonesia.15 Other live-attenuated OCVs are currently in development, including Peru-15 (US); V. cholerae 638 (Cuba); VA 1.4 (India) and IEM 108 (China).
When evaluating vaccine protection, a common concern relates to the extremely high efficacy rate that is required for these vaccines to be useful as a public health intervention. Re-analysis of OCV field trials have suggested that OCVs provide herd immunity against cholera among non-vaccinees16 and have been deemed cost-effective by World Bank criteria. An updated WHO recommendation also suggests that OCVs be used to help control cholera in endemic and epidemic situations.17
Reduction of Typhoid Fever
Typhoid fever, caused by Salmonella enterica serotype Typhi, is a food- and waterborne disease characterized by high-grade fever and gastrointestinal symptoms. Although the disease was controlled in developed countries with improvements of sanitation and hygiene, resource-limited countries remain unable to control the spread of typhoid. Conservative estimates report that S. typhi causes 21 million infections and 217,000 deaths annually.18 In endemic areas, most cases presenting to health care facilities are children and young adults aged 5 to 19 years, yet Asianbased population studies report a significant burden of typhoid in children aged 1 to 5 years.19 Presence of a prolonged carrier state and emerging multiresistant strains of S. typhi have compounded risks that complicate treatment.
Two typhoid vaccines are currently licensed. Virulence antigen (Vi) polysaccharide vaccine is a subunit vaccine that has shown 64% efficacy 21 months after vaccination, but this drops to 55% after 3 years in children aged 5 to 15 years.20 In typhoid vaccination programs in Asia, Vi vaccine has resulted in significant reductions across endemic populations.21 Despite a recommendation for use by WHO in these countries, administration of this vaccine has been limited because of doubt regarding adequate protection in preschool-aged children.
Results of a cluster, randomized effectiveness trial in more than 37,000 participants in urban slums of India indicated that 61% fewer episodes of typhoid were reported in the vaccine recipients compared with the control group, and 80% protection was noted in 2- to 5-year-olds. Unvaccinated neighbors of those who received the Vi vaccine also had a 44% lower risk of typhoid, which suggests that Vi vaccine conferred substantial herd protection.22 Its safety profile, single-dose regimen and affordable price (<$1 USD/dose manufactured in resourcelimited countries) make this a preferred option. Still, like other polysaccharide vaccines, it is poorly immunogenic in children aged younger than 2 years and provides only short-term protection. To address these issues, a conjugate vaccine that is under development by the National Institutes of Health binds the Vi capsular antigen to the recombinant exoprotein A of Pseudomonas aeruginosa (Vi-rEPA). In early appraisal, this investigational vaccine has been shown to be safe and immunogenic in a pediatric population.23
The other licensed vaccine is a live, oral typhoid vaccine Ty21a, containing a mutant strain of S. typhi. This vaccine is given in three or four doses every other day. It is safe, has a long duration of protection, and is licensed for children older than 5 years of age. The vaccine is heat labile and requires a strict cold chain. Field studies in Egypt and Chile found the vaccine offered 62% efficacy over 7 years, but the vaccine demonstrated lower efficacy in hyperendemic areas.24 Studies are under way for other live-attenuated vaccines, including a combination typhoid-enterotoxigenic E. coli (ETEC) vaccine.25
Uptake of the licensed typhoid vaccines must be increased in the endemic countries and in travelers to these countries to improve disease control. As herd immunity has been demonstrated for both of the licensed vaccines, a large-scale vaccination program will play a major role in reducing the disease burden of typhoid in these settings. Furthermore, other strains of salmonella-caused infections, including S. paratyphi and non-typhoidal salmonellae. S. paratyphi now accounts for an additional 5.4 million infections worldwide.18 Development of combination vaccines that include these other strains will be essential to reduce the overall burden of enteric fever and invasive salmonellosis.
Emergence of ETEC
Although diarrhea can be caused by numerous strains of E. coli, ETEC is the predominant cause of infantile diarrhea in the poorest countries and in travelers from industrialized nations to resource-limited nations. ETEC may be responsible for as many as 400 million episodes of diarrhea and up to 380,000 deaths annually, with a peak incidence occurring in the first 2 years of life and a declining incidence as age increases.26 Of note, the likelihood of ETEC to cause dehydrating diarrhea in young children is lower than that of RV (ETEC 5% vs. RV 36%). However, because the incidence of childhood diarrhea is considerably higher than that of RV, the absolute number of dehydrating diarrhea episodes due to ETEC approaches 70% of those caused by RV.27
Key mechanisms of pathogenicity include the production of colonization factor antigens (CFAs) and a heat-labile toxin (LT); heat-stable toxin (ST); or LTST enterotoxin. The development of acquired immunity is supported by observations of decreased ETEC diarrhea with increasing age and rapid declines of travelers’ diarrhea during prolonged stays, supporting the prospect of an effective ETEC vaccine. Vaccine development has focused on the most prevalent CFAs and the heat-labile enterotoxin, which are expected to provide protection against up to 80% of ETEC strains worldwide.28 Unfortunately, no ETEC candidate vaccine has provided adequate protection of infants and young children who reside in endemic areas.
A suitable vaccine must provide at least 50% protection during the first 2 years of life. Several methods have been attempted in pursuit of a suitable ETEC vaccine, including killed and live formulations. ETEC’s LT shares more than 80% homology with cholera toxin, and investigators have shown the killed, oral whole-cell/recombinant B subunit cholera vaccine (WC/rBS) to offer short-term protection against ETEC diarrhea.29 This vaccine afforded 75% protection against severe diarrhea in healthy US adult tourists to Guatemala and Mexico, but did not reduce the overall rate of ETEC or other types of travelers’ diarrhea.30 However, a RCT of a three-dose regimen using an oral, inactivated whole-cell ETEC vaccine with the B-subunit of cholera toxin in children aged 6 to 18 months failed to confer protection against non-severe ETEC diarrhea (20% efficacy; 95% confidence interval, −29% to 50%).31 Early clinical phase testing of newer live-attenuated oral ETEC vaccines have established immunogenicity.32 Research is under way into using different strategies to employ non-pathogenic E.coli, attenuated Shigella, V. cholerae, or Salmonella, and express different colonization factor components, alone or in combination with LT toxoid.33
Given the changing seroepidemiology, suggestion of limited cross-protection between similar CFA phenotypes, and a lack of data to establish efficacy of the leading ETEC vaccine candidate,34 several alternate vaccine development approaches have been explored. Because purified colonization factors are easily degradable and denatured in the acidic stomach environment, researchers encapsulated these antigens in biodegradable microspheres, but this has resulted in low immunogenicity and high reactogenicity in phase 1 trials.35
Another approach involves bypassing the stomach completely. Transcutaneous immunization via skin patches that contain a mixture of fimbrial antigens and toxoid induce a serum antibody response in adult volunteers.36 This needs further evaluation to determine if mucosal immunity can be achieved.
Shigellosis and Bacillary Dysentery
Shigellosis accounts for 165 million cases and 1.1 million deaths worldwide every year, with almost 95% occurring in resource-limited countries. Children aged younger than 5 years experience approximately 65% of these infections and are noted to have a higher mortality rate when compared with adults.37 Shigellosis spreads via fecal-oral transmission and starts as watery diarrhea, followed by dysentery, abdominal cramps, and tenesmus. Although Shigella species respond well to treatment, increasing drug resistance to commonly used antimicrobials is limiting the treatment options.38
The four species of Shigella responsible for bacillary dysentery are: S. flexneri; S. sonnei; S. dysenteriae; and S. boydii, which are further divided into 47 serotypes. S. flexneri is the most frequently isolated species and is endemic in resource-poor countries. S. sonnei is the most common cause of shigellosis in industrialized nations, comprising 77% of cases, compared with only 15% of cases in resourcelimited countries. Epidemic dysentery is caused by S. dysenterae serotype 1 (Sd1) and can cause violent outbreaks in impoverished and confined populations, such as refugee camps. Their increased virulence is conferred via their ability to invade colonic epithelium and the expression of Shiga toxin, resulting in severe acute complications, such as hemolytic uremic syndrome, seizures and higher case fatality rates.
Currently, there are no vaccines licensed for use against Shigella. Epidemiologic and volunteer studies suggest that immunity to Shigella is directed toward the somatic O-antigen in the outer domain of its LPS. When hen antibodies are directed against this antigen, protective immunity is conferred.39 Although type-specific immunity has been shown, there is conflicting evidence regarding protection across different serotypes or species. Because of the wide range of antigenic variation, a multivalent vaccine containing the prevalent serotypes will be necessary. Parenteral conjugate vaccines consisting of Shigella LPS tested in a RCT displayed 74% efficacy in Israeli military volunteers.40 A phase 3 double blind RCT of S. sonnei conjugate vaccine resulted in only a 28% efficacy, but provided 71% efficacy in children aged 3 to 4 years.41
Advanced Shigella candidate vaccines include killed and live vaccines that are mostly targeted against S. flexneri.42 Progress in developing liveattenuated oral Shigella vaccines has been observed with numerous candidates directed toward combinations of S. sonnei and S. flexneri strains. The greatest challenge in vaccine development has been achieving the fine balance of attenuation but still generating a robust immune response with the avoidance of a reactogenic response and adverse events.
Recent study results for a conjugate S. sonnei vaccine suggest efficacy in patients older than 3 years, and conjugation of synthetic oligosaccharides mimicking the O-antigen to specific protein carriers offer hope for an improved and less expensive future generation of conjugate Shigella vaccines.43 Other approaches include the development of an inactivated whole-cell vaccine, a well as an oral combination travelers’ diarrhea vaccine that contains Campylobacter, Shigella and ETEC, which will undergo clinical testing in the near future.27 Novel techniques based on the immunogenic activity of Shigella antigens associated with proteosomes and ribosomes are being developed. Preclinical testing in mice after intranasal vaccination has been safe and immunogenic.44
Barriers to Public Health
Diminished immune responses to oral vaccines have been noted among populations living in areas with limited resources. The intestinal physiology of young children in poor countries differs from that of healthy children in industrialized countries because the former are usually heavily colonized, which leads to an inflammatory state and may contribute to a dulled immune response.45 Chronic environmental enteropathy (CEE) is manifested by blunting of the small intestinal epithelial villi, heightened degree of inflammation, small bowel bacterial overgrowth, altered gut flora, and subsequent nutrient malabsorption. A high pathogen burden can lead to hyporesponsiveness of mucosal immunity, perhaps mediated through regulatory T cells. This is supported by a report that demonstrated improved immunogenicity to the live cholera vaccine, CVD 103-HgR, after Ascaris treatment of Ecuadorian children with albendazole.46 Strategies for coping with CEE include co-administration of vaccines with agents that improve gut integrity, such as zinc and vitamin A.47
One important challenge related to inducing enteric immunity in infants is the possible inhibition of immune responses to vaccines in the presence of maternal antibodies. Because of the potential neutralizing effects of maternal antibody, some experts have advocated for withdrawal of breast-feeding for 30 to 60 minutes before oral rotavirus vaccination in infancy.48 Other approaches include delaying infant immunization, adding a later dose or increasing the strength of the vaccine, but these options likely would not adequately address the severe disease and mortality seen most commonly in infants younger than 12 months.
With major subsidies being exhausted, new funding sources must be identified for resource-poor countries to afford these vaccines. Cost-competitive alternatives for vaccine introduction into these countries include novel financing options, such as cross-subsidization, in which the cost of administration to one segment of the population is subsidized by fee collection from another to counter increasing costs incurred by governments. Recent mass vaccination campaigns using the typhoid Vi polysaccharide vaccine in Karachi, Pakistan, and modified, oral, killed whole-cell cholera vaccine in Orissa, India, were funded via cost-sharing strategies between public and private sectors, as well as through government public health systems. These campaigns have created awareness in sensitive local populations of the importance of vaccination, and will help to facilitate introduction of enteric vaccines in the future.
Incorporation of vaccines for diarrheal diseases into public health programs is essential to combat enteric diseases and to their potential impact on reversing associated conditions, such as malnutrition and cognitive impairment.
WHO prequalification of these vaccines helps increase uptake, especially in less-developed countries, as does optimizing vaccine-delivery options. Oral vaccination provides many benefits, as discussed above, and new and promising modes of vaccination are reviewed in the Table (see page 352). Achieving mucosal immunization by a simple method will be key for successful introduction into resource-limited areas.
Table. Newer Modes of Vaccine Delivery
The increased recognition of antimicrobial resistance, along with the gradual process of enhancing sanitation, hygiene, and clean water supplies, accentuates the need for enteric vaccines. Continued need for ongoing epidemiologic surveillance of bacterial, viral, and protozoal agents causing severe disease is essential to define the etiological burden of disease in countries with the highest infant mortality rates. In a global climate in which funding is scarce, the challenge of consistent and committed funding is a formidable obstacle to achieving practical vaccines against the common childhood enteric diseases. Successful use of technology transfer offers the potential for increased vaccine delivery at lower costs by keeping production in resource-limited countries, where the burden of disease is high.
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Newer Modes of Vaccine Delivery
|Method of Transmission||Characteristics|
|Nasal||Easy to administer, but does not induce immune responses in the gut of humans.|
|Sublingual||Induction of mucosal and systemic T-cell and antibody responses with broad dissemination to different mucosa.|
|Transcutaneous||Administered via skin patch and can elicit specific cellular and humoral responses systemically in the mucosa.|