Abstract: In October 2010, a virulent South Asian strain of El Tor cholera began to spread in Haiti. Interventions have included treatment of cases and improved sanitation. Use of cholera vaccines would likely have further reduced morbidity and mortality, but such vaccines are in short supply and little is known about effective vaccination strategies for epidemic cholera. We use a mathematical cholera transmission model to assess different vaccination strategies. With limited vaccine quantities, concentrating vaccine in high-risk areas is always most efficient. We show that targeting one million doses of vaccine to areas with high exposure to Vibrio cholerae, enough for two doses for 5% of the population, would reduce the number of cases by 11%. The same strategy with enough vaccine for 30% of the population with modest hygienic improvement could reduce cases by 55% and save 3,320 lives. For epidemic cholera, we recommend a large mobile stockpile of enough vaccine to cover 30% of a country's population to be reactively targeted to populations at high risk of exposure.

Abstract: Background: Killed oral cholera vaccines (OCVs) have been licensed for use in developing countries, but protection conferred by licensed OCVs beyond two years of follow-up has not been demonstrated in randomized, clinical trials. Methods/Principal Findings: We conducted a cluster-randomized, placebo-controlled trial of a two-dose regimen of a lowcost killed whole cell OCV in residents 1 year of age and older living in 3,933 clusters in Kolkata, India. The primary endpoint was culture-proven Vibrio cholerae O1 diarrhea episodes severe enough to require treatment in a health care facility. Of the 66,900 fully dosed individuals (31,932 vaccinees and 34,968 placebo recipients), 38 vaccinees and 128 placebo-recipients developed cholera during three years of follow-up (protective efficacy 66%; one-sided 95%CI lower bound=53%, p,0.001). Vaccine protection during the third year of follow-up was 65% (one-sided 95%CI lower bound=44%, p,0.001). Significant protection was evident in the second year of follow-up in children vaccinated at ages 1–4 years and in the third year in older age groups. Conclusions/Significance: The killed whole-cell OCV conferred significant protection that was evident in the second year of follow-up in young children and was sustained for at least three years in older age groups. Continued follow-up will be important to establish the vaccine’s duration of protection.

Abstract: Background: Cholera is a cause of acute watery diarrhoea which can cause dehydration and death if not adequately treated. It usually occurs in epidemics, and is associated with poverty and poor sanitation. Effective, cheap, and easy to administer vaccines could help prevent epidemics. Objectives: To assess the effectiveness and safety of oral cholera vaccines in preventing cases of cholera and deaths from cholera. Search methods: In October 2010, we searched the Cochrane Infectious Disease Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; the metaRegister of Controlled Trials (mRCT), and the WHO International Clinical Trials Registry Platform (ICTRP) for relevant published and ongoing trials. Selection criteria: Randomized or quasi-randomized controlled trials of oral cholera vaccines in healthy adults and children. Data collection and analysis: Each trial was assessed for eligibility and risk of bias by two authors working independently. Data was extracted by two independent reviewers and analysed using the Review Manager 5 software. Outcomes are reported as vaccine protective efficacy (VE) with 95% confidence intervals (CIs). Main results: Seven large efficacy trials, four small artificial challenge studies, and 29 safety trials contributed data to this review. Five variations of a killed whole cell vaccine have been evaluated in large scale efficacy trials (four trials, 249,935 participants). The overall vaccine efficacy during the first year was 52% (95% CI 35% to 65%), and during the second year was 62% (95% CI 51% to 62%). Protective efficacy was lower in children aged less than 5 years; 38% (95% CI 20% to 53%) compared to older children and adults; 66% (95% CI 57% to 73%). One trial of a killed whole cell vaccine amongst military recruits demonstrated 86% protective efficacy (95% CI 37% to 97%) in a small epidemic occurring within 4 weeks of the 2-dose schedule (one trial, 1426 participants). Efficacy data is not available beyond two years for the currently available vaccine formulations, but based on data from older trials is unlikely to last beyond three years. The safety data available on killed whole cell vaccines have not demonstrated any clinically significant increase in adverse events compared to placebo. Only one live attenuated vaccine has reached Phase III clinical evaluation and was not effective (one trial, 67,508 participants). Two new candidate live attenuated vaccines have demonstrated clinical effectiveness in small artificial challenge studies, but are still in development. Authors' conclusions: The currently available oral killed whole cell vaccines can prevent 50 to 60% of cholera episodes during the first two years after the primary vaccination schedule. The impact and cost-effectiveness of adopting oral cholera vaccines into the routine vaccination schedule of endemic countries will depend on the prevalence of cholera, the frequency of epidemics, and access to basic services providing rapid rehydration therapy.

Abstract: Methods. The study was conducted in a cholera-endemic population in Bangladesh. Patients with cholera (index patients) detected between 1991 and 2000 were age-matched to 4 cholera-free controls and then followed up during the subsequent 3 years. Results. El Tor cholera was associated with a 65% (95% confidence interval [CI], 37%–81%; P , .001) lower risk of a subsequent El Tor episode. Reduction of the risk of subsequent El Tor cholera was similar for children ,5 years and for older persons and was sustained during all 3 years of follow-up. Having El Tor Inaba cholera was associated with lower risks of both El Tor Inaba and El Tor Ogawa cholera, but having El Tor Ogawa cholera was associated only with a reduced risk of El Tor Ogawa cholera. O139 cholera was associated with a 63% (95% CI, 261% to 92%; P 5 .18) lower risk of subsequent O139 cholera, but there was no evidence of cross-protection between the O1 and O139 serogroups. Conclusions. Live oral cholera vaccines designed to protect against the O1 and O139 serogroups should contain at least the Inaba serotype and strains of both serogroups. Vibrio cholerae serogroup O1 and O139 organisms cause acute, watery diarrhea, with an estimated 100 000–

Abstract: It was shown earlier that immune responses against cholera toxin (CT) as well as Vibrio cholerae lipopolysaccharide (LPS) or whole bacterial cells (WC) were protective and that these different antibody specificities co-operated synergistically for protection against experimental cholera. Similarly, antibodies against the heat-labile toxin (LT) and major colonization factors (CFs) of enterotoxingenic Escherichia coli (ETEC) co-operated synergistically for protection against LT-producing ETEC expressing homologous CFs. Studies in humans revealed that repeated oral antigen administration was optimal in inducing intestinal immune responses. Based on these findings oral inactivated vaccines consisting of toxin antigen and whole cells, i.e. the licensed recombinant cholera B subunit (rCTB)-WC cholera vaccine Dukoral®, and candidate ETEC vaccines have been developed. In different trials the rCTB-WC cholera vaccine has provided very high (85-100%) short term protection, which was significantly higher than that induced by the WC component alone, whereas rCTB-WC and WC alone provided comparable (50-60%), long term protection. An oral ETEC vaccine consisting of rCTB and formalin-inactivated E. coli bacteria expressing major CFs was shown to be safe and immunogenic in adults and children in different countries. The vaccine also induced significant protection against non-mild ETEC diarrhoea, i.e. diarrhoea interfering with daily activity in American travellers but not against ETEC diarrhoea in young children in Egypt. Against this background, a modified ETEC vaccine consisting of recombinant E. coli strains overexpressing the major CFs and a more LT like hybrid toxoid (LCTBA) has been developed. This vaccine will be tested soon alone and together with a mucosal adjuvant, i.e. dmLT, in clinical trials.

Abstract: Currently, vaccines are not widely used in the control of cholera, but new-generation orally administered vaccines may well become important tools in the public health armamentarium against this disease. This Review focuses on selected aspects of the disease, its pathogenesis and immunology, clinical features, epidemiology and treatment, and summarizes the status of new-generation cholera vaccines.

Abstract: Background Killed oral cholera vaccines (OCVs) are available but not used routinely for cholera control except in Vietnam, which produces its own vaccine. In 2007–2008, unprecedented cholera outbreaks occurred in the capital, Hanoi, prompting immunization in two districts. In an outbreak investigation, we assessed the effectiveness of killed OCV use after a cholera outbreak began. Methodology/Principal Findings From 16 to 28 January 2008, vaccination campaigns with the Vietnamese killed OCV were held in two districts of Hanoi. No cholera cases were detected from 5 February to 4 March 2008, after which cases were again identified. Beginning 8 April 2008, residents of four districts of Hanoi admitted to one of five hospitals for acute diarrhea with onset after 5 March 2008 were recruited for a matched, hospital-based, case-control outbreak investigation. Cases were matched by hospital, admission date, district, gender, and age to controls admitted for non-diarrheal conditions. Subjects from the two vaccinated districts were evaluated to determine vaccine effectiveness. 54 case-control pairs from the vaccinated districts were included in the analysis. There were 8 (15%) and 16 (30%) vaccine recipients among cases and controls, respectively. The vaccine was 76% protective against cholera in this setting (95% CI 5% to 94%, P = 0.042) after adjusting for intake of dog meat or raw vegetables and not drinking boiled or bottled water most of the time. Conclusions/Significance This is the first study to explore the effectiveness of the reactive use of killed OCVs during a cholera outbreak. Our findings suggest that killed OCVs may have a role in controlling cholera outbreaks.

Abstract: The ability of Vibrio cholerae to persist in bodies of water will continue to confound our ability to eradicate cholera through improvements to infrastructure, and thus cholera vaccines are needed. We aim for an inexpensive vaccine that can provide long-lasting protection from all epidemic cholera infections, currently caused by O1 or O139 serogroups. Recent insights into correlates of protection, epidemiology and pathogenesis may help us design improved vaccines. This notwithstanding, we have come to appreciate that even marginally protective vaccines, such as oral whole-cell killed vaccines, if widely distributed, can provide significant protection, owing to herd immunity. Further efforts are still required to provide more effective protection of young children.

Abstract: Vibrio cholerae O1 is a noninvasive enteric pathogen and serves as a model for studies of mucosal immunity. Although symptomatic V. cholerae infection induces durable protection against subsequent disease, vaccination with oral killed whole-cell V. cholerae stimulates less long-lasting protection against cholera. In this study, we demonstrated that cholera induces an early proinflammatory cellular immune response that results in priming of Th1- and Th17-type cytokine responses to ex vivo antigenic stimulation and an increase in the ratio of Th1 to Th2 CD4(+) T-cell responses. Comparable priming of Th1 and Th17 responses, with an increased ratio of Th1 to Th2 CD4(+) T-cell responses, was not observed in subjects who received two doses of the oral cholera vaccine Dukoral (a whole-cell cholera toxin B subunit containing [WC-CTB] vaccine). These findings suggest that natural V. cholerae infection induces an early, proinflammatory cellular immune response, despite the apparent lack of clinical signs of inflammation. The failure of the WC-CTB vaccine to activate equivalent, CD4(+) T-cell responses is a potential explanation for the shorter duration of protection following immunization with this vaccine. Additional studies are needed to determine whether these early T-cell-mediated events predict the subsequent duration of immunologic memory.

Abstract: Children bear a large component of the global burden of cholera. Despite this, little is known about immune responses to cholera in children, especially those under 5 years of age. Cholera vaccine studies have demonstrated lower long-term protective efficacy in young children than in older children and adults. Memory B cell (MBC) responses may correlate with duration of protection following infection and vaccination. Here we report a comparison of immune responses in young children (3 to 5 years of age; n 17), older children (6 to 17 years of age; n 17), and adults (18 to 60 years of age; n 68) hospitalized with cholera in Dhaka, Bangladesh. We found that young children had lower baseline vibriocidal antibody titers and higher fold increases in titer between day 2 and day 7 than adults. Young children had higher baseline IgG plasma antibody levels to Vibrio cholerae antigens, although the magnitudes of responses at days 7 and 30 were similar across age groups. As a surrogate marker for mucosal immune responses, we assessed day 7 antibody-secreting cell (ASC) responses. These were comparable across age groups, although there was a trend for older age groups to have higher levels of lipopolysaccharide-specific IgA ASC responses. All age groups developed comparable MBC responses to V. cholerae lipopolysaccharide and cholera toxin B subunit at day 30. These findings suggest that young children are able to mount robust vibriocidal, plasma antibody, ASC, and MBC responses against V. cholerae O1, suggesting that under an optimal vaccination strategy, young children could achieve protective efficacy comparable to that induced in adults. Cholera is an acute dehydrating diarrheal disease caused predominantly by the Vibrio cholerae O1 or O139 serogroup. Globally, the vast majority of cholera is caused by V. cholerae O1. Cholera is endemic in over 50 countries and affects 3 to 5 million people each year, causing more than 100,000 deaths (2, 41). In areas of the world in which cholera is endemic, children under 5 years of age have the highest burden of disease (12, 31), and during cholera epidemics, children and adults are both at risk of dehydrating illness (21, 24, 34). In a rural area of Bangladesh in which cholera is endemic, 80% of the population had detectable vibriocidal antibodies by the age of 15 years (26). Similarly, in a recent observational study in urban Bangladesh, household contacts of patients with V. cholerae O1 infection who were 5 years of age had a significantly higher risk of developing infection than older family members in a 21-day observational period following identification of the index household case (15).

Abstract: Background Human genetic factors such as blood group antigens may affect the severity of infectious diseases. Presence of specific ABO and Lewis blood group antigens has been shown previously to be associated with the risk of different enteric infections. The aim of this study was to determine the relationship of the Lewis blood group antigens with susceptibility to cholera, as well as severity of disease and immune responses to infection. Methodology We determined Lewis and ABO blood groups of a cohort of patients infected by Vibrio cholerae O1, their household contacts, and healthy controls, and analyzed the risk of symptomatic infection, severity of disease if infected and immune response following infection. Principal Findings We found that more individuals with cholera expressed the Le(a+b−) phenotype than the asymptomatic household contacts (OR 1.91, 95% CI 1.03–3.56) or healthy controls (OR 1.90, 95% CI 1.13–3.21), as has been seen previously for the risk of symptomatic ETEC infection. Le(a–b+) individuals were less susceptible to cholera and if infected, required less intravenous fluid replacement in hospital, suggesting that this blood group may be associated with protection against V. cholerae O1. Individuals with Le(a–b−) blood group phenotype who had symptomatic cholera had a longer duration of diarrhea and required higher volumes of intravenous fluid replacement. In addition, individuals with Le(a–b−) phenotype also had lessened plasma IgA responses to V. cholerae O1 lipopolysaccharide on day 7 after infection compared to individuals in the other two Lewis blood group phenotypes. Conclusion Individuals with Lewis blood type Le(a+b−) are more susceptible and Le(a–b+) are less susceptible to V. cholerae O1 associated symptomatic disease. Presence of this histo-blood group antigen may be included in evaluating the risk for cholera in a population, as well as in vaccine efficacy studies, as is currently being done for the ABO blood group antigens.

Abstract: Cholera is a substantial health burden in many countries in Africa and Asia, where it is endemic It is as well responsible for ongoing epidemics in sub-Saharan Africa which are becoming greater in terms of frequency, extension, and duration Given the availability of two oral cholera vaccines and the new data on their efficacy, field effectiveness, feasibility, and acceptance in cholera-affected populations and in travelers, these vaccines should be used in endemic areas, in travelers for these areas and should be considered in areas at risk for outbreaks The two vaccines currently available in worldwide are: (1) The killed oral vaccine (Dukoral, licensed by SBL-Sweden to Crucell-Holland) is recommended since 1999 by WHO and consists of a mixture of four preparations of heat or formalin killed whole cell Vibrio cholera O1 (Inaba and Ogaba serotypes, and classical and El Tor biotypes) that are then added with purified recombinant cholera toxin (CT) B subunit Because CT cross-reacts with Escherichia coli LT the vaccine also provides short-term protection against ETEC (enterotoxigenic E coli) which is of added benefit for travelers It is available in more than 60 countries (2) A bivalent O1 and O139 whole cell oral vaccine without CT B subunit (Shanchol) has been lately developed in Vietnam (licensed by VaBiotech-Viet Nam to Shantha Biotechnics-India It is available in India and Indonesia A structured search of papers in PubMed and reports on cholera vaccines by WHO and CDC, as well as critical reading and synthesis of the information was accomplished Inclusion criteria were defined according to reports quality and relevance

Abstract: Despite improvements in sanitation and water supply, cholera remains a serious public health burden. Vaccination is included among recommendations for cholera control. Cultural concepts of illness are likely to affect vaccine acceptance. This study examined social and cultural determinants of anticipated acceptance of an oral cholera vaccine (OCV) prior to a mass vaccination campaign in Zanzibar. Using a cultural epidemiological approach, 356 unaffected adult residents were studied with vignette-based semi-structured interviews. Anticipated acceptance was high for a free OCV (94%), but declined with increasing price. Logistic regression models examined social and cultural determinants of anticipated acceptance at low (USD 0.9), medium (USD 4.5) and high (USD 9) price. Models including somatic symptoms (low and high price), social impact (low and medium) and perceived causes (medium and high) explained anticipated OCV acceptance better than models containing only socio-demographic characteristics. Identifying thirst with cholera was positively associated with anticipated acceptance of the low-priced OCV, but acknowledging the value of home-based rehydration was negatively associated. Concern about spreading the infection to others was positively associated at low price among rural respondents. Confidence in the health system response to cholera outbreaks was negatively associated at medium price among peri-urban respondents. Identifying witchcraft as cause of cholera was negatively associated at medium and high price. Anticipated acceptance of free OCVs is nearly universal in cholera-endemic areas of Zanzibar; pre-intervention assessments of community demand for OCV should not only consider the social epidemiology, but also examine local socio-cultural features of cholera-like illness that explain vaccine acceptance.

Abstract: Cholera is an acute form of diarrhoeal disease that plagued human civilization over the centuries. The sudden and explosive onset of the disease in the form of an outbreak or epidemic, coupled with high mortality and morbidity rates, had a tragic impact on the personal as well as social life of people living in the affected areas. The enormity of human sufferings led clinicians and scientists to carry out extensive research on cholera and Vibrio cholerae (the causative bacterium of the disease) leading to major discoveries that opened up novel areas of research or new disciplines in biomedical sciences. An attempt is made here to summarize some of these breakthroughs and outline their significance in broader perspectives. Finally, the possible impact of the global socio-political scenario on the spread of cholera epidemics (pandemicity of cholera) is briefly discussed.

Abstract: Since the early 1800s, there have been 7 cholera pandemics, and 2011 marks not only the 1-year anniversary of the reappearance of cholera in Haiti but also the 50th anniversary of the onset of the current cholera pandemic that began in Indonesia in 1961. All previous pandemics lasted 5–25 years before burning out. However, the current pandemic has shown no evidence of abating. Cholera is a disease of impoverishment, displacement, and unrest, and the 2010–2011 Haiti and global cholera milestones are integrally related. In addition to Haiti, during the past 10 years, there have been major cholera epidemics in Zimbabwe, Kenya, Nigeria, Afghanistan, Iraq, Somalia, Angola, Guinea-Bissau, Sudan, South Africa, Malawi, Liberia, and Vietnam. Cholera is endemic to >50 countries, affects 3–5 million persons each year, and kills 100,000. Most of these cases never come to public or media attention, and many of them occur in areas where cholera is deeply entrenched and often affects children. In some areas of southern Asia, most residents will have serologic evidence of infection with Vibrio cholerae by their teenage years. Why has this pandemic persisted for so long? The answer is that we do not know, but several factors seem to be major contributors to its longevity. First, the organism is different from the version microbiologically associated with previous pandemics. Previous pandemics for which we have data were caused by the classical V. cholerae O1 biotype, but the current pandemic is caused by the El Tor biotype. V. cholerae persists in aquatic reservoirs, and for unclear reasons, the El Tor biotype seems to have a distinct transmission or environmental survival advantage and has replaced the V. cholerae classical biotype worldwide. This advantage may translate into increased likelihood that V. cholerae will become endemic and persist in a local environment after its introduction into new areas. The El Tor biotype is also associated with more prolonged clinical outbreaks, often featuring multiple waves, and has the ability to cause mild disease or short-term asymptomatic passage once established in a population. These features contribute to the silent introduction of cholera into new areas, as unfortunately occurred this past year in Haiti. During the current pandemic, the El Tor biotype has continued to evolve. In the early 1990s, this biotype mutated to a new serogroup, O139, and rapidly spread to several countries in Asia, joining O1 as a cause of epidemic cholera. Previous immunity to V. cholerae O1 provided no protection against O139. The number of cases caused by O139 then decreased, leaving the O1 El Tor biotype as the predominant cause of cholera, perhaps again underscoring some poorly understood survival or transmission advantage of this biotype. During the past 2 decades, the organism again evolved and became hybrid, keeping its El Tor biotype characteristics but incorporating classical biotype cholera toxin, a feature that may be contributing to high case-fatality rates associated with many recent cholera outbreaks. V. cholerae continues to evolve, and resistance to antimicrobial drugs is complicating treatment options in areas with limited resources. However, changes in the organism only partly explain the complexity of our current pandemic situation. Cholera is a disease of the most impoversished, but it is first and foremost a disease affected by the global economy and transportation, initially spreading from its ancestral home in southern Asia along trading and commerce routes of the nascent global economy of the early 1800s. Although cholera spreads through global interactions, it paradoxically predominantly affects those most estranged from the benefits of globalization. In the long term, economic investment and civil stability will lead to the demise of cholera, but with ≈1 billion persons currently lacking safe water, and 2.6 billion currently lacking adequate sanitation, our current war with cholera will go on for decades. Do we just grin and bear it, or is it time to change our response strategy? No one would argue that cholera response programs need to be based on case detection, appropriate fluid management, and provision of safe water and improved sanitation. However, is it time to integrate new tools? Previous response plans grew from previous experience: wild fire cholera epidemics that burned out quickly, ability of rehydration strategies to decrease case-fatality rates to <1%, and a problematic parenteral cholera vaccine. However, with the propensity of the El Tor biotype to cause prolonged and recurrent outbreaks, high likelihood of becoming endemic, ability to be carried asymptomatically, association with case-fatality rates of 2%–6% among patients who receive clinical care during complex emergencies, and availabilty of improved oral cholera vaccines, is it time to rethink our plans? Should vaccines be used more broadly? Strong evidence would support use of cholera vaccines in disease-endemic settings, and an evolving body of evidence, largely from increased interest in cholera after its appearance in Haiti, suggests that cholera vaccines might be beneficial in reactive situations, i.e., after an outbreak has started. However, such use would first require additional field and cost-effectiveness evaluations and intricate planning and commitment. Would an international stockpile of vaccine be beneficial? Who would support and manage it? What would be the triggers for its use? How would its benefit be measured? Similarly, should there be wider or more specific use of antimicrobial drugs in the initial stages of a cholera outbreak with the goal of blunting transmission? Would this buy time? Would such distribution be not only useless, but also detrimental, accelerating the development of antimicrobial drug resistance? And why is it so hard to get clean water and adequate sanitation to those who need it most? What are the obstacles? How can we improve our track record? Quite simply, we do not yet know the answers to many of these questions, but we should not only view the cholera epidemic in Haiti as a true catastrophe, which it is of immense proportions, but we should also view it as an opportunity. Will we use the hydra-headed reappearance of cholera in Haiti as an impetus to adapt and respond, learning from our successes and failures, or will we be ill-prepared when cholera appears in the next Zimbabwe, the next Afghanistan, the next Haiti? The next Haiti will be here sooner than we think.

Abstract: Background Young children are one of the most vulnerable groups who may be infected with cholera. The following literature review of the efficacy of the currently available cholera vaccines provides a clear evidence base for the clinical administration of cholera vaccine, particularly in an epidemic situation. Aim To assess the efficacy of oral cholera vaccines in preventing cases of cholera in young children. Methods A systematic literature review was undertaken for the period 1983 to 2011 using PubMed and the search terms "oral cholera vaccines," "children," and "efficacy," limited to "clinical trials" and "human studies". Results Oral cholera vaccine provides an acceptable level of protection in young children, with the level of protection being greater at 12 or 24 months following immunization. Conclusions Children exposed to a potential risk of cholera are recommended to be vaccinated with an oral cholera vaccine, irrespective of whether its constituents include the B subunit.

Abstract: The Gram negative bacterium, Vibrio cholerae (Vc) causes cholera, an enteric disease that has killed untold numbers of humans. In the 19 th century, whole-cell (W-C) cholera vaccines were tested in humans. Field trials (1960s- 70s) of injected, killed W-C (kW-C) Vc showed cholera-specific immune responses (antibodies, Abs) could be induced with a single dose in certain cohorts, but more durable immunity was sought with oral cholera vaccines. Newer, killed (two doses) and later modified live (one dose) W-C cholera vaccines for oral delivery were developed and extensively tested. After over 200 years, no consensus exists as to what are protective Vc antigens or how to identify them. An endur- ing cholera vaccine for children <5 years of age and Vc-antigen naive individuals is still needed. The cholera outbreak in Haiti underscores some unresolved issues associated with the current cholera vaccines. Annually, is there enough cholera vaccine for those who need it? Who needs to be vaccinated and when? Given the displacement of populations during flooding like in Pakistan or in Haiti due to an earthquake, can a single dose of the kW-C cholera vaccine function to pre- vent or to contain an outbreak? What does 'working' entail: solely preventing deaths, or that plus long term immunity? Can a single formulation of Vc antigens be used for endemic or epidemic cholera which may require reactive vaccination for epidemics, but prophylactic vaccination for endemic cholera? The immunologic realities given the logistic issues for the different needs of a cholera vaccine are discussed.

Abstract: The Asia Pacific Pediatric Association Vaccinology Update 2010 was held in Mumbai on November 13–14, 2010 to discuss the latest information on burden of infectious diseases, recent developments in vaccines and their impact on immunization practices against infectious diseases occurring in Indian children. During the conference the importance of including conjugate Haemophilus influenzae type b vaccine and anti-rabies vaccines in routine immunization was stressed. Also, the need for giving a second dose of measles mumps rubella vaccine at school entry; and the need for a two-dose varicella vaccine regimen (first dose at 12–15 months of age and a second dose at age 4–6 years) was elucidated. Information related to vaccines which have become available in India in recent years, namely, inactivated poliovirus vaccine; diphtheria, tetanus, acellular pertussis (DTaP) vaccine; conjugate pneumococcal vaccine; rotavirus vaccines; H1N1 vaccines; live attenuated hepatitis A virus vaccine; oral cholera vaccine; tetanus, reduced-dose diphtheria, acellular pertussis (Tdap) vaccine; and human papillomavirus vaccines were discussed.

Abstract: The disease cholera has persisted in Asia since time immemorial. Almost all the pandemic phases of cholera had its origin from the Indian subcontinent. Historically, waves of cholera have wiped many million lives in this region mainly due to the general insanitary conditions and poor management of the disease. All the three cholera causing vibrios namely classical, El Tor, and the O139 have emerged from Asia at different times and one was replaced by the other by overcoming the acquired immunity. Antimicrobial resistance was not a big problem in the early 1960s as its use was very limited. With the use of third-generation drugs, Vibrio cholerae has acquired many resistance mechanisms over the passage of time and also due to prevailing antibiotic pressure. With its biotypes/serotypes there are considerable variations at the genetic level and many clones of V. cholerae have been detected. Recently, the hybrid strain of El Tor has spread in many Asian countries causing several cholera outbreaks. However, the importance of such genetic changes was not fully strengthened in epidemiological perspective. The perspectives of cholera vaccines have shown to be encouraging in many recent vaccine trials in Asia. Traditional medicine has lost its glory as it lacks the scientific evidence in curing infectious diseases. Some of the herbal formulations are now reconsidered for extensive research. The control measures for preventing cholera are yet to gain momentum in many Asian countries, as it involves coordination of government and the public with adequate funds to revamp the water supply and waste disposal systems. On the other hand, the clinical management of cholera and other diarrheal diseases are largely under the control in Asia.

Abstract: The 50-year commemoration of S.N. De's seminal 1959 publication in Nature provides an opportunity to reflect on scientific discovery, recognition, and public health. De's paper marked the first major conceptual advance in cholera research since 1884, when Robert Koch definitively identified Der Kommabazillus as the aetiological agent of cholera. Unfortunately, Koch reported that systemic toxinosis and multi-organ failure led to severe dehydrating diarrhoea, thereby mistaking cause for effect. As a consequence, while work on other microbial pathogens advanced into the development of vaccines and therapeutics, cholera research languished as scientists injected animals parenterally in decades of futile effort to develop an animal model of diarrhoea. This fundamental misconception in cholera pathogenesis was swept away when S.N. De used ligated loops of rabbit ileum to demonstrate lumenal fluid accumulation in the presence of Vibrio cholerae culture filtrates. After some delay, De's observation of a diarrhoeagenic exotoxin became the founding principle of modern cholera research, vaccination, and treatment; and a burst of discovery saw V. cholerae transformed into the enteric pathogen best understood at the molecular level. The scientific basis for orally administering vaccines to induce mucosal immunity was established, and the success of oral rehydration, what has been described as one of the 20 th century's most important medical advances, was explained. Nobel laureate Joshua Lederberg wrote of De's iconoclastic creativity, experimental skill, and observational mastery, and many other leaders in the field concurred. De was nominated for the Nobel Prize in Physiology or Medicine more than once. But despite the passage of half a century from De's work, cholera remains a frustrating problem: we are clearly missing something. In reviewing the scientific and programmatic impact of S.N. De on cholera, it is clear that a defining victory against the disease is achievable, but only if basic scientific discoveries are relentlessly driven towards progress in public health.

Abstract: The rational design of attenuated Vibrio cholerae strains has been an attractive method for live cholera vaccine development because the major mechanisms of V cholerae virulence are well defined and convalescence from cholera, the disease it causes, is a strongly immunizing process After decades of effort to develop safe live attenuated cholera vaccines, however, the appearance of reactogenicity, defined as adverse symptoms in immunized volunteers, has precluded further development of most live vaccine candidates We now know that V cholerae flagellar motility is associated with human and animal reactogenicity in early live attenuated cholera vaccines, and recently developed nonflagellated V cholerae mutant strains have shown great promise as live attenuated vaccines in volunteer studies This chapter briefly summarizes our current understanding of V cholerae pathogenesis and describes efforts to use this knowledge to design immunogenical and nonreactogenic live cholera vaccines