Abstract: Vibrio cholerae is the causative agent of cholera and annually leads to death of thousands of people around the globe. Two factors in the pathogenesis of this bacterium are its pili and flagella. The main subunits of pili TcpA, TcpB, and FlaA are the constituent subunit of flagella. In this study, we studied the ability of pili and flagella subunits to stimulate immune responses in mice. After amplification of TcpA, TcpB, and FlaA genes using PCR, they were cloned in expression plasmids. After production of the above-mentioned proteins by using IPTG, the proteins were purified and then approved using immunoblot method. After injection of the purified proteins to a mice model, immune response stimulation was evaluated by measuring the levels of IgG1 and IgG2a antibody titers, IL5 and IFN-γ. Immune response stimulation against pili and flagella antigens was adequate. Given the high levels of IL5 titer and IgG1 antibody, the stimulated immune response was toward Th1. Humoral immune response stimulation is of key importance in prevention of cholera. Our immunological analysis shows the appropriate immune response in mice model after vaccination with recombinant proteins. The high level of IL5 and low level of IFN-γ show the activation of Th2 cell response.

Abstract: Background The communities in fishing villages in the Great Lakes Region of Africa and particularly in Uganda experience recurrent cholera outbreaks that lead to considerable mortality and morbidity. We evaluated cholera epidemiology and population characteristics in the fishing villages of Uganda to better target prevention and control interventions on cholera and contribute to its elimination from those communities. Methodology/Principal findings We conducted a prospective study between 2011–15 in fishing villages in Uganda. We collected, reviewed and documented epidemiological and socioeconomic data for 10 cholera outbreaks that occurred in fishing communities located along the African Great Lakes and River Nile in Uganda. These outbreaks caused 1,827 suspected cholera cases and 43 deaths, with a Case-Fatality Ratio (CFR) of 2.4%. Though the communities in the fishing villages make up only 5–10% of the Ugandan population, they bear the biggest burden of cholera contributing 58% and 55% of all reported cases and deaths in Uganda during the study period. The CFR was significantly higher among males than females (3.2% vs. 1.3%, p = 0.02). The outbreaks were seasonal with most cases occurring during the months of April-May. Male children under age of 5 years, and 5–9 years had increased risk. Cholera was endemic in some villages with well-defined “hotspots”. Practices predisposing communities to cholera outbreaks included: the use of contaminated lake water, poor sanitation and hygiene. Additional factors were: ignorance, illiteracy, and poverty. Conclusions/Significance Cholera outbreaks were a major cause of morbidity and mortality among the fishing communities in Uganda. In addition to improvements in water, sanitation, and hygiene, oral cholera vaccines could play an important role in the prevention and control of these outbreaks, particularly when targeted to high-risk areas and populations. Promotion and facilitation of access to social services including education and reduction in poverty should contribute to cholera prevention, control and elimination in these communities.

Abstract: With Yemen experiencing one of the largest cholera outbreaks in recent history, greater funding for the cholera vaccine stockpile and more work on the development of both improved predictive tools and improved water and sanitation are important priorities.

Abstract: The fifth annual meeting of the African cholera surveillance network (Africhol) took place on 10–11 June 2015 in Lome, Togo. Together with international partners, representatives from the 11 member countries -Cameroon, Cote d’Ivoire, Democratic Republic of Congo, Guinea, Kenya, Mozambique, Nigeria, Tanzania, Togo, Uganda, Zimbabwe- and an invited country (Malawi) shared their experience. The meeting featured three sessions: i) cholera surveillance, prevention and control in participating countries, ii) cholera surveillance methodology, such as cholera mapping, cost-effectiveness studies and the issue of overlapping epidemics from different diseases, iii) cholera laboratory diagnostics tools and capacity building. The meeting has greatly benefitted from the input of technical expertise from participating institutions and the observations emerging from the meeting should enable national teams to make recommendations to their respective governments on the most appropriate and effective measures to be taken for the prevention and control of cholera. Recommendations for future activities included collecting precise burden estimates in surveillance sites; modeling cholera burden for Africa; setting up cross-border collaborations; strengthening laboratory capacity for the confirmation of suspected cholera cases and for vaccine impact assessment in settings where oral cholera vaccine would be used; adapting cholera surveillance to concurrent issues (e.g., Ebola); and developing national cholera control plans including rationale vaccination strategies together with other preventive and control measures such as improvements in water, sanitation and hygiene (WASH).

Abstract: An outer membrane vesicle (OMV)-based cholera vaccine is highly efficacious in preventing intestinal colonization in the suckling mouse model. Immunity from OMVs comes from immunoglobulin (Ig), particularly IgG, in the milk of mucosally immunized dams. Anti-OMV IgG renders Vibrio cholerae organisms immotile, thus they pass through the small intestine without colonizing. However, the importance of motility inhibition for protection and the mechanism by which motility is inhibited remain unclear. By using both in vitro and in vivo experiments, we found that IgG inhibits motility by specifically binding to the O-antigen of V. cholerae We demonstrate that the bivalent structure of IgG, although not required for binding to the O-antigen, is required for motility inhibition. Finally, we show using competition assays in suckling mice that inhibition of motility appears to be responsible for most, if not all, of the protection engendered by OMV vaccination, thus providing insight into the mechanism of immune protection.

Abstract: Cholera, caused by infection with toxigenic Vibrio cholerae bacteria of serogroup O1 (>99% of global cases) or O139, is characterized by watery diarrhea that can be severe and rapidly fatal without prompt rehydration. Cholera is endemic in approximately 60 countries and causes epidemics as well. Globally, cholera results in an estimated 2.9 million cases of disease and 95,000 deaths annually (1). Cholera is rare in the United States, and most U.S. cases occur among travelers to countries where cholera is endemic or epidemic. Forty-two U.S. cases were reported in 2011 after a cholera epidemic began in Haiti (2); however, <25 cases per year have been reported in the United States since 2012.

Abstract: During November-December 2015, as part of the 2015 cholera outbreak response in Iraq, the Iraqi Ministry of Health targeted ≈255,000 displaced persons >1 year of age with 2 doses of oral cholera vaccine (OCV). All persons who received vaccines were living in selected refugee camps, internally displaced persons camps, and collective centers. We conducted a multistage cluster survey to obtain OCV coverage estimates in 10 governorates that were targeted during the campaign. In total, 1,226 household and 5,007 individual interviews were conducted. Overall, 2-dose OCV coverage in the targeted camps was 87% (95% CI 85%-89%). Two-dose OCV coverage in the 3 northern governorates (91%; 95% CI 87%-94%) was higher than that in the 7 southern and central governorates (80%; 95% CI 77%-82%). The experience in Iraq demonstrates that OCV campaigns can be successfully implemented as part of a comprehensive response to cholera outbreaks among high-risk populations in conflict settings.

Abstract: Introduction The World Health Organization (WHO) estimates that there are 1.3 to 4.0 million cholera cases annually and that 21 000 to 143 000 of them result in death. (1) Additionally, in choleraendemic countries, 1.3 billion people are at risk of cholera. (2) The high morbidity and consequent mortality caused by cholera is attributable to several factors, including lack of access to safe drinking water, poor sanitation and poor hygiene practices (WASH). (3) Recent estimates suggest that cholera is endemic in 69 countries, with sub-Saharan Africa accounting for the majority of cases between 2008 and 2012 (7.0 of 11.6 million; 60%), followed by South East Asia (3.4 of 11.6 million; 29%). (2) Improving water and sanitation is the preferred choice for cholera control in the long-term. Although progress has been made towards providing universal access to piped water and water treatment, (4) 663 million people worldwide still do not use improved drinking water sources that can reduce the spread of contaminants such as fecal matter. (4) Sanitation is likewise lacking for 2.4 billion people, 950 million of whom still practise open defecation. (5) Vaccination has been shown to be a cost-effective, more immediate option for cholera control and prevention. (6-8) Two oral cholera vaccines have been available for years, but have not been widely used due to either cost or licensing restrictions. With the availability of lower-cost options, cholera vaccine is increasingly being considered for use in endemic countries or during outbreaks. Table 1 provides an overview of oral cholera vaccines that are currently, or soon to be, available on the market. Current vaccines are two-dose inactivated vaccines. Several live oral cholera vaccines, including a single-dose vaccine that was recently approved by the United States Food and Drug Administration, (9) are currently under consideration for future vaccination policy. A single-dose regimen would have great potential for use in emergency or epidemic situations. In 2011 the first low-cost oral cholera vaccine obtained prequalification by WHO for international use. (10) Prequalification certifies the acceptability of a vaccine for purchase by the United Nations Children's Fund (UNICEF) and other United Nations (UN) agencies; the main vaccine procurers for low-income countries. (11) In 2013, Gavi, the Vaccine Alliance approved financing of a stockpile of an oral cholera vaccine for use in endemic and epidemic settings. Although the financing (115 million United States dollars) could support a stockpile of 20 million doses over the following 5 years, full capacity could not be achieved due to a short supply of vaccine. Thus, vaccine deployment was low, despite demand for the vaccine. (12) To help overcome anticipated supply constraints, the International Vaccine Institute facilitated the transfer of the vaccine technology to a second manufacturer, which led to WHO prequalification of a second affordable oral cholera vaccine for global use in December 2015 (Table 1). This has already begun contributing to the global stockpile of oral cholera vaccines (12) and is projected to increase the supply significantly in 2017. (13) The same manufacturing technology for the vaccine was transferred to a third manufacturer, who is expected to begin production of the first-ever oral cholera vaccine registered and licensed for use in Bangladesh--one of the countries most affected by cholera--in the near future. (14,15) As demonstrated by the creation of the stockpile, global interest in cholera control has increased, (16) which should help pave the way to global use, availability and distribution of the vaccine, particularly in low-income countries through the UNICEF and Gavi procurement mechanisms. It is still not known, however, what the demand would be for oral cholera vaccines. Based on experiences from other vaccines, even with increased production capacity, adoption of new vaccines into policy takes time, and actual demand may not meet projected demand. …

Abstract: Immunologic correlates of protection can be used to infer vaccine efficacy for populations in which challenge trials or field studies are infeasible In a recent cholera challenge trial (WH Cohen et al, Clinical Infectious Disease 62: 1329-1335, 2016), 134 North American cholera-naive volunteers were randomized to receive either the live, attenuated single-dose cholera vaccine CVD 103-HgR or placebo, and titers of vibriocidal antibodies against classical Inaba were assessed 10 days after treatment Subsequent to the immunologic evaluation, each subject ingested a fixed quantity of virulent V cholerae O1 El Tor Inaba Data from this trial suggest that vaccine-induced increase in vibriocidal antibody titer prior to challenge is tightly linked with protection: 51/51 vaccinees with post-vaccination vibriocidal titers >= 2560 were protected against moderate/severe cholera, and 60/62 vaccinees who seroconverted, or experienced a 4-fold or greater increase in vibriocidal titer relative to pre-vaccination levels, were similarly protected Atypically high vibriocidal titers were observed in some placebo subjects; protection was limited in these individuals and differed substantially from the level of protection experienced by vaccinees with the same post-vaccination titers Since only 1 of 66 placebo recipients experienced seroconversion, seroconversion was found to be uniquely associated with vaccination and insensitive to the effects of factors that can cause titers to be elevated but are weakly associated with protection Thus, vibriocidal seroconversion was found to be better than vibriocidal titer for inferring vaccine efficacy in cholera-naive populations for which studies based upon exposure to V cholerae are impractical

Abstract: Summary Shortages of vaccines for epidemic diseases, such as cholera, meningitis, and yellow fever, have become common over the past decade, hampering efforts to control outbreaks through mass reactive vaccination campaigns. Additionally, various epidemiological, political, and logistical challenges, which are poorly documented in the literature, often lead to delays in reactive campaigns, ultimately reducing the effect of vaccination. In June 2015, a cholera outbreak occurred in Juba, South Sudan, and because of the global shortage of oral cholera vaccine, authorities were unable to secure sufficient doses to vaccinate the entire at-risk population—approximately 1 million people. In this Personal View, we document the first public health use of a reduced, single-dose regimen of oral cholera vaccine, and show the details of the decision-making process and timeline. We also make recommendations to help improve reactive vaccination campaigns against cholera, and discuss the importance of new and flexible context-specific dose regimens and vaccination strategies.

Abstract: Cholera remains an important but neglected public health threat, affecting the health of the poorest populations and imposing substantial costs on public health systems. Cholera can be eliminated where access to clean water, sanitation, and satisfactory hygiene practices are sustained, but major improvements in infrastructure continue to be a distant goal. New developments and trends of cholera disease burden, the creation of affordable oral cholera vaccines (OCVs) for use in developing countries, as well as recent evidence of vaccination impact has created an increased demand for cholera vaccines. The global OCV stockpile was established in 2013 and with support from Gavi, has assisted in achieving rapid access to vaccine in emergencies. Recent WHO prequalification of a second affordable OCV supports the stockpile goals of increased availability and distribution to affected populations. It serves as an essential step toward an integrated cholera control and prevention strategy in emergency and endemic settings.

Abstract: Introduction In June 2015, a cholera outbreak was declared in Juba, South Sudan. In addition to standard outbreak control measures, oral cholera vaccine (OCV) was proposed. As sufficient doses to cover the at-risk population were unavailable, a campaign using half the standard dosing regimen (one-dose) targeted high-risk neighborhoods and groups including neighbors of suspected cases. Here we report the operational details of this first public health use of a single-dose regimen of OCV and illustrate the feasibility of conducting highly targeted vaccination campaigns in an urban area. Methodology/Principal findings Neighborhoods of the city were prioritized for vaccination based on cumulative attack rates, active transmission and local knowledge of known cholera risk factors. OCV was offered to all persons older than 12 months at 20 fixed sites and to select groups, including neighbors of cholera cases after the main campaign (‘case-triggered’ interventions), through mobile teams. Vaccination coverage was estimated by multi-stage surveys using spatial sampling techniques. 162,377 individuals received a single-dose of OCV in the targeted neighborhoods. In these neighborhoods vaccine coverage was 68.8% (95% Confidence Interval (CI), 64.0–73.7) and was highest among children ages 5–14 years (90.0%, 95% CI 85.7–94.3), with adult men being less likely to be vaccinated than adult women (Relative Risk 0.81, 95% CI: 0.68–0.96). In the case-triggered interventions, each lasting 1–2 days, coverage varied (range: 30–87%) with an average of 51.0% (95% CI 41.7–60.3). Conclusions/Significance Vaccine supply constraints and the complex realities where cholera outbreaks occur may warrant the use of flexible alternative vaccination strategies, including highly-targeted vaccination campaigns and single-dose regimens. We showed that such campaigns are feasible. Additional work is needed to understand how and when to use different strategies to best protect populations against epidemic cholera.

Abstract: Background Information on the impact of hygiene interventions on severe outcomes is limited. As a pre-specified secondary outcome of a cluster-randomized controlled trial among >400 000 low-income residents in Dhaka, Bangladesh, we examined the impact of cholera vaccination plus a behaviour change intervention on diarrhoea-associated hospitalization. Methods Ninety neighbourhood clusters were randomly allocated into three areas: cholera-vaccine-only; vaccine-plus-behaviour-change (promotion of hand-washing with soap plus drinking water chlorination); and control. Study follow-up continued for 2 years after intervention began. We calculated cluster-adjusted diarrhoea-associated hospitalization rates using data we collected from nearby hospitals, and 6-monthly census data of all trial households. Results A total of 429 995 people contributed 500 700 person-years of data (average follow-up 1.13 years). Vaccine coverage was 58% at the start of analysis but continued to drop due to population migration. In the vaccine-plus-behaviour-change area, water plus soap was present at 45% of hand-washing stations; 4% of households had detectable chlorine in stored drinking water. Hospitalization rates were similar across the study areas [events/1000 person-years, 95% confidence interval (CI), cholera-vaccine-only: 9.4 (95% CI: 8.3-10.6); vaccine-plus-behaviour-change: 9.6 (95% CI: 8.3-11.1); control: 9.7 (95% CI: 8.3-11.6)]. Cholera cases accounted for 7% of total number of diarrhoea-associated hospitalizations. Conclusions Neither cholera vaccination alone nor cholera vaccination combined with behaviour-change intervention efforts measurably reduced diarrhoea-associated hospitalization in this highly mobile population, during a time when cholera accounted for a small fraction of diarrhoea episodes. Affordable community-level interventions that prevent infection from multiple pathogens by reliably separating faeces from the environment, food and water, with minimal behavioural demands on impoverished communities, remain an important area for research.

Abstract: Summary Background Pregnancy increases the risk of harmful effects from cholera for both mothers and their fetuses. A killed oral cholera vaccine, Shanchol (Shantha Biotechnics, Hydrabad, India), can protect against the disease for up to 5 years. However, cholera vaccination campaigns have often excluded pregnant women because of insufficient safety data for use during pregnancy. We did an observational cohort study to assess the safety of Shanchol during pregnancy. Methods This observational cohort study was done in two adjacent districts (Nsanje and Chikwawa) in Malawi. Individuals older than 1 year in Nsanje were offered oral cholera vaccine during a mass vaccination campaign between March 30 and April 30, 2015, but no vaccines were administered in Chikwawa. We enrolled women who were exposed to oral cholera vaccine during pregnancy in Nsanje district, and women who were pregnant in Chikwawa district (and thus not exposed to oral cholera vaccine) during the same period. The primary endpoint of our analysis was pregnancy loss (spontaneous miscarriage or stillbirth), and the secondary endpoints were neonatal deaths and malformations. We evaluated these endpoints using log-binomial regression, adjusting for the imbalanced baseline characteristics between the groups. This study is registered with ClinicalTrials.gov, number NCT02499172. Findings We recruited 900 women exposed to oral cholera vaccine and 899 women not exposed to the vaccine between June 16 and Oct 10, 2015, and analysed 835 in each group. 361 women exposed to the vaccine and 327 not exposed to the vaccine were recruited after their pregnancies had ended. The incidence of pregnancy loss was 27·54 (95% CI 18·41–41·23) per 1000 pregnancies among those exposed to the vaccine and 21·56 (13·65–34·04) per 1000 among those not exposed. The adjusted relative risk for pregnancy loss among those exposed to oral cholera vaccine was 1·24 (95% CI 0·64–2·43; p=0·52) compared with those not exposed to the vaccine. The neonatal mortality rate was 11·78 (95% CI 5·92–23·46) per 1000 livebirths for infants whose mothers were exposed to oral cholera vaccine versus 8·91 (4·02–19·77) per 1000 livebirths for infants whose mothers were not exposed to the vaccine (crude relative risk 1·32, 95% CI 0·46–3·84; p=0·60). Only three newborn babies had malformations, two in the vaccine exposure group and one in the no-exposure group, yielding a relative risk of 2·00 (95% CI 0·18–22·04; p=0·57), although this estimate is unreliable because of the small number of outcomes. Interpretation Our study provides evidence that fetal exposure to oral cholera vaccine confers no significantly increased risk of pregnancy loss, neonatal mortality, or malformation. These data, along with findings from two retrospective studies, support use of oral cholera vaccine in pregnant women in cholera-affected regions. Funding Bill & Melinda Gates Foundation.

Abstract: Hurricane Matthew exacerbated the cholera epidemic that began in Haiti in 2010. Now an expert panel offers recommendations for combating cholera transmission, including mass administration of oral cholera vaccine along with water, sanitation, and hygiene interventions.

Abstract: Oral cholera vaccination was used as part of cholera control in Haiti, but the vaccine does not provide complete protection. We conducted secondary data analyses of a vaccine effectiveness study in Haiti to evaluate risk factors for cholera among cholera vaccine recipients. Individuals vaccinated against cholera that presented with acute watery diarrhea and had a stool sample positive for Vibrio cholerae O1 were included as cases. Up to four vaccinated individuals who did not present for treatment of diarrhea were included as controls for each case, and matched by location of residence, enrollment time, and age. We evaluated sociodemographic characteristics and risk factors for cholera. Univariable and multivariable logistic regression were performed to identify risk factors for cholera among vaccinees. Thirty-three vaccine recipients with culture-confirmed cholera were included as cases. One-hundred-and-seventeen of their matched controls reported receiving vaccine and were included as controls. In a multivariable analysis, self-reporting use of branded household water disinfection products as a means of treating water (adjusted relative risk [aRR] = 44.3, 95% confidence interval [CI] = 4.19-468.05, P = 0.002), and reporting having a latrine as the main household toilet (aRR = 4.22, 95% CI = 1.23-14.43, P = 0.02), were independent risk factors for cholera. Self-reporting always treating water (aRR = 0.09, 95% CI = 0.01-0.57, P = 0.01) was associated with protection against cholera. The field effectiveness of water, sanitation, and hygiene interventions used in combination with cholera vaccination in cholera control should be measured and monitored over time to identify and remediate shortcomings, and ensure successful impact on disease control.

Abstract: Introduction: Cholera’s impact is greatest in resource-limited countries. In the last decade several large epidemics have led to a global push to improve and implement the tools for cholera prevention and control.Areas covered: PubMed, Google Scholar and the WHO website were searched to review the literature and summarize the current status of cholera vaccines to make recommendations on improving immunization approaches to cholera. Oral cholera vaccines (OCVs) have demonstrated their effectiveness in endemic, outbreak response and emergency settings, highlighting their potential for wider adoption. While two doses of the currently available OCVs are recommended by manufacturers, a single dose would be easier to implement. Encouragingly, recent studies have shown that cold chain requirements may no longer be essential. The establishment of the global OCV stockpile in 2013 has been a major advance in cholera preparedness. New killed and live-attenuated vaccines are being actively explored as candida...

Abstract: The devastating 2010 cholera epidemic in Haiti prompted the government to introduce oral cholera vaccine (OCV) in two high-risk areas of Haiti. We evaluated the direct costs associated with the government's first vaccine campaign implemented in August-September 2013. We analyzed data for major cost categories and assessed the efficiency of available campaign resources to vaccinate the target population. For a target population of 107,906 persons, campaign costs totaled $624,000 and 215,295 OCV doses were dispensed. The total vaccine and operational cost was $2.90 per dose; vaccine alone cost $1.85 per dose, vaccine delivery and administration $0.70 per dose, and vaccine storage and transport $0.35 per dose. Resources were greater than needed-our analyses suggested that approximately 2.5-6 times as many persons could have been vaccinated during this campaign without increasing the resources allocated for vaccine delivery and administration. These results can inform future OCV campaigns in Haiti.

Abstract: Cholera is a diarrheal disease that produces rapid dehydration. The infection is a significant cause of mortality and morbidity. Oral cholera vaccine (OCV) has been propagated for the prevention of cholera. Evidence on OCV delivery cost is insufficient in the African context. This study aims to analyze Shanchol vaccine delivery costs, focusing on the vaccination campaign in response of a cholera outbreak in Lake Chilwa, Malawi. The vaccination campaign was implemented in two rounds in February and March 2016. Structured questionnaires were used to collect costs incurred for each vaccination related activity, including vaccine procurement and shipment, training, microplanning, sensitization, social mobilization and vaccination rounds. Costs collected, including financial and economic costs were analyzed using Choltool, a standardized cholera cost calculator. In total, 67,240 persons received two complete doses of the vaccine. Vaccine coverage was higher in the first round than in the second. The two-dose coverage measured with the immunization card was estimated at 58%. The total financial cost incurred in implementing the campaign was US$480275 while the economic cost was US$588637. The total financial and economic costs per fully vaccinated person were US$7.14 and US$8.75, respectively, with delivery costs amounting to US$1.94 and US$3.55, respectively. Vaccine procurement and shipment accounted respectively for 73% and 59% of total financial and economic costs of the total vaccination campaign costs while the incurred personnel cost accounted for 13% and 29% of total financial and economic costs. Cost for delivering a single dose of Shanchol was estimated at US$0.97. This study provides new evidence on economic and financial costs of a reactive campaign implemented by international partners in collaboration with MoH. It shows that involvement of international partners’ personnel may represent a substantial share of campaign’s costs, affecting unit and vaccine delivery costs.

Abstract: Background Mozambique suffers recurrent annual cholera outbreaks especially during the rainy season between October to March. The African Cholera Surveillance Network (Africhol) was implemented in Mozambique in 2011 to generate accurate detailed surveillance data to support appropriate interventions for cholera control and prevention in the country. Methodology/Principal findings Africhol was implemented in enhanced surveillance zones located in the provinces of Sofala (Beira), Zambezia (District Mocuba), and Cabo Delgado (Pemba City). Data were also analyzed from the three outbreak areas that experienced the greatest number of cases during the time period under observation (in the districts of Cuamba, Montepuez, and Nampula). Rectal swabs were collected from suspected cases for identification of Vibrio cholerae, as well as clinical, behavioral, and socio-demographic variables. We analyzed factors associated with confirmed, hospitalized, and fatal cholera using multivariate logistic regression models. A total of 1,863 suspected cases and 23 deaths (case fatality ratio (CFR), 1.2%) were reported from October 2011 to December 2015. Among these suspected cases, 52.2% were tested of which 23.5% were positive for Vibrio cholerae O1 Ogawa. Risk factors independently associated with the occurrence of confirmed cholera were living in Nampula city district, the year 2014, human immunodeficiency virus infection, and the primary water source for drinking. Conclusions/Significance Cholera was endemic in Mozambique during the study period with a high CFR and identifiable risk factors. The study reinforces the importance of continued cholera surveillance, including a strong laboratory component. The results enhanced our understanding of the need to target priority areas and at-risk populations for interventions including oral cholera vaccine (OCV) use, and assess the impact of prevention and control strategies. Our data were instrumental in informing integrated prevention and control efforts during major cholera outbreaks in recent years.

Abstract: The use of cholera vaccines has been increasingly recognized as an effective control measure in cholera endemic countries. Also, the disease transmissions are getting more complicated and thus comprehensive strategies to implement public health control measures are worthwhile to be investigated. In this paper, we aim to better understand the effects of HI states of vibrios from the environment and from human contacts that cause cholera outbreaks. We also present and analyze our cholera mathematical model with vaccine incorporated. Equilibrium analysis is conducted in the case with constant control for both epidemic and endemic dynamics. Optimal control theory is applied to seek cost-effective solutions of time-dependent vaccination strategies against cholera outbreaks. Our results show that using vaccination during cholera outbreaks at the very beginning of the onset can reduce the number of infections significantly.

Abstract: Cholera is a serious dehydrating diarrhoeal disease caused by toxigenic serogroups (O1 and O139) of Vibrio cholerae, which is spread by faecal contamination of water and food. It is a disease of poverty and is closely linked to poor sanitation and lack of clean water. Cholera aff ects up to 2·8 million people and kills approximately 91 000 each year. Children aged younger than 5 years have the greatest incidence of disease in endemic areas. Among pregnant women, cholera can cause serious complications—namely, fetal loss, with rates varying from 2% to 36%. Three vaccines have been prequalifi ed by WHO: Dukoral (Crucell Sweden AB, Stockholm, Sweden), a monovalent oral killed vaccine based on whole cells of V cholerae O1 and recombinant cholera toxin B subunit, and Shanchol (Shanta Biotechnics Ltd, Telangana, India) and Euvichol (Eubiologics, Chuncheonsi, South Korea), both bivalent oral killed vaccines based on serogroups O1 and O139. The ranges of protective effi cacy for Dukoral and Shanchol are 66–86% at 4–6 months after vaccination, 45–62% at 1 year, and 58–77% at 2 years. For Euvichol, effi cacy was 65% after 5 years for those older than 5 years. Findings from studies done before licensure and after marketing of these vaccines have shown favourable safety profi les. Additionally, a small number of safety evaluations have been done in pregnant women during cholera outbreaks; their fi ndings suggested that these vaccines are safe during pregnancy. However, pregnant women have not generally been included in studies intended to assess the safety of these cholera vaccines. Now, in an observational cohort study reported in The Lancet Infectious Diseases, Mohammad Ali and colleagues provide evidence for the safety of Shanchol in this population, which was used in a 2015 cholera outbreak in Malawi. The investigators assessed the risk of pregnancy loss in 835 women who received the vaccine and 835 women not exposed to the vaccine. They found that the vaccine was not associated with an increased risk of stillbirth or neonatal mortality. Although they noted no increased risk of spontaneous abortion in vaccinated women, few of the enrolled women received the vaccine during the fi rst trimester. Moreover, the rate of spontaneous abortion was well below the national background rates (15%) of spontaneous abortion in both study groups. The study’s fi ndings also showed no increased risk of birth defects in pregnant women exposed to the vaccine. However, the small number of exposures in the fi rst trimester limits the clinical importance of this fi nding. Additionally, this study was not powered to assess for the risk of birth defects, which are rare. Only two other studies, both retrospective cohort studies, have assessed the safety of cholera vaccines in pregnancy. Hashim and colleagues assessed the safety of Dukoral among 196 pregnant women in Zanzibar and compared pregnancy and infant outcomes with those of 955 unvaccinated pregnant women. They noted no statistically signifi cant diff erences in spontaneous abortions, infant deaths, or infant abnormalities among both groups. In a second study, Grout and colleagues assessed the safety of Shanchol in 1543 pregnant women in Guinea. Among 1312 fetuses exposed to the vaccine and 272 fetuses unexposed to the vaccine from these pregnancies, no statistically signifi cant diff erences were reported in the rate of pregnancy loss, infant deaths, or malformations. In both studies, the rates of spontaneous abortion in vaccinated and unvaccinated groups were well below the expected background rate of spontaneous abortion in the populations studied. In an ideal study, pregnant women would be randomly assigned to receive the cholera vaccine or a placebo. However, pregnant women are considered special populations in clinical research, with specifi c regulations to protect the pregnant woman and her fetus. For this reason, there are ethical considerations for administering the vaccine in a clinical trial. However, because pregnant women are at an increased risk of morbidity and mortality from disease, there are also ethical considerations in withholding a potentially life-saving vaccine during a cholera epidemic. Although the study by Ali and colleagues adds important safety information about Shanchol in pregnant women, gaps in knowledge about the safety of this vaccine in pregnancy—specifi cally, if administered during the fi rst trimester—persist. Future studies will need to further clarify the safety of cholera vaccines through inclusion of more pregnant women exposed during the fi rst trimester and active capture of data about early losses, which might be missed or not reported. Lancet Infect Dis 2017

Abstract: Reactive immunization with a single-dose cholera vaccine that could rapidly (within days) protect immunologically naive individuals during virgin soil epidemics, when cholera reaches immunologically naive populations that have not experienced cholera for decades, would facilitate cholera control. One dose of attenuated Vibrio cholerae O1 classical Inaba vaccine CVD 103-HgR (Vaxchora) containing ≥2 × 108 CFU induces vibriocidal antibody seroconversion (a correlate of protection) in >90% of U.S. adults. A previous CVD 103-HgR commercial formulation required ≥2 × 109 CFU to elicit high levels of seroconversion in populations in developing countries. We compared the vibriocidal responses of Malians (individuals 18 to 45 years old) randomized to ingest a single ≥2 × 108-CFU standard dose (n = 50) or a ≥2 × 109-CFU high dose (n = 50) of PaxVax CVD 103-HgR with buffer or two doses (n = 50) of Shanchol inactivated cholera vaccine (the immunologic comparator). To maintain blinding, participants were dosed twice 2 weeks apart; CVD 103-HgR recipients ingested placebo 2 weeks before or after ingesting vaccine. Seroconversion (a ≥4-fold vibriocidal titer rise) between the baseline and 14 days after CVD 103-HgR ingestion and following the first and second doses of Shanchol were the main outcomes measured. By day 14 postvaccination, the rates of seroconversion after ingestion of a single standard dose and a high dose of CVD 103-HgR were 71.7% (33/46 participants) and 83.3% (40/48 participants), respectively. The rate of seroconversion following the first dose of Shanchol, 56.0% (28/50 participants), was significantly lower than that following the high dose of CVD 103-HgR (P = 0.003). The vibriocidal geometric mean titer (GMT) of the high dose of CVD 103-HgR exceeded the GMT of the standard dose at day 14 (214 versus 95, P = 0.045) and was ∼2-fold higher than the GMT on day 7 and day 14 following the first Shanchol dose (P > 0.05). High-dose CVD 103-HgR is recommended for accelerated evaluation in developing countries to assess its efficacy and practicality in field situations. (This study has been registered at ClinicalTrials.gov under registration no. NCT02145377.).

Abstract: Cholera is an acute diarrheal disease caused by toxigenic serogroups (O1 and O139) of Vibrio cholerae that is spread by ingestion of contaminated food or water. The exact global burden of cholera is unknown due to under-reporting, but it has been estimated that 2.8 million cases and 91,000 deaths occur annually due to cholera in 51 endemic countries. Cholera can cause serious complications including fetal loss at an estimated rate of 2% to 36%. However, oral cholera vaccines (OCVs) are not recommended during pregnancy. A few OCVs have been prequalified by the World Health Organization (WHO): (i) Dukoral (Crucell Sweden AB, Stockholm, Sweden); (ii) Shanchol (Sanofi); and (iii) Euvichol (Eubiologics, Chuncheonsi, South Korea). Dukoral is a monovalent oral killed vaccine based on whole V. cholerae O1 and the recombinant cholera toxin B subunit, whereas the other 2 are bivalent oral killed vaccines based on serogroup O1 and O139. The ranges of protective efficacy for Dukoral and Shanchol according to different age groups are 66–86% at 4–6 months after vaccination, 45–62% at one year, and 58–77% at 2 y. The efficacy for Shanchol was 65% after 5 y of vaccination for individuals over 5 y of age. Pregnant women are vulnerable to complications in cholera, and maternal infection with cholera may adversely affect pregnancy outcomes, an observation dating back to the 19 century and now strengthened with more evidence. Maternal vaccination may boost maternal levels of pathogen-specific antibodies and provide protection to the mother as well as to newborn infant by passive transfer of antibodies. Therefore, evaluation of the safety of OCVs is needed to potentially allow pregnant women to be vaccinated to prevent the complications of cholera in pregnancy.

Abstract: The killed bivalent (O1 and O139) whole cell oral cholera vaccine (OCV) (Shanchol™) was first licensed in India in 2009 and World Health Organization pre-qualified in 2011. We assessed the safety and immunogenicity of this OCV in the Philippines. This was a phase IV, single-arm, descriptive, open-label study. We recruited 336 participants from 2 centers: 112 participants in each age group (1-4, 5-14 and ≥ 15 years). Participants received 2 OCV doses 14 d apart. Safety was monitored throughout the trial. Blood samples were collected at baseline (pre-vaccination) and 14 d after each dose. Serum vibriocidal antibody titers to V. cholerae O1 (El Tor Inaba and El Tor Ogawa) and O139 strains were assessed, with seroconversion defined as ≥ 4-fold increase from baseline in titers. No immediate unsolicited systemic adverse events/reactions were observed. Unsolicited systemic adverse events were mostly grade 1 intensity. One serious adverse event occurred after the first dose, but was unrelated to vaccination. High seroconversion rates (range 69-92%) were achieved against the O1 serotypes with a trend toward higher rates in the 1-4 y (86-92%) and 5-14 y (86-88%) age groups than the ≥ 15 y age group (69-83%). Lower seroconversion rates were achieved against the O139 serotype (35-70%), particularly in those aged ≥ 15 y (35-42%). The 2-dose regimen of the killed bivalent whole cell OCV was well-tolerated in this study conducted in the Philippines, a cholera-endemic country. Robust immune responses were observed even after a single-dose.