Exploring Survey-Based Water, Sanitation, and Animal Associations With Enteric Pathogen Carriage: Comparing Results in a Cohort of Cases With Moderate-to-Severe Diarrhea to Those in Controls in the Vaccine Impact on Diarrhea in Africa (VIDA) Study, 2015-2018.

BACKGROUND: The magnitude of pediatric enteric pathogen exposures in low-income settings necessitates substantive water and sanitation interventions, including animal feces management. We assessed associations between pediatric enteric pathogen detection and survey-based water, sanitation, and animal characteristics within the Vaccine Impact on Diarrhea in Africa case-control study. METHODS: In The Gambia, Kenya, and Mali, we assessed enteric pathogens in stool of children aged <5 years with moderate-to-severe diarrhea and their matched controls (diarrhea-free in prior 7 days) via the TaqMan Array Card and surveyed caregivers about household drinking water and sanitation conditions and animals living in the compound. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using modified Poisson regression models, stratified for cases and controls and adjusted for age, sex, site, and demographics. RESULTS: Bacterial (cases, 93%; controls, 72%), viral (63%, 56%), and protozoal (50%, 38%) pathogens were commonly detected (cycle threshold <35) in the 4840 cases and 6213 controls. In cases, unimproved sanitation (RR, 1.56; 95% CI, 1.12-2.17), as well as cows (RR, 1.61; 95% CI, 1.16-2.24) and sheep (RR, 1.48; 95% CI, 1.11-1.96) living in the compound, were associated with Shiga toxin-producing Escherichia coli. In controls, fowl (RR, 1.30; 95% CI, 1.15-1.47) were associated with Campylobacter spp. In controls, surface water sources were associated with Cryptosporidium spp., Shigella spp., heat-stable toxin-producing enterotoxigenic E. coli, and Giardia spp. CONCLUSIONS: Findings underscore the importance of enteric pathogen exposure risks from animals alongside more broadly recognized water and sanitation risk factors in children.

Cholera Vaccine: Recommendations of the Advisory Committee on Immunization Practices, 2022.

THIS REPORT SUMMARIZES ALL RECOMMENDATIONS FROM CDC'S ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES (ACIP) FOR THE USE OF LYOPHILIZED CVD 103-HGR VACCINE (CVD 103-HGR) (VAXCHORA, EMERGENT BIOSOLUTIONS, GAITHERSBURG, MD) IN THE UNITED STATES. THE LIVE ATTENUATED ORAL CHOLERA VACCINE IS DERIVED FROM: Vibrio cholerae O1 and is administered in a single dose. Cholera is a toxin-mediated bacterial gastrointestinal illness caused by toxigenic V. cholerae serogroup O1 or, uncommonly, O139. Up to 10% of infections manifest as severe cholera (i.e., cholera gravis), profuse watery diarrhea that can cause severe dehydration and death within hours. Fluid replacement therapy can reduce the fatality rate to <1%. Risk factors for cholera gravis include high dose exposure, blood group O, increased gastric pH (e.g., from antacid therapy), and partial gastrectomy. Cholera is rare in the United States, but cases occur among travelers to countries where cholera is endemic or epidemic and associated with unsafe water and inadequate sanitation. Travelers might be at increased risk for poor outcomes from cholera if they cannot readily access medical services or if they have a medical condition that would be worsened by dehydration, such as cardiovascular or kidney disease. This report describes previously published ACIP recommendations about use of CVD 103-HgR for adults aged 18-64 years and introduces a new recommendation for use in children and adolescents aged 2-17 years. ACIP recommends CVD 103-HgR, the only cholera vaccine licensed for use in the United States, for prevention of cholera among travelers aged 2-64 years to an area with active cholera transmission. Health care providers can use these guidelines to develop the pretravel consultation for persons traveling to areas with active cholera transmission.

Immunogenicity and waning immunity from the oral cholera vaccine (Shanchol™) in adults residing in Lukanga Swamps of Zambia.

INTRODUCTION: In cholera endemic areas, the periodicity of cholera outbreaks remains unpredictable, making it difficult to organize preventive efforts. Lack of data on duration of protection conferred by oral cholera vaccines further makes it difficult to determine when to deploy preemptive vaccination. We report on the immunogenicity and waning of immunity to Shanchol™ in Lukanga Swamps. METHODS: We enrolled a cohort of 223 participants aged between 18 and 65 years old from whom serum samples were collected at baseline, day 28 before administration of the second dose, and consecutively at 6, 12, 24, 30, 36, and 48 months. Vibriocidal antibody titres were measured and expressed as geometric mean titres. Box plots and 95% CI were computed at each visit for both Inaba and Ogawa. Seroconversion was defined as a four fold or greater increase in antibody titres compared to baseline titres. RESULTS: Overall, seroconversion against V. cholerae Inaba and Ogawa after 1st dose was 35/134 (26%) and 34/134 (25%) respectively. We observed a statistical difference in seroconversion between the two subgroups of baseline titres (low <80 and high ≥80) for both Inaba (p = 0.02) and Ogawa (p<0.0001). From a baseline of 13.58, anti-Ogawa GMT increased to 21.95 after the first dose, but rapidly waned to 14.52, 13.13, and 12.78 at months 6, 12 and 24 respectively, and then increased to 13.21, 18.67 and 23.65 at months 30, 36 and 48 respectively. A similar trend was observed for anti-Inaba GMT across the same time points. CONCLUSION: We found that Shanchol™ was immunogenic in our study population and that vibriocidal antibodies may not be a good marker for long-term immunity. The observed rise in titres after 36 months suggests natural exposure, and this may be a critical time window opening for natural transmission in an endemic areas. We recommend re-vaccination at this time point in high risk areas.

Cholera risk in cities in Uganda: understanding cases and contacts centered strategy (3CS) for rapid cholera outbreak control.

INTRODUCTION: in the recent past, cities in sub-Saharan Africa have reported serious cholera outbreaks that last for several months. Uganda is one of the African countries where cities are prone to cholera outbreaks. Studies on cholera in Bangladesh show increased risk of cholera for the immediate household members (contacts) yet the control interventions mainly target cases with little or no focus on contacts. This study aimed to describe the rapid control of cholera outbreaks in Kampala and Mbale cities, Uganda, using, "Cases and Contacts Centered Strategy (3CS)" that consisted of identification and treatment of cases, promotion of safe water, sanitation, hygiene (WaSH) and selective chemoprophylaxis for the contacts. METHODS: a cross-sectional study was conducted in 2015-2016 in the Kampala and Mbale cities during cholera outbreaks. Cholera cases were treated and 816 contacts from 188 households were listed and given cholera preventive packages. Data were collected, cleaned, analysed and stored in spreadsheet. Comparison of categories was done using Chi-Square test. RESULTS: a total of 58 and 41 confirmed cholera cases out of 318 and 153 suspected cases were recorded in Kampala and Mbale cities respectively. The outbreaks lasted for 41 days in both cities. Case fatality rates were high; 12.1% (5/41) for Mbale city and 1.7% (1/58) for Kampala city. Fifty-five percent (210/379) of stool samples were tested by culture to confirm V. choleraeO1. No contacts listed and given cholera preventive package developed cholera. Both sexes and all age groups were affected. In Kampala city, the males were more affected than the females in the age groups less than 14 years, p-value of 0.0097. CONCLUSION: this study showed that by implementing 3CS, it was possible to rapidly control cholera outbreaks in Kampala and Mbale cities and no cholera cases were reported amongst the listed household contacts. The findings on 3CS and specifically, selective antibiotic chemoprophylaxis for cholera prevention, could be used in similar manner to oral cholera vaccines to complement the core cholera control interventions (disease surveillance, treatment of cases and WaSH). However, studies are needed to guide such rollout and to understand the age-sex differences in Kampala city.

Factors associated with diarrheal disease among children aged 1-5 years in a cholera epidemic in rural Haiti.

Diarrheal illness is a major cause of morbidity and mortality among children in Haiti, and the impact of diarrheal illness was compounded by a cholera outbreak between 2010 and 2019. Our understanding of risk factors for diarrhea among children during this outbreak is limited. We conducted a secondary analysis of data collected as part of a cholera vaccine effectiveness study to identify factors associated with medically attended diarrhea among children in central Haiti from October of 2012 through November of 2016. We identified 47 children aged one to five years old who presented to medical clinics with acute, watery diarrhea, and 166 matched controls who did not have diarrhea, and we performed conditional logistic regression to identify factors associated with diarrhea. Discontinuing exclusive breastfeeding within one month of birth was associated with increased risk of diarrhea (RR 6.9, 95% CI 1.46-32.64), and diarrhea was inversely associated with reported history of supplementation with vitamin A (RR 0.05, 95% CI 0.004-0.56) and zinc (reported among 0% of cases vs. 17% of controls). Because of the concordance in supplementation patterns, it was not possible to attribute the association to vitamin A or zinc independently. While having a respondent who correctly identified ≥3 means of avoiding cholera was associated with reduced risk of diarrhea (RR 0.43, 95% CI 0.19-1.01), reported household sanitation practices and knowledge of cholera were not consistently associated with risk of diarrhea. These findings support ongoing efforts to reduce barriers to breastfeeding and promote pediatric supplementation with vitamin A and zinc in Haiti. Given the reduced efficacy of current oral cholera vaccines (OCV) among children, the results reinforce the importance of breastfeeding and micronutrient supplementation in preventing all-cause pediatric diarrheal illness generally and during cholera outbreaks.

Challenges for Programmatic Implementation of Oral Cholera Vaccine in India.

Cholera remains a major contributor of diarrheal diseases and leads to substantial morbidity and mortality, particularly in low socioeconomic settings. Nonavailability of a national cholera control plan in India, compounded by underreporting of cholera cases and deficient accurate cholera hotspot estimates, has made cholera control a challenge. Obstacles in the programmatic introduction of oral cholera vaccine (OCV) lie within the infrastructure-stockpile, costing, distribution system, cold-chain mechanism, vaccine logistics, and lack of strengthened surveillance systems for adverse events following immunization. Sustained political commitment along with collaboration of people working in the media will also determine the policy outcome of OCV introduction in India.

Life-Course Approach to Vaccination in Bangladesh for Meeting the Health and Health-Related Sustainable Development Goals: A Commentary.

Bangladesh is entering from low-income to lower-middle-income status in 2020, and this will be completed in the next 5 years. With gross national income growing, vaccines will need to be procured through private market for the Expanded Program on Immunization. A cost-benefit analysis is needed to evaluate vaccine demand in different socioeconomic groups in the country, to inform this procurement. Moreover, disease burden studies and awareness of importance of specific vaccines are needed as we move forward. A life-course approach to vaccination may enable whole society to realize the full potential of vaccination and address most significant threats to its success over time.

Mathematical Modeling of Endemic Cholera Transmission.

Mathematical modeling can be used to project the impact of mass vaccination on cholera transmission. Here, we discuss 2 examples for which indirect protection from mass vaccination needs to be considered. In the first, we show that nonvaccinees can be protected by mass vaccination campaigns. This additional benefit of indirect protection improves the cost-effectiveness of mass vaccination. In the second, we model the use of mass vaccination to eliminate cholera. In this case, a high population level of immunity, including contributions from infection and vaccination, is required to reach the "herd immunity" threshold needed to stop transmission and achieve elimination.

Reactive mass vaccination campaign against cholera in the COVID-19 context in Cameroon: challenges, best practices and lessons learned.

INTRODUCTION: since 1971, Cameroon is facing a growing series of cholera epidemics despite all the efforts made by the government to address this huge public health threat. In 2020, in addition to the COVID-19 pandemic, Cameroon recorded a high cholera case fatality rate of 4.3% following epidemics noted in the South, Littoral and South-West regions. The Cameroon Ministry of Public Health, has thus organized a reactive vaccination campaign against cholera to address the high mortality rate in the affected health districts of those regions. The objective of this study was to describe the challenges, best practices and lessons learned drawing from daily experiences from this reactive vaccination campaign against cholera. METHODS: we conducted a cross-sectional study drawn from the results of the campaign. We had a target population of 631,109 participants aged 1 year and above resident of the targeted health areas. RESULTS: the overall vaccination coverage was 64.4% with a refusal rate ranging from 0-10% according to health districts. Vaccination coverage was the lowest among people aged 20 years and above. The main challenge was difficulty maintaining physical distanciation, the main best practice was the screening of all actors taking part at the vaccination against COVID-19 and we found that emphasizing on thorough population sensitization through quarter heads and social mobilizers and adequately programming the campaign during a good climate season is crucial to achieving good vaccination coverage. CONCLUSION: lessons learned from this study could serve to inform various agencies in the event of planning rapid mass vaccination programs during pandemics.

Assessment of Vaccine Herd Protection: Lessons Learned From Cholera and Typhoid Vaccine Trials.

Vaccine herd protection is the extension of the defense conferred by immunization beyond the vaccinated to unvaccinated persons in a population, as well as the enhancement of the protection among the vaccinated, due to vaccination of the surrounding population. Vaccine herd protection has traditionally been inferred from observations of disease trends after inclusion of a vaccine in national immunization schedules. Rather than awaiting outcomes of widescale vaccine deployment, earlier-stage evaluation of vaccine herd protection during trials or mass vaccination projects could help inform policy decisions about potential vaccine introduction. We describe the components, influencing factors, and implications of vaccine herd protection and discuss various methods for assessing herd protection, using examples from cholera and typhoid vaccine studies.

Gut Microbiota and Development of Vibrio cholerae-Specific Long-Term Memory B Cells in Adults after Whole-Cell Killed Oral Cholera Vaccine.

Cholera is a diarrheal disease caused by Vibrio cholerae that continues to be a major public health concern in populations without access to safe water. IgG- and IgA-secreting memory B cells (MBC) targeting the V. cholerae O-specific polysaccharide (OSP) correlate with protection from infection in persons exposed to V. cholerae and may be a major determinant of long-term protection against cholera. Shanchol, a widely used oral cholera vaccine (OCV), stimulates OSP MBC responses in only some people after vaccination, and the gut microbiota is a possible determinant of variable immune responses observed after OCV. Using 16S rRNA sequencing of feces from the time of vaccination, we compared the gut microbiota among adults with and without MBC responses to OCV. Gut microbial diversity measures were not associated with MBC isotype or OSP-specific responses, but individuals with a higher abundance of Clostridiales and lower abundance of Enterobacterales were more likely to develop an MBC response. We applied protein-normalized fecal supernatants of high and low MBC responders to THP-1-derived human macrophages to investigate the effect of microbial factors at the time of vaccination. Feces from individuals with higher MBC responses induced significantly different IL-1ß and IL-6 levels than individuals with lower responses, indicating that the gut microbiota at the time of vaccination may "prime" the mucosal immune response to vaccine antigens. Our results suggest the gut microbiota could impact immune responses to OCVs, and further study of microbial metabolites as potential vaccine adjuvants is warranted.

Defining Polysaccharide-Specific Antibody Targets against Vibrio cholerae O139 in Humans following O139 Cholera and following Vaccination with a Commercial Bivalent Oral Cholera Vaccine, and Evaluation of Conjugate Vaccines Targeting O139.

Cholera caused by Vibrio cholerae O139 could reemerge, and proactive development of an effective O139 vaccine would be prudent. To define immunoreactive and potentially immunogenic carbohydrate targets of Vibrio cholerae O139, we assessed immunoreactivities of various O-specific polysaccharide (OSP)-related saccharides with plasma from humans hospitalized with cholera caused by O139, comparing responses to those induced in recipients of a commercial oral whole-cell killed bivalent (O1 and O139) cholera vaccine (WC-O1/O139). We also assessed conjugate vaccines containing selected subsets of these saccharides for their ability to induce protective immunity using a mouse model of cholera. We found that patients with wild-type O139 cholera develop IgM, IgA, and IgG immune responses against O139 OSP and many of its fragments, but we were able to detect only a moderate IgM response to purified O139 OSP-core, and none to its fragments, in immunologically naive recipients of WC-O1/O139. We found that immunoreactivity of O139-specific polysaccharides with antibodies elicited by wild-type infection markedly increase when saccharides contain colitose and phosphate residues, that a synthetic terminal tetrasaccharide fragment of OSP is more immunoreactive and protectively immunogenic than complete OSP, that native OSP-core is a better protective immunogen than the synthetic OSP lacking core, and that functional vibriocidal activity of antibodies predicts in vivo protection in our model but depends on capsule thickness. Our results suggest that O139 OSP-specific responses are not prominent following vaccination with a currently available oral cholera vaccine in immunologically naive humans and that vaccines targeting V. cholerae O139 should be based on native OSP-core or terminal tetrasaccharide. IMPORTANCE Cholera is a severe dehydrating illness of humans caused by Vibrio cholerae serogroup O1 or O139. Protection against cholera is serogroup specific, and serogroup specificity is defined by O-specific polysaccharide (OSP). Little is known about immunity to O139 OSP. In this study, we used synthetic fragments of the O139 OSP to define immune responses to OSP in humans recovering from cholera caused by V. cholerae O139, compared these responses to those induced by the available O139 vaccine, and evaluated O139 fragments in next-generation conjugate vaccines. We found that the terminal tetrasaccharide of O139 is a primary immune target but that the currently available bivalent cholera vaccine poorly induces an anti-O139 OSP response in immunologically naive individuals.

Effectiveness of a killed whole-cell oral cholera vaccine in Bangladesh: further follow-up of a cluster-randomised trial.

BACKGROUND: Killed whole-cell oral cholera vaccines (OCVs) are widely used for prevention of cholera in developing countries. However, few studies have evaluated the protection conferred by internationally recommended OCVs for durations beyond 2 years of follow-up. METHODS: In this study, we followed up the participants of a cluster-randomised controlled trial for 2 years after the end of the original trial. Originally, we had randomised 90 geographical clusters in Dhaka slums in Bangladesh in equal numbers (1:1:1) to a two-dose regimen of OCV alone (targeted to people aged 1 year or older), a two-dose regimen of OCV plus a water-sanitation-hygiene (WASH) intervention, or no intervention. There was no masking of group assignment. The WASH intervention conferred little additional protection to OCV and was discontinued at 2 years of follow-up. Surveillance for severe cholera was continued for 4 years. Because of the short duration and effect of the WASH intervention, we combined the two OCV intervention groups. The primary outcomes were OCV overall protection (protection of all members of the intervention clusters) and total protection (protection of individuals who got vaccinated in the intervention clusters) against severe cholera, which we assessed by multivariable survival models appropriate for cluster-randomised trials. This trial is registered on ClinicalTrials.gov, NCT01339845. FINDINGS: The study was done between April 17, 2011, and Nov 1, 2015. 268 896 participants were present at the time of the first dose, with 188 206 in the intervention group and 80 690 in the control group. OCV coverage of the two groups receiving OCV was 66% (123 659 of 187 214 participants). During 4 years of follow-up, 441 first episodes of severe cholera were detected (243 episodes in the vaccinated groups and as 198 episodes in the unvaccinated group). Overall OCV protection was 36% (95% CI 19 to 49%) and total OCV protection was 46% (95% CI 32 to 58). Cumulative total vaccine protection was notably lower for people vaccinated before the age of 5 years (24%; -30 to 56) than for people vaccinated at age 5 years or older (49%; 35 to 60), although the differences in protection for the two age groups were not significant (p=0·3308). Total vaccine protection dropped notably (p=0·0115) after 3 years in children vaccinated at 1-4 years of age. INTERPRETATION: These findings provide further evidence of long-term effectiveness of killed whole-cell OCV, and therefore further support for the use of killed whole-cell OCVs to control endemic cholera, but indicate that protection is shorter-lived in children vaccinated before the age of 5 years than in people vaccinated at the age of 5 years or older. FUNDING: Bill & Melinda Gates Foundation. TRANSLATION: For the Bengali translation of the abstract see Supplementary Materials section.

Chitosan and alginate salt as biomaterials are potential natural adjuvants for killed cholera vaccine.

Chitosan and alginate salts are natural biopolymers that have gained recent attention in the biomedical sectors. Their properties allow them to become potential candidates as safe, cheap, and effective vaccine adjuvants. The present study aimed to enhance the immunogenic response of a current injectable killed cholera vaccine (KCV) using chitosan and alginate salt as natural adjuvants against alum. We tested KCV adjuvanted with alum, chitosan, and sodium alginate in mice. Mice were immunized intraperitoneally with KCV adjuvanted with alum, chitosan, or alginate salt and compared with a control unadjuvanted immunized group. Humoral, cellular, and functional immune responses were evaluated in all groups. The addition of adjuvants, particularly natural adjuvants, to KCV significantly improved the immune response as demonstrated by specific antibody increase, strong proliferation effects, and high protection rate against different challenge doses of cholera strains. Our findings demonstrate that chitosan and alginate salt are superior adjuvants for boosting the KCV immune response and highlights the requirement for further vaccine development.

Decades of cholera in Odisha, India (1993-2015): lessons learned and the ways forward.

Cholera is one of the major public health problems in the state of Odisha, India since centuries. The current paper is a comprehensive report on epidemiology of cholera in Odisha, which was documented from 1993. PubMed and Web of Knowledge were searched for publications reporting cholera in Odisha during the period 1993-2015. The search was performed using the keywords 'Odisha' and/or 'Orissa' and 'Cholera'. In addition, manual search was undertaken to find out relevant papers. During the study period, a total of 37 cholera outbreaks were reported with an average of >1.5 cholera outbreaks per year and case fatality ratio was 0.3%. Vibrio cholerae O1 Ogawa serotype was the major causative agent in most of the cholera cases. The recent studies demonstrated the prevalence of V. cholerae O1, El Tor variants carrying ctxB1, ctxB7 and Haitian variant tcpA allele associated with polymyxin B sensitivity and these variants are replacing the proto type El Tor. The first report of variant ctxB7 in Odisha during super-cyclone 1999 predicted its emergence and subsequent spread causing cholera outbreaks. The prevalence of multidrug-resistant V. cholerae at different time periods created alarming situation. The efficacy trial of oral cholera vaccine (OCV, Shanchol) in a public health set-up in Odisha has shown encouraging results which should be deployed for community level vaccination among the vulnerable population. This paper has taken an effort to disseminate the valuable information of epidemiology of cholera that will influence the policy-makers and epidemiologists for constant surveillance in other parts of Odisha, India and around the globe.

Parenteral Vaccination with a Cholera Conjugate Vaccine Boosts Vibriocidal and Anti-OSP Responses in Mice Previously Immunized with an Oral Cholera Vaccine.

Oral cholera vaccination protects against cholera; however, responses in young children are low and of short duration. The best current correlates of protection against cholera target Vibrio cholerae O-specific polysaccharide (anti-OSP), including vibriocidal responses. A cholera conjugate vaccine has been developed that induces anti-OSP immune responses, including memory B-cell responses. To address whether cholera conjugate vaccine would boost immune responses following oral cholera vaccination, we immunized mice with oral cholera vaccine Inaba CVD 103-HgR or buffer only (placebo) on day 0, followed by parenteral boosting immunizations on days 14, 42, and 70 with cholera conjugate vaccine Inaba OSP: recombinant tetanus toxoid heavy chain fragment or phosphate buffered saline (PBS)/placebo. Compared with responses in mice immunized with oral vaccine alone or intramuscular cholera conjugate vaccine alone, mice receiving combination vaccination developed significantly higher vibriocidal, IgM OSP-specific serum responses and OSP-specific IgM memory B-cell responses. A combined vaccination approach, which includes oral cholera vaccination followed by parenteral cholera conjugate vaccine boosting, results in increased immune responses that have been associated with protection against cholera. These results suggest that such an approach should be evaluated in humans.

A Systems Biology Approach Identifies B Cell Maturation Antigen (BCMA) as a Biomarker Reflecting Oral Vaccine Induced IgA Antibody Responses in Humans.

Vaccines against enteric diseases could improve global health. Despite this, only a few oral vaccines are currently available for human use. One way to facilitate such vaccine development could be to identify a practical and relatively low cost biomarker assay to assess oral vaccine induced primary and memory IgA immune responses in humans. Such an IgA biomarker assay could complement antigen-specific immune response measurements, enabling more oral vaccine candidates to be tested, whilst also reducing the work and costs associated with early oral vaccine development. With this in mind, we take a holistic systems biology approach to compare the transcriptional signatures of peripheral blood mononuclear cells isolated from volunteers, who following two oral priming doses with the oral cholera vaccine Dukoral®, had either strong or no vaccine specific IgA responses. Using this bioinformatical method, we identify TNFRSF17, a gene encoding the B cell maturation antigen (BCMA), as a candidate biomarker of oral vaccine induced IgA immune responses. We then assess the ability of BCMA to reflect oral vaccine induced primary and memory IgA responses using an ELISA BCMA assay on a larger number of samples collected in clinical trials with Dukoral® and the oral enterotoxigenic Escherichia coli vaccine candidate ETVAX. We find significant correlations between levels of BCMA and vaccine antigen-specific IgA in antibodies in lymphocyte secretion (ALS) specimens, as well as with proportions of circulating plasmablasts detected by flow cytometry. Importantly, our results suggest that levels of BCMA detected early after primary mucosal vaccination may be a biomarker for induction of long-lived vaccine specific memory B cell responses, which are otherwise difficult to measure in clinical vaccine trials. In addition, we find that ALS-BCMA responses in individuals vaccinated with ETVAX plus the adjuvant double mutant heat-labile toxin (dmLT) are significantly higher than in subjects given ETVAX only. We therefore propose that as ALS-BCMA responses may reflect the total vaccine induced IgA responses to oral vaccination, this BCMA ELISA assay could also be used to estimate the total adjuvant effect on vaccine induced-antibody responses, independently of antigen specificity, further supporting the usefulness of the assay.

Long-Term Immunogenicity of Live Oral Cholera Vaccine CVD 103-HgR in Adolescents Aged 12-17 Years in the United States.

As part of a phase 4, randomized, double-blind, placebo-controlled trial to assess the immunogenicity and safety of PXVX0200 in children and adolescents aged 2-17 years, a subset of 73 adolescent subjects aged 12-17 years was followed for 2 years after vaccination and had blood collected for antibody assays on days 1, 11, 29, 91, 181, 365, 547, and 730. Endpoints included serum vibriocidal antibody (SVA) seroconversion, defined as a 4-fold or greater rise in antibody titer over baseline; geometric mean titers (GMTs); and geometric mean fold increase (GMFI) over baseline. Serum vibriocidal antibody seroconversion persisted in most subjects, with a rate of 64.5% noted at day 730. Geometric mean titers and GMFI both peaked at day 11 and remained greater than baseline at all time points, including day 730. Vaccination with PXVX0200 produces an immune response which persists for at least 2 years in adolescents aged 12-17 years.

Home Administration of CVD 103-HgR: A Live Attenuated Oral Cholera Vaccine.

Vaccination is a well-established means for prevention and spread of disease in people traveling abroad. Although vaccines to diseases such as cholera are recommended by world health agencies, they are seldom required even when traveling to endemic regions. Consequences of noncompliance can affect traveler's health and spread diseases to new regions, as occurred in Haiti in 2010 when United Nations peacekeepers from Nepal, where a cholera outbreak was underway, introduced the disease to the region. Steps to increase vaccine recommendation compliance should therefore be an integral part of vaccine development. PXVX0200 contains Center for Vaccine Development 103-HgR live, attenuated recombinant Vibrio cholerae vaccine strain, and is indicated for single-dose immunization against the bacteria that causes cholera. It is supplied as one buffer and one active component packet to be mixed into water and ingested. Administration instructions are designed to be "user friendly" with flexibility for self-administration, thus promoting compliance. Studies to support self-administration were conducted to cover stability of the vaccine outside of normal storage conditions, potency in case of misadministration, and disposal procedures to minimize environmental impact. The principal findings showed that the stability of vaccine was maintained under conditions allowing for transport times and temperature conditions as well as when misadministration errors were made. Finally, the vaccine was effectively neutralized with hot water and soap to prevent bacterial environmental contamination in the event of an accidental spill. The conclusion is that PXVX0200 oral vaccine is stable, easy to formulate and dispose of, and is amenable to self-administration.