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Objectives: The developmental origins of health and disease (DOHaD) hypothesis describes how early childhood stress affects morbidity and mortality later in life. The role of early childhood stress in mortality from infectious disease is understudied. Stressors in early childhood that weaken the immune system may result in increased susceptibility to infectious disease in adulthood. Weaning is one of the earliest potential periods of significant stress in early childhood. This research investigates the effect of weaning after ~6 months of age on cholera mortality among 18th-19th-century Italian populations by determining if earlier breastfeeding cessation is associated with earlier mortality, analyzing childhood dietary variation and physiological stress markers, and determining if age-at-weaning completion differs between catastrophic and attritional populations., Methods: Serial dentin stable carbon and nitrogen isotope analyses from canines are compared between catastrophic (n = 45) and attritional groups (n = 23). Canines are sectioned serially from crown to apex, and the increment's δ 15 N and δ 13 C are used to estimate age-at-weaning completion., Results: Catastrophic and attritional groups exhibit similar age-at-weaning completion (~2.8 years). Seventy-four percent of individuals lack elevated δ 15 N values in dentin that formed during infancy., Conclusions: Age-at-weaning completion was not a predisposing factor in cholera mortality in adulthood in this sample. Age-at-weaning completion may not be significantly associated with infectious disease mortality because weaning completion likely occurred after infants had adapted to consuming contaminated weanling foods. Individuals without detectable weaning curves may represent infants who received supplementary foods since birth or were weaned before the age of 6-9 months., (© 2023 Wiley Periodicals LLC.)

The paper argues that historic events in the western Irish town of Sligo were more substantial in shaping Bram Stoker's novel Dracula (1897) than previously thought. Biographers of Stoker have credited his mother, Charlotte Thornley Stoker, for influencing her son's gothic imagination during his childhood by sharing tales of the Sligo cholera epidemic she had witnessed in 1832. While Charlotte Stoker's written account of Sligo's epidemic Experiences of the Cholera in Ireland (1873) influenced Bram Stoker, it is argued that as a voracious library researcher he is likely to have cross-referenced it with other historical accounts. Furthermore, by viewing the text of Dracula through the lens of Charlotte Stoker's account and the historical reportage of the epidemic, clear parallels emerge. Ultimately, the striking similarities between Sligo's cholera are marshaled to argue that Count Dracula may be read as the personification of Sligo's cholera., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cholera is responsible for 1.3 to 4.0 million cholera cases globally and poses a significant threat, with Zambia reporting 17,169 cases as of 4th February 2024. Recognizing the crucial link between natural cholera infections and vaccine protection, this study aimed to assess immune responses post cholera infection and vaccination. This was a comparative study consisting of 50 participants enrolled during a cholera outbreak in Zambia's Eastern Province and an additional 56 participants who received oral cholera vaccinations in Zambia's Central Province. Vibriocidal antibodies were plotted as geometric mean titres in the naturally infected and vaccinated individuals. A significant difference (p < 0.047) emerged when comparing naturally infected to fully vaccinated individuals (2 doses) on day 28 against V. cholerae Ogawa. Those who received two doses of the oral cholera vaccine had higher antibody titres than those who were naturally infected. Notably, the lowest titres occurred between 0-9 days post onset, contrasting with peak responses at 10-19 days. This study addresses a critical knowledge gap in understanding cholera immunity dynamics, emphasizing the potential superiority of vaccination-induced immune responses. We recommend post infection vaccination after 40 days for sustained immunity and prolonged protection, especially in cholera hotspots., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Diverse modelling techniques in cholera epidemiology have been developed and used to (1) study its transmission dynamics, (2) predict and manage cholera outbreaks, and (3) assess the impact of various control and mitigation measures. In this study, we carry out a critical and systematic review of various approaches used for modelling the dynamics of cholera. Also, we discuss the strengths and weaknesses of each modelling approach. A systematic search of articles was conducted in Google Scholar, PubMed, Science Direct, and Taylor & Francis. Eligible studies were those concerned with the dynamics of cholera excluding studies focused on models for cholera transmission in animals, socio-economic factors, and genetic & molecular related studies. A total of 476 peer-reviewed articles met the inclusion criteria, with about 40% (32%) of the studies carried out in Asia (Africa). About 52%, 21%, and 9%, of the studies, were based on compartmental (e.g., SIRB), statistical (time series and regression), and spatial (spatiotemporal clustering) models, respectively, while the rest of the analysed studies used other modelling approaches such as network, machine learning and artificial intelligence, Bayesian, and agent-based approaches. Cholera modelling studies that incorporate vector/housefly transmission of the pathogen are scarce and a small portion of researchers (3.99%) considers the estimation of key epidemiological parameters. Vaccination only platform was utilized as a control measure in more than half (58%) of the studies. Research productivity in cholera epidemiological modelling studies have increased in recent years, but authors used diverse range of models. Future models should consider incorporating vector/housefly transmission of the pathogen and on the estimation of key epidemiological parameters for the transmission of cholera dynamics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Cholera is a severe gastrointestinal disease that manifests with rapid onset of diarrhea, vomiting, and high mortality rates. Due to its widespread occurrence in impoverished communities with poor water sanitation, there is an urgent demand for a cost-effective and highly efficient vaccine. Multi-epitope vaccines containing dominant immunological epitopes and adjuvant compounds have demonstrated potential in boosting the immune response., Material and Methods: B and T epitopes of OMPU, OMPW, TCPA, CTXA, and CTXB proteins were predicted using bioinformatics methods. Subsequently, highly antigenic multi-epitopes that are non-allergenic and non-toxic were synthesized. These multi-epitopes were then cloned into the pCOMB phagemid. A plasmid M13KO7ΔpIII containing all helper phage proteins except pIII was created to produce the recombinant phage. Female Balb/c mice were divided into three groups and immunized accordingly. The mice received the helper phage, recombinant phage or PBS via gavage feeding thrice within two weeks. Serum samples were collected before and after immunization for the ELISA test as well as evaluating immune system induction through ELISpot testing of spleen lymphocytes., Results: The titer of the recombinant phage was determined to be 10 11 PFU/ml. The presence of the recombinant phage was confirmed through differences in optical density between sample and control groups in the ELISA phage technique, as well as by observing transduction activity, which demonstrated successful production of a recombinant phage displaying the Vibrio multi-epitope on M13 phage pIII. ELISA results revealed significant differences in phage antibodies before and after inoculation, particularly notable in the negative control mice. Mice treated with multi-epitope phages exhibited antibodies against Vibrio cholerae lysate. Additionally, ELISpot results indicated activation of cellular immunity in mice receiving both Vibrio and helper phage., Conclusion: This study emphasizes the potential of multi-epitope on phage to enhance both cellular and humoral immunity in mice, demonstrating how phages can be used as adjuvants to stimulate mucosal immunity and act as promising candidates for oral vaccination., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The recurring cholera outbreaks in sub-Saharan Africa are of growing concern, especially considering the potential acceleration in the global trend of larger and more lethal cholera outbreaks due to the impacts of climate change. However, there is a scarcity of evidence-based research addressing the environmental and infrastructure factors that sustain cholera recurrence in Africa. This study adopts a statistical approach to investigate over two decades of endemic cholera outbreaks and their relationship with five environmental factors: water provision, sanitation provision, raising temperatures, increased rainfall and GDP. The analysis covers thirteen of the forty-two countries in the mainland sub-Saharan region, collectively representing one-third of the region's territory and half of its population. This breadth enables the findings to be generalised at a regional level. Results from all analyses consistently associate water provision with cholera reduction. The stratified model links increased water provision with a reduction in cholera risk that ranged from 4.2 % to 84.1 % among eight countries (out of 13 countries) as well as a reduction of such risk that ranged from 9.8 % to 68.9 % when there is increased sanitation provision, which was observed in nine countries (out of 13). These results indicate that the population's limited access to water and sanitation, as well as the rise in temperatures, are critical infrastructure and environmental factors contributing to endemic cholera and the heightened risk of outbreaks across the sub-Saharan region. Therefore, these are key areas for targeted interventions and cross-border collaboration to enhance resilience to outbreaks and lead to the end of endemic cholera in the region. However, it is important to interpret the results of this study with caution; hence, further investigation is recommended to conduct a more detailed analysis of the impact of infrastructure and environmental factors on reducing cholera risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Despite being a preventable and treatable disease, cholera remains a public health problem in Sudan. The objective of the outbreak investigation was to identify associated risk factors that would help institute appropriate control measures., Material and Methods: A case control study design was chosen to identify the risk factors for cholera in Gadarif State., Results: Multi-variate analysis of identified two risk factors and three preventive factors for cholera in Gadarif City., Risk Factors: Buying foods or drinks from street vendors (OR = 71.36), 95 % CI: 16.58-307.14), living in an urban setting (Gadarif City) (OR = 5.38), 95 % CI: 2.10-13.81); and the preventive factors were: Washing hands with water after defecation but without soap (OR = 0.16), 95 % CI: 0.04-0.63) or with soap (OR = 0.01), 95 % CI: 0.00-0.03), washing hands before eating (OR = 0.15), 95 % CI: 0.05-0.51) and taking Oral Cholera Vaccine (OCV) (OR = 0.19, 95 % CI: 0.08-0.44). The effectiveness of OCV (VE) was (Unadjusted VE: 80 %, 95 % CI: 69 %-87 %) or (Adjusted VE = 81.0 %, 95 % CI: 56.0 %-92.0 %)., Discussion: Cholera outbreaks, especially in the setting of a complex humanitarian crises, can spread rapidly, resulting in many deaths, and quickly become a public health crisis. Implementation of a community-wide vaccination campaign using OCV as early as possible during the outbreak while implementing other control measures to target hotspots and at-risk populations would expedite halting outbreaks of cholera and save lives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier India Pvt Ltd.)

John Snow, the London doctor who studied cholera in the 1840s and 1850s, argued in Snow (1856) that water exerted an "overwhelming influence" on mortality in a region of south London during the 1854 outbreak. In a paper re-assessing Snow's analysis, Koch and Denike (2006) claim that "Snow made not merely minor arithmetic errors but more importantly critical, conceptual mistakes that adversely affected his results." The claim of errors and mistakes is incorrect and due to a misreading or misunderstanding of Snow's data and analysis. Koch and Denike apply an inappropriate statistical test to Snow's original data (and do so incorrectly). More importantly, due to the misreading of the historical record they alter the underlying primary-source data, rendering their results invalid. Analysis of the data following Snow's approach but with modern statistical tools strongly supports Snow's claim for the primacy of water in accounting for variation in cholera mortality., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cholera, caused by Vibrio cholerae, is a severe diarrheal disease that necessitates prompt diagnosis and effective treatment. This review comprehensively examines various diagnostic methods, from traditional microscopy and culture to advanced nucleic acid testing like polymerase spiral reaction and rapid diagnostic tests, highlighting their advantages and limitations. Additionally, we explore evolving treatment strategies, with a focus on the challenges posed by antibiotic resistance due to the activation of the SOS response pathway in V. cholerae. We discuss promising alternative treatments, including low-pressure plasma sterilization, bacteriophages, and selenium nanoparticles. The paper emphasizes the importance of multidisciplinary approaches combining novel diagnostics and treatments in managing and preventing cholera, a persistent global health challenge. The current re-emergent 7th pandemic of cholera commenced in 1961 and shows no signs of abeyance. This is probably due to the changing genetic profile of V. cholerae concerning bacterial pathogenic toxins. Given this factor, we argue that the disease is effectively re-emergent, particularly in Eastern Mediterranean countries such as Lebanon, Syria, etc. This review considers the history of the current pandemic, the genetics of the causal agent, and current treatment regimes. In conclusion, cholera remains a significant global health challenge that requires prompt diagnosis and effective treatment. Understanding the history, genetics, and current treatments is crucial in effectively addressing this persistent and re-emergent disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of Applied Microbiology International.)

The bacterial agent that causes fowl cholera, Pasteurella multocida, was isolated from two deceased wild waterbirds in Victoria, Australia, in 2013. Whole genome sequence analysis placed the isolates into ST20, a subtype described in farmed chickens from Queensland, Australia and more recently in feedlot cattle and in pigs across a broader area of the continent. This study also found ST20 between 2009 and 2022 on three chicken farms and two turkey farms located in four Australian states. The sequences of 25 of these ST20 isolates were compared to 280 P. multocida genomes from 23 countries and to 94 ST20 Illumina datasets from Queensland that have been deposited in public databases. The ST20 isolates formed a single phylogenetic clade and were clustered into four sub-groups with highly similar genomes, possessing either LPS type 1 or type 3 loci. Various repertoires of mobile genetic elements were present in isolates from farmed, but not wild birds, suggesting complex histories of spill-over between avian populations and gene acquisition within farm environments. No major antimicrobial resistance was predicted in any of the ST20 isolates by the genomic analysis. The closest relative of these isolates was a ST394 bovine respiratory tract isolate from Queensland, which differed from ST20 by only one allele and carried beta-lactam and tetracycline resistance genes. These findings underline the importance of understanding the role of wild and commercial birds in the maintenance of fowl cholera, and of implementing regular epidemiological surveillance and biosecurity management programmes in wildlife, as well as free-range poultry farms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Globally, there has been a significant rise in cholera cases and deaths, with an increase in the number of low- and middle-income countries (LMICs) reporting outbreaks. In parallel, plastic pollution in LMICs is increasing, and has become a major constituent of urban dump sites. The surfaces of environmental plastic pollution can provide a habitat for complex microbial biofilm communities; this so-called 'plastisphere' can also include human pathogens. Under conditions simulating a peri-urban environmental waste pile, we determine whether toxigenic Vibrio cholerae (O1 classical; O1 El Tor; O139) can colonise and persist on plastic following a simulated flooding event. Toxigenic V. cholerae colonized and persisted on plastic and organic waste for at least 14 days before subsequent transfer to either fresh or brackish floodwater, where they can further persist at concentrations sufficient to cause human infection. Taken together, this study suggests that plastics in the environment can act as significant reservoirs for V. cholerae, whilst subsequent transfer to floodwaters demonstrates the potential for the wider dissemination of cholera. Further understanding of how diseases interact with plastic waste will be central for combating infection, educating communities, and diminishing the public health risk of plastics in the environment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Cholera remains a major public health problem that threatens human health worldwide and its severity is continuing. In this paper, an edge-based model for cholera transmission on random networks is proposed and investigated. The model assumes that two communities share a common water source and includes three transmission routes, namely intra- and inter-community human-to-human transmission as well as water-to-human transmission. Intra-community human-to-human contacts are modeled through a random contact network, while both inter-community and water-to-human transmission are modeled through external nodes that reach each individual in the network to the same extent. The basic reproduction number and the equations of the final epidemic size are obtained. In addition, our study considers the cholera situation in Banadir, which is one of the most severely infected regions in Somalia, during the period (2019-2021). According to the geographical location, two adjacent districts are selected and our model fits well with the real data on the monthly cumulative cholera cases of these two districts during the above-mentioned period. From the perspective of network topology, cutting off high-risk contacts by supervising, isolating, quarantining and closing places with high-degree cholera-infected individuals to reduce degree heterogeneity is an effective measure to control cholera transmission. Our findings might offer some useful insights on cholera control., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The bacteria Vibrio cholerae relies heavily upon an aquatic reservoir as a transmission route with two distinct serotypes observed in many recent outbreaks. In this paper, we extend previously studied ordinary differential equation epidemiological models to create a two-strain SIRP (susceptible-infectious-recovered-pathogen) system which incorporates both partial cross-immunity between disease strains and environmental pathogen transmission. Of particular interest are undamped anti-phase periodic solutions, as these display a type of coexistence where strains routinely switch dominance, and understanding what drives this switch can optimize the efficiency of the host population's control measures against the disease. We derive the basic reproduction number R 0 and use stability analysis to examine the disease free and single-strain equilibria. We formulate a unique coexistence equilibrium and prove uniform persistence of both strains when R 0 >1. In addition, we simulate solutions to this system, along with seasonally forced versions of the model with and without host coinfection. Cross-immunity and transmission pathways influence damped or sustained oscillatory dynamics, where the presence of seasonality can modify, amplify or synchronize the period and phase of serotypes, driving epidemic waves. Cycling of serotypes over large time intervals, similar to observed data, is found for a range of cross-immunity levels, and the inclusion of coinfection in the model contributes to sustained anti-phase periodic solutions., Competing Interests: Declaration of competing interest The authors confirm that there is no financial/personal interest or belief that could affect their objectivity, or if there is, stating the source and nature of that potential conflict., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: According to data from the World Health Organization (WHO), in the last year cholera has re-emerged in various areas of the planet, particularly in Africa. The resurgence of this disease is closely linked to poor hygiene, which is sometimes the result of wars or environmental disasters, as in Lebanon and Syria since autumn 2022 and today in Libya., Discussion: The spread of cholera is chiefly caused by the presence of contaminated water, in environments with inadequate hygiene and sanitation. Another cause, however, is the lack of access to adequate vaccination and treatment campaigns., Method: In this short paper, the authors highlight the possibility of a resurgence of epidemic cholera in Libya, especially in light of the consequences of the devastating cyclone Daniel and the simultaneous collapse of two dams upstream of the city of Derna. They also highlight the concern that cholera and other infectious diseases may also spread in Morocco, which was hit by a severe earthquake on 8 September last. The focus of the paper is the awareness that the spread of epidemic diseases is very often linked to human actions, which may trigger or exacerbate the effects of natural disasters., Conclusions: Since these events have devastating effects both on the environment and on people and their psychophysical balance, it is evident that we need to devote greater attention to the health of the planet, to which the health and survival of the human species is strictly and inextricably linked. Indeed, disasters related to phenomena of anthropization facilitate the spread of infectious diseases, placing a heavy burden on local and global health organizations and the health of entire populations. A change of course is therefore essential, in that human actions must be aimed at limiting rather than aggravating the spread of diseases., Competing Interests: The authors declare no conflict of interest., (©2023 Pacini Editore SRL, Pisa, Italy.)

Cholera is an environmentally driven disease where the human hosts both ingest the pathogen from polluted environment and shed the pathogen to the environment, generating a two-way feedback cycle. In this paper, we propose a bidirectionally linked immuno-epidemiological model to study the interaction of within- and between-host cholera dynamics. We conduct a rigorous analysis for this multiscale model, with a focus on the stability and bifurcation properties of each feasible equilibrium. We find that the parameter that represents the bidirectional connection is a key factor in shaping the rich dynamics of the system, including the occurrence of the backward bifurcation and Hopf bifurcation. Numerical results illustrate a practical application of our model and add new insight into the prevention and intervention of cholera epidemics., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Oral cholera vaccine is one of the key interventions used in our fight to end the longest pandemic of our time, cholera. The immune response conferred by the currently available cholera vaccines, as measured by serum antibody levels, is variable amongst its recipients. We undertook a genome wide association study (GWAS) on antibody response to the cholera vaccine; globally, the first GWAS on cholera vaccine response. We identified three clusters of bi-allelic SNPs, in high within-cluster linkage disequilibrium that were moderately (p < 5 × 10 -6 ) associated with antibody response to the cholera vaccine and mapped to chromosomal regions 4p14, 4p16.1 and 6q23.3. Intronic SNPs of TBC1D1 comprised the cluster on 4p14, intronic SNPs of TBC1D14 comprised that on 4p16.1 and SNPs upstream of TNFAIP3 formed the cluster on 6q23.3. SNPs within and around these clusters have been implicated in immune cell function and immunological aspects of autoimmune or infectious diseases (e.g., diseases caused by Helicobacter pylori and malarial parasite). 6q23.3 is a prominent region harbouring many loci associated with immune related diseases, including multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus, as well as IL2 and INFα response to a smallpox vaccine. The gene clusters identified in this study play roles in vesicle-mediated pathway, autophagy and NF-κB signaling. No significant effect of O blood group on antibody response to the cholera vaccine was observed in this study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This paper provides an analysis of Andrija Štampar's activities after World War II on the establishment of effective international health. Analyzed archival materials have confirmed with numerous evidence that Štampar as the president of the Interim Commission of the World Health Organization (WHO) played a crucial role in the establishment of the ideological starting points and organization of the WHO system, which remain relevant to date. Apart from the strategic foundations, it has been shown that his principles regarding the need for practical action based on the best professional knowledge and experience have no alternatives. The above is presented in the paper with the details of Štampar's activities during the cholera epidemic in Egypt and associated with the experiences of the recent global crisis caused by the COVID pandemic.

Due to the large number of waterborne bacteria presenting in drinking water, their rapid and accurate identification has become a global priority. The surface plasmon resonance (SPR) biosensor with prism (BK7)-silver(Ag)-MXene(Ti 3 T 2 Cx)-graphene- affinity-sensing medium is examined in this paper, in which the sensing medium includes pure water, vibrio cholera ( V. cholera ), and escherichia coli ( E. coli ). For the Ag-affinity-sensing medium, the maximum sensitivity is obtained by E. coli , followed by V. cholera , and the minimum is pure water. Based on the fixed-parameter scanning (FPS) method, the highest sensitivity is 246.2 °/RIU by the MXene and graphene with monolayer, and with E. coli sensing medium. Therefore, the algorithm of improved differential evolution (IDE) is obtained. By the IDE algorithm, after three iterations, the maximum fitness value (sensitivity) of the SPR biosensor achieves 246.6 °/RIU by using the structure of Ag (61 nm)-MXene (monolayer)-graphene (monolayer)-affinity (4 nm)- E. coli . Compared with the FPS and differential evolution (DE) algorithm, the highest sensitivity is more accurate and efficient, and with fewer iterations. The performance optimization of multilayer SPR biosensors provides an efficient platform.

The feared diarrheal disease cholera remains an important global health problem. Use of oral cholera vaccine (OCV) from a global stockpile against both epidemic and endemic cholera is a cornerstone in the World Health Organisations (WHOs) global program for "Ending cholera by 2030". Three liquid inactivated whole-cell OCVs (Dukoral®, Shanchol TM , and Euvichol-Plus®) are WHO prequalified and have proved to be safe and effective. However, their multicomponent composition and cold-chain requirement increase manufacturing, storage and transport costs. Shanchol TM and Euvichol-Plus® OCVs used in WHOs global vaccine stockpile also lack the protective cholera toxin B-subunit (CTB) antigen present in Dukoral®, which results in suboptimal efficacy. WHOs Global Task Force on Cholera Control (GTFCC) has identified a thermostable, dry formulation vaccine as a priority for further OCV development. We describe here the development of such a vaccine, based on a lyophilized mixture of a single strain of formalin-killed Hikojima bacteria together with a low-cost, recombinantly produced CTB. The new vaccine, which is easy and inexpensive to manufacture, could be stored for at least 26 months at 25 °C and for at least 8 months at 40 °C with preservation of cell morphology and with no loss of protective Ogawa and Inaba lipopolysaccharides or CTB. It also proved to be well tolerated and to have equivalent oral immunogenicity in mice as Shanchol TM and Dukoral® OCVs with regard to both serum and intestinal-mucosal antibody responses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cholera and milder diarrheal disease are caused by Vibrio cholerae and enterotoxigenic Escherichia coli and are still a prominent public health concern. Evaluation of suspicious isolates is essential for the rapid containment of acute diarrhea outbreaks or prevention of epidemic cholera. Existing detection techniques require expensive equipment, trained personnel and are time-consuming. Antibody-based methods are also available, but cost and stability issues can limit their applications for point-of-care testing. This study focused on the selection of single stranded DNA aptamers as simpler, more stable and more cost-effective alternatives to antibodies for the co-detection of AB 5 toxins secreted by enterobacteria causing acute diarrheal infections. Cholera toxin and Escherichia coli heat-labile enterotoxin, the key toxigenicity biomarkers of these bacteria, were immobilized on magnetic beads and were used in a SELEX-based selection strategy. This led to the enrichment of sequences with a high % GC content and a dominant G-rich motif as revealed by Next Generation Sequencing. Enriched sequences were confirmed to fold into G-quadruplex structures and the binding of one of the most abundant candidates to the two enterotoxins was confirmed. Ongoing work is focused on the development of monitoring tools for potential environmental surveillance of epidemic cholera and milder diarrheal disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cholera is a highly contagious and lethal waterborne disease induced by an infection with Vibrio cholerae (V. cholerae) secreting cholera toxin (CTx). Cholera toxin subunit B (CTxB) from the CTx specifically binds with monosialo-tetra-hexosyl-ganglioside (GM1) found on the exterior cell membrane of an enterocyte. Bioinspired by the pathological process of CTx, we developed an electrochemical biosensor with GM1-expressing Caco-2 cell membrane (CCM) on the electrode surface. Briefly, the electrode surface was functionalized with CCM using the vesicle fusion method. We determined the CTxB detection performances of Caco-2 cell membrane-coated biosensor (CCB) using electrochemical impedance spectroscopy (EIS). the CCB had an excellent limit of detection of ∼11.46 nM and a detection range spanning 100 ng/mL - 1 mg/mL. In addition, the CCB showed high selectivity against various interfering molecules, including abundant constituents of intestinal fluid and various bacterial toxins. The long-term stability of the CCBs was also verified for 3 weeks using EIS. Overall, the CCB has excellent potential for practical use such as point-of-care and cost-effective testing for CTxB detection in developing countries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The current global initiative to end Cholera by 2030 emphasizes the use of oral cholera vaccine (OCV) combined with feasible household Water-Sanitation-Hygiene (WASH) interventions. However, little is known about how improved WASH practices and behaviors and OCV interact to reduce the risk of cholera. We reanalyzed two arms of a cluster-randomized trial in urban Bangladesh, to evaluate the effectiveness of OCV given as a 2-dose regimen. One arm (30 clusters, n = 94,675) was randomized to vaccination of persons aged one year and older with OCV, and the other arm (30 clusters, n = 80,056) to no intervention. We evaluated the prevention of cholera by household WASH, classified at baseline using a previously validated rule, and OCV over 2 years of follow-up. When analyzed by assignment to OCV clusters rather than receipt of OCV, in comparison to persons living in "Not Better WASH" households in the control clusters, reduction of severe cholera (the primary outcome) was similar for persons in "Not Better WASH" households in vaccine clusters (46%, 95% CI:24,62), for persons in "Better WASH" households in the control clusters (48%, 95% CI:25,64), and for persons in "Better WASH" households in the vaccine clusters (48%, 95% CI:16,67). In contrast, when analyzed by actual receipt of a complete OCV regimen, , in comparison to persons in "Not Better WASH" households in the control clusters, protection against severe cholera increased steadily from 39% (95% CI:13,58) in residents of "Better WASH" households in the control clusters to 57% (95% CI:35,72) in vaccinated persons in "Not Better WASH" households to 63% (95% CI:21,83) in vaccinated persons in "Better WASH" households. This analysis suggests that improved household WASH and OCV received may interact to provide greater protection against cholera. However, the divergence between findings related to intent to vaccinate versus those pertaining to actual receipt of OCV underscores the need for further research on this topic., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: On 14 August 2017, massive landslides and floods hit Freetown (Sierra Leone). More than 1,000 people lost their lives while approximately 6,000 people were displaced. The areas most affected included parts of the town with challenged access to basic water and sanitation facilities, with communal water sources likely contaminated by the disaster. To avert a possible cholera outbreak following this emergency, the Ministry of Health and Sanitation (MoHS), supported by the World Health Organization (WHO) and international partners, including Médecins Sans Frontières (MSF) and UNICEF, launched a two-dose pre-emptive vaccination campaign using Euvichol™, an oral cholera vaccine (OCV)., Methods: We conducted a stratified cluster survey to estimate vaccination coverage during the OCV campaign and also monitor adverse events. The study population - subsequently stratified by age group and residence area type (urban/rural) - included all individuals aged 1 year or older, living in one of the 25 communities targeted for vaccination., Results: In total 3,115 households were visited, 7,189 individuals interviewed; 2,822 (39%) people in rural and 4,367 (61%) in urban areas. The two-dose vaccination coverage was 56% (95% confidence interval (CI): 51.0-61.5), 44% (95%CI: 35.2-53.0) in rural and 57% (95%CI: 51.6-62.8) in urban areas. Vaccination coverage with at least one dose was 82% (95%CI: 77.3-85.5), 61% (95%CI: 52.0-70.2) in rural and 83% (95%CI: 78.5-87.1) in urban areas., Conclusions: The Freetown OCV campaign exemplified a timely public health intervention to prevent a cholera outbreak, even if coverage was lower than expected. We hypothesised that vaccination coverage in Freetown was sufficient in providing at least short-term immunity to the population. However, long-term interventions to ensure access to safe water and sanitation are needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

It is crucial for human health that the immune system of the gastrointestinal tract works effectively. Dietary modulation is one of the factors that regulate the immune response in the gut. This study aims to develop a safe human challenge model to study gastrointestinal inflammation and immune function. This study focuses on evaluating gut stimulation induced by the oral cholera vaccine in healthy people. In addition, this paper describes the study design for assessing the efficacy and safety of a probiotic lysate, identifying whether functional ingredients in food can modulate inflammatory response induced by oral cholera vaccine. Forty-six males aged 20 to 50 with healthy bowel habits will be randomly allocated to the placebo or intervention group. Participants will consume 1 capsule of probiotic lysate or placebo twice daily for 6 weeks, take oral cholera vaccines on visit 2 (day 15) and visit 5 (day 29). The level of fecal calprotectin, a marker of gut inflammation, will be the primary outcome. The changes of cholera toxin-specific antibody levels and local/systemic inflammatory responses will be evaluated in blood. The purpose of this study is to evaluate gut stimulation of the oral cholera vaccine and investigate the effect of a probiotic lysate on improving the mild inflammatory response induced by the vaccine or supporting the immune response in healthy subjects. Trial registration: * This trial is registered in the International Clinical Trials Registry Platform of WHO (ICTRP, registration number: KCT0002589)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Park et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cholera continues to inflict high rates of morbidity and mortality. Prompt identification of cholera cases facilitates rapid outbreak responses in the short term while providing reliable surveillance data to guide long-term policies and interventions. Microbiological stool culture, the current recognized gold standard for diagnosing cholera, has significant limitations. Rapid diagnostic tests (RDTs) represent promising alternatives for diagnosing cholera in areas with limited laboratory infrastructure. However, studies conducted with the current cholera RDTs demonstrated wide variations in sensitivity and specificity. To address this gap in the diagnosis of cholera, we developed a simple, rapid, and sensitive diagnostic assay, "Rapid LAMP based Diagnostic Test (RLDT)." With a novel, simple sample preparation method directly from the fecal samples along with lyophilized reaction strips and using established Loop-mediated Isothermal Amplification (LAMP) platform, cholera toxin gene (ctxA) and O1 (O1rfb) gene could be detected in less than an hour. Cholera RLDT assay is cold chain and electricity-free. To avoid any end-user bias, a battery-operated, handheld reader was used to read the RLDT results. The performance specifications of the cholera RLDT assay, including analytical sensitivity and specificity, were evaluated using direct fecal samples, dried fecal samples on filter paper, and environmental water samples spiked with cholera strain. The limit of detection (LOD) was ~104 CFU/gm of stool for both ctxA and O1 genes, corresponding to about 1 CFU of Vibrio cholerae per reaction within 40 minutes. The LOD was 10 bacteria per ml of environmental water when tested with RLDT directly, without enrichment. Being simple, RLDT has the potential to be applied in resource-poor endemic settings for rapid, sensitive, and reliable diagnosis of cholera., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Chakraborty et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Extent health humanities readings of Gabriel García Márquez's Love in the Time of Cholera have focused on the doctor-patient relationship, the physician-scientist as a model for aspiring practitioners, and how individuals relate to the novel's health themes of death, disease, and disability. However, such medicine-focused readings neglect the population-level public health concerns of the novel as they relate to contagion, community, and quarantine. This paper contributes to the growing field of public health humanities by using a close reading method to explore how the competing endemic and epidemic public health issues shape the plot and metaphors of the novel., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this paper, we consider an age-structured cholera model with saturation incidence, vaccination age of vaccinated individuals, infection age of infected individuals, and biological age of pathogens. First, the basic reproduction number is calculated. When the basic reproduction number is less than one, the disease-free equilibrium is locally stable. Further, the existence of backward bifurcation of the model is obtained. Numerically, we also compared the effects of various control measures, including basic control measures and vaccination, on the number of infected individuals.

Bangladesh remains cholera endemic with biannual seasonal peaks causing epidemics. At least 300,000 severe cases and over 4,500 deaths occur each year. The available oral cholera vaccineshave not yet been adopted for cholera control in Bangladesh due to insufficient number of doses available for endemic control. With a public private partnership, icddr,b initiated a collaboration between vaccine manufacturers in Bangladesh and abroad. A locally manufactured Oral Cholera Vaccine (OCV) named Cholvax became available for testing in Bangladesh. We evaluated the safety and immunogenicity of this locally produced Cholvax (Incepta Vaccine Ltd) inexpensive OCV comparatively to Shanchol (Shantha Biotechnics-Sanofi Pasteur) which is licensed in several countries. We conducted a randomized non-inferiority clinical trial of bivalent, killed oral whole-cell cholera vaccine Cholvax vs. Shanchol in the cholera-endemic area of Mirpur, Dhaka, among three different age cohorts (1-5, 6-17 and 18-45 years) between April 2016 and April 2017. Two vaccine doses were given at 14 days apart to 2,052 healthy participants. No vaccine-related serious adverse events were reported. There were no significant differences in the frequency of solicited (7.31% vs. 6.73%) and unsolicited (1.46% vs. 1.07%) adverse events reported between the Cholvax and Shanchol groups. Vibriocidal antibody responses among the overall population for O1 Ogawa (81% vs. 77%) and O1 Inaba (83% vs. 84%) serotypes showed that Cholvax was non-inferior to Shanchol, with the non-inferiority margin of -10%. For O1 Inaba, GMT was 462.60 (Test group), 450.84 (Comparator group) with GMR 1.02(95% CI: 0.92, 1.13). For O1 Ogawa, GMT was 419.64 (Test group), 387.22 (Comparator group) with GMR 1.12 (95% CI: 1.02, 1.23). Cholvax was safe and non-inferior to Shanchol in terms of immunogenicity in the different age groups. These results support public use of Cholvax to contribute for reduction of the cholera burden in Bangladesh. ClinicalTrials.gov number: NCT027425581., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In Bangladesh and West Bengal cholera is seasonal, transmission occurs consistently annually. By contrast, in most African countries, cholera has inconsistent seasonal patterns and long periods without obvious transmission. Transmission patterns in Africa occur during intermittent outbreaks followed by elimination of that genetic lineage. Later another outbreak may occur because of reintroduction of new or evolved lineages from adjacent areas, often by human travelers. These then subsequently undergo subsequent elimination. The frequent elimination and reintroduction has several implications when planning for cholera's elimination including: a) reconsidering concepts of definition of elimination, b) stress on rapid detection and response to outbreaks, c) more effective use of oral cholera vaccine and WASH, d) need to readjust estimates of disease burden for Africa, e) re-examination of water as a reservoir for maintaining endemicity in Africa. This paper reviews major features of cholera's epidemiology in African countries which appear different from the Ganges Delta., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

In a recent paper, Che et al. [5] used a continuous-time Ordinary Differential Equation (ODE) model with risk structure to study cholera infections in Cameroon. However, the population and the reported cholera cases in Cameroon are censored at discrete-time annual intervals. In this paper, unlike in [5], we introduce a discrete-time risk-structured cholera model with no spatial structure. We use our discrete-time demographic equation to 'fit' the annual population of Cameroon. Furthermore, we use our fitted discrete-time model to capture the annually reported cholera cases from 1987 to 2004 and to study the impact of vaccination, treatment and improved sanitation on the number of cholera infections from 2004 to 2019. Our discrete-time cholera model confirms the results of the ODE model in [5]. However, our discrete-time model predicts a decrease in the number of cholera cases in a shorter period of cholera intervention (2004-2019) as compared to the ODE model's period of intervention (2004-2022).

It was in 1907 when Korea was annexed by Japan in the field of health care systems as the Gwangje Hospital, Uihakgyo the National Medical School and the Korean Red Cross Hospital were merged into the colonial Daehan Hospital, and massive cholera epidemic controls by the Japanese Army were enforced. However, despite their importance, the cholera epidemic of 1907 in Korea and preventive measures taken at that time have not yet been studied extensively as a single research subject. The purpose of this paper is to contribute to a more concrete and broader understanding of the Korea-Japan annexation of health care systems under the rule of the Japanese Resident-General of Korea by revealing new facts and correcting existing errors. In 1907, cholera was transmitted to Korea from China and Japan and spread across the Korean Peninsula, resulting in a major public health crisis, perhaps one of the most serious cholera outbreaks in the twentieth century Korea. Although Busan and Pyeongyang were the cities most infected with cholera, the targets for the most intensive interventions were Gyeongseong (Seoul) and Incheon, where the Japanese Crown Prince were supposed to make a visit. The Japanese police commissioner took several anti-cholera preventive measures in Gyeongseong, including searching out patients, disinfecting and blocking infected areas, and isolating the confirmed or suspected. Nevertheless, cholera was about to be rampant especially among Japanese residents. In this situation, Itō Hirobumi, the first Resident-General of Korea, organized the temporary cholera control headquarters to push ahead the visit of the Japanese Crown Prince for his political purposes to colonize Korea. To dispel Emperor Meiji's concerns, Itō had to appoint Satō Susumu, the famous Japanese Army Surgeon General, as an advisor, since he had much credit at Court. In addition, as the Japanese-led Korean police lacked epidemic control ability and experience, the headquarters became an improvised organization commanded by the Japanese Army in Korea and wielded great influence on the formation of the colonial disease control systems. Its activities were forced, violent, and negligent, and many Korean people were quite uncooperative in some anti-cholera measures. As a result, the Japanese Army in Korea took the initiative away from the Korean police in epidemic controls, serving the heavy-handed military policy of early colonial period. In short, the cholera epidemic and its control in 1907 were important events that shaped the direction of Japan's colonial rule.

There is a need to develop cholera vaccines that are protective in young children under 5 years of age, which induce long-term immunity, and which can be incorporated into the Expanded Programme of Immunization (EPI) in cholera-endemic countries. The degree of protection afforded by currently available oral cholera vaccines (OCV) to young children is significantly lower than that induced by vaccination of older vaccine recipients. Immune responses that protect against cholera target the O-specific polysaccharide (OSP) of Vibrio cholerae, and young children have poor immunological responses to bacterial polysaccharides, which are T cell independent antigens. To overcome this, we have developed a cholera conjugate vaccine (CCV) containing the OSP of V. cholerae O1, the main cause of endemic and epidemic cholera. Here, we describe production of CCV through a scalable manufacturing process and preclinical evaluation of immunogenicity in the presence and absence of aluminum phosphate (alum) as an adjuvant. The vaccine displays V. cholerae O1 Inaba OSP in sun-burst display via single point attachment of core oligosaccharide to a recombinant tetanus toxoid heavy chain fragment (rTTHc). Two different pilot-scale production batches of non-GMP CCV were manufactured and characterized in terms of physico-chemical properties and immunogenicity. In preclinical testing, the vaccine induced OSP- and lipopolysaccharide (LPS)-specific IgG and IgM responses, vibriocidal responses, memory B cell responses, and protection in a V. cholerae O1 challenge model. The addition of alum to the administered vaccine increased OSP-specific immune responses. These results support evaluation of CCV in humans., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

During the 1854 cholera outbreak in Florence, Italy, Filippo Pacini documented that the cause of the infection was a bacterium. This conclusion was also independently reached by John Snow during the 1854 cholera outbreak in London. By using an epidemiological method, Snow found that the infection spread through a polluted water network. Snow identified a water pump as the source of the disease. After removing the infected handle of this pump, the cases of cholera rapidly began to decrease. A microscopic examination of the water showed organic impurities but no bacteria. This discovery was ignored during Snow's lifetime. In contrast, through microscopy during the autopsies of cholera victims, Pacini observed that the disruption of their intestinal mucosa was closely associated with millions of the bacteria that he called Vibrio cholerae . Via histological techniques, Pacini detected that intestinal mucosa reabsorption dysfunction was the cause of debilitating diarrhoea, vomiting, severe dehydration and death. Nevertheless, his discovery of Vibrio cholerae was ignored during Pacini's lifetime. A survey of Pacini's autographic manuscripts suggests that Pacini and Snow may have shared mutual knowledge within their respective seminal papers. This survey also facilitates, for the first time, the creation of maps that illustrate the worldwide distribution of Pacini's cholera papers from 1854 to 1881. The consistent neglect of Pacini's discovery remains a true enigma.

Recently, there has been a surge in cholera cases in Nigeria. With the exhausting health resources and the overwhelming attention towards COVID-19, Nigeria is in danger of worsening the epidemiological profile of cholera in the country. Thus, it is pertinent to address the surge to prevent further weakening of the country's health system. In this paper, we, therefore, explore the various interrelated factors accounting for the surge in Nigeria. It is therefore suggested that multifaceted public health strategies be employed that leverage the current level of disease preparedness and response capacities to the COVID-19 pandemic to reduce the impacts of cholera. These measures will not only help in strengthening the country's health system but also enhance the achievement of the relevant strategies toward eradicating cholera., (© 2021 John Wiley & Sons Ltd.)

This study is to examine the cost-effectiveness of deployment strategies of oral cholera vaccines (OCVs) in controlling cholera in Bangladesh. We developed a dynamic compartment model to simulate costs and health outcomes for 12 years for four OCVs deployment scenarios: (1) vaccination of children aged one and above with two doses of OCVs, (2) vaccination of population aged 5 and above with a single dose of OCVs, (3) vaccination of children aged 1-4 with two doses of OCVs; and (4) combined strategy of (2) and (3). We obtained all parameters from the literature and performed a cost-effectiveness analysis from both health systems and societal perspectives, in comparison with the base scenario of no vaccination.The incremental cost-effectiveness ratios (ICERs) for the four strategies from the societal perspective were $2,236, $2,250, $1,109, and $2,112 per DALY averted, respectively, with herd immunity being considered. Without herd immunity, the ICERs increased substantially for all four scenarios except for the scenario that vaccinates children aged 1-4 only. The major determinants of ICERs were the case fatality rate and the incidence of cholera, as well as the efficacy of OCVs. The projection period and frequency of administering OCVs would also affect the cost-effectiveness of OCVs. With the cut-off of 1.5 times gross domestic product per capita, the four OCVs deployment strategies are cost-effective. The combined strategy is more efficient than the strategy of vaccinating the population aged one and above with two doses of OCVs and could be considered in the resource-limited settings., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The Far North Region of Cameroon, a high risk cholera endemic region, has been experiencing serious and recurrent cholera outbreaks in recent years. Cholera outbreaks in this region are associated with cultural practices (traditional and religious beliefs). In this paper, we introduce a mathematical model of the influence of cultural practices on the dynamics of cholera in the Far North Region. Our model is an SEIR type model with a pathogen class and multiple susceptible classes based on traditional and religious beliefs. Using daily reported cholera cases from three health districts (Kaélé, Kar Hay and Moutourwa) in the Far North Region from June 25, 2019 to August 16, 2019, we estimate parameter values of our model and use Akaike information criterion (AIC) to demonstrate that our model gives a good fit for our data on cholera cases. We use sensitivity analysis to study the impact of each model parameter on the threshold parameter (control reproduction number), R c , and the number of model predicted cholera cases. Finally, we investigate the effect of cultural practices on the number of cholera cases in the region.

Background: Vaccine herd protection assessed in a cluster-randomized trial (CRT) may be masked by disease transmission into the cluster from outside. However, herd effects can be unmasked using a 'fried-egg' approach whereby the analysis, restricted to the innermost households of clusters, 'yolk', creates an insulating 'egg-white' periphery. This approach has been demonstrated to unmask vaccine herd protection in reanalyses of cholera and typhoid vaccine CRTs. We applied this approach to an earlier CRT in Bangladesh of rotavirus vaccine (RV) whose overall analysis had failed to detect herd protection. Herein we present the results of this analysis., Methods: In the study area, infants in 142 villages were randomized to receive two doses of RV with routine EPI vaccines (RV villages) or only EPI vaccines (non-RV villages). We analyzed RV protection against acute rotavirus diarrhoea for the entire cluster (P100) and P75, P50, P25 clusters, representing 75%, 50% and 25% of the innermost households for each cluster, respectively., Results: During 2 years of follow-up, there was evidence of 27% overall (95 %CI: 7, 43) and 42% total protection (95 %CI: 23, 56) in the P100 cluster, but it did not increase when moved in smaller yolks. There was no evidence of indirect vaccine protection in the yolks at any cluster size., Conclusion: Our reanalysis of the CRT using the fried- egg approach did not detect RV herd protection. Whether these findings reflect a true inability of the RV to confer herd protection in this setting, or are due to limitations of the approach, requires further study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Italian born and long term resident in England, Sir Aldo Castellani (1874-1971), is usually credited with "several discoveries of great importance in tropical medicine", most notably for his role in determining the aetiology of sleeping sickness and yaws. This contribution tries to highlight his role in the history of vaccinology as a pioneer in the design and use of combined and polyvalent vaccines. In the light of existing data, while acting as Director of the Bacteriological Institute of Colombo (Ceylon) in the decade before the First World War, Castellani was the first to experiment with both different strains of "antigens belonging to the same group" like in his typhoid-paratyphoid vaccine (TAB), as well as the simultaneous use of more pathogens, or part of them, for protection against different diseases, like in his "tetravaccine" (TAB + cholera) and "pentavaccine" (TAB + cholera + Malta fever). At the beginning of the War, based on the results of thousands of vaccinations, he strongly maintained that those combined or mixed vaccines were harmless and effective. The Allied Armies became more and more interested in Castellani's methods. His TAB vaccine was extensively used among the soldiers and his contributions were largely acknowledged especially in the Anglo-Saxon world in the following years, when it was plainly stated that "to Castellani is due the credit of having first proposed, prepared, and used, combined vaccines". The path to widespread use of combination and polyvalent vaccines - which is usually dated back only to the late 1940s - was still long and winding. Castellani himself abandoned that field of research after the War and this is probably why that early history is nowadays often forgotten., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)