Abstract: Cholera outbreaks have been rapidly increasing around the world. While long-term cholera prevention and control measures rely on improvements in water, sanitation, and hygiene, oral cholera vaccines (OCVs) are used for prevention and control in the short-to-medium term. OCVs lack the market incentives available in other more profitable disease areas. The development of OCVs was made possible through an alternative innovation model, which sustained innovation across multiple generations of the product for more than three decades. To examine how this alternative innovation model worked, we conducted 18 semi-structured interviews with key stakeholders related to the development of several OCVs, including "Dukoral", "Shanchol", and "Euvichol-Plus", as well as additional cholera vaccines currently under development. Interview data was analyzed thematically according to the resources used by organizations (including funding, knowledge, relationships, and manufacturing), and the practices they implemented during each stage of the R&D process (including knowledge management and intellectual property strategies, approaches to transparency, and global access strategies). Next, we created participatory network maps to illustrate the structure of the relationships between stakeholders and how these evolved over time. We found that a core group of stakeholders were able to influence policies to promote the use of OCVs, and successfully develop, finance, and obtain WHO Prequalification for safe, effective, and affordable OCVs for global procurement and distribution. The evolution of OCVs demonstrates how a collaborative network innovation model can successfully develop new pharmaceutical products that are affordable and well-suited for use in context. This model could be applied to other areas of pharmaceutical innovation, such as pandemic preparedness, for more equitable outcomes for global public health.

Abstract: Abstract Background Oral cholera vaccines (OCVs) prevent cholera and save lives. Given the recent 2024 country-wide cholera epidemic in Zambia, we determined self-reported OCV uptake, acceptance and confidence among adults living in a high-risk, cholera-prone township in Zambia. Methods A descriptive cross-sectional study was conducted from April to August 2024, involving 385 randomly selected adult participants residing in the Kanyama township of Lusaka, Zambia. Data were collected using an interviewer-administered questionnaire and statistically analysed. Results Self-reported uptake of at least one dose of the OCV was 18%, with the majority (315 [82%]) reporting being unvaccinated against cholera. Among those who were unvaccinated, vaccine acceptance was <10% (95% confidence interval [CI] 6.8 to 13.7), with higher rates reported among women than men (p=0.002). Despite this, the majority (210 [84.3%]) expressed confidence in the vaccination program. Those knowledgeable about the OCV were twice as likely to get vaccinated (adjusted odds ratio 2.60 [95% CI 1.19 to 5.68]). Knowledge, attitudes and perceptions were associated with OCV uptake. Conclusions Self-reported OCV uptake and acceptance were low in a high-risk cholera-prone township in Zambia. Community education on the benefits of the vaccine is urgently needed to enhance confidence and attitudes towards the OCV and improve vaccination rates in the future.

Abstract: BACKGROUND Cholera remains a persistent public health challenge, particularly in resource-limited and conflict-affected settings where inadequate water, sanitation, and hygiene infrastructure exacerbate disease transmission. Sudan has experienced recurrent cholera outbreaks, with two major waves occurring between April 2023 and November 2024, affecting 63,112 individuals and resulting in 1377 fatalities. Given the ongoing armed conflict and humanitarian crisis, traditional cholera prevention measures are often insufficient, necessitating the rapid deployment of Oral Cholera Vaccine (OCV) as a key outbreak response strategy. METHODS This study evaluates the administrative coverage, operational performance, and economic efficiency of Sudan's OCV campaigns during this period. A cross-sectional analysis was conducted on Sudan's nationwide OCV campaigns from November 2023 to November 2024. The study assessed vaccination strategies, cold chain resilience, social mobilization efforts, and operational costs per dose. RESULTS A total of 8,584,190 doses were administered to a target population of 8,654,546, achieving an administrative coverage rate of 99%. Coverage varied across implementation sites. The campaign was conducted under extreme conflict conditions, requiring innovative strategies such as house-to-house vaccination, mobile teams, and integration with novel Oral Polio Vaccine (nOPV) campaigns. Vaccine wastage was minimal (<0.0001 %), and the average operational cost per dose was $0.65. Despite logistical challenges, Sudan reduced the lead time from outbreak confirmation to vaccine request submission to just three days, though vaccine arrival delays of 2-4 weeks remained a bottleneck. CONCLUSION Sudan's experience demonstrates the feasibility and cost-effectiveness of OCV campaigns in conflict-affected and resource-limited settings. The high coverage rate, efficient vaccine utilization, and successful adaptation of vaccination strategies highlight the resilience of Sudan's health system in responding to outbreaks amid ongoing conflict and provide critical insights for future cholera control efforts in fragile settings, using partnerships, agile vaccine deployment mechanisms, and innovative implementation approaches.

Abstract: Abstract Background and objective The World Health Organization (WHO) appeal of January 15, 2024, stated “The current number, size and concurrence of multiple outbreaks, the spread to areas free of cholera for decades and alarmingly high mortality rates present a major threat to global health security.” The current state is extremely worrying, considering the difficulties of countries in dealing with cholera epidemics due to the lack of funding and the difficulty in oral cholera vaccine production and administration. This study aims to analyse the past and current influence of anthropization on cholera onset. Methods We analysed the literature, particularly of the last 5 years, on the influence of human actions that impact the spread of cholera. Results The epidemiological data published by WHO and the available literature highlight a strong impact of human actions on the epidemic spread of cholera, the government’s difficulty in making decisions on epidemic prevention or containment, and the fear of the population. Conclusions Cholera should be considered an anthropogenic disaster, considering the historical health analysis of the cholera epidemics in Italy in the last two centuries and in southern Italy and in Naples in 1973.

Abstract: Abstract Oral vaccines have several advantages compared with parenteral administration: they can be relatively cheap to produce in high quantities, easier to administer, and induce intestinal mucosal immunity that can protect against infection. These characteristics have led to successful use of oral vaccines against rotavirus, polio, and cholera. Unfortunately, oral vaccines for all three diseases have demonstrated lower performance in the highest-burden settings where they are most needed. Rotavirus vaccines are estimated to have &gt;85% effectiveness against hospitalization in children &lt;12 months in countries with low child mortality, but only ~65% effectiveness in countries with high child mortality. Similarly, oral polio vaccines have lower immunogenicity in developing country settings compared with high-resource settings. Data are more limited for oral cholera vaccines, but suggest lower titers among children compared with adults, and, for some vaccines, lower efficacy in endemic settings compared with non-endemic settings. These disparities are likely multifactorial, and available evidence suggests a role for maternal factors (e.g., transplacental antibodies, breastmilk), host factors (e.g., genetic polymorphisms—with the best evidence for rotavirus—or previous infection), and environmental factors (e.g., gut microbiome, coinfections). Overall, these data highlight the rather ambiguous and often contradictory nature of evidence on factors affecting oral vaccine response, cautioning against broad extrapolation of outcomes based on one population or one vaccine type. Meaningful impact on performance of oral vaccines will likely only be possible with a suite of interventions, given the complex and multifactorial nature of the problem and the degree to which contributing factors are intertwined.

Abstract: Background/Objectives: Cholera remains a significant global health challenge. Shanchol (ShantaBiotech, India), one of the WHO prequalified Oral Cholera Vaccines (OCVs) available until recently, has been used to immunize people as a two-dose regimen (14 days apart, on day 0 and 14). However, growing evidence suggests that a single-dose strategy may mediate short-term protection, especially in those over 5 years of age. Hence, it is crucial to design a suitable and effective administration scheme for Shanchol, particularly in cholera-endemic regions. Methods: In this study, adult volunteers were vaccinated with either a single dose, a two-dose regimen with a 14-day interval, or a two-dose regiment with a 30-day interval. We studied the antigen-specific helper memory (CD4+CD45RO+) and cytotoxic memory (CD8+CD45RO+) T cells responses of vaccinees along with the specific mucosal immune responses to gut-homing ß7 lipopolysaccharides (LPSs). Results: By day 7 post-vaccination, Shanchol induced robust helper and cytotoxic memory T cell responses to V. cholerae membrane protein (AKI-MP) following a single dose of vaccination. In the two-dose groups, we observed a significant elevation of AKI-MP-specific responses after the 2nd dose. We found that circulatory gut homing (β7+) LPS-specific IgA responses of antibody-secreting cells (ASCs) peaked at D7 among all vaccine groups. Moreover, we observed that β7+ LPS-specific ASCs at D7 significantly correlated with the LPS-specific antibody titer in plasma. Conclusions: These findings suggest that a single dose of OCV in adults induces immune responses comparable to a two-dose regimen, suggesting a single-dose vaccination may be adequate to mediate protection against cholera in cholera endemic zones-especially in reactive campaigns.

Abstract: Background Cholera is a public health threat in resource-limited settings and is responsible for causing over 3 million cases globally. Mucosal immune responses play an important role in protecting against Vibrio cholerae infection, a non-invasive mucosal pathogen, yet traditional plasma-based assays are invasive and logistically challenging, particularly during outbreaks in low- and middle-income countries (LMICs). Saliva offers a unique window into mucosal immunity and may serve as a non-invasive alternative for seroprevalence and vaccine immunogenicity studies. Methods We conducted a cross-sectional antibody profiling study to analyse cholera-specific antibodies in saliva and plasma samples from 74 participants upon presenting to the cholera treatment centres. These were collected from four treatment centres in Lusaka during Zambia’s most severe cholera outbreak in 2024 caused by Vibrio cholerae O1 Ogawa. Levels of total IgG, IgG1-3, IgM, secretory IgA, and IgA1–2 isotypes were used to compare the biomarker profile between the two sample types. Results Saliva and plasma antibody profiles were comparable, with elevated IgA1 and IgA2 responses to cholera toxin-B (CtxB), sialidase, HlyA, and TcpA in saliva. Broader systemic responses were seen in plasma, including high CtxB-specific IgM, IgA1, and total IgG levels. Notably, biomarkers such as HlyA, Ogawa O-specific polysaccharide (OSP), and sialidase exhibited significant positive correlations between plasma and saliva. Elevated biomarker levels of HlyA, Ogawa O-specific polysaccharide (OSP), and sialidase in people living with HIV/AIDS (PLWHA) suggested immunological differences that warrant further exploration. Conclusion We demonstrate that saliva is a viable, non-invasive alternative for cholera antibody-based profiling, offering practical advantages in resource-constrained settings. Given its strong correlation with systemic antibody profiles, saliva may be a practical sample for sero-surveillance in resource-limited settings. Future studies should investigate the duration of these salivary responses to further substantiate their use in estimating disease burden and immunity.

Abstract: Abstract Background We assessed whether the Preventative Intervention for Cholera for 7 Days (PICHA7) WASHmobile program reduced diarrhea and cholera serological responses and improved child growth in the Democratic Republic of the Congo (DRC). Methods The PICHA7 WASHmobile cluster-randomized controlled trial enrolled diarrhea patient households in urban Bukavu, DRC. Households were randomized into 2 arms: single in-person visit for the DRC government's diarrhea patient standard message on oral rehydration solution use and a basic water, sanitation, and hygiene (WASH) message (standard arm); or this standard message and the PICHA7 program with weekly voice and text mobile health (mHealth) messages and quarterly in-person visits (PICHA7 arm). The primary outcome was diarrhea in the past 2 weeks assessed monthly for 12 months. Secondary outcomes were healthcare facility visits for diarrhea, Vibrio cholerae serological response, stunting, underweight, wasting, and diarrhea with rice water stool over 12 months. A Vibrio cholerae serological response was defined by a rise in serum V. cholerae O1 O-specific polysaccharide (OSP) immunoglobulin A (IgA) or immunoglobulin G (IgG) from baseline to the 1-month follow-up. Generalized estimating equations were used for regression models to account for clustering at the individual and household level. Results Between December 2021 and December 2022, 2334 participants were randomly allocated to 2 arms: 1138 standard arm and 1196 PICHA7 arm. Diarrhea prevalence during the 12-month surveillance period was significantly lower among PICHA7 arm participants compared to standard arm participants (prevalence ratio, 0.39 [95% confidence interval {CI}: .32–.48]). PICHA7 arm participants had lower odds of visiting a healthcare facility for diarrhea during the 12-month surveillance period (OR: 0.44 [95% CI: .25–.77]) and lower odds of diarrhea with rice water stool (OR: 0.48 [95% CI: .27–.86]). Significantly lower V. cholerae IgA serological responses were observed in the PICHA7 arm compared to the standard arm, defined by a change in serum IgA to V. cholerae O1 OSP from baseline to the 1-month follow-up (coefficient of between-arm difference from baseline to 1 month: −0.85 [95% CI: −1.60 to −.09]). PICHA7 arm children aged &lt;5 years were significantly less likely to be stunted (52% vs 63% standard arm) (OR: 0.65 [95% CI: .43–.99]) at the 12-month follow-up. All WASH components had high adherence. Conclusions The PICHA7 WASHmobile program, which combines mHealth with quarterly in-person visits, lowered healthcare facility visits for diarrhea, cholera serological responses, and stunting in the DRC. Clinical Trials Registration NCT05166850.

Abstract: Cholera rapid diagnostic tests (RDTs) can strengthen existing surveillance systems by offering a cost-effective screening method that improves understanding of cholera burden allowing for targeted prevention and control efforts. The RDT Implementation Strategy and Evaluation (RISE) project is the pilot study for Gavi’s innovative Diagnostic Procurement Platform which provides cholera RDTs to enhance national surveillance. Implementation of cholera RDTs was evaluated following their distribution in 2023 to facilities within Nepal’s Early Warning and Reporting System (EWARS). Quantitative data was collected through EWARS surveillance reports, national-level and individual-level REDCap surveys from select facilities in Kathmandu. Key-informant interviews were also conducted in Kathmandu with personnel involved in cholera surveillance and response. Interviews were conducted using a semi-structured interview guide and analyzed according to inductively identified themes. Qualitative findings indicated generally positive perceptions of cholera RDTs, highlighting their speed and ease of use, and suitability for deployment in under-resourced areas by unskilled personnel. However, a lack of awareness of the RDTs, limited training, and concerns about the RDTs’ quality, availability, and costs were challenges raised consistently. Quantitative findings revealed underreporting of acute gastroenteritis (AGE) and cholera in EWARS and an underutilization of the cholera RDTs, with only 2.6% of reported AGE cases screened using an RDT. This field evaluation demonstrated that RDTs can have an important role in cholera surveillance but highlighted significant challenges with cholera lab capacity, reporting, and training. Both the qualitative and quantitative findings showed gaps in surveillance reporting, which were exacerbated by the complexity of adding RDTs without strong guidance as well as beliefs about the RDTs’ poor validity. These misconceptions and challenges need to be addressed at the local and national level to successfully scale-up cholera RDTs in Nepal and beyond.

Abstract: Cholera Priority Areas for Multisectoral Interventions (PAMIs), formerly known as “hotspots”, are limited geographical areas where cholera persists or regularly reappears due to cultural, environmental, and socioeconomic conditions. Focusing interventions on PAMIs will help to effectively control and ultimately eliminate cholera among the most at-risk populations. The 2023 GTFCC Methodology was used to identify PAMIs for cholera control in Kenya. The analysis was conducted between February and March 2024, selecting PAMIs based on the previous six years’ epidemiological data (Jan 2018 - Dec 2023) at the sub-county level. Epidemiological data was sourced from cholera outbreak line lists. The line list included both confirmed and suspected cholera cases of all ages admitted or reported to health facilities. The numerical priority index was calculated as a sum of four epidemiological indicators: incidence, mortality, persistence, and laboratory testing. Following a validation workshop, stakeholders selected a priority index threshold, identifying 78 sub-counties as initial PAMIs. There were 29 additional PAMIs included in the final list of 107 priority sub-counties based on country-specific vulnerability factors. This evidence-based approach will inform the targeting and implementation of multi-sectoral interventions in line with the Kenya National Cholera Plan.

Abstract: Background Current whole-cell killed oral cholera vaccines have utility but require multiple doses and have limited efficacy in young children. PanChol is a single-dose live-attenuated cholera vaccine derived from the current seventh pandemic Vibrio cholerae O1 strain. It co-expresses Inaba and Ogawa antigens, over- expresses the non-toxic cholera toxin B subunit, and is designed to minimize reactogenicity and prevent toxigenic reversion. We assessed safety and immunogenicity in a first-in-human trial. Methods In a dose-escalation phase at Brigham and Women's Hospital (Boston, MA, USA), seven cohorts received one dose of 10 4 -10 10 colony-forming-units (CFU) PanChol. Two dosing groups of 2*10 7 and 2*10 8 were subsequently evaluated in a double-blind, placebo-controlled module. Fecal shedding was assessed until day five; safety and immunogenicity were monitored for six months. This trial is registered with ClinicalTrials.gov, NCT05657782 . Findings Between Dec 2022 and Feb 2025, 57 healthy adults were enrolled (dose-escalation: n=21; expansion n=28 vaccine and n=8 placebo recipients). PanChol was safe and well-tolerated at all doses, and no safety concerns were identified including no vaccine-related serious adverse events. In the dose-escalation phase, 81% (17/21) of participants had 39 unsolicited adverse events (AE). In the randomized module, at least one AE occurred in 64% (9/14) at 10 7 dose and in all 10 8 (13/13) and placebo (7/7) recipients. Most AEs were mild and only four were >grade 2 (all unrelated to vaccine). Shedding was detected in 44 recipients of ≥10 5 CFU, with no relationship to dose. All 45 vaccinees given ≥ 10 5 CFU seroconverted vibriocidal antibodies to both serotypes, with comparable mean titers across doses. IgM responses targeting Inaba or Ogawa polysaccharides were detected in 44 and 41 vaccinees respectively, and anti-toxin IgG responses were measured in 21 vaccinees. Antibody lymphocyte supernatant assays demonstrated mucosal IgA to these antigens and to colonization factor, TcpA. Interpretation A single oral dose of PanChol induced 100% vibriocidal seroconversion over a 100,000-fold dose range with no safety concerns. These findings support further development of PanChol as a new tool for cholera prevention, including studies in endemic settings and in children. Funding: Wellcome Trust.

Abstract: Background We conducted three serial cross-sectional representative surveys after a mass cholera vaccination campaign in Uvira, Democratic Republic of the Congo to (1) estimate the vaccination coverage and explore heterogeneity by geographic and demographic factors; (2) examine barriers and facilitators of vaccine uptake and (3) describe the changes in coverage over time and predict future coverage. Methods We collected data on sociodemographics, self-reported vaccination status, population movement and knowledge, attitudes and behaviours related to killed oral cholera vaccines (kOCVs) in August 2021, April 2022 and April 2023, approximately 11, 19 and 30 months postvaccination. We compared the characteristics of participants by vaccination status and explored the potential role of population movement as a cause for low coverage. We used an exponential decay model to predict the proportion of the population vaccinated with ≥1 dose of kOCV over time based on age-specific coverage. Results We enrolled 8735 participants from 1433 households across all surveys. Coverage in survey 1 (August 2021) was 55% for ≥1 dose of kOCV (95% CI 51 to 60) and 23% for ≥2 doses (95% CI 20 to 27). Vaccine refusal was associated with a lack of confidence in the vaccine’s safety, and 29% of unvaccinated adults reported it was unlikely they would accept kOCVs if an additional mass vaccination campaign was conducted in their area. Coverage of ≥1 one dose of kOCV declined on average by 18% per year (95% credible interval 14 to 23) and was 39% (95% CI 36 to 43) by survey 3 (approx. 30 months after second dose campaign). Conclusions Our findings suggest that in settings like Uvira, efforts to strengthen vaccine confidence are needed to achieve higher campaign coverage, and vaccine coverage dilution may be reduced by more frequent and coordinated geographic vaccination efforts.

Abstract: Introduction: Cholera is recurrent in Zambia particularly in Lusaka district where outbreaks occur with regularity, typically during the rainy season. Despite the progress in improving Water, Sanitation, and hygiene (WASH) interventions, outbreaks are still persistent. This research aimed at assessing the effectiveness of Oral Cholera Vaccine in reducing cholera related mortality in the hotspot zones of Lusaka District, with a goal to inform public health strategies for cholera prevention and control. Methods: Retrospective cross-sectional study from April 2022 to April 2024, among 385 reported cholera cases meeting clinical/laboratory definitions in high-risk sub-districts (Kanyama, Matero, Mandevu, Chawama) on the effectiveness of the Oral Cholera Vaccine. Data was collected from health facilities, and surveillance databases. Descriptive statistics, and multivariable regression analysis were performed to evaluate the association between the independent variables and the outcome at a P value less than 0.05 with 95% confidence interval (CI). Results: Among the 385 cases reported, only 59.2% of the participants were vaccinated. Vaccination reduced cholera severity (coefficient=0.815, p<0.001), while hospitalization worsened outcomes (-0.193, p<0.001). Longer hospital stays improved recovery (0.108, p<0.001). Older age (0.002, p=0.020) and male gender (0.066, p=0.026) were linked to better outcomes. Access to clean water (-0.051, p=0.099) and improved water sources (-0.077, p=0.001) reduced the risk of disease. Sanitation and geographic location had no significant effects. Conclusion: OCV had a significant reduction on mortality and disease severity during cholera outbreaks in the hotspot zones. The results affirm the role of OCV in cholera prevention and emphasize the need to expand vaccine coverage, improve WASH infrastructure, and tailor healthcare interventions based on demographic differences.