Real-world effectiveness of oral cholera vaccine amid fragility: A case-control study from Eastern Sudan, 2024

Highlights

• •Reactive vaccination was vital in outbreak control amid fragility.
• •Oral cholera vaccine cut cholera infection risk by 93% in Kassala, Sudan.
• •Poor hygiene and street food strongly increased infection risk.
• •Overcrowding and exposure at funerals fueled transmission.
• •Lasting control needs water sanitation, and hygiene (WASH), and risk communication.

Abstract

Objectives

Cholera is a serious public health threat, especially in fragile conflict-affected areas. Reactive oral cholera vaccine (rOCV) during outbreaks is a key response strategy recommended by the World Health Organization. Sudan implemented a large-scale reactive campaign during 2024 cholera outbreak in Kassala State.

Methods

This unmatched case-control study was conducted between 6 and 26 October 2024 in Kassala locality, targeted by the national rOCV campaign using Euvichol-Plus. Data were collected through structured interviews using a pre-tested questionnaire, and analyzed in Epi Info 7 with logistic regression to estimate vaccine effectiveness and identify predictors of infection.

Results

The mean age was significantly lower in cases (30.6 years, standard deviation = 20.8, P < 0.001). Cases had bigger households and multiple families per household (P < 0.001). Only 42.5% of cases used soap after defecation vs 97.5% of controls (odds ratio [OR] = 0.018), while 57% used only water (OR = 52.9). Street food consumption (OR = 4.04), funeral exposure (OR = 13.3), and family history (OR = 124.4) were strong predictors. OCV reduced infection odds by 93% (adjusted OR = 0.07, 95% confidence interval: 0.037-0.13, P < 0.001).

Conclusions

Findings reaffirm OCV effectiveness, but emphasize the need for sustainable investment in water sanitation, and hygiene (WASH), hygiene promotion, and risk communication in fragile settings.

Introduction

Cholera is an infectious diarrheal illness caused by the bacterium Vibrio cholerae. The disease represents a significant global health risk with a recently increasing trends, especially in Africa and Asia [1,2]. Cholera overwhelms the healthcare systems and exacerbates humanitarian crises [3,4]. Rapid spread of cholera takes place during humanitarian emergencies where poor settings are caused by disruption of infrastructure and massive population movement [5].

Vaccination is a crucial component of cholera prevention and control strategies, particularly when implemented in conjunction with improvements in water sanitation, and hygiene (WASH) [6,7].

Since the 1980s, either killed or live oral cholera vaccine (OCV) has been developed, and efficacy and effectiveness studies have been conducted on it [8]. The vaccine has proven to be a valuable tool for reducing the burden of cholera in diverse settings. Recent outbreaks in Africa and other regions experiencing humanitarian crises have demonstrated the effectiveness of OCVs in providing protection and contributing to outbreak control [7,8].

Shanchol and Euvichol-Plus: These inactivated vaccines target V. cholerae O1 and O139 serogroups. They are the World Health Organization (WHO)’s option for massive campaigns for cholera control and prevention [6]. The WHO recommends these vaccines for high-risk populations, with typical administration involving two doses spaced 1-6 weeks apart. In recent years due to vaccine shortage in the global stockpile, the strategy is shifted to one dose strategy in reactive campaigns which provides protection for only 6-8 months buying time for strengthening of other interventions [9]. Sudan used OCV multiple times to control cholera, as pre-emptive campaign in 2019, and as a reactive campaign for the first time in 2023 [5,10,11]. Although OCV had an observable role in controlling the outbreaks in Sudan, in-depth studies are recommended to analyze its actual impact in protecting against cholera and contribution to overall outbreak control [5].

This study aims to assess the effectiveness of OCVs in protecting against cholera amidst a reactive campaign conducted in Kassala State as part of the country efforts to limit the spread. The study will build on the existing real-world evidence from Sudan regarding OCV effectiveness [12], and the common risk factors and epidemic spread mediators to inform public health policy and long-term control efforts nationally, regionally and globally. Although several studies have demonstrated the effectiveness, what is unique about this research is that it studied the effectiveness during fragility and conflict-affected settings. It provided and added critical evidence on effectiveness of single-dose OCV amid complex emergencies where actors and stakeholders may question the usefulness and capacity to preserve vaccine potency and success of implementing reactive campaigns despite operational constrains. The study also benefited from one similar study done in Sudan and tried to fix many of its limitations to produce stronger and more valid evidence [12].

Material and methods

Study design and settings

This study is an unmatched case-control study conducted between 6 and 26 October 2024 to evaluate the effectiveness of the OCV during the 2023-2024 cholera outbreak in Kassala State. The study was done in Kassal locality which was targeted by a national reactive OCV (rOCV) campaign intended to vaccinate around 1.2 million people, conducted form 16-21 of September 2024. The type of vaccine used in the campaign was Euvichol-Plus which contains killed whole-cell Vibreo Cholerae O1 strain (Inaba and Ogawa), manufactured by EuBiologics Co., Ltd in South Korea. The state is located in eastern Sudan bordering Eritrea where a long cholera outbreak began in July 22, 2024, affected around 6859 cases and 198 deaths as of October 26, 2024 (Figure 1). The main drivers of this outbreak were the large number of displaced people hosted in Kassala, estimated to be 354,527 as of December 2024 [13], the disruption of WASH infrastructure, and the unusual torrential rain fall in 2024 that caused a lot of damage.

Figure 1.

The epidemic curve showing the distribution of cholera cases by date of onset during the outbreak with demonstration of the timing of rOCV campaign implementation (16-21 September 2024) in Kassala, 2024.

rOCV, reactive oral cholera vaccine.

Population and sampling

We calculated the sample size using the Open Epi calculator for unmatched case-control study. We opt for case: control ratio of 1:2, with confidence level of 95% and statistical power of 80%. The sample size for the cases and controls was identified to be 200 and 400 respectively. We enrolled more cases and controls to avoid non-response.

Case definition of cholera

The study adopted the standard case definition of cholera as used by the national epidemiological surveillance at Ministry of Health (MoH). A suspect case is “any patient aged 5 years or older presenting with a sudden onset of watery diarrhea, without abdominal pain, with or without vomiting. The presence of severe dehydration or death from acute watery diarrhea increases the probability of cholera”. A confirmed cholera case is “a suspected case with Vibrio cholerae isolated through culture or confirmation done by RT-PCR”.

Selection of cases and controls (Figure 2)

Figure 2.

The process of selection of cases and controls for enrolment in the study.

Cases: Cases were selected from two main cholera treatment facilities in Kassala City:

• 1.The primary Cholera Treatment Centre located in central Kassala.
• 2.A Cholera Treatment Unit serving the northern parts of the city.

We employed systematic random sampling to enroll cases from the admitted patients during the study period. Both mild and severe cholera cases were included, based on standard case classification criteria.

Controls: Controls were defined as individuals from the same community (neighborhoods) who did not have suspected or confirmed cholera.

Controls were selected from households in the same neighborhoods of the cases. The selection process involved the following steps:

• 1.Identification of affected neighborhoods was done by analyzing the case data.
• 2.The total control sample was then proportionally distributed across these neighborhoods.
• 3.Each neighborhood was divided into four sectors: north, south, east, and west to ensure geographic representation.
• 4.Within each sector, we applied a systematic household selection approach:

• ∘ A starting house was selected randomly.

• ∘ Every third house was then selected (e.g., 1, 4, 7, 10, interval K = 3).

• ∘ This cycle continued until the required number of controls was reached in each sector.

This method ensured spatial and demographic comparability between cases and controls.

Data collection

A structured administered questionnaire was designed following a thorough literature review of cholera risks and variables considering Sudan context. Researchers made adaptation to a previous similar study questionnaire, which was conducted in Gadaref state, Sudan, by Elbushra et al. [12].

The questionnaire then converted into a Google form, then the data collectors were recruited, trained and deployed in the field.

Data collection was started 15 days after the end of the immunization campaign (the campaign ended on September 21, study started on October 06, 2024) and extended for 20 days. Collection done first from the cases and then from the households’ controls. The questionnaire included both open- and closed-ended questions covering the following variables, residence, age, gender, vaccination status, number of doses, family history of cholera, consumption foods or drinks form street venders, hand washing before and after defection and eating, attending cholera funerals, family size, displacement status, deaths.

Data analysis

Data was extracted from Google forms as an Excel sheet, then cleaned, and analyzed using Epi Info™ 7. Descriptive statistics was done for demographic variables and potential risk factors, with means and standard deviations (SD) reported for continuous variables, and proportions for categorical variables. Differences in means between cases and controls were compared using the independent sample t-test, with statistical significance set at P < 0.05. Odds ratios (ORs) were estimated through univariate analysis with 95% confidence intervals (CI) for the association between cholera infection and potential risk factors.

Multivariate logistic regression was computed to identify the predictors of cholera infection, controlling for confounding variables. The model included variables that revealed significant association in univariate analysis.

The effectiveness of OCV was measured using the formula:

$$\text{Vaccine}\text{effectiveness}=\left(1-\text{aOR}\right)\times 100$$

Ethical considerations

This study was done as part of the MoH’s, represented by the Directorate General of Health Emergencies and Epidemic Control (HEEC), effort to document the effectiveness of the OCV in a real-world setting in Sudan. The study protocol was reviewed and approved by HEEC at the national and state level and granted the permission. All participants were participated voluntarily after provision of an informed consent. Confidentiality and anonymity of participants were strictly maintained, and all data were securely stored and accessed only by the research team. No human biological samples collected, and participation was entirely voluntary with no risks or benefits.

Results

General characteristics

A total of 637 individuals were enrolled, 228 cholera cases and 409 unmatched household controls. The mean age of cases was 30.6 years (SD = 20.8), while controls showed a significantly slightly higher mean age of 36.4 years (SD = 15) (P < 0.001) (Table 1). The male to female ratio were nearly equal for both cases and controls with no gender dominance. Cases had larger family sizes, with an average of 9.7 members per household compared to 5.2 for controls (P < 0.001), with cases more likely to have multiple families per household (mean: 1.7 vs 1.0, P < 0.001).

Table 1.

Age and family size parameters of cases and controls.

Age and family size parameters of cases and controls	Mean	SDV	P-value
Age
Cases	30.6	20.8	0.000
Control	36.4	15
Number of families per household
Cases	1.7	1.1
Control	1	0.3	0.000
Number of family member per household
Cases	9.7	5.3
Control	5.2	2.7	0.000

Potential cholera risk factors (Table 2)

Table 2.

comparison between cases and controls regarding the risk factors for cholera.

Factor	Control (N = 409)		Cases (N = 228)		Odds ratio	95% confidence interval
	N	%	N	%
Age group
>5-10	44	10.7%	73	18.3%
10-20	89	21.7%	46	21.1%
20-40	91	22.2%	29	18.8%
40-60	98	23.9%	36	21%
>60	87	21.2%	44	20.5%
Female gender	211	51.5%	123	53.9%	0.9	0.65-1.25
Family history of cholera	9	2.2%	168	73%	124.4	60.3-256.5
Being displaced	77	18%	66	22%
Using soap after defecation	399	97.5%	97	42.5%	0.018	0.009-0.036
Using only water after defecation	10	2.4%	130	57%	52.9	26.8-104.4
Using soap before eating	399	97.5%	64	28%	0.009	0.004-0.019
Eating from street vendors	130	31.7%	149	65.3%	4.04	2.8-5.7
Attending cholera patient funeral	15	96.3%	77	33.7.7%	13.3	7.4-24
Washed cholera dead body	0	0	13	5.7%
Toilet (bore hall)	155	37.9%	98	42.9%
Toilet (septic tank)	248	60.6%	57	25%
No Toilet	6	1.4%	73	32%
Comorbidity: diabetes	0	0	12	5.2%
Comorbidity: pulmonary diseases.			8	3.2%
Comorbidity: renal diseases			4	1.7%
Comorbidity: malnutrition.			7	3%
Comorbidity: heart diseases.			25	11%
Vaccinated against cholera	297	72.6%	58	25.4%	0.128	0.089-0.186

Regarding vaccination status, only 25.4% of cases had received OCV compared to 72.6% of controls (OR = 0.128 [95% CI: 0.089-0.186]) indicating a strong protective effect.

For hand hygiene after defecation, 97.5% of controls used soap compared to only 42.5% of cases (OR = 0.018, 95% CI: 0.009-0.036). In contrast, using only water after defecation was significantly more common among cases (57%) than controls (2.4%), OR = 52.9 (95% CI: 26.8-104.4).

Street food consumption was also an identified risk factors as a higher proportion of cases reported eating from street vendors (65.3%) compared to controls (31.7%), OR = 4.04 (95% CI: 2.8-5.7).

The possible exposure to cholera through attending a cholera funeral (OR = 13.3, 95% CI: 7.4-24) and having a family history of cholera (OR = 124.4, 95% CI: 60.3-256.5) were strongly associated with disease occurrence. A considerable proportion of cases (13, 5.7%) reporting participating in cholera dead body washing.

Regarding sanitation access, 32% of cases had no access to any toilet facility, compared to only 1.4% of controls.

Multivariate logistic regression results

Logistic regression identified independent predictors of cholera infection as follows (Table 3): Oral cholera vaccination significantly reduced the odds of infection (adjusted OR [aOR] = 0.07, 95% CI: 0.037-0.13, P < 0.001). The age of <20 years was associated with a lower risk (aOR = 0.74, 95% CI: 0.58-0.93, P = 0.01). Consumption of food from street venders remained a significant risk factor (aOR = 2.5, 95% CI: 1.3-4.8, P = 0.004). Big family size (≥2 families per household) was strongly associated with cholera risk (OR = 10.2, 95% CI: 5.7-18.1, P < 0.001). In addition, washing hands with soap after defecation lowered the risk of cholera (aOR = 0.08, 95% CI: 0.01-0.37, P = 0.001), washing hands with water only after defecation significantly increased the risk of cholera (aOR = 14.8, 95% CI: 3.5-61.8, P < 0.001). In addition, attending cholera funerals was associated with higher risk (aOR = 9.1, 95% CI: 3.4-24.4, P < 0.001).

Table 3.

The results of the multivariate logistic regression.

Term	Odds ratio	95%	CI	Coefficient	SE	Z-Statistic	P-Value
Vaccination	0.0706	0.0374	0.1335	–2.6503	0.3250	-8.1553	0.0000
Age less than 20 years	0.7402	0.5872	0.9331	–0.3008	0.1181	-2.5463	0.0109
Number of families (≥2)	10.2314	5.7862	18.0914	2.3255	0.2908	7.9965	0.0000
Eating from street venders)	2.5582	1.3494	4.8500	0.9393	0.3264	2.8782	0.0040
Using soap after defecation	0.0824	0.0180	0.3762	–2.4962	0.7748	-3.2219	0.0013
Using only water after defecation	14.8879	3.5834	61.8543	2.7005	0.7267	3.7164	0.0002
Attending cholera funeral	9.1332	3.4144	24.4307	2.2119	0.5020	4.4061	0.0000
Constant	a	a	a	1.0549	0.8468	1.2458	0.2128

^aConstant represents the model intercept corresponding to the reference categories of all covariates.

Vaccine effectiveness

OCV showed a protective effectiveness of 87.2% against cholera based on unadjusted analysis (OR = 0.128; 95% CI: 0.089-0.186). After adjusting for potential confounders, the effectiveness is even higher at 93% (aOR = 0.07, 95% CI: 0.037-0.13, P < 0.001), reflecting a strong protective effect in a real-world outbreak setting (Table 3).

Discussion

The interplay of massive population displacement, disruption in WASH, and the unusual torrential rainfall in Kassala State in 2024 has led to a massive cholera resurgence, making the rapid use of the vaccine a life-saving intervention and key to controlling the spread. The study found that the adjusted OCV effectiveness was 93%, a finding that aligns with prior studies from Sudan in a similar outbreak and humanitarian emergency context [12]. That highlights the very important role of OCV in protection against cholera and controlling outbreaks in fragile settings, demonstrating high real-world OCV effectiveness in humanitarian emergencies [14]. However, reliance solely on reactive vaccination without concurrent WASH and community engagement may lead to resurgence once vaccine-derived immunity wanes [15], and was recently observed in Sudan during the second-wave cholera outbreak amidst the current conflict crisis [11].

Policymakers in Sudan need to shift to integrated planning, combining OCV campaigns—preventive not only reactive ones—with sustainable WASH and health system strengthening. That should be based on evidence-based risk mapping to and targeting of the priority hotspot areas as recommended by the Global Task Force on Cholera Control (GTFCC) [16].

A very important area for investment for more strategic is working at the community level, to improve raise awareness on cholera and promote hygiene practices. The study showed stark disparity in soap use (97.5% of controls vs 42.5% of cases) and high odds of cholera with water-only hygiene (aOR 14.8). This observation underlines the critical role of hand hygiene in cholera prevention, proving the conclusions from a meta-analysis which confirm that good hygiene results in approximately 66% reduction in cholera risk (pooled OR ∼0.34) [17]. Both findings highlight both behavioral gaps and structural barriers to effective hygiene practice. Integration of mass hygiene promotion campaigns is highly recommended and prioritizing distribution of hygiene kits in cholera high-risk zones, both for response and also as a preparedness intervention, especially in hotspot areas where there is reported seasonality.

Attendance at cholera funerals (aOR 9.1) and corpse-washing rituals (5.7% cases) were strongly associated with infection. WHO and Médecins Sans Frontières guidelines consistently warn against traditional burial practices and unsafe corpse handling as cholera transmission pathways [18,19]. Development and implementation of culturally sensitive funeral protocols with community and religious leader involvement is key to address that challenge, in addition to integrating that in the health education and risk communication messages.

Cholera risk is also linked to overcrowded living conditions, as households with ≥2 families exhibited a significantly increased risk (aOR 10.2). This is one of the well-documented drivers of cholera outbreaks [20]. In displaced settings, it is crucial to integrate outbreak preparedness into shelter planning and ensuring safe, uncrowded housing. Health authorities must give focus to displaced people who are not in structured camps, and those who are hosted by relatives or gathered in rented houses. Strengthening multi-sector coordination between health and shelter partners to reach all displaced people inside and outside camps. in addition to the previously identified risk factors, street food consumption was associated with higher risk (aOR 2.5), reflecting a common link between informal food vendors and cholera transmission [21,22]. Revisiting food safety regulations and careful monitoring of their implementation is necessary as a preventive and a response measure.

Conclusion

Our findings reaffirm the role of OCV as a critical intervention in cholera outbreak response, especially in fragile settings. However, controlling cholera sustainably requires parallel strategic investment in safe water and sanitation, hygiene promotion, and risk communication—particularly targeting funeral practices, food safety, and overcrowded households. Cholera risk mapping is critical for more targeted intervention in high-risk areas, particularly those with known disease seasonality. Policymakers should prioritize these integrated approaches alongside rapid vaccine deployment to reduce transmission and mortality in complex emergencies.

Declaration of competing interest

The authors have no competing interests to declare.