Healthcare Providers' and Frontline Workers' Experiences of an Ebola Vaccine Trial in the Boende Health District of the Democratic Republic of the Congo.

This study explored the experiences of healthcare providers (HCPs) and frontline workers who were involved in an Ebola vaccine trial in the Democratic Republic of the Congo. The researchers interviewed a total of 99 participants (HCPs and frontline workers) living and working in the Boende health district during the period of the study, from February to March 2022. These individuals included a mix of trial participants and non-trial participants (staff of the trial, local health authorities, and head nurses of health centers). In-depth individual interviews, as well as focus group discussions (FGDs), were used to understand interviewees' experiences and perceptions. The data were analyzed to identify the main themes. The findings unveiled a multitude of positive experiences among interviewees/FGD participants. The commitment of the trial investigators to improve the study site and to equip the volunteers with necessary skills and knowledge greatly contributed to a positive trial experience. However, some interviewees felt that the reimbursement for time and travel expenses during their trial visits was insufficient in comparison with their expectations. Additionally, there were expressions of worry about the frequency of blood draws during scheduled trial visits. Our findings emphasize the critical importance of addressing and continuously considering the perspectives and concerns of trial participants before designing and implementing vaccine trials. By actively incorporating their inputs, researchers can mitigate concerns and tailor communication strategies, potentially enhancing the overall success and impact of the vaccine trial.

An ancillary care policy in a vaccine trial conducted in a resource-constrained setting: evaluation and policy recommendations.

INTRODUCTION: Clear guidelines to implement ancillary care (AC) in clinical trials conducted in resource-constrained settings are lacking. Here, we evaluate an AC policy developed for a vaccine trial in the Democratic Republic of the Congo and formulate policy recommendations. METHODS: To evaluate the AC policy, we performed a longitudinal cohort study, nested in an open-label, single-centre, randomised Ebola vaccine trial conducted among healthcare personnel. Participants' demographic information, residence distance to the study site and details on the financial and/or medical support provided for any (serious) adverse events ((S)AE) were combined and analysed. To assess the feasibility of the AC policy, an expenditure analysis of the costs related to AC support outcomes was performed. RESULTS: Enrolment in this evaluation study started on 29 November 2021. The study lasted 11 months and included 655 participants from the Ebola vaccine trial. In total, 393 participants used the AC policy, mostly for AE management (703 AE and 94 SAE) via medication provided by the study pharmacy (75.3%). Men had a 35.2% (95% CI 4.0% to 56.6%) lower likelihood of reporting AE compared with women. Likewise, this was 32.3% lower (95% CI 5.8% to 51.4%) for facility-based compared with community-based healthcare providers. The daily AE reporting was 78.8% lower during the passive vs the active trial stage, and 97.4% lower during unscheduled vs scheduled visits (p<0.001). Participants living further than 10 km from the trial site more frequently reported the travel distance as a reason for not using the policy (p<0.04). In practice, only 1.1% of the operational trial budget was used for AC policy support. CONCLUSION: The trial design, study population and local health system impacted the use of the AC policy. Nonetheless, the AC policy implementation in this remote and resource-constrained setting was feasible, had negligible budgetary implications and contributed to participants' healthcare options and well-being.

Prevention of Malaria in Pregnant Women and Its Effects on Maternal and Child Health, the Case of Centre Hospitalier de Kingasani II in the Democratic Republic of the Congo.

This study aimed to evaluate scientific evidence of the benefit of the use of insecticide-treated nets (ITNs) and Intermittent preventive treatment (IPT) on the birth weight of newborns and the hemoglobin level of the mother when used to prevent malaria during pregnancy. This cross-sectional analytical study was conducted on 467 hospitalized women in the Maternity Ward of Centre Hospitalier de Kingasani II, in the Democratic Republic of the Congo. Data were collected using a structured questionnaire that was pre-tested during a face-to-face interview. Apart from basic statistics, the chi-square test was used to compare proportions. Multivariate analysis (logistic regression) was used to identify variables significantly associated with the 95% confidence interval (CI). The ITN ownership rate was 81% (95% CI: 77-84) and the ITN use rate was 66% (95% CI: 62-70). Sixty-five percent (95% CI: 60-69) reported having received at least three doses of IPT during pregnancy with sulfadoxine-pyramethemine (IPTp-SP). There was a statistically significant difference in hemoglobin levels between hospitalized women who did not use the ITN (9.4 g/dL IIQ: 8.7-9.9) and those who did (11 g/dL IIQ: 9.8-12.2). The non-use of the ITN was associated with low birth weight (aOR = 3.6; 95% CI: 2.1-6.2; p < 0.001) and anemia in pregnant women (cOR = 2.41; 95% CI: 1.16-5.01; p = 0.018). The use of ITN and taking at least three doses of ITP during pregnancy are associated with good birth weight. The number of doses of IPTp received during antenatal care is associated with the maternal hemoglobin level in the third trimester of pregnancy.

Ad26.ZEBOV, MVA-BN-Filo Ebola virus disease vaccine regimen plus Ad26.ZEBOV booster at 1 year versus 2 years in health-care and front-line workers in the Democratic Republic of the Congo: secondary and exploratory outcomes of an open-label, randomised, phase 2 trial.

BACKGROUND: Health-care providers and front-line workers are at risk of contracting Ebola virus disease during an Ebola virus outbreak and consequently of becoming drivers of the disease. We aimed to assess the long-term immunogenicity of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen and the safety of and immune memory response to an Ad26.ZEBOV booster vaccination at 1 year or 2 years after the first dose in this at-risk population. METHODS: This open-label, single-centre, randomised, phase 2 trial was conducted at one study site within a hospital in Boende, Democratic Republic of the Congo. Adult health-care providers and front-line workers, excluding those with a known history of Ebola virus disease, were vaccinated with a two-dose heterologous regimen administered at a 56-day interval via a 0·5 mL intramuscular injection in the deltoid muscle, comprising Ad26.ZEBOV as the first dose and MVA-BN-Filo as the second dose. After the initial vaccination on day 1, participants were randomly assigned (1:1) via randomisation envelopes, opened in a sequential order, to receive an Ad26.ZEBOV booster vaccination at 1 year (group 1) or 2 years (group 2) after the first dose. We present the secondary and exploratory objectives of the trial-results of the primary objective have been published elsewhere. We measured immunogenicity at six timepoints per group as geometric mean concentrations (GMCs) of Ebola virus glycoprotein-specific IgG binding antibodies, using the Filovirus Animal Non-Clinical Group ELISA. We assessed serious adverse events occurring up to 6 months after the last dose and local and systemic solicited and unsolicited adverse events reported for 7 days after the booster vaccination. Antibody responses were analysed per protocol, serious adverse events per full analysis set (FAS), and adverse events for all boosted FAS participants. This trial is registered as completed on ClinicalTrials.gov (NCT04186000). FINDINGS: Between Dec 18, 2019, and Feb 8, 2020, 699 health-care providers and front-line workers were enrolled and 698 were randomly assigned (350 to group 1 and 348 to group 2 [FAS]); 534 (77%) participants were male and 164 (23%) were female. 319 in group 1 and 317 in group 2 received the booster. 29 (8%) in group 1 and 26 (7%) in group 2 did not complete the study, mostly due to loss to follow-up or moving out of the study area. In both groups, injection-site pain or tenderness (87 [27%] of 319 group 1 participants vs 90 [28%] of 317 group 2 participants) and headache (91 [29%] vs 93 [29%]) were the most common solicited adverse events related to the investigational product. One participant (in group 2) had a related serious adverse event after booster vaccination (fever of ≥40·0°C). Before booster vaccination, Ebola virus glycoprotein-specific IgG binding antibody GMCs were 279·9 ELISA units (EU) per mL (95% CI 250·6-312·7) in 314 group 1 participants (1 year after first dose) and 274·6 EU/mL (242·1-311·5) in 310 group 2 participants (2 years after first dose). These values were 5·2 times higher in group 1 and 4·9 times higher in group 2 than before vaccination on day 1. 7 days after booster vaccination, these values increased to 10 781·6 EU/mL (9354·4-12 426·4) for group 1 and 10 746·9 EU/mL (9208·7-12 542·0) for group 2, which were approximately 39 times higher than before booster vaccination in both groups. 1 year after booster vaccination in 299 group 1 participants, a GMC that was 7·6-times higher than before booster vaccination was still observed (2133·1 EU/mL [1827·7-2489·7]). INTERPRETATION: Overall, the vaccine regimen and booster dose were well tolerated. A similar and robust humoral immune response was observed for participants boosted 1 year and 2 years after the first dose, supporting the use of the regimen and flexibility of booster dose administration for prophylactic vaccination in at-risk populations. FUNDING: Innovative Medicines Initiative 2 Joint Undertaking and Coalition for Epidemic Preparedness Innovations.

Longitudinal assessment of an Ebola vaccine trial understanding among healthcare providers in the Democratic Republic of the Congo.

BACKGROUND: The long-term retention of information disclosed during the informed consent in clinical trials lasting over a year cannot be guaranteed for all volunteers. This study aimed to assess the level of participants' retention and understanding of the trial information after two years of participation in a vaccine trial. METHODS: In total, 699 health care providers (HCPs) and frontline workers were enrolled in the EBL2007 vaccine trial conducted between February 2019 and September 2022 in the Health District of Boende, Democratic Republic of the Congo (DRC). Individual scores obtained from a questionnaire (test of understanding, TOU), specifically designed to assess the understanding of the consent at baseline, were collected before the clinical trial started and at one-year and two-year intervals. RESULTS: TOU scores were high in the beginning of the trial (median TOU = 10/10), but significantly decreased in both the first and second years following (median TOU = 8/10 in year 1 and median TOU = 9/10 in year 2, p-value < 0.0001). The decrease in scores was significantly higher among individuals with occupations requiring shorter education such as midwives (median TOU = 7/10 in year 1 and 8/10 in year 2, pvalue = 0.025). Furthermore, older participants exhibited poorer retention of information compared to younger individuals (median TOU = 8/10 vs 9/10, p-value = 0.007). CONCLUSION: We observed a significant decline in the informational knowledge of informed consent, specifically in terms of basic knowledge on the study vaccine and trial procedures. As participant safety and understanding is a paramount ethical concern for researchers, it is crucial for participants to fully comprehend the study's objectives and potential risks. Therefore, our findings suggest the need for clinical researchers to re-explain participants to optimize the protection of their rights and wellbeing during the research.

Safety and Immunogenicity of the Heterologous 2-Dose Ad26.ZEBOV, MVA-BN-Filo Vaccine Regimen in Health Care Providers and Frontliners of the Democratic Republic of the Congo.

BACKGROUND: In response to recent Ebola epidemics, vaccine development against the Zaire ebolavirus (EBOV) has been fast-tracked in the past decade. Health care providers and frontliners working in Ebola-endemic areas are at high risk of contracting and spreading the virus. METHODS: This study assessed the safety and immunogenicity of the 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo vaccine regimen (administered at a 56-day interval) among 699 health care providers and frontliners taking part in a phase 2, monocentric, randomized vaccine trial in Boende, the Democratic Republic of Congo. The first participant was enrolled and vaccinated on 18 December 2019. Serious adverse events were collected up to 6 months after the last received dose. The EBOV glycoprotein FANG ELISA (Filovirus Animal Nonclinical Group enzyme-linked immunosorbent assay) was used to measure the immunoglobulin G-binding antibody response to the EBOV glycoprotein. RESULTS: The vaccine regimen was well tolerated with no vaccine-related serious adverse events reported. Twenty-one days after the second dose, an EBOV glycoprotein-specific binding antibody response was observed in 95.2% of participants. CONCLUSIONS: The 2-dose vaccine regimen was well tolerated and led to a high antibody response among fully vaccinated health care providers and frontliners in Boende.

Conducting an Ebola vaccine trial in a remote area of the Democratic Republic of the Congo: Challenges, mitigations, and lessons learned.

Conducting a vaccine trial in a low- and middle-income country (LMIC) can present unique challenges and lessons learned. This Ebola vaccine trial, enrolling 699 healthcare providers and frontliners and jointly set up by the University of Antwerp (Sponsor) and the University of Kinshasa (Principal Investigator (PI)), was conducted in Boende, a remote city in the Democratic Republic of the Congo (DRC), between December 2019 and October 2022 (ClinicalTrials.gov: NCT04186000). While being bound by strict ICH-GCP and international funder regulations, this trial, exemplary for being a public-private partnership, required collaboration between several international stakeholders (e.g., two universities, a pharmaceutical company, and a clinical research organization), local communities and government agencies. Here we address several logistical and administrative challenges, cultural differences, language barriers and regulatory, political, and ethical considerations over the trial's 2.5-year duration, while tailoring and adapting the study to the specific local context. Lessons learned include the importance of clear communication with participants in all phases of the study, but also within the study team and among different stakeholders. Challenges, mitigations, and lessons learned are presented in nine categories (e.g., safety management; trial documentation, tools, and materials; communication, staff training and community engagement/sensitization; financial and administrative hurdles; and more). Ultimately, to reach the successful end of the vaccine trial in this remote Ebola endemic area in the DRC, careful planning, collaboration, and great flexibility and adaptability was often required from all involved partners. Despite the encountered challenges, the vaccine trial discussed in this paper was able to obtain high participant retention rates (i.e., 92% of participants completed the study). We hope that other international teams aspiring to conduct similar trials in remote areas of LMICs can learn from the way our challenges were addressed, mitigations developed, and lessons were learned.

Performance of ultra-sensitive malaria rapid diagnostic test to detect Plasmodium falciparum infection in pregnant women in Kinshasa, the Democratic Republic of the Congo.

BACKGROUND: Low peripheral parasitaemia caused by sequestration of Plasmodium falciparum in the placenta hampers the diagnosis of malaria in pregnant women, leading to microscopy or conventional rapid diagnostic tests (RDTs) false-negative results. Although mainly asymptomatic, maternal malaria remains harmful to pregnant women and their offspring in endemic settings and must be adequately diagnosed. Ultra-sensitive RDTs (uRDTs) are thought to be more sensitive than RDTs, and their diagnostic performance was assessed in the current study in pregnant women living in Kinshasa, a stable malaria transmission area in the Democratic Republic of the Congo. METHODS: To assess and compare the diagnostic performances of both RDTs and uRDTs, 497 peripheral blood samples were tested using microscopy and quantitative polymerase chain reaction (qPCR) as the index and the reference tests, respectively. The agreement between the different diagnostic tests assessed was estimated by Cohen's Kappa test. RESULTS: The median parasite density by qPCR was 292 p/µL of blood [IQR (49.7-1137)]. Using qPCR as the reference diagnostic test, the sensitivities of microscopy, RDT and uRDT were respectively [55.7% (95% CI 47.6-63.6)], [81.7% (95%CI 74.7-87.3)] and [88% (95% CI 81.9-92.6)]. The specificities of the tests were calculated at 98.5% (95% CI 96.6-99.5), 95.2% (95% CI 92.5-97.2) and 94.4% (95% CI 91.4-96.6) for microscopy, RDT and uRDT, respectively. The agreement between qPCR and uRDT was almost perfect (Kappa = 0.82). For parasite density (qPCR) below 100 p/µL, the sensitivity of RDT was 62% (95% CI 47.1-75.3) compared to 68% (95% CI 53.3-80.4) for uRDT. Between 100 and 200 p/µL, the sensitivity of RDT was higher, but still lower compared to uRDT: 89.4% (95% CI 66.8-98.7) for RDT versus 100% (95% CI 82.3-100) for uRDT. In both cases, microscopy was lower, with 20% (95% CI 10-33.7) and 47.3% (95% CI 24.4-71.1) respectively. CONCLUSIONS: uRDT has the potential to improve malaria management in pregnant women as it has been found to be slightly more sensitive than RDT in the detection of malaria in pregnant women but the difference was not significant. Microscopy has a more limited value for the diagnosis of malaria during the pregnancy, because of its lower sensitivity.

Low seroprevalence of Ebola virus in health care providers in an endemic region (Tshuapa province) of the Democratic Republic of the Congo.

INTRODUCTION: A serosurvey among health care providers (HCPs) and frontliners of an area previously affected by Ebola virus disease (EVD) in the Democratic Republic of the Congo (DRC) was conducted to assess the seroreactivity to Ebola virus antigens. METHODS: Serum samples were collected in a cohort of HCPs and frontliners (n = 698) participants in the EBL2007 vaccine trial (December 2019 to October 2022). Specimens seroreactive for EBOV were confirmed using either the Filovirus Animal Nonclinical Group (FANG) ELISA or a Luminex multiplex assay. RESULTS: The seroreactivity to at least two EBOV-Mayinga (m) antigens was found in 10 (1.4%: 95% CI, 0.7-2.6) samples for GP-EBOV-m + VP40-EBOV-m, and 2 (0.3%: 95% CI, 0.0-1.0) samples for VP40-EBOV-m + NP-EBOV-m using the Luminex assay. Seroreactivity to GP-EBOV-Kikwit (k) was observed in 59 (8.5%: 95%CI, 6.5-10.9) samples using FANG ELISA. CONCLUSION: In contrast to previous serosurveys, a low seroprevalence was found in the HCP and frontline population participating in the EBL2007 Ebola vaccine trial in Boende, DRC. This underscores the high need for standardized antibody assays and cutoffs in EBOV serosurveys to avoid the broad range of reported EBOV seroprevalence rates in EBOV endemic areas.

Prevalence and predictors of adverse events following exposure to long-lasting insecticidal nets used for malaria prevention: a community based cross-sectional study in the Democratic Republic of the Congo.

BACKGROUND: Malaria morbidity and mortality increase in the Democratic Republic of the Congo (DRC) may be the consequence of the low utilization rate of long-lasting insecticidal nets (LLINs) resulting from poor compliance due to adverse events (AEs). This study aimed at determining the prevalence and predictors of AEs following the mass distribution of LLINs in the Kisantu Health Zone (KHZ), a high malaria-endemic region in the DRC. METHODS: A community-based cross-sectional study embedded was conducted within a randomized controlled trial (RCT) after the mass distribution of LLINs in 30 villages located in DRC KHZ. A three-stage sampling method was used without replacement to select 1790 children. Data was collected on adverse events (AEs) using a reporting form and information on demographics, nutritional status, and house characteristics. This was done using a structured questionnaire administered to household heads. Logistic regression models were used to identify predictors of AEs following the mass distribution of LLINs. RESULT: In a total of 1790 children enrolled, 17.8% (95% CI 16.1-19.7) experienced AEs. The most common AEs were respiratory-related (61%). Around 60% of AEs occurred within 24 h of use, and 51% were resolved without treatment. Sleeping under deltamethrin LLINs (Adjusted OR, 95% CI 5.5 [3.8-8.0]) and zinc roofing (Adjusted OR, 95% CI 1.98 [1.1-3.57]) were associated with the risk of reporting an AE following the mass distribution of LLINs. CONCLUSION: Approximately 1 out of 5 children had an AE within 24 h following LLIN use. These adverse events were often respiratory-related. LLINs and roofing types were associated with a higher risk of reporting AEs. However, further research using a robust study design is needed to confirm these findings. Future studies should design and implement interventions aiming to reduce AEs and improve compliance with LLINs.

Malaria among children under 10 years in 4 endemic health areas in Kisantu Health Zone: epidemiology and transmission.

BACKGROUND: The Democratic Republic of the Congo (DRC) is the second most malaria-affected country in the world with 21,608,681 cases reported in 2019. The Kongo Central (KC) Province has a malaria annual incidence of 163 cases/per 1000 inhabitants which are close to the national average of 153.4/1000. However, the malaria prevalence varies both between and within health zones in this province. The main objective of this study was to describe the epidemiology and transmission of malaria among children aged 0 to 10 years in the 4 highest endemic health areas in Kisantu Health Zone (HZ) of KC in DRC. METHODS: A community-based cross-sectional study was conducted from October to November 2017 using multi-stage sampling. A total of 30 villages in 4 health areas in Kisantu HZ were randomly selected. The prevalence of malaria was measured using a thick blood smear (TBS) and known predictors and associated outcomes were assessed. Data are described and association determinants of malaria infection were analysed. RESULTS: A total of 1790 children between 0 and 10 years were included in 30 villages in 4 health areas of Kisantu HZ. The overall prevalence in the study area according to the TBS was 14.8% (95% CI: 13.8-16.6; range: 0-53). The mean sporozoite rate in the study area was 4.3% (95% CI: 2.6-6.6). The determination of kdr-west resistance alleles showed the presence of both L1014S and L1014F with 14.6% heterozygous L1014S/L1014F, 84.4% homozygous 1014F, and 1% homozygous 1014S. The risk factors associated with malaria infection were ground or wooden floors aOR: 15.8 (95% CI: 8.6-29.2), a moderate or severe underweight: 1.5 (1.1-2.3) and to be overweight: 1.9 (95% CI: 1.3-2.7). CONCLUSION: Malaria prevalence differed between villages and health areas within the same health zone. The control strategy activities must be oriented by the variety in the prevalence and transmission of malaria in different areas. The policy against malaria regarding long-lasting insecticidal nets should be based on the evidence of metabolic resistance.

Comparison of intermittent screening (using ultra-sensitive malaria rapid diagnostic test) and treatment (using a newly registered antimalarial pyronaridine-artesunate-PYRAMAX®) to standard intermittent preventive treatment with sulfadoxine-pyrimethamine for the prevention of malaria in pregnant women living in endemic areas: ULTRAPYRAPREG.

BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is an important malaria control strategy in sub-Saharan Africa. Indeed, it overcomes the risk of misdiagnosis due to low peripheral parasitemia during pregnancy by treating women with SP on predetermined schedules. However, over time, the spread of Plasmodium-resistant strains has threatened this strategy in many countries. As an alternative, the intermittent screening and treatment for pregnancy (ISTp) aims at a monthly screening of pregnant women, preferably by using very sensitive tests such as ultrasensitive rapid diagnostic tests (us-RDTs) and the treatment of positive cases with artemisinin-based combination therapy (ACT) regardless of the presence of symptoms. Unlike IPTp-SP, ISTp prevents overuse of antimalarials limiting the drug pressure on parasites, an advantage which can be potentiated by using an ACT like pyronaridine-artesunate (Pyramax®) that is not yet used in pregnant women in the field. METHODS: This study aims to compare the non-inferiority of ISTp using us-RDTs and Pyramax® versus IPTp-SP on malaria in pregnancy through a randomized clinical trial performed in Kisenso, Kinshasa, the Democratic Republic of the Congo, a malaria perennial transmission area. DISCUSSION: The results will be essential for the National Malaria Control Program to update the malaria prevention policy in pregnant women in the Democratic Republic of the Congo. TRIAL REGISTRATION: ClinicalTrials.gov NCT04783051.

Boosting ethics review capacity in public health emergency situations: Co-creation of a training model for French-speaking research ethics committees.

BACKGROUND: Ethics review preparedness is a major foundation for national effective response to public health emergencies, because it promotes pertinent research and enhances the protection of research participants and communities. In low-income countries, it can also promote equitable research partnership. However, most relevant literature is in English and not easily accessible for the members of research ethics committees in French-speaking African countries. METHODS: A training module in French, addressing the issue of research ethics review during outbreaks and other public health emergencies, was designed based on a non-systematic literature review, and in order to be complementary to the Democratic Republic of Congo (DRC) national guidelines for ethics review. The module was administered to 42 members of the five ethics committees in DRC that expressed their interest for the training. RESULT: This training, co-designed with local stakeholders, in the local working language and taking into account local circumstances and regulation, provided participants with up-to-date insights of research ethics (and research ethics preparedness) in public health emergencies. It resulted in rich reflection and knowledge-sharing on good practices across the ethics committees. CONCLUSION: As most participating ethics committees do not have yet explicit standard operating procedures for expedited review of protocols submitted in emergency situations, this would be a next important step to facilitate emergency reviews in the most efficient way.

Phase 3 Evaluation of an Innovative Simple Molecular Test for the Diagnosis of Malaria and Follow-Up of Treatment Efficacy in Pregnant Women in Sub-Saharan Africa (Preg-Diagmal).

The malaria parasite Plasmodium falciparum (Pf) can sequester in the placenta resulting in low density of peripheral parasitemia and consequently in false negative malaria diagnosis (by microscopy) in pregnant women. Moreover, the use of rapid diagnostic tests (RDTs) in diagnostic strategies, including those for the detection of a malaria infection during pregnancy, is constrained by either persistent malaria antigen (histidine-rich protein 2; HRP2) after successful treatment, leading to false positive test results, or by false negative results as previously mentioned due to parasite sequestration (which is further exacerbated due to the low limited of detection [LoD] of conventional RDTs) or to HRP2 deletion. Recently, a direct blood polymerase chain reaction combined with a nucleic acid lateral flow immunoassay (dbPCR-NALFIA) has been developed, which circumvents these challenges and has demonstrated its diagnostic potential in phase 1 and 2 studies. The PREG-DIAGMAL trial presented in this manuscript will assess the diagnostic performance of dbPCR-NALFIA for the diagnostic of malaria in pregnant women and its potential to monitor treatment efficacy in these subjects. The work is ancillary embedded in an ongoing EDCTP funded trial, the PyraPreg project (PACTR202011812241529) in which the safety and efficacy of a newly registered Artemisinin-Based Combination (Pyronaridine-Artesunate) is being evaluated in pregnant women. This is a Phase 3 diagnostic evaluation conducted in 2 African countries: Democratic Republic of the Congo (DRC) and Burkina Faso. Pregnant women fulfilling the inclusion criteria of the PyraPreg study will be also invited to participate in the PREG-DIAGMAL study. Diagnostic accuracy will be assessed following the WHO/TDR guidelines for the evaluation of diagnostics and reported according to STARD principles. Due to the lack of a 100% specific and sensitive standard diagnostic test for malaria, the sensitivity and specificity of the new test will be compared to the available diagnostic practice in place at the selected settings (microscopy and/or RDT) and to quantitative PCR as the reference test. This phase 3 diagnostic study is designed towards the evaluation of the performance of a new diagnostic tool for the screening of malaria and the monitoring of treatment in pregnant women under real conditions life. If successful, the dbPCR-NALFIA could be a valuable tool to add to the diagnostic arsenal for malaria, in particular during pregnancy. Trial registration: Pan African Clinical Trial Registry database (PACTR202203780981413). Registered on 17 March 2022.

Setting-up an Ebola vaccine trial in a remote area of the Democratic Republic of the Congo: Challenges, mitigations, and lessons learned.

Since the largest Ebola outbreak in West Africa (2013-2016) highlighted the potential threat of the Ebola virus to the world, several vaccines have been under development by different pharmaceutical companies. To obtain vaccine licensure, vaccine trials assessing the safety, immunogenicity and efficacy of new vaccines among different populations (e.g. different in age, gender, race, and ethnicity) play a crucial role. However, while this deadly disease mainly affects Central and West Africa, clinical trial regulations are becoming increasingly complex and consequently more expensive, influencing the affected low- and middle-income countries (LMICs) in performing high quality clinical trials. Consequently, the completion of such trials in LMICs takes more time and vaccines and drugs take longer to be licensed. To overcome some of the obstacles faced, the EBOVAC3 consortium, funded by the European Union's Innovative Medicines Initiative and the Coalition for Epidemic Preparedness Innovations, enabled high quality vaccine trials in Central and West Africa through extensive North-South collaborations. In this article, the encountered challenges, mitigations, recommendations and lessons learned from setting-up an Ebola vaccine trial in a remote area of the Democratic Republic of Congo are presented. These challenges are grouped into eight categories: (1) Regulatory, political and ethical, (2) Trial documents, (3) International collaborations, (4) Local trial staff, (5) Community engagement and sensitization, (6) Logistics, (7) Remoteness and climate conditions, (8) Financial. By sharing the encountered challenges, implemented mitigations and lessons learned for each of these categories, we hope to prepare and inform other researchers aspiring a well-functioning clinical trial unit in similar remote settings in LMICs. ClinicalTrials.gov identifier: NCT04186000.

Open-label, randomised, clinical trial to evaluate the immunogenicity and safety of a prophylactic vaccination of healthcare providers by administration of a heterologous vaccine regimen against Ebola in the Democratic Republic of the Congo: the study protocol.

INTRODUCTION: This article describes the protocol of an Ebola vaccine clinical trial which investigates the safety and immunogenicity of a two-dose prophylactic Ebola vaccine regimen comprised of two Ebola vaccines (Ad26.ZEBOV and MVA-BN-Filo) administered 56 days apart, followed by a booster vaccination with Ad26.ZEBOV offered at either 1 year or 2 years (randomisation 1:1) after the first dose. This clinical trial is part of the EBOVAC3 project (an Innovative Medicines Initiative 2 Joint Undertaking), and is the first to evaluate the safety and immunogenicity of two different booster vaccination arms in a large cohort of adults. METHODS AND ANALYSIS: This study is an open-label, monocentric, phase 2, randomised vaccine trial. A total of 700 healthcare providers and frontliners are planned to be recruited from the Tshuapa province in the Democratic Republic of the Congo (DRC). The primary and secondary objectives of the study assess the immunogenicity of the first (Ad26.ZEBOV), second (MVA-BN-Filo) and booster (Ad26.ZEBOV) dose. Immunogenicity is assessed through the evaluation of EBOV glycoprotein binding antibody responses after vaccination. Safety is assessed through the collection of serious adverse events from the first dose until 6 months post booster vaccination and the collection of solicited and unsolicited adverse events for 1 week after the booster dose. ETHICS AND DISSEMINATION: The protocol was approved by the National Ethics Committee of the Ministry of Health of the DRC (n°121/CNES/BN/PMMF/2019). The clinical trial was registered on 4 December 2019 on ClinicalTrials.gov. Trial activities are planned to finish in October 2022. All participants are required to provide written informed consent and no study-related procedures will be performed until consent is obtained. The results of the trial will be added on ClinicalTrials.gov, published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT04186000; Pre-results.

Use of Iris Scanning for Biometric Recognition of Healthy Adults Participating in an Ebola Vaccine Trial in the Democratic Republic of the Congo: Mixed Methods Study.

BACKGROUND: A partnership between the University of Antwerp and the University of Kinshasa implemented the EBOVAC3 clinical trial with an Ebola vaccine regimen administered to health care provider participants in Tshuapa Province, Democratic Republic of the Congo. This randomized controlled trial was part of an Ebola outbreak preparedness initiative financed through Innovative Medicines Initiative-European Union. The EBOVAC3 clinical trial used iris scan technology to identify all health care provider participants enrolled in the vaccine trial, to ensure that the right participant received the right vaccine at the right visit. OBJECTIVE: We aimed to assess the acceptability, accuracy, and feasibility of iris scan technology as an identification method within a population of health care provider participants in a vaccine trial in a remote setting. METHODS: We used a mixed methods study. The acceptability was assessed prior to the trial through 12 focus group discussions (FGDs) and was assessed at enrollment. Feasibility and accuracy research was conducted using a longitudinal trial study design, where iris scanning was compared with the unique study ID card to identify health care provider participants at enrollment and at their follow-up visits. RESULTS: During the FGDs, health care provider participants were mainly concerned about the iris scan technology causing physical problems to their eyes or exposing them to spiritual problems through sorcery. However, 99% (85/86; 95% CI 97.1-100.0) of health care provider participants in the FGDs agreed to be identified by the iris scan. Also, at enrollment, 99.0% (692/699; 95% CI 98.2-99.7) of health care provider participants accepted to be identified by iris scan. Iris scan technology correctly identified 93.1% (636/683; 95% CI 91.2-95.0) of the participants returning for scheduled follow-up visits. The iris scanning operation lasted 2 minutes or less for 96.0% (656/683; 95% CI 94.6-97.5), and 1 attempt was enough to identify the majority of study participants (475/683, 69.5%; 95% CI 66.1-73.0). CONCLUSIONS: Iris scans are highly acceptable as an identification tool in a clinical trial for health care provider participants in a remote setting. Its operationalization during the trial demonstrated a high level of accuracy that can reliably identify individuals. Iris scanning is found to be feasible in clinical trials but requires a trained operator to reduce the duration and the number of attempts to identify a participant. TRIAL REGISTRATION: ClinicalTrials.gov NCT04186000; https://clinicaltrials.gov/ct2/show/NCT04186000.

Algorithm for the support of non-related (serious) adverse events in an Ebola vaccine trial in the Democratic Republic of the Congo.

Implementing an Ebola vaccine trial in a remote area in the Democratic Republic of the Congo (DRC), and being confronted with a dysfunctional health care system and acute unmet health needs of participants, ethical considerations were made regarding the ancillary care obligations of the sponsor and researchers. Spurred by the occurrence of non-related (serious) adverse events (NR-SAEs), the Universities of Antwerp and Kinshasa jointly developed an algorithm, accompanied by an algorithm policy. The algorithm consists of a set of consecutive questions with binary response options, leading to structured, non-arbitrary and consistent support and management for each NR-SAE. It is the result of dialogue and collaboration between the sponsor (University of Antwerp) and the principal investigator (University of Kinshasa), consultation of literature, and input of research ethics and social sciences experts. The characteristics of the project and its budgetary framework were taken into account, as well as the local socioeconomic and healthcare situation. The algorithm and related policy have been approved by the relevant ethics committee (EC), so field implementation will begin when the study activities resume in November 2021. Lessons learnt will be shared with the relevant stakeholders within and outside DRC.If NR-SAEs are not covered by a functioning social welfare system, sponsors and researchers should develop a feasible, standardised and transparent approach to the provision of ancillary care. National legislation and contextualised requirements are therefore needed, particularly in low/middle-income countries, to guide researchers and sponsors in this process. Protocols, particularly of clinical trials conducted in areas with 'access to care' constraints, should include adequate ancillary care arrangements. Furthermore, it is essential that local ECs systematically require ancillary care provisions to enhance the well-being and protection of the rights of research participants. This project was funded by the European Union's Horizon 2020 research and innovation programme, European Federation of Pharmaceutical Industries and Associations, and the Coalition for Epidemic Preparedness Innovations.

Uncomplicated Clinical Malaria Features, the Efficacy of Artesunate-Amodiaquine and Their Relation with Multiplicity of Infection in the Democratic Republic of Congo.

BACKGROUND: In the Democratic Republic of Congo, artesunate-amodiaquine (ASAQ) is the first-line medication recommended for uncomplicated malaria treatment. We conducted a study in Kinshasa to describe the clinical features of the disease and assess the efficacy of ASAQ and its impact on the multiplicity of infection in children with uncomplicated malaria. METHODS: Children aged 12 to 59 months with uncomplicated P. falciparum malaria were treated with ASAQ and followed up passively for 42 days. To distinguish new infections from recrudescent parasites, samples were genotyped using a stepwise strategy with three molecular markers (GLURP, MSP2 and MSP1). We then assessed PCR-corrected and -uncorrected day-42 cure rates and multiplicity of infection (MOI). RESULTS: In total, 2,796 patients were screened and 865 enrolled in the study. Clinical features were characterized by history of fever (100%), coryza (59.9%) and weakness (59.4%). The crude and PCR-corrected efficacies of ASAQ were 55.3% (95%CI: 51.8-58.8) and 92.8% (95%CI: 91.0-94.6) respectively, as 83.6% (95%CI: 79.1-87.2) of the recurrences were new infections. Compared to monoclonal infections, polyclonal infections were more frequent at enrollment (88.1%) and in recurrences (80.1%; p = 0.005; OR: 1.8, 95%CI: 1.20-2.8). The median MOI at enrollment (MOI = 3.7; IQR: 0.7-6.7) decreased to 3 (IQR: 1-5) in the recurrent samples (p<0.001). Patients infected with a single haplotype on day 0 had no recrudescence; the risk of recrudescence increased by 28% with each additional haplotype (HR: 1.3, 95%CI: 1.24-1.44). CONCLUSION: The PCR-corrected efficacy of ASAQ at day 42 was 92.8%, but crude efficacy was relatively poor due to high reinfection rates. Treatment outcomes were positively correlated with MOI. Continued monitoring of the efficacy of ACTs-ASAQ, in this case-is paramount. TRIAL REGISTRATION: ClinicalTrials.gov NCT01374581.

The Challenges of Research Informed Consent in Socio-Economically Vulnerable Populations: A Viewpoint From the Democratic Republic of Congo.

In medical research, the ethical principle of respect for persons is operationalized into the process of informed consent. The consent tools should be contextualized and adapted to the different socio-cultural environment, especially when research crosses the traditional boundaries and reaches poor communities. We look at the challenges experienced in the malaria Quinact trial, conducted in the Democratic Republic of Congo, and describe some lessons learned, related to the definition of acceptable representative, the role of independent witness and the impact of socio-economic vulnerability. To ensure children's protection, consent is required by the parents or, in their absence, by a legally mandated representative. In our setting, children's responsibility is often entrusted permanently or temporarily to relatives or friends without a tribunal mandate. Hence, a notion of 'culturally acceptable representative' under supervision of the local Ethics Committee may be more suitable. To ensure protection of illiterate subjects, an independent witness is required to confirm that the consent was freely given. However, in low-literacy contexts, potential witnesses often don't have any previous relationship with patient and there may be power-unbalance in their relationship, rather than genuine dialogue. In poor communities, trial participation may be seen as an opportunity to secure access to healthcare. Poverty may also lead to 'competition' to access the research-related benefits, with a risk of disturbance at societal or household level. Adjusting consent procedures to sociocultural and socioeconomic realities is essential for fulfilling the underlying ethical principles. This requires a collaborative dialogue between researchers, regulators and ethics committees.