Functional Simulation Exercise on Functionality of National Public Health Emergency Operations Centers in the African Region: Review of Strengths and Gaps.

National public health emergency operations centers (PHEOCs) serve as hubs for coordinating information and resources for effective emergency management. In the International Health Regulations (IHR 2005) Monitoring and Evaluation Framework, a simulation exercise is 1 of 4 components that can be used to test the functionality of a country's emergency response capabilities in a simulated situation. To test the functionality of PHEOCs in World Health Organization African Region member states, a regional functional exercise simulating an Ebola virus disease outbreak was conducted. The public health actions taken in response to the simulated outbreak were evaluated against the exercise objectives. Thematic analysis was conducted to summarize key strengths and areas for improvement. From December 6 to 7, 2022, more than 1,000 representatives from 36 of the 47 African Region member states participated in the exercise from their respective PHEOCs. Approximately 95% of the 461 participants polled agreed with the positive responses to the postexercise survey. More than half of the PHEOC participants were able to test their existing emergency preparedness and response plans and became familiar with the expected roles to be fulfilled during an event. Of the participants who responded to the survey, over 90% reported that the exercise helped them understand their roles during emergency management. The exercise met its objectives and provided an opportunity to test the functionality of PHEOCs using realistic scenarios, and it helped participants understand existing response systems and procedures. However, the exercise also revealed areas for improvement in terms of the timing and preparation of participants. We recommend conducting functional exercises at the regional and national levels at least once a year, early or midyear, to allow many stakeholders to take part in the exercise. Moreover, there is a need to train country-level evaluators and controllers in designing and conducting functional exercises.

Challenges associated with the implementation of institutional quarantine and isolation strategies during major multicountry viral outbreaks in Africa (2000-2023): a scoping review.

BACKGROUND: Quarantine and isolation (Q&I) are interrelated but not mutually exclusive public health practices for disease control, which may face public resistance in the context of health emergencies due to associated challenges. Hence, it is often tough for most countries to implement Q&I even in the context of health emergencies. Therefore, this scoping review examines the challenges associated with the implementation of institutional Q&I strategies during major multicountry viral outbreaks (Ebola, Lassa and COVID-19) in Africa between 2000 and 2023. METHODS: This scoping review was designed based on Arksey and O'Malley's guidelines. A systematic literature search, using nine online research databases, was conducted with the aid of relevant search terms, Boolean operators and truncations. All articles obtained from the literature search were electronically imported into Rayyan web application for deduplication based on specific inclusion and exclusion criteria. From the included literature, relevant data were charted, summarized, collated, and presented. RESULTS: This review included 24 of the 787 retrieved articles. Sixteen of the 24 selected articles investigated issues related to COVID-19 prevention and control in Africa. Two assessed precautionary practices for Lassa fever, while five were on Ebola virus disease. However, one article explored knowledge, preventive practices, and general isolation precautions. The review identified various challenges that hindered the implementation of successful Q&I practices during viral infection outbreaks in Africa. Essential healthcare infrastructure, equipment (medical supplies including personal protective equipment and testing kits) and facilities that are essential for Q&I were deficient. Q&I implementation was often threatened by low human resource capacity and inefficiencies in the healthcare system which portray Africa as unprepared to handle complex public health crises. CONCLUSIONS: This review shows that Q&I implementation in Africa is often threatened by low human resource capacity and inefficiencies in the healthcare system and also portrays Africa as unprepared to handle complex public health crises. Hence, Q&I for major multicountry outbreaks in Africa is very challenging. Therefore, continuous efforts to address these identified challenges are crucial to enhancing health emergency preparedness in Africa.

Mpox in East Africa: Learning from COVID-19 and Ebola to Strengthen Public Health Responses.

The Africa Centers for Disease Control and Prevention declared mpox a Public Health Emergency of Continental Security (PHECS) in Africa. African public health systems have moved to mobilize a response against a backdrop of inherent significant challenges. With this commentary, we discuss how lessons from past public health emergencies, particularly COVID-19 and Ebola outbreaks, have prepared the region for improved disease surveillance, rapid response strategies, and effective public health communication and how these lessons can be applied to the mpox response, emphasizing the importance of strong healthcare infrastructure, effective data sharing, community engagement, targeted interventions, and robust contact tracing. Additionally, addressing misinformation and building public trust are crucial for controlling the spread of any disease. By leveraging these strategies, African countries can enhance their response to mpox. This includes improving diagnostic capabilities, strengthening cross-border collaborations, and prioritizing vaccination campaigns where needed. Ultimately, by applying the hard-earned lessons from the COVID-19 pandemic and Ebola outbreak, the East Africa region can better address the challenges posed by mpox and safeguard public health.

Readiness to manage Ebola Virus Disease among emergency healthcare workers in Uganda: a nationwide multicenter survey.

BACKGROUND: Emerging infectious diseases like the Ebola Virus Disease (EVD) pose significant global public health threats. Uganda has experienced multiple EVD outbreaks, the latest occurring in 2022. Frontline healthcare workers (HCWs) are at increased risk, yet there is insufficient evidence of existing knowledge of EVD of these HCWs. We aimed to assess the readiness of Uganda's emergency HCWs to manage EVD and identify their training needs to inform targeted capacity-building interventions for future outbreaks. METHODS: This multicentre nationwide cross-sectional study was conducted from July to September 2023 among HCWs providing emergency care in 14 secondary and tertiary hospitals across Uganda. Participants were consecutively recruited using the probability-proportional-to-size sampling technique, and data was collected using a self-reported questionnaire. Factors associated with EVD knowledge were identified through a mixed-effect linear model. RESULTS: Data from 691 eligible HCWs with a median age of 32 (IQR: 28-38) was analyzed (response rate: 92%). Only one-third (34.4%, n = 238) had received EVD training in the past year. The median EVD knowledge score was 77.4% (IQR: 71.2 - 83.4%). EVD knowledge was associated with longer professional experience in years (ß: 0.21, 95% CI: 0.03 to 0.39, p = 0.024) and higher level of education: diploma (ß: 3.37, 95% CI: 1.49 to 5.25, p < 0.001), undergraduate degree (ß: 6.45, 95% CI: 4.11 to 8.79) and postgraduate degree (ß: 7.13, 95% CI: 4.01 to 10.25, p < 0.001). Being a doctor (ß: 2.55, 95% CI: 0.35 to 4.74, p = 0.023), providing care in the obstetrics/gynecology department (ß: -1.90, 95% CI: -3.47 to - 0.32, p = 0.018), previous EVD training (ß: 2.27, 95% CI: 0.96 to 3.59, p = 0.001) and accessing EVD information through social media (ß: 2.52, 95% CI: 1.17 to 3.88, p < 0.001) were also significantly associated with EVD knowledge. HCWs were mostly interested in training on management (92.9%), infection prevention and control (87.1%), and clinical presentation (84.1%), and preferred physical (51.5%) and hybrid (38.2%) training modes. CONCLUSION: Our study shows that the readiness of HCWs in Uganda to respond to EVD outbreaks varies by individual factors and information sources. We recommend targeted training and suggest future research on educational innovations and social media's potential to fill knowledge gaps.

Community perspectives of Ebola Viral Disease in high-risk transmission border regions of Tanzania: a qualitative inquiry.

BACKGROUND: Tanzania faces ever-rising concerns due to the recurrence of the Ebola Virus Disease (EVD) in neighbouring Democratic Republic of Congo (DRC) and Uganda. This necessitates a better understanding of the community perspectives in high-risk regions for effective risk communication and preparedness. METHODS: This rapid ethnographic assessment study used explorative qualitative methods to collect data. People from diverse backgrounds participated in 59 in-depth interviews, 57 Key Informant interviews, and 35 focus group discussions. Data was analysed using a thematic analysis approach. FINDING: The study revealed existence of awareness of EVD and its symptoms, with radio and television being the main sources of information. However, there were varied perceptions of EVD's cause and transmission, some attributed it to bats, monkeys, and wild animal meat, while others associated it with high fever, a dirty environment, changing dietary patterns, and the COVID-19 virus. Physical contact with an infected person's body fluids and eating meat from infected animals were perceived as EVD transmission routes. Women, school children, boda-boda (motorcycle) riders, and fishermen were considered the most susceptible to EVD infections due to their daily activities. Preventive measures included avoiding physical contact, touching fluids, and refraining from eating wild animal meat. Prompt reporting of suspected cases to health facilities was deemed crucial for earlier outbreak identification and containment. CONCLUSION: The high-risk regions of Tanzania had a high level of awareness and perceived susceptibility to EVD, coupled with varying degrees of misperception about the etiology and its transmission. To improve community perspectives and preparedness in the case of an outbreak, there is a need for ongoing risk communication and participation in EVD prevention and responses.

Local governance of the 2014 ebola Epidemic: a PhD synthesis.

BACKGROUND: The doctoral dissertation examines how local response efforts were integrated into overall emergency management. OBJECTIVES: It seeks to understand the role and effectiveness of community-based actors in addressing collective action problems. METHODS: Sixty-seven semi-structured interviews were conducted from January to July 2017 in Liberia and Sierra Leone. Key informants include healthcare workers, traditional leaders, and community stakeholders, such as non-governmental organization representatives and volunteers. RESULTS: Findings show that traditional and community leaders responded to the public health emergency via rulemaking, quarantine, travel limitation, healthcare referrals, health sensitization, and door-to-door contact tracing. These actions by local leaders helped to change behaviors and improve cooperation. Sierra Leone had 32.3% more Ebola cases than Liberia but 18% fewer deaths. Sierra Leone had integrated traditional and community leaders before the scale up of international aid resources. CONCLUSION: This suggests that actions taken by traditional and community leaders improved overall efforts, and in some areas, before scaled-up humanitarian interventions. Bilateral engagement with local community actors should be integrated in every public health response to improve cooperation, and it should be done before an intervention is conceived and executed.

Main findings: Bottom-up legislation and community-led action were significant in containing the EVD spread in Liberia and Sierra Leone.Contribution to knowledge: Theoretical contribution centers on the governance patterns of Traditional Local Institutions. Evidence-based contribution was the observation of polycentric governance patterns of demand and supply-side barriers between traditional, state, and aid institutions.Global health impact for policy and action: Policymakers should contextualize soft factors such as trust, which can hamper technical advice. Any intervention should include bilateral engagement with local community leaders.

Rational design of self-amplifying virus-like vesicles with Ebola virus glycoprotein as vaccines.

As emerging and re-emerging pathogens, filoviruses, especially Ebola virus (EBOV), pose a great threat to public health and require sustained attention and ongoing surveillance. More vaccines and antiviral drugs are imperative to be developed and stockpiled to respond to unpredictable outbreaks. Virus-like vesicles, generated by alphavirus replicons expressing homogeneous or heterogeneous glycoproteins (GPs), have demonstrated the capacity of self-propagation and shown great potential in vaccine development. Here, we describe a novel class of EBOV-like vesicles (eVLVs) incorporating both EBOV GP and VP40. The eVLVs exhibited similar antigenicity as EBOV. In murine models, eVLVs were highly attenuated and elicited robust GP-specific antibodies with neutralizing activities. Importantly, a single dose of eVLVs conferred complete protection in a surrogate EBOV lethal mouse model. Furthermore, our VLVs strategy was also successfully applied to Marburg virus (MARV), the representative member of the genus Marburgvirus. Taken together, our findings indicate the feasibility of an alphavirus-derived VLVs strategy in combating infection of filoviruses represented by EBOV and MARV, which provides further evidence of the potential of this platform for universal live-attenuated vaccine development.

Improving Ebola virus disease outbreak control through targeted post-exposure prophylaxis.

Ebola virus disease kills more than half of people infected. Since the disease is transmitted via close human contact, identifying individuals at the highest risk of developing the disease is possible on the basis of the type of contact (correlated with viral exposure). Different candidates for post-exposure prophylaxis (PEP; ie, vaccines, antivirals, and monoclonal antibodies) each have their specific benefits and limitations, which we discuss in this Viewpoint. Approved monoclonal antibodies have been found to reduce mortality in people with Ebola virus disease. As monoclonal antibodies act swiftly by directly targeting the virus, they are promising candidates for targeted PEP in contacts at high risk of developing disease. This intervention could save lives, halt viral transmission, and, ultimately, help curtail outbreak propagation. We explore how a strategic integration of monoclonal antibodies and vaccines as PEP could provide both immediate and long-term protection against Ebola virus disease, highlighting ongoing clinical research that aims to refine this approach, and discuss the transformative potential of a successful PEP strategy to help control viral haemorrhagic fever outbreaks.

Long-term cellular immunity of vaccines for Zaire Ebola Virus Diseases.

Recent Ebola outbreaks underscore the importance of continuous prevention and disease control efforts. Authorized vaccines include Merck's Ervebo (rVSV-ZEBOV) and Johnson & Johnson's two-dose combination (Ad26.ZEBOV/MVA-BN-Filo). Here, in a five-year follow-up of the PREVAC randomized trial (NCT02876328), we report the results of the immunology ancillary study of the trial. The primary endpoint is to evaluate long-term memory T-cell responses induced by three vaccine regimens: Ad26-MVA, rVSV, and rVSV-booster. Polyfunctional EBOV-specific CD4+ T-cell responses increase after Ad26 priming and are further boosted by MVA, whereas minimal responses are observed in the rVSV groups, declining after one year. In-vitro expansion for eight days show sustained EBOV-specific T-cell responses for up to 60 months post-prime vaccination with both Ad26-MVA and rVSV, with no decline. Cytokine production analysis identify shared biomarkers between the Ad26-MVA and rVSV groups. In secondary endpoint, we observed an elevation of pro-inflammatory cytokines at Day 7 in the rVSV group. Finally, we establish a correlation between EBOV-specific T-cell responses and anti-EBOV IgG responses. Our findings can guide booster vaccination recommendations and help identify populations likely to benefit from revaccination.

Using mHealth Technologies for Case Finding in Tuberculosis and Other Infectious Diseases in Africa: Systematic Review.

BACKGROUND: Mobile health (mHealth) technologies are increasingly used in contact tracing and case finding, enhancing and replacing traditional methods for managing infectious diseases such as Ebola, tuberculosis, COVID-19, and HIV. However, the variations in their development approaches, implementation scopes, and effectiveness introduce uncertainty regarding their potential to improve public health outcomes. OBJECTIVE: We conducted this systematic review to explore how mHealth technologies are developed, implemented, and evaluated. We aimed to deepen our understanding of mHealth's role in contact tracing, enhancing both the implementation and overall health outcomes. METHODS: We searched and reviewed studies conducted in Africa focusing on tuberculosis, Ebola, HIV, and COVID-19 and published between 1990 and 2023 using the PubMed, Scopus, Web of Science, and Google Scholar databases. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to review, synthesize, and report the findings from articles that met our criteria. RESULTS: We identified 11,943 articles, but only 19 (0.16%) met our criteria, revealing a large gap in technologies specifically aimed at case finding and contact tracing of infectious diseases. These technologies addressed a broad spectrum of diseases, with a predominant focus on Ebola and tuberculosis. The type of technologies used ranged from mobile data collection platforms and smartphone apps to advanced geographic information systems (GISs) and bidirectional communication systems. Technologies deployed in programmatic settings, often developed using design thinking frameworks, were backed by significant funding and often deployed at a large scale but frequently lacked rigorous evaluations. In contrast, technologies used in research settings, although providing more detailed evaluation of both technical performance and health outcomes, were constrained by scale and insufficient funding. These challenges not only prevented these technologies from being tested on a wider scale but also hindered their ability to provide actionable and generalizable insights that could inform public health policies effectively. CONCLUSIONS: Overall, this review underscored a need for organized development approaches and comprehensive evaluations. A significant gap exists between the expansive deployment of mHealth technologies in programmatic settings, which are typically well funded and rigorously developed, and the more robust evaluations necessary to ascertain their effectiveness. Future research should consider integrating the robust evaluations often found in research settings with the scale and developmental rigor of programmatic implementations. By embedding advanced research methodologies within programmatic frameworks at the design thinking stage, mHealth technologies can potentially become technically viable and effectively meet specific contact tracing health outcomes to inform policy effectively.

Fully human monoclonal antibodies against Ebola virus possess complete protection in a hamster model.

Ebola disease is a lethal viral hemorrhagic fever caused by ebolaviruses within the Filoviridae family with mortality rates of up to 90%. Monoclonal antibody (mAb) based therapies have shown great potential for the treatment of EVD. However, the potential emerging ebolavirus isolates and the negative effect of decoy protein on the therapeutic efficacy of antibodies highlight the necessity of developing novel antibodies to counter the threat of Ebola. Here, 11 fully human mAbs were isolated from transgenic mice immunized with GP protein and recombinant vesicular stomatitis virus-bearing GP (rVSV-EBOV GP). These mAbs were divided into five groups according to their germline genes and exhibited differential binding activities and neutralization capabilities. In particular, mAbs 8G6, 2A4, and 5H4 were cross-reactive and bound at least three ebolavirus glycoproteins. mAb 4C1 not only exhibited neutralizing activity but no cross-reaction with sGP. mAb 7D8 exhibited the strongest neutralizing capacity. Further analysis on the critical residues for the bindings of 4C1 and 8G6 to GPs was conducted using antibodies complementarity-determining regions (CDRs) alanine scanning. It has been shown that light chain CDR3 played a crucial role in binding and neutralization and that any mutation in CDRs could not improve the binding of 4C1 to sGP. Importantly, mAbs 7D8, 8G6, and 4C1 provided complete protections against EBOV infection in a hamster lethal challenge model when administered 12 h post-infection. These results support mAbs 7D8, 8G6, and 4C1 as potent antibody candidates for further investigations and pave the way for further developments of therapies and vaccines.

Replication, safety and immunogenicity of the vectored Ebola vaccine rVSV-ΔG-ZEBOV-GP in a sub-Saharan African paediatric population: A randomised controlled, open-label trial in children aged 1-12 years living in Lambaréné, Gabon.

BACKGROUND: Unlike adults, children experienced stronger and longer vector replication in plasma and shedding in saliva following rVSVΔG-ZEBOV-GP vaccination. The resulting risks of immunosuppression or immune hyperactivation leading to increased Adverse Events (AEs) and altered antibody responses are concerns that have been addressed in the present manuscript. METHODS: Children aged 1-12 years living in Gabon received either rVSVΔG-ZEBOV-GP (ERVEBO®) vaccine or the varicella-zoster virus (VZV) vaccine (VZV). The concentration of rVSVΔG vector in blood and saliva, the occurrence of AEs up to day 28; the anti-rVSVΔG-ZEBOV-GP and anti-VZV IgG antibody titres, neutralising and avidity functions of anti-rVSVΔG-ZEBOV-GP by day 365; were assessed in serum. (PACTR202005733552021) FINDINGS: In the rVSVΔG-ZEBOV-GP group, 70% and 7% of children had >0 copies/ml of rVSVΔG respectively in plasma by day 3 and in saliva by day 14 after vaccination, with no detection on day 28. Significantly higher but transient AEs occurred in the rVSVΔG-ZEBOV-GP group. Both vaccines induced seroconversion on day 28 and sustainable IgG antibody titres by day 365. Avidity and neutralisation functions of the anti-rVSVΔG-ZEBOV-GP antibodies peaked at day 28 and were maintained by day 365. INTERPRETATION: The replication and shedding do not affect the favourable risk-benefit balance of the rVSVΔG-ZEBOV-GP in children.

Feasibility Assessment of a Novel Isolation Care Tent in Uganda During the 2022 Sudan ebolavirus Outbreak.

This case study describes a feasibility assessment of a novel isolation care tent used in health facilities in Uganda during the 2022 Sudan ebolavirus outbreak. The Isolation System for Treatment and Agile Response to High-Risk Infections Model 1B (ISTARI 1B) is a single-occupancy, portable, negative-pressure isolation tent designed for the safe delivery of standard care to patients with a communicable disease, including Ebola disease (Sudan). At the request of the Uganda Ministry of Health, the Makerere University Infectious Diseases Institute and University of Nebraska Medical Center partnered to evaluate 7 health facilities across 4 districts in Uganda for infrastructure, case management, and infection prevention and control (IPC) capacity relevant to isolation care and ISTARI 1B use. A 3-day workshop was held with IPC leaders to provide familiarization and hands-on experience with the ISTARI 1B, delineate appropriate use scenarios in Ugandan healthcare settings, contextualize ISTARI 1B use in case management and IPC workflows, develop a framework for site assessment and implementation readiness, and consider ongoing monitoring, assessment, and intervention tools. Workshop participants performed a comprehensive site assessment and mock deployment of the ISTARI 1B. In this case study, we describe lessons learned from health facility assessments and workshop outcomes and offer recommendations to support successful ISTARI 1B implementation. Use scenarios and implementation strategies were identified across facility levels, including tools for site assessment, training, risk communication, and ongoing quality and safety monitoring.

Beyond SIRD models: a novel dynamic model for epidemics, relating infected with entries to health care units and application for identification and restraining policy.

Epidemic models of susceptibles, exposed, infected, recovered and deceased (SΕIRD) presume homogeneity, constant rates and fixed, bilinear structure. They produce short-range, single-peak responses, hardly attained under restrictive measures. Tuned via uncertain I,R,D data, they cannot faithfully represent long-range evolution. A robust epidemic model is presented that relates infected with the entry rate to health care units (HCUs) via population averages. Model uncertainty is circumvented by not presuming any specific model structure, or constant rates. The model is tuned via data of low uncertainty, by direct monitoring: (a) of entries to HCUs (accurately known, in contrast to delayed and non-reliable I,R,D data) and (b) of scaled model parameters, representing population averages. The model encompasses random propagation of infections, delayed, randomly distributed entries to HCUs and varying exodus of non-hospitalized, as disease severity subdues. It closely follows multi-pattern growth of epidemics with possible recurrency, viral strains and mutations, varying environmental conditions, immunity levels, control measures and efficacy thereof, including vaccination. The results enable real-time identification of infected and infection rate. They allow design of resilient, cost-effective policy in real time, targeting directly the key variable to be controlled (entries to HCUs) below current HCU capacity. As demonstrated in ex post case studies, the policy can lead to lower overall cost of epidemics, by balancing the trade-off between the social cost of infected and the economic contraction associated with social distancing and mobility restriction measures.

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.

Prevention and control of Ebola virus transmission: mathematical modelling and data fitting.

The Ebola virus disease (EVD) has been endemic since 1976, and the case fatality rate is extremely high. EVD is spread by infected animals, symptomatic individuals, dead bodies, and contaminated environment. In this paper, we formulate an EVD model with four transmission modes and a time delay describing the incubation period. Through dynamical analysis, we verify the importance of blocking the infection source of infected animals. We get the basic reproduction number without considering the infection source of infected animals. And, it is proven that the model has a globally attractive disease-free equilibrium when the basic reproduction number is less than unity; the disease eventually becomes endemic when the basic reproduction number is greater than unity. Taking the EVD epidemic in Sierra Leone in 2014-2016 as an example, we complete the data fitting by combining the effect of the media to obtain the unknown parameters, the basic reproduction number and its time-varying reproduction number. It is shown by parameter sensitivity analysis that the contact rate and the removal rate of infected group have the greatest influence on the prevalence of the disease. And, the disease-controlling thresholds of these two parameters are obtained. In addition, according to the existing vaccination strategy, only the inoculation ratio in high-risk areas is greater than 0.4, the effective reproduction number can be less than unity. And, the earlier the vaccination time, the greater the inoculation ratio, and the faster the disease can be controlled.

Computational mining of B cell receptor repertoires reveals antigen-specific and convergent responses to Ebola vaccination.

Outbreaks of Ebolaviruses, such as Sudanvirus (SUDV) in Uganda in 2022, demonstrate that species other than the Zaire ebolavirus (EBOV), which is currently the sole virus represented in current licensed vaccines, remain a major threat to global health. There is a pressing need to develop effective pan-species vaccines and novel monoclonal antibody-based therapeutics for Ebolavirus disease. In response to recent outbreaks, the two dose, heterologous Ad26.ZEBOV/MVA-BN-Filo vaccine regimen was developed and was tested in a large phase II clinical trial (EBL2001) as part of the EBOVAC2 consortium. Here, we perform bulk sequencing of the variable heavy chain (VH) of B cell receptors (BCR) in forty participants from the EBL2001 trial in order to characterize the BCR repertoire in response to vaccination with Ad26.ZEBOV/MVA-BN-Filo. We develop a comprehensive database, EBOV-AbDab, of publicly available Ebolavirus-specific antibody sequences. We then use our database to predict the antigen-specific component of the vaccinee repertoires. Our results show striking convergence in VH germline gene usage across participants following the MVA-BN-Filo dose, and provide further evidence of the role of IGHV3-15 and IGHV3-13 antibodies in the B cell response to Ebolavirus glycoprotein. Furthermore, we found that previously described Ebola-specific mAb sequences present in EBOV-AbDab were sufficient to describe at least one of the ten most expanded BCR clonotypes in more than two thirds of our cohort of vaccinees following the boost, providing proof of principle for the utility of computational mining of immune repertoires.

Optimizing the timing of an end-of-outbreak declaration: Ebola virus disease in the Democratic Republic of the Congo.

Following the apparent final case in an Ebola virus disease (EVD) outbreak, the decision to declare the outbreak over must balance societal benefits of relaxing interventions against the risk of resurgence. Estimates of the end-of-outbreak probability (the probability that no future cases will occur) provide quantitative evidence that can inform the timing of an end-of-outbreak declaration. An existing modeling approach for estimating the end-of-outbreak probability requires comprehensive contact tracing data describing who infected whom to be available, but such data are often unavailable or incomplete during outbreaks. Here, we develop a Markov chain Monte Carlo-based approach that extends the previous method and does not require contact tracing data. Considering data from two EVD outbreaks in the Democratic Republic of the Congo, we find that data describing who infected whom are not required to resolve uncertainty about when to declare an outbreak over.

Using real-time modelling to inform the 2017 Ebola outbreak response in DR Congo.

Important policy questions during infections disease outbreaks include: i) How effective are particular interventions?; ii) When can resource-intensive interventions be removed? We used mathematical modelling to address these questions during the 2017 Ebola outbreak in Likati Health Zone, Democratic Republic of the Congo (DRC). Eight cases occurred before 15 May 2017, when the Ebola Response Team (ERT; co-ordinated by the World Health Organisation and DRC Ministry of Health) was deployed to reduce transmission. We used a branching process model to estimate that, pre-ERT arrival, the reproduction number was R = 1.49 (95% credible interval ( 0.67, 2.81 ) ). The risk of further cases occurring without the ERT was estimated to be 0.97 (97%). However, no cases materialised, suggesting that the ERT's measures were effective. We also estimated the risk of withdrawing the ERT in real-time. By the actual ERT withdrawal date (2 July 2017), the risk of future cases without the ERT was only 0.01, indicating that the ERT withdrawal decision was safe. We evaluated the sensitivity of our results to the estimated R value and considered different criteria for determining the ERT withdrawal date. This research provides an extensible modelling framework that can be used to guide decisions about when to relax interventions during future outbreaks.

Delayed treatment of cynomolgus macaques with a FVM04/CA45 monoclonal antibody cocktail provides complete protection against lethal Sudan virus infection.

Sudan ebolavirus (SUDV) is a member of the genus Ebolavirus (Family Filoviridae) and has caused sporadic outbreaks of Ebola disease (EBOD), or more specifically Sudan virus disease (SVD), with high mortality rates in Africa. Current vaccines and therapies that have been developed for filoviruses are almost all specific for Ebola virus (EBOV; of the species Zaire ebolavirus), and there is a current lack of therapeutics specific for SUDV. The recent SUDV outbreak in Uganda, which was distributed across multiple districts, including Kampala, a densely populated urban center, highlights the critical need for the development of novel SUDV-specific or pan-Ebola virus therapeutics. Previous work has characterized two monoclonal antibodies, FVM04 and CA45, which have neutralization capabilities against both EBOV and SUDV and have shown protective efficacy in animal challenge studies. Here, we expand upon this work, showing that treatment with a monoclonal antibody cocktail consisting of FVM04 and CA45 provides full protection against lethal SUDV infection in cynomolgus macaques. Studies that evaluate outcomes at late time points after infection, once clinical signs of illness are apparent, are vital for assessing the therapeutic efficacy of antibody therapeutics. We have shown that when treatment is initiated as late as 5 days after infection, with a second dose given on day 8, that treated groups showed few clinical signs or morbidity, with complete survival. This work provides further evidence that FVM04 and CA45 have strong therapeutic potential against SUDV and their development as a pan-Ebola virus therapeutic should be pursued. IMPORTANCE: There are currently no approved vaccines or therapeutics for Sudan virus, a filovirus which is highly related to Ebola virus and causes similar disease and outbreaks. In this study, a cocktail of two potent monoclonal antibodies that effectively neutralize Sudan virus was tested in a nonhuman primate model of Sudan virus disease. Treatment was highly effective, even when initiated as late as 5 days after infection, when clinical signs of infection were already evident. All treated animals showed complete recovery from infection, with little evidence of disease, while all animals that received a control treatment succumbed to infection within 8 days. The study further demonstrated the strong therapeutic potential of the antibody treatment and supported further development for use in Sudan virus outbreaks.