Randomized Trial of Vaccines for Zaire Ebola Virus Disease.

BACKGROUND: Questions remain concerning the rapidity of immune responses and the durability and safety of vaccines used to prevent Zaire Ebola virus disease. METHODS: We conducted two randomized, placebo-controlled trials - one involving adults and one involving children - to evaluate the safety and immune responses of three vaccine regimens against Zaire Ebola virus disease: Ad26.ZEBOV followed by MVA-BN-Filo 56 days later (the Ad26-MVA group), rVSVΔG-ZEBOV-GP followed by placebo 56 days later (the rVSV group), and rVSVΔG-ZEBOV-GP followed by rVSVΔG-ZEBOV-GP 56 days later (the rVSV-booster group). The primary end point was antibody response at 12 months, defined as having both a 12-month antibody concentration of at least 200 enzyme-linked immunosorbent assay units (EU) per milliliter and an increase from baseline in the antibody concentration by at least a factor of 4. RESULTS: A total of 1400 adults and 1401 children underwent randomization. Among both adults and children, the incidence of injection-site reactions and symptoms (e.g., feverishness and headache) was higher in the week after receipt of the primary and second or booster vaccinations than after receipt of placebo but not at later time points. These events were largely low-grade. At month 12, a total of 41% of adults (titer, 401 EU per milliliter) and 78% of children (titer, 828 EU per milliliter) had a response in the Ad26-MVA group; 76% (titer, 992 EU per milliliter) and 87% (titer, 1415 EU per milliliter), respectively, had a response in the rVSV group; 81% (titer, 1037 EU per milliliter) and 93% (titer, 1745 EU per milliliter), respectively, had a response in the rVSV-booster group; and 3% (titer, 93 EU per milliliter) and 4% (titer, 67 EU per milliliter), respectively, had a response in the placebo group (P<0.001 for all comparisons of vaccine with placebo). In both adults and children, antibody responses with vaccine differed from those with placebo beginning on day 14. CONCLUSIONS: No safety concerns were identified in this trial. With all three vaccine regimens, immune responses were seen from day 14 through month 12. (Funded by the National Institutes of Health and others; PREVAC ClinicalTrials.gov number, NCT02876328; EudraCT numbers, 2017-001798-18 and 2017-001798-18/3rd; and Pan African Clinical Trials Registry number, PACTR201712002760250.).

Risk Prediction Score for Pediatric Patients with Suspected Ebola Virus Disease.

Rapid diagnostic tools for children with Ebola virus disease (EVD) are needed to expedite isolation and treatment. To evaluate a predictive diagnostic tool, we examined retrospective data (2014-2015) from the International Medical Corps Ebola Treatment Centers in West Africa. We incorporated statistically derived candidate predictors into a 7-point Pediatric Ebola Risk Score. Evidence of bleeding or having known or no known Ebola contacts was positively associated with an EVD diagnosis, whereas abdominal pain was negatively associated. Model discrimination using area under the curve (AUC) was 0.87, which outperforms the World Health Organization criteria (AUC 0.56). External validation, performed by using data from International Medical Corps Ebola Treatment Centers in the Democratic Republic of the Congo during 2018-2019, showed an AUC of 0.70. External validation showed that discrimination achieved by using World Health Organization criteria was similar; however, the Pediatric Ebola Risk Score is simpler to use.

Association between oral antimalarial medication administration and mortality among patients with Ebola virus disease: a multisite cohort study.

BACKGROUND: Empiric antimalarial treatment is a component of protocol-based management of Ebola virus disease (EVD), yet this approach has limited clinical evidence for patient-centered benefits. METHODS: This retrospective cohort study evaluated the association between antimalarial treatment and mortality among patients with confirmed EVD. The data was collected from five International Medical Corps operated Ebola Treatment Units (ETUs) in Sierra Leone and Liberia from 2014 through 2015. The standardized protocol used for patient care included empiric oral treatment with combination artemether and lumefantrine, twice daily for three days; however, only a subset of patients received treatment due to resource variability. The outcome of interest was mortality, comparing patients treated with oral antimalarials within 48-h of admission to those not treated. Analysis was conducted with logistic regression to generate adjusted odds ratios (aORs). Multivariable analyses controlled for ETU country, malaria rapid diagnostic test result, age, EVD cycle threshold value, symptoms of bleeding, diarrhea, dysphagia and dyspnea, and additional standard clinical treatments. RESULTS: Among the 424 cases analyzed, 376 (88.7%) received early oral antimalarials. Across all cases, mortality occurred in 57.5% (244). In comparing unadjusted mortality prevalence, early antimalarial treated cases yielded 55.1% mortality versus 77.1% mortality for those untreated (p = 0.005). Multivariable analysis demonstrated evidence of reduced aOR for mortality with early oral antimalarial treatment versus non-treatment (aOR = 0.34, 95% Confidence Interval: 0.12, 0.92, p = 0.039). CONCLUSION: Early oral antimalarial treatment in an EVD outbreak was associated with reduced mortality. Further study is warranted to investigate this association between early oral antimalarial treatment and mortality in EVD patients.

Impact of Intravenous Fluid Therapy on Survival Among Patients With Ebola Virus Disease: An International Multisite Retrospective Cohort Study.

BACKGROUND: Intravenous fluid (IVF) is a frequently recommended intervention in Ebola virus disease (EVD), yet its impact on patient outcomes remains unclear. METHODS: This retrospective cohort study evaluated patients with EVD admitted to 5 Ebola treatment units (ETUs) in West Africa. The primary outcome was the difference in 28-day survival between cases treated and not treated with IVF. To control for demographic and clinical factors related to both IVF exposure and survival, cases were compared using propensity score matching. To control for time-varying patient and treatment factors over the course of ETU care, a marginal structural proportional hazards model (MSPHM) with inverse probability weighting was used to assess for 28-day survival differences. RESULTS: Among 424 EVD-positive cases with data for analysis, 354 (83.5%) were treated with IVF at some point during their ETU admission. Overall, 146 (41.3%) cases treated with IVF survived, whereas 31 (44.9%) cases not treated with any IVF survived (P = .583). Matched propensity score analysis found no significant difference in 28-day survival between cases treated and not treated with IVF during their first 24 and 48 hours of care. Adjusted MSPHM survival analyses also found no significant difference in 28-day survival for cases treated with IVF (27.3%) compared to those not treated with IVF (26.9%) during their entire ETU admission (P = .893). CONCLUSIONS: After adjustment for patient- and treatment-specific time-varying factors, there was no significant difference in survival among patients with EVD treated with IVF as compared to those not treated with IVF.

Phase 2 Placebo-Controlled Trial of Two Vaccines to Prevent Ebola in Liberia.

BACKGROUND: The safety and efficacy of vaccines to prevent Ebola virus disease (EVD) were unknown when the incidence of EVD was peaking in Liberia. METHODS: We initiated a randomized, placebo-controlled, phase 3 trial of the chimpanzee adenovirus 3 vaccine (ChAd3-EBO-Z) and the recombinant vesicular stomatitis virus vaccine (rVSV∆G-ZEBOV-GP) in Liberia. A phase 2 subtrial was embedded to evaluate safety and immunogenicity. Because the incidence of EVD declined in Liberia, the phase 2 component was expanded and the phase 3 component was eliminated. RESULTS: A total of 1500 adults underwent randomization and were followed for 12 months. The median age of the participants was 30 years; 36.6% of the participants were women. During the week after the administration of vaccine or placebo, adverse events occurred significantly more often with the active vaccines than with placebo; these events included injection-site reactions (in 28.5% of the patients in the ChAd3-EBO-Z group and 30.9% of those in the rVSV∆G-ZEBOV-GP group, as compared with 6.8% of those in the placebo group), headache (in 25.1% and 31.9%, vs. 16.9%), muscle pain (in 22.3% and 26.9%, vs. 13.3%), feverishness (in 23.9% and 30.5%, vs. 9.0%), and fatigue (in 14.0% and 15.4%, vs. 8.8%) (P<0.001 for all comparisons); these differences were not seen at 1 month. Serious adverse events within 12 months after injection were seen in 40 participants (8.0%) in the ChAd3-EBO-Z group, in 47 (9.4%) in the rVSV∆G-ZEBOV-GP group, and in 59 (11.8%) in the placebo group. By 1 month, an antibody response developed in 70.8% of the participants in the ChAd3-EBO-Z group and in 83.7% of those in the rVSV∆G-ZEBOV-GP group, as compared with 2.8% of those in the placebo group (P<0.001 for both comparisons). At 12 months, antibody responses in participants in the ChAd3-EBO-Z group (63.5%) and in those in the rVSV∆G-ZEBOV-GP group (79.5%) remained significantly greater than in those in the placebo group (6.8%, P<0.001 for both comparisons). CONCLUSIONS: A randomized, placebo-controlled phase 2 trial of two vaccines that was rapidly initiated and completed in Liberia showed the capability of conducting rigorous research during an outbreak. By 1 month after vaccination, the vaccines had elicited immune responses that were largely maintained through 12 months. (Funded by the National Institutes of Allergy and Infectious Diseases and the Liberian Ministry of Health; PREVAIL I ClinicalTrials.gov number, NCT02344407 .).

Association between treatment with oral third-generation cephalosporin antibiotics and mortality outcomes in Ebola virus disease: a multinational retrospective cohort study.

OBJECTIVE: To evaluate the association between oral third-generation cephalosporin antibiotic treatment and mortality in Ebola virus disease (EVD). METHODS: This retrospective cohort studied EVD-infected patients admitted to five Ebola Treatment Units in Sierra Leone and Liberia during 2014-15. Empiric treatment with cefixime 400 mg once daily for five days was the clinical protocol; however, due to resource variability, only a subset of patients received treatment. Data on sociodemographics, clinical characteristics, malaria status and Ebola viral loads were collected. The primary outcome was mortality compared between cases treated with cefixime within 48 h of admission to those not treated within 48 h. Propensity scores were derived using clinical covariates. Mortality between treated and untreated cases was compared using propensity-matched conditional logistic regression and bootstrapped log-linear regression analyses to calculate an odds ratio (OR) and relative risk (RR), respectively, with associated 95% confidence intervals (CI). RESULTS: Of 424 cases analysed, 360 (84.9%) met the cefixime treatment definition. The mean age was 30.5 years and 40.3% were male. Median cefixime treatment duration was 4 days (IQR: 3, 5). Among cefixime-treated patients, mortality was 54.7% (95% CI: 49.6-59.8%) vs. 73.4% (95% CI: 61.5-82.7%) in untreated patients. In conditional logistic regression, mortality likelihood was significantly lower among cases receiving cefixime (OR = 0.48, 95% CI: 0.32-0.71; P = 0.01). In the bootstrap analysis, a non-significant risk reduction was found with cefixime treatment (RR = 0.82, 95% CI: 0.64-1.16, P = 0.11). CONCLUSION: Early oral cefixime may be associated with reduced mortality in EVD and warrants further investigation.

OBJECTIF: Evaluer l'association entre le traitement antibiotique oral avec des céphalosporine de troisième génération et la mortalité dans la maladie au virus Ebola (MVE). MÉTHODES: Cette étude de cohorte rétrospective a été menée chez des patients infectés par la maladie au virus Ebola admis dans cinq unités de traitement Ebola en Sierra Leone et au Libéria en 2014-2015. Le traitement empirique avec Cefixime 400 mg une fois par jour pendant cinq jours était le protocole clinique. Cependant, en raison de la variabilité des ressources, seul un sous-ensemble de patients a reçu un traitement. Des données sur la sociodémographie, les caractéristiques cliniques, le statut du paludisme et les charges virales d'Ebola ont été collectées. Le critère principal était la mortalité comparée entre les cas traités au céfixime dans les 48 heures suivant l'admission et ceux non traités dans les 48 heures. Les scores de propension ont été dérivés à l'aide de covariables cliniques. La mortalité entre les cas traités et non traités a été comparée à l'aide d'analyses de régression logistique conditionnelle et de régression log-linéaire bootstrapées pour calculer respectivement un rapport de cotes (OR) et un risque relatif (RR), avec des intervalles de confiance (IC) à 95% associés. RÉSULTATS: Sur 424 cas analysés, 360 (84,9%) répondaient à la définition du traitement au céfixime. L'âge moyen était de 30,5 ans et 40,3% étaient des hommes. La durée médiane du traitement par le céfixime était de 4 jours (IQR: 3, 5). Parmi les patients traités au Cefixime, la mortalité était de 54,7% (IC95%: 49,6 à 59,8%) vs 73,4% (IC95%: 61,5 à 82,7%) chez les patients non traités. Dans la régression logistique conditionnelle, la probabilité de mortalité était significativement plus faible parmi les cas recevant du céfixime (OR = 0,48 ; IC95%: 0,32 à 0,71; P = 0,01). Dans l'analyse bootstrap, une réduction du risque non significative a été trouvée avec le traitement au céfixime (RR = 0,82, IC95%: 0,64 à 1,16 ; P = 0,11). CONCLUSION: Le céfixime par voie orale rapide peut être associé à une mortalité réduite dans la MVE et mérite une investigation plus approfondie.

PREVAIL I Cluster Vaccination Study With rVSVΔG-ZEBOV-GP as Part of a Public Health Response in Liberia.

OBJECTIVE: In November 2015, a 15-year-old boy received a diagnosis of Ebola virus disease (EVD) at the John F. Kennedy Medical Center in Monrovia, Liberia. Two additional family members received a diagnosis of EVD. The protocol for a phase 2 placebo-controlled trial of 2 Ebola vaccines was amended and approved; in 4 days, a single-arm cluster vaccination trial using the Merck rVSVΔG-ZEBOV-GP vaccine was initiated. Here, we evaluate the safety and immunogenicity of the vaccine and discuss challenges for its implementation in a small Ebola outbreak. METHOD: We conducted a ring vaccination study among contacts and contacts of close contacts of EVD cases a in Monrovia. Participants were evaluated 1 and 6 months after vaccination. RESULTS: Among 650 close contacts and contacts of close contacts of EVD cases, 210 (32%) consented and were vaccinated with rVSVΔG-ZEBOV-GP. Of those vaccinated, 189 (90%) attended the month 1 follow-up visit; 166 (79%) attended the month 6 visit. No serious adverse events were reported. Among 88 participants without an elevated antibody level at baseline, 77.3% (95% confidence interval, 68.5-86.1) had an antibody response at 1 month. CONCLUSIONS: The Merck rVSVΔG-ZEBOV-GP vaccine appeared to be safe and immunogenic among the vaccinated individuals. However, fewer than one third of eligible individuals consented to vaccination. These data may help guide implementation decisions for of cluster vaccination programs in an Ebola cluster outbreak response situation.

Vitamin A Supplementation Was Associated with Reduced Mortality in Patients with Ebola Virus Disease during the West African Outbreak.

BACKGROUND: Micronutrient supplementation is recommended in Ebola virus disease (EVD); however, there are limited data on therapeutic impacts of specific micronutrients. OBJECTIVE: To evaluate the association between vitamin A supplementation and mortality in EVD. METHODS: This retrospective cohort included patients with EVD admitted to 5 International Medical Corps Ebola Treatment Units (ETUs) in 2 countries during 2014-2015. Protocolized treatments with micronutrients were used at all ETUs: however, because of resource constraints, only a subset of patients received vitamin A. Standardized data on demographics, clinical characteristics, malaria status, and Ebola viral loads (cycle threshold values) were collected. The outcome of interest was mortality between cases treated with 200,000 IU of vitamin A on care days 1 and/or 2, and those not. Propensity scores based on the first 48 h of care were derived using covariates of age, ETU duration, malaria status, cycle threshold values, and clinical symptoms. Patients were matched 1:1 using nearest neighbors with replacement. Mortality between cases treated and not treated with vitamin A was compared using generalized estimating equations to calculate RR with associated 95% CI. RESULTS: There were 424 cases analyzed, of which 330 (77.8%) were treated with vitamin A. The mean age was 30.5 y and 40.3% were men. The most common symptoms were diarrhea (85.6%), anorexia (80.7%), and abdominal pain (76.9%). Mortality proportions among cases treated and not treated with vitamin A were 55.0% and 71.9%, respectively. In the propensity-matched analysis, mortality was significantly lower among cases receiving vitamin A (RR = 0.77, 95% CI: 0.59, 0.99; P = 0.041). In a subgroup analysis of patients treated with multivitamins already containing vitamin A, additional vitamin A supplementation did not impact mortality. CONCLUSION: Early vitamin A supplementation was associated with reduced mortality in patients with EVD, and should be further studied and considered for use in future epidemics.

Environmental temperature and case fatality of patients with Ebola virus disease in Sierra Leone and Liberia, 2014-2015: a retrospective cohort study.

OBJECTIVE: Fluid loss during Ebola virus disease (EVD) infections from gastrointestinal dysfunction leads to volume depletion. It is possible that high environmental temperatures may exacerbate volume depletion or interfere with the provision of medical care by providers in full personal protective equipment. We investigated the effect of environmental temperature on case fatality. METHODS: The International Medical Corps (IMC) operated five Ebola Treatment Units (ETUs) in Liberia and Sierra Leone during the 2014-2016 epidemic. Demographic and outcomes variables for 465 patients with EVD were sourced from a de-identified, quality-checked clinical database collected by IMC. Daily environmental temperature data for Liberia and Sierra Leone were collected from a publicly available database (Weather Underground). Mean daily environmental temperatures were averaged across each patient's ETU stay and environmental temperature thresholds were determined. Multiple logistic regression was utilised, with forward variable selection and threshold for entry of P < 0.1. Statistical significance was defined as P < 0.05. The following variables were analysed as potential confounders: age, sex, ETU, length of ETU operation and date of treatment. RESULTS: Case fatality was 57.6% among patients diagnosed with EVD. Analysis of case fatality across environmental temperature quintiles indicated a threshold effect; the optimal threshold for average environmental temperature during a patient's ETU stay was determined empirically to be 27.4 °C (81.3 °F). Case fatality was significantly greater for patients with average environmental temperatures above the threshold (70.4%) vs. below (52.0%) (P < 0.001). In multiple regression, patients with average environmental temperature above the threshold during their ETU stay were significantly more likely to die than patients below the threshold (aOR = 2.5, 95% CI 1.6-3.8, P < 0.001). This trend was observed only among patients treated in white tent ETUs, and not in ETUs with aluminium roofs. DISCUSSION: These findings suggest that an average environmental temperature above 27.4 °C (81.3 °F) during patients' ETU stay is associated with greater risk of death among patients with EVD. Further studies should investigate this effect. These results have potential implications for reducing case fatality through improved ETU construction or other temperature control methods within ETUs during future outbreaks.

Implementation of an Ebola virus disease vaccine clinical trial during the Ebola epidemic in Liberia: Design, procedures, and challenges.

The index case of the Ebola virus disease epidemic in West Africa is believed to have originated in Guinea. By June 2014, Guinea, Liberia, and Sierra Leone were in the midst of a full-blown and complex global health emergency. The devastating effects of this Ebola epidemic in West Africa put the global health response in acute focus for urgent international interventions. Accordingly, in October 2014, a World Health Organization high-level meeting endorsed the concept of a phase 2/3 clinical trial in Liberia to study Ebola vaccines. As a follow-up to the global response, in November 2014, the Government of Liberia and the US Government signed an agreement to form a research partnership to investigate Ebola and to assess intervention strategies for treating, controlling, and preventing the disease in Liberia. This agreement led to the establishment of the Joint Liberia-US Partnership for Research on Ebola Virus in Liberia as the beginning of a long-term collaborative partnership in clinical research between the two countries. In this article, we discuss the methodology and related challenges associated with the implementation of the Ebola vaccines clinical trial, based on a double-blinded randomized controlled trial, in Liberia.

Poliovirus antibodies following two rounds of campaigns with a type 2 novel oral poliovirus vaccine in Liberia: a clustered, population-based seroprevalence survey.

BACKGROUND: Novel oral poliovirus vaccine type 2 (nOPV2) was administered in Liberia in response to an outbreak of circulating vaccine-derived poliovirus type 2 (cVDPV2) in 2021. We conducted a serological survey of polio antibodies after two national campaigns with nOPV2. METHODS: This clustered, cross-sectional, population-based seroprevalence survey was conducted in children aged 0-59 months, more than 4 weeks after the second nOPV2 vaccination round. We used a clustered sampling method in four geographical regions of Liberia, followed by a simple random sampling of households. One eligible child was randomly selected per household. Dried blood spot specimens were taken and vaccination history was recorded. The antibody titres against all three poliovirus serotypes were assessed using standard microneutralisation assays done at the US Centers for Disease Control and Prevention in Atlanta, GA, USA. FINDINGS: Analysable data were obtained from 436 (87%) of 500 enrolled participants. Of these, 371 (85%) children were reported via parental recall to have received two nOPV2 doses, 43 (10%) received one dose, and 22 (5%) received no doses. The seroprevalence against type 2 poliovirus was 38·3% (95% CI 33·7-43·0; 167 of 436 participants). No significant difference was observed between type 2 seroprevalence in children aged 6 months or older who were reported to have received two doses of nOPV2 (42·1%, 95% CI 36·8-47·5; 144 of 342), one dose (28·0%, 12·1-49·4; seven of 25), or no doses (37·5%, 8·5-75·5; three of eight; p=0·39). The seroprevalence against type 1 was 59·6% (54·9-64·3; 260 of 436), and the seroprevalence against type 3 was 53·0% (48·2-57·7; 231 of 436). INTERPRETATION: Unexpectedly, the data showed low type 2 seroprevalence after two reported doses of nOPV2. This finding is probably affected by the lower oral poliovirus vaccine immunogenicity previously demonstrated in resource-limited settings, with high prevalence of chronic intestinal infections in children and other factors discussed herein. Our results provide the first assessment of nOPV2 performance in outbreak response in the African region. FUNDING: WHO and Rotary International.

Immune response of a two-dose heterologous Ebola vaccine regimen: summary of three African clinical trials using a single validated Filovirus Animal Nonclinical Group enzyme-linked immunosorbent assay in a single accredited laboratory.

BACKGROUND: This analysis evaluated the immune response to the two-dose, heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccine regimen, administered 56-days apart, from multiple African sites based on results from one analytic laboratory. METHODS: Immunogenicity across three trials (EBL2002, EBL2004/PREVAC, EBL3001) conducted in East and West Africa is summarised. Vaccine-induced Ebola glycoprotein-binding antibody concentrations were analysed by Q2 Solutions laboratory at baseline, 21 days (EBL2002 and EBL3001) or 28 days (EBL2004) post-dose 2 (regimen completion), and 12 months post-dose 1 using the validated Filovirus Animal Nonclinical Group Ebola glycoprotein enzyme-linked immunosorbent assay (ELISA). Responders were defined as those with a >2.5-fold increase from baseline or the lower limit of quantification (LLOQ) if 

Immunogenicity of rVSVΔG-ZEBOV-GP Ebola vaccine (ERVEBO®) in African clinical trial participants by age, sex, and baseline GP-ELISA titer: A post hoc analysis of three Phase 2/3 trials.

BACKGROUND: ERVEBO®, a live recombinant vesicular stomatitis virus (VSV) vaccine containing the Zaire ebolavirus glycoprotein (GP) in place of the VSV GP (rVSVΔG-ZEBOV-GP), was advanced through clinical development by Merck & Co., Inc., Rahway, NJ, USA in collaboration with multiple partners to prevent Ebola virus disease (EVD) and has been approved for human use in several countries. METHODS: We evaluated data from three Phase 2/3 clinical trials conducted in Liberia (PREVAIL), Guinea (FLW), and Sierra Leone (STRIVE) during the 2013-2016 West African EVD outbreak to assess immune responses using validated assays. We performed a post hoc analysis of the association of vaccine response with sex, age (18-50 yrs & >50 yrs), and baseline (BL) GP-enzyme-linked immunosorbent assay (ELISA) titer (<200 & ≥200 EU/mL), including individual study (PREVAIL, FLW, or STRIVE) data and pooled data from all 3 studies. The endpoints were total IgG antibody response (EU/mL) measured by the GP-ELISA and neutralizing antibody response measured by the plaque reduction neutralization test (PRNT) to rVSVΔG-ZEBOV-GP at Days 28, 180, and 365 postvaccination. RESULTS: In the overall pooled population, in all subgroups, and in each trial independently, GP-ELISA and PRNT geometric mean titers increased from BL, generally peaking at Day 28 and persisting through Day 365. Immune responses were greater in women and participants with BL GP-ELISA ≥ 200 EU/mL, but did not differ across age groups. CONCLUSION: These data demonstrate that rVSVΔG-ZEBOV-GP elicits a robust and durable immune response through 12 months postvaccination in participants regardless of age, sex, or BL GP-ELISA titer. The higher immune responses observed in women and participants with pre-existing immunity are consistent with those described previously and for other vaccines. Trials were registered as follows: PREVAIL: ClinicalTrials.gov NCT02344407; FLW: Pan African Clinical Trials Registry PACTR201503001057193; STRIVE: ClinicalTrials.gov NCT02378753. Protocols V920-009, 011, and 018.

Constructing, validating, and updating machine learning models to predict survival in children with Ebola Virus Disease.

BACKGROUND: Ebola Virus Disease (EVD) causes high case fatality rates (CFRs) in young children, yet there are limited data focusing on predicting mortality in pediatric patients. Here we present machine learning-derived prognostic models to predict clinical outcomes in children infected with Ebola virus. METHODS: Using retrospective data from the Ebola Data Platform, we investigated children with EVD from the West African EVD outbreak in 2014-2016. Elastic net regularization was used to create a prognostic model for EVD mortality. In addition to external validation with data from the 2018-2020 EVD epidemic in the Democratic Republic of the Congo (DRC), we updated the model using selected serum biomarkers. FINDINGS: Pediatric EVD mortality was significantly associated with younger age, lower PCR cycle threshold (Ct) values, unexplained bleeding, respiratory distress, bone/muscle pain, anorexia, dysphagia, and diarrhea. These variables were combined to develop the newly described EVD Prognosis in Children (EPiC) predictive model. The area under the receiver operating characteristic curve (AUC) for EPiC was 0.77 (95% CI: 0.74-0.81) in the West Africa derivation dataset and 0.76 (95% CI: 0.64-0.88) in the DRC validation dataset. Updating the model with peak aspartate aminotransferase (AST) or creatinine kinase (CK) measured within the first 48 hours after admission increased the AUC to 0.90 (0.77-1.00) and 0.87 (0.74-1.00), respectively. CONCLUSION: The novel EPiC prognostic model that incorporates clinical information and commonly used biochemical tests, such as AST and CK, can be used to predict mortality in children with EVD.

Transactional sex among youths in post-conflict Liberia.

This paper presents findings on sexual risk behaviours of Liberian youths based on five focus-group discussions conducted with 6th and 7th graders (n = 36) attending an elementary/middle school in Monrovia, Liberia. The purpose of the focus-group discussions was to gain an understanding of the sexual behaviours of in-school Liberian adolescents. The focus-group discussions were part of a larger study to adapt an evidence-based HIV-prevention intervention-Making Proud Choices!-for in-school youths. Post-conflict conditions were discussed as a contributor to the emergence of high-risk sexual behaviours, including transactional sex, sexual violence, and lack of condom-use. Transactional sex was often described by the focus-group participants as occurring between young females and older, more financially-secure males to obtain cash, food, clothing, western commodities, and school-fees and was often encouraged by parents and promoted by peers. The findings also indicate that female adolescents make choices to engage in transactional sex to gain access to a continuum of material and consumer needs. These findings suggest that individual risk-taking behaviours are nested within complex sexual economies and that HIV-prevention interventions should be considered that leverage females' agency and control.

Estimation of the correlates of protection of the rVSVΔG-ZEBOV-GP Zaire ebolavirus vaccine: a post-hoc analysis of data from phase 2/3 clinical trials.

BACKGROUND: Establishment of immune correlates of protection can provide a measurable criterion for assessing protection against infection or disease. For some vaccines, such as the measles vaccine, antibodies serve as the correlate of protection, but for others, such as human papillomavirus, the correlate of protection remains unknown. Merck & Co, Kenilworth, NJ, USA, in collaboration with multiple partners, developed a live recombinant vesicular stomatitis virus vaccine (rVSVΔG-ZEBOV-GP [ERVEBO]) containing the Zaire ebolavirus glycoprotein (GP) in place of the recombinant vesicular stomatitis virus GP to prevent Ebola virus disease. Seroresponse, defined as post-vaccination GP-ELISA of 200 ELISA units (EU) per mL or higher and two-times or more above baseline, was proposed; however, correlates of protection have not been determined. The objective of this post-hoc analysis was to infer possible correlates of protection for rVSVΔG-ZEBOV-GP. METHODS: In this post-hoc analysis we included vaccinated participants with serology data from three phase 2/3 immunogenicity trials in Guinea, Sierra Leone, and Liberia (n=2199). Two of the trials were open-label, single-arm trials (one randomised [STRIVE], one non-randomised [FLW]); and one trial was randomised, placebo-controlled with two vaccine comparators (PREVAIL). Endpoints were total IgG antibody response (EU per mL) to rVSVΔG-ZEBOV-GP measured by GP-ELISA and neutralising antibody response to rVSVΔG-ZEBOV-GP measured by plaque reduction neutralisation test at days 14, 28, 180, and 365 after vaccination. Reverse cumulative distribution curves of the antibody concentrations were used to estimate statistical correlates of protection between 70% and 100% that might be applied to vaccine efficacy and effectiveness estimates. FINDINGS: Although GP-ELISA and plaque reduction neutralisation tests showed similar response patterns, GP-ELISA provided a wider range of measurable titres and better differentiation for estimating correlates of protection compared with the plaque reduction neutralisation test. At day 14 after vaccination in the FLW trial, 1060 (100%) of 1060 participants had GP-ELISA levels at or above 68 EU per mL and 742 (70%) of 1060 had levels at or above 313 EU per mL. At day 28 after vaccination in the pooled population, 1953 (100%) of 1953 participants had levels at or above 73 EU per mL and 1368 (70%) of 1953 participants had levels at or above 735 EU per mL. GP-ELISA seroresponse 200 EU per mL or higher and two-times or more increase in antibody level from baseline occurred in 80% or higher of participants at each assessment and in 94% or higher of participants at any time after vaccination. INTERPRETATION: Our results are consistent with previous work suggesting that seroresponse defined as GP-ELISA of 200 EU per mL or higher and two-times or more from baseline associated with vaccination might be the most appropriate dichotomous correlate of protection and falls within the seroprotective threshold range described herein. FUNDING: Merck Sharp & Dohme, Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, US Department of Health and Human Services.

The impact of the 2014 Ebola epidemic on HIV disease burden and outcomes in Liberia West Africa.

BACKGROUND: Detailed longitudinal studies of HIV-positive individuals in West Africa are lacking. Here the HIV prevalence, incidence, all-cause mortality, and the proportion of individuals receiving treatment with cART in two cohorts of participants in Ebola-related studies are described. SETTING: Individuals of all ages were enrolled and followed at four sites in the area of Monrovia, Liberia. METHODS: Two cohorts identified in response to the Ebola epidemic are described to provide insights into the current state of the HIV epidemic. HIV testing was performed at baseline for participants in both cohorts and during follow-up in one cohort. RESULTS: Prevalence and incidence of HIV (prevalence of 3.1% for women and 1.4% for men and incidence of 3.3 per 1,000) were higher in these cohorts compared to 2018 national estimates (prevalence of 1.3% and incidence of 0.39 per 1,000). Most participants testing positive did not know their status prior to testing. Of those who knew they were HIV positive, 7.9% reported being on antiretroviral treatment. The death rate among those with HIV was 12.3% compared to 1.9% in HIV-negative individuals (adjusted odds ratio of 6.87). While higher levels of d-dimer were associated with increased mortality, this was not specific to those with HIV, however lower hemoglobin levels were associated with increased mortality among those with HIV. CONCLUSION: These findings point to a need to perform further research studies aimed at fulfilling these knowledge gaps and address current shortcomings in the provision of care for those living with HIV in Liberia.

Partnership for Research on Ebola VACcination (PREVAC): protocol of a randomized, double-blind, placebo-controlled phase 2 clinical trial evaluating three vaccine strategies against Ebola in healthy volunteers in four West African countries.

INTRODUCTION: The Ebola virus disease (EVD) outbreak in 2014-2016 in West Africa was the largest on record and provided an opportunity for large clinical trials and accelerated efforts to develop an effective and safe preventative vaccine. Multiple questions regarding the safety, immunogenicity, and efficacy of EVD vaccines remain unanswered. To address these gaps in the evidence base, the Partnership for Research on Ebola Vaccines (PREVAC) trial was designed. This paper describes the design, methods, and baseline results of the PREVAC trial and discusses challenges that led to different protocol amendments. METHODS: This is a randomized, double-blind, placebo-controlled phase 2 clinical trial of three vaccine strategies against the Ebola virus in healthy volunteers 1 year of age and above. The three vaccine strategies being studied are the rVSVΔG-ZEBOV-GP vaccine, with and without a booster dose at 56 days, and the Ad26.ZEBOV,MVA-FN-Filo vaccine regimen with Ad26.ZEBOV given as the first dose and the MVA-FN-Filo vaccination given 56 days later. There have been 4 versions of the protocol with those enrolled in Version 4.0 comprising the primary analysis cohort. The primary endpoint is based on the antibody titer against the Ebola virus surface glycoprotein measured 12 months following the final injection. RESULTS: From April 2017 to December 2018, a total of 5002 volunteers were screened and 4789 enrolled. Participants were enrolled at 6 sites in four countries (Guinea, Liberia, Sierra Leone, and Mali). Of the 4789 participants, 2560 (53%) were adults and 2229 (47%) were children. Those < 18 years of age included 549 (12%) aged 1 to 4 years, 750 (16%) 5 to 11 years, and 930 (19%) aged 12-17 years. At baseline, the median (25th, 75th percentile) antibody titer to Ebola virus glycoprotein for 1090 participants was 72 (50, 116) EU/mL. DISCUSSION: The PREVAC trial is evaluating-placebo-controlled-two promising Ebola candidate vaccines in advanced stages of development. The results will address unanswered questions related to short- and long-term safety and immunogenicity for three vaccine strategies in adults and children. TRIAL REGISTRATION: ClinicalTrials.gov NCT02876328 . Registered on 23 August 2016.

Serostatus cutoff levels and fold increase to define seroresponse to recombinant vesicular stomatitis virus - Zaire Ebola virus envelope glycoprotein vaccine: An evidence-based analysis.

The recombinant vesicular stomatitis virus - Zaire Ebola virus envelope glycoprotein (rVSVΔG-ZEBOV-GP) vaccine is a live recombinant vesicular stomatitis virus (VSV) where the VSV G protein is replaced with ZEBOV-GP. To better understand the immune response after receiving the rVSVΔG-ZEBOV-GP vaccine, the current analyses evaluated different definitions of seroresponse that differentiate vaccine and placebo recipients enrolled in a placebo-controlled clinical trial (PREVAIL; NCT02344407) in which a subset of the study participants had elevated baseline titers. Alternative values for serostatus cutoff (SSCO; 200-500 EU/mL) and/or fold rise (two- to five-fold) were applied to compare their ability to distinguish between participants receiving rVSVΔG-ZEBOV-GP or placebo. The results indicate that an SSCO of 200 EU/mL can be used to define seropositivity at baseline (i.e. pre-vaccination). The use of dual criteria of the same SSCO (200 EU/mL) together with a two-fold rise in antibody level from baseline provided the definition of seroresponse that maximized the statistical significance between vaccine recipients and placebo recipients post-vaccination. Clinical trial registration: NCT02344407.