Quantifying the value of viral genomics when inferring who infected whom in the 2014-16 Ebola virus outbreak in Guinea.

Transmission trees can be established through detailed contact histories, statistical or phylogenetic inference, or a combination of methods. Each approach has its limitations, and the extent to which they succeed in revealing a 'true' transmission history remains unclear. In this study, we compared the transmission trees obtained through contact tracing investigations and various inference methods to identify the contribution and value of each approach. We studied eighty-six sequenced cases reported in Guinea between March and November 2015. Contact tracing investigations classified these cases into eight independent transmission chains. We inferred the transmission history from the genetic sequences of the cases (phylogenetic approach), their onset date (epidemiological approach), and a combination of both (combined approach). The inferred transmission trees were then compared to those from the contact tracing investigations. Inference methods using individual data sources (i.e. the phylogenetic analysis and the epidemiological approach) were insufficiently informative to accurately reconstruct the transmission trees and the direction of transmission. The combined approach was able to identify a reduced pool of infectors for each case and highlight likely connections among chains classified as independent by the contact tracing investigations. Overall, the transmissions identified by the contact tracing investigations agreed with the evolutionary history of the viral genomes, even though some cases appeared to be misclassified. Therefore, collecting genetic sequences during outbreak is key to supplement the information contained in contact tracing investigations. Although none of the methods we used could identify one unique infector per case, the combined approach highlighted the added value of mixing epidemiological and genetic information to reconstruct who infected whom.

An introduction to the Marburg virus vaccine consortium, MARVAC.

The emergence of Marburg virus (MARV) in Guinea and Ghana triggered the assembly of the MARV vaccine "MARVAC" consortium representing leaders in the field of vaccine research and development aiming to facilitate a rapid response to this infectious disease threat. Here, we discuss current progress, challenges, and future directions for MARV vaccines.

A platform trial design for preventive vaccines against Marburg virus and other emerging infectious disease threats.

BACKGROUND: The threat of a possible Marburg virus disease outbreak in Central and Western Africa is growing. While no Marburg virus vaccines are currently available for use, several candidates are in the pipeline. Building on knowledge and experiences in the designs of vaccine efficacy trials against other pathogens, including SARS-CoV-2, we develop designs of randomized Phase 3 vaccine efficacy trials for Marburg virus vaccines. METHODS: A core protocol approach will be used, allowing multiple vaccine candidates to be tested against controls. The primary objective of the trial will be to evaluate the effect of each vaccine on the rate of virologically confirmed Marburg virus disease, although Marburg infection assessed via seroconversion could be the primary objective in some cases. The overall trial design will be a mixture of individually and cluster-randomized designs, with individual randomization done whenever possible. Clusters will consist of either contacts and contacts of contacts of index cases, that is, ring vaccination, or other transmission units. RESULTS: The primary efficacy endpoint will be analysed as a time-to-event outcome. A vaccine will be considered successful if its estimated efficacy is greater than 50% and has sufficient precision to rule out that true efficacy is less than 30%. This will require approximately 150 total endpoints, that is, cases of confirmed Marburg virus disease, per vaccine/comparator combination. Interim analyses will be conducted after 50 and after 100 events. Statistical analysis of the trial will be blended across the different types of designs. Under the assumption of a 6-month attack rate of 1% of the participants in the placebo arm for both the individually and cluster-randomized populations, the most likely sample size is about 20,000 participants per arm. CONCLUSION: This event-driven design takes into the account the potentially sporadic spread of Marburg virus. The proposed trial design may be applicable for other pathogens against which effective vaccines are not yet available.

Advances and gaps in SARS-CoV-2 infection models.

The global response to Coronavirus Disease 2019 (COVID-19) is now facing new challenges such as vaccine inequity and the emergence of SARS-CoV-2 variants of concern (VOCs). Preclinical models of disease, in particular animal models, are essential to investigate VOC pathogenesis, vaccine correlates of protection and postexposure therapies. Here, we provide an update from the World Health Organization (WHO) COVID-19 modeling expert group (WHO-COM) assembled by WHO, regarding advances in preclinical models. In particular, we discuss how animal model research is playing a key role to evaluate VOC virulence, transmission and immune escape, and how animal models are being refined to recapitulate COVID-19 demographic variables such as comorbidities and age.

SARS-CoV-2 Variants and Vaccines.

Viral variants of concern may emerge with dangerous resistance to the immunity generated by the current vaccines to prevent coronavirus disease 2019 (Covid-19). Moreover, if some variants of concern have increased transmissibility or virulence, the importance of efficient public health measures and vaccination programs will increase. The global response must be both timely and science based.

COVID-19 vaccine trials: The potential for "hybrid" analyses.

BACKGROUND: Although several COVID-19 vaccines have been found to be effective in rigorous evaluation and have emerging availability in parts of the world, their supply will be inadequate to meet international needs for a considerable period of time. There also will be continued interest in vaccines that are more effective or have improved scalability to facilitate mass vaccination campaigns. Ongoing clinical testing of new vaccines also will be needed as variant strains continue to emerge that may elude some aspects of immunity induced by current vaccines. Randomized clinical trials meaningfully enhance the efficiency and reliability of such clinical testing. In clinical settings with limited or no access to known effective vaccines, placebo-controlled randomized trials of new vaccines remain a preferred approach to maximize the reliability, efficiency and interpretability of results. When emerging availability of licensed vaccines makes it no longer possible to use a placebo control, randomized active comparator non-inferiority trials may enable reliable insights. METHODS: In this article, "hybrid" methods are proposed to address settings where, during the conduct of a placebo-controlled trial, a judgment is made to replace the placebo arm by a licensed COVID-19 vaccine due to emerging availability of effective vaccines in regions participating in that trial. These hybrid methods are based on proposed statistics that aggregate evidence to formally test as well as to estimate the efficacy of the experimental vaccine, by combining placebo-controlled data during the first period of trial conduct with active-controlled data during the second period. RESULTS: Application of the proposed methods is illustrated in two important scenarios where the active control vaccine would become available in regions engaging in the experimental vaccine's placebo-controlled trial: in the first, the active comparator's vaccine efficacy would have been established to be 50%-70% for the 4- to 6-month duration of follow-up of its placebo-controlled trial; in the second, the active comparator's vaccine efficacy would have been established to be 90%-95% during that duration. These two scenarios approximate what has been seen with adenovirus vaccines or mRNA vaccines, respectively, assuming the early estimates of vaccine efficacy for those vaccines would hold over longer-term follow-up. CONCLUSION: The proposed hybrid methods could readily play an important role in the near future in the design, conduct and analysis of randomized clinical trials performed to address the need for multiple additional vaccines reliably established to be safe and have worthwhile efficacy in reducing the risk of symptomatic disease from SARS-CoV-2 infections.

COVID-19 vaccine trials: The use of active controls and non-inferiority studies.

BACKGROUND: Recently emerging results from a few placebo-controlled randomized trials of COVID-19 vaccines revealed estimates of 62%-95% relative reductions in risk of virologically confirmed symptomatic COVID-19 disease, over approximately 2-month average follow-up period. Additional safe and effective COVID-19 vaccines are needed in a timely manner to adequately address the pandemic on an international scale. Such safe and effective vaccines would be especially appealing for international deployment if they also have favorable stability, supply, and potential for implementation in mass vaccination campaigns. Randomized trials provide particularly reliable insights about vaccine efficacy and safety. While enhanced efficiency and interpretability can be obtained from placebo-controlled trials, in settings where their conduct is no longer possible, randomized non-inferiority trials may enable obtaining reliable evaluations of experimental vaccines through direct comparison with active comparator vaccines established to have worthwhile efficacy. METHODS: The usual objective of non-inferiority trials is to reliably assess whether the efficacy of an experimental vaccine is not unacceptably worse than that of an active control vaccine previously established to be effective, likely in a placebo-controlled trial. This is formally achieved by ruling out a non-inferiority margin identified to be the minimum threshold for what would constitute an unacceptable loss of efficacy. This article not only investigates non-inferiority margins, denoted by δ, that address the usual objective of determining whether the experimental vaccine is "at least similarly effective to" the active comparator vaccine in the non-inferiority trial, but also develops non-inferiority margins, denoted by δo, intended to address the worldwide need for multiple safe and effective vaccines by satisfying the less stringent requirement that the experimental vaccine be "at least similarly effective to" an active comparator vaccine having efficacy that satisfies the widely accepted World Health Organization-Food and Drug Administration criteria for "worthwhile" vaccine efficacy. RESULTS: Using the margin δ enables non-inferiority trials to reliably evaluate experimental vaccines that truly are similarly effective to an active comparator vaccine having any level of "worthwhile" efficacy. When active comparator vaccines have efficacy in the range of 50%-70%, non-inferiority trials designed to use the margin δo have appealing properties, especially for experimental vaccines having true efficacy of approximately 60%. CONCLUSION: Non-inferiority trials using the proposed margins may enable reliable randomized evaluations of efficacy and safety of experimental COVID-19 vaccines. Such trials often require approximately two- to three-fold the person-years follow-up than a placebo-controlled trial. This could be achieved, without substantive increases in sample size, by increasing the average duration of follow-up from 2 months to approximately 4-6 months, assuming efficacy of the active comparator vaccine has been reliably evaluated over that longer duration.

Longitudinal antibody and T cell responses in Ebola virus disease survivors and contacts: an observational cohort study.

BACKGROUND: The 2013-16 Ebola virus disease epidemic in west Africa caused international alarm due to its rapid and extensive spread resulting in a significant death toll and social unrest within the affected region. The large number of cases provided an opportunity to study the long-term kinetics of Zaire ebolavirus-specific immune response of survivors in addition to known contacts of those infected with the virus. METHODS: In this observational cohort study, we worked with leaders of Ebola virus disease survivor associations in two regions of Guinea, Guéckédou and Coyah, to recruit survivors of Ebola virus disease, contacts from households of individuals known to have had Ebola virus disease, and individuals who were not knowingly associated with infected individuals or had not had Ebola virus disease symptoms to serve as negative controls. We did Zaire ebolavirus glycoprotein-specific T cell analysis on peripheral blood mononuclear cells (PBMCs) on location in Guinea and transported plasma and PBMCs back to Europe for antibody quantification by ELISA, functional neutralising antibody analysis using live Zaire ebolavirus, and T cell phenotype studies. We report on the longitudinal cellular and humoral response among Ebola virus disease survivors and highlight potentially paucisymptomatic infection. FINDINGS: We recruited 117 survivors of Ebola virus disease, 66 contacts, and 23 negative controls. The mean neutralising antibody titre among the Ebola virus disease survivors 3-14 months after infection was 1/174 (95% CI 1/136-1/223). Individual results varied greatly from 1/10 to more than 1/1000 but were on average ten times greater than that induced after 1 month by single dose Ebola virus vaccines. Following reactivation with glycoprotein peptide, the mean T cell responses among 116 Ebola virus disease survivors as measured by ELISpot was 305 spot-forming units (95% CI 257-353). The dominant CD8+ polyfunctional T cell phenotype, as measured among 53 Ebola virus disease survivors, was interferon γ+, tumour necrosis factor+, interleukin-2-, and the mean response was 0·046% of total CD8+ T cells (95% CI 0·021-0·071). Additionally, both neutralising antibody and T cell responses were detected in six (9%) of 66 Ebola virus disease contacts. We also noted that four (3%) of 117 individuals with Ebola virus disease infections did not have circulating Ebola virus-specific antibodies 3 months after infection. INTERPRETATION: The continuous high titre of neutralising antibodies and increased T cell response might support the concept of long-term protective immunity in survivors. The existence of antibody and T cell responses in contacts of individuals with Ebola virus disease adds further evidence to the existence of sub-clinical Ebola virus infection. FUNDING: US Food & Drug Administration, Horizon 2020 EU EVIDENT, Wellcome, UK Department for International Development. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.

BACKGROUND: World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS: We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS: At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS: These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).

Respuestas rápidas a la pandemia de COVID-19 a través de la ciencia y la colaboración global: el ensayo clínico Solidaridad.

COVID-19 represents a global crisis. Rapidly conducting a clinical trial with the rigor necessary to obtain reliable results requires the collaboration of various participants involved in the development, evaluation and authorization of clinical trials (CT) such as the trial sponsor, researchers, regulatory authority and the ethics committee (EC). Carrying out these studies is not only scientifically appropriate, but an ethical and moral obligation to guarantee our patients effective treatment. SOLIDARITY is a mega clinical trial that recruited thousands of subjects with moderate to severe disease, who were randomly assigned to one of the treatment groups under evaluation, including hydroxychloroquine, lopinavir/ritonavir associated or not with interferon; or remdesivir compared to standard therapy. Peru has joined the list of countries where the trial will be reproduced, through which it will be possible to quickly identify if any of these drugs offers a real benefit to patients.

La COVID-19 representa una crisis global. La realización rápida de un ensayo clínico con la rigurosidad necesaria para obtener resultados confiables requiere la colaboración de diversos actores que participan en el desarrollo, evaluación y autorización de los ensayos clínicos (EC), como el patrocinador del ensayo, los investigadores, la autoridad regulatoria y el comité de ética (CE). Llevar a cabo estos estudios no solo es científicamente apropiado, sino una obligación ética y moral para ofrecer a las personas infectadas con COVID-19 un tratamiento efectivo. Solidaridad es un megaensayo clínico que reclutará miles de sujetos de investigación con enfermedad moderada a grave, a quienes se les asignará aleatoriamente a uno de los grupos de tratamiento en evaluación incluyendo hidroxicloroquina, lopinavir/ritonavir asociado o no a interferón; o remdesivir en comparación con el manejo estándar. El Perú se ha sumado a la lista de países donde se reproducirá el ensayo, mediante el cual se podrá identificar rápidamente si alguno de estos fármacos ofrece un beneficio real a los pacientes.

Humoral and cellular immune response induced by rVSVΔG-ZEBOV-GP vaccine among frontline workers during the 2013-2016 West Africa Ebola outbreak in Guinea.

BACKGROUND: As part of a Phase III trial with the Ebola vaccine rVSVΔG-ZEBOV-GP in Guinea, we invited frontline workers (FLWs) to participate in a sub-study to provide additional information on the immunogenicity of the vaccine. METHODS: We conducted an open-label, non-randomized, single-arm immunogenicity evaluation of one dose of rVSVΔG-ZEBOV-GP among healthy FLWs in Guinea. FLWs who refused vaccination were offered to participate as a control group. We followed participants for 84 days with a subset followed-up for 180 days. The primary endpoint was immune response, as measured by ELISA for ZEBOV-glycoprotein-specific antibodies (ELISA-GP) at 28 days. We also conducted neutralization, whole virion ELISA and enzyme-linked immunospot (ELISPOT) assay for cellular response. RESULTS: A total of 1172 participants received one dose of vaccine and were followed-up for 84 days, among them 114 participants were followed-up for 180 days. Additionally, 99 participants were included in the control group and followed up for 180 days. Overall, 86.4% (95% CI 84.1-88.4) of vaccinated participants seroresponded at 28 days post-vaccination (ELISA- GP) with 65% of these seroresponding at 14 days post-vaccination. Among those who seroresponded at 28 days, 90.7% (95% CI 82.0-95.4) were still seropositive at 180 days. The proportion of seropositivity in the unvaccinated group was 0.0% (95% CI 0.0-3.8) at 28 days and 5.4% (95% CI 2.1-13.1) at 180 days post-vaccination. We found weak correlation between ELISA-GP and neutralization at baseline but significant pairwise correlation at 28 days post-vaccination. Among samples analysed for cellular response, only 1 (2.2%) exhibited responses towards the Zaire Ebola glycoprotein (Ebola GP ≥ 10) at baseline, 10 (13.5%) at day 28 post-vaccination and 27 (48.2%) at Day 180. CONCLUSIONS: We found one dose of rVSVΔG-ZEBOV-GP to be highly immunogenic at 28- and 180-days post vaccination among frontline workers in Guinea. We also found a cellular response that increased with time.

Respuestas rápidas a la pandemia de COVID-19 a través de la ciencia y la colaboración global: el ensayo clínico Solidaridad

RESUMEN La COVID-19 representa una crisis global. La realización rápida de un ensayo clínico con la rigurosidad necesaria para obtener resultados confiables requiere la colaboración de diversos actores que participan en el desarrollo, evaluación y autorización de los ensayos clínicos (EC), como el patrocinador del ensayo, los investigadores, la autoridad regulatoria y el comité de ética (CE). Llevar a cabo estos estudios no solo es científicamente apropiado, sino una obligación ética y moral para ofrecer a las personas infectadas con COVID-19 un tratamiento efectivo. Solidaridad es un megaensayo clínico que reclutará miles de sujetos de investigación con enfermedad moderada a grave, a quienes se les asignará aleatoriamente a uno de los grupos de tratamiento en evaluación incluyendo hidroxicloroquina, lopinavir/ritonavir asociado o no a interferón; o remdesivir en comparación con el manejo estándar. El Perú se ha sumado a la lista de países donde se reproducirá el ensayo, mediante el cual se podrá identificar rápidamente si alguno de estos fármacos ofrece un beneficio real a los pacientes.

ABSTRACT COVID-19 represents a global crisis. Rapidly conducting a clinical trial with the rigor necessary to obtain reliable results requires the collaboration of various participants involved in the development, evaluation and authorization of clinical trials (CT) such as the trial sponsor, researchers, regulatory authority and the ethics committee (EC). Carrying out these studies is not only scientifically appropriate, but an ethical and moral obligation to guarantee our patients effective treatment. SOLIDARITY is a mega clinical trial that recruited thousands of subjects with moderate to severe disease, who were randomly assigned to one of the treatment groups under evaluation, including hydroxychloroquine, lopinavir/ritonavir associated or not with interferon; or remdesivir compared to standard therapy. Peru has joined the list of countries where the trial will be reproduced, through which it will be possible to quickly identify if any of these drugs offers a real benefit to patients.

Arranging good clinical practices training and trial monitoring for a vaccine efficacy study during a public health emergency of international concern.

The 2014-2015 outbreak of Ebola Virus Disease (EVD) in West Africa was unprecedented in size and scope. The World Health Organization, government of Guinea and other partners undertook a field trial of efficacy of an Ebola vaccine in Guinea, with a parallel immunogenicity study in front-line workers. However, several obstacles had to be overcome. One was the need to teach Good Clinical Practices to a large group of field workers who had never participated in vaccine clinical trial research. Because the trial design was complex, performing this efficacy trial during an Ebola outbreak would have been challenging even for experienced investigators. For field workers who had never previously participated in a clinical trial, this constituted a daunting challenge. Another challenge was to provide independent monitoring to document the quality and validity of the field trial data to support future regulatory agency licensure. Here we discuss how these challenges were overcome, and what lessons can be drawn for the future. Intensive GCP was expeditiously arranged for 251 clinical study staff on-site in Guinea. The trials were initiated within days after completion of training. Monitoring (100% of participants in the efficacy trial and 50% in the immunogenicity trial) began at the onset of the trials. Early monitoring detected many minor errors but prompt feedback and guidance from the monitors, who explained the mistakes and proposed corrective actions, diminished error frequency as the trials progressed. Monitoring later in the trials showed what one would expect in a study conducted by experienced investigators. Should a vaccine field trial have to be hastily arranged during a future emerging disease outbreak in a developing country setting, our methods of training and monitoring could provide a model.

Postexposure Prophylaxis With rVSV-ZEBOV Following Exposure to a Patient With Ebola Virus Disease Relapse in the United Kingdom: An Operational, Safety, and Immunogenicity Report.

BACKGROUND: In October 2015, 65 people came into direct contact with a healthcare worker presenting with a late reactivation of Ebola virus disease (EVD) in the United Kingdom. Vaccination was offered to 45 individuals with an initial assessment of high exposure risk. METHODS: Approval for rapid expanded access to the recombinant vesicular stomatitis virus-Zaire Ebola virus (rVSV-ZEBOV) vaccine as an unlicensed emergency medicine was obtained from the relevant authorities. An observational follow-up study was carried out for 1 year following vaccination. RESULTS: Twenty-six of 45 individuals elected to receive vaccination between 10 and 11 October 2015 following written informed consent. By day 14, 39% had seroconverted, increasing to 87% by day 28 and 100% by 3 months, although these responses were not always sustained. Neutralizing antibody responses were detectable in 36% by day 14 and 73% at 12 months. Common side effects included fatigue, myalgia, headache, arthralgia, and fever. These were positively associated with glycoprotein-specific T-cell but not immunoglobulin (Ig) M or IgG antibody responses. No severe vaccine-related adverse events were reported. No one exposed to the virus became infected. CONCLUSIONS: This paper reports the use of the rVSV-ZEBOV vaccine given as an emergency intervention to individuals exposed to a patient presenting with a late reactivation of EVD. The vaccine was relatively well tolerated, but a high percentage developed a fever ≥37.5°C, necessitating urgent screening for Ebola virus, and a small number developed persistent arthralgia.