Field Epidemiology and Public Health Microbiology training: capturing the alumni perspectives of the training's impact.

We present the findings from the European Programme for Intervention Epidemiology Training (EPIET) Alumni Network (EAN) Member Survey conducted in October to December 2021. The EAN consists of field epidemiologists (EPIET) and public health microbiologists (European Public Health Microbiology Training Programme (EUPHEM)) who stay connected after their 2-year fellowship. This active alumni network provides opportunities for career development, mentorship, knowledge exchange and sharing of best practices for community members, affiliated professionals and public health organisations in Europe. Overall, 281 of 732 members participated in the survey. Of the 192 European fellowship alumni respondents, 173 (90%) indicated that skills and competencies acquired during their fellowship improved performance in their role compared with their abilities before the fellowship. Reported skills and competencies that could be further strengthened included data management/analysis, communication, mathematical modelling and leadership/team management. The EAN Member Survey provides valuable feedback to the EAN, as well as the fellowship programme offices at the European Centre for Disease Prevention and Control (ECDC) and affiliated field epidemiology programmes. The COVID-19 pandemic was a stark reminder of how essential cross-border collaborations are for continued European health security. Maintaining and increasing the professional, well-trained workforce remains crucial for optimal response to infectious diseases and protection of public health.

Protection against symptomatic SARS-CoV-2 infection conferred by the Pfizer-BioNTech Original/BA.4-5 bivalent vaccine compared to the mRNA Original monovalent vaccines - A matched cohort study in France.

This cohort study evaluated the protection against symptomatic Omicron BA.5 infection conferred by the Pfizer-BioNTech Original/BA.4-5 bivalent vaccine compared to mRNA Original monovalent vaccines (Pfizer- BioNTech or Moderna). Individuals of ≥60 years old, who received a booster dose between 03/10/2022 and 06/11/2022, when both bivalent and monovalent vaccines were used in France, were included and matched according to the type of booster vaccine received. The outcome of interest was a positive SARS-CoV-2 RT-PCR or antigenic test associated to self-reported symptoms, ≥ seven days after receiving the booster dose. Data were analysed with a Cox Proportional-Hazards model adjusted for the presence of previous infection, age, sex, and the presence of medium risk comorbidities. A total of 136,852 individuals were included and followed for a median period of 77 days. The bivalent vaccine conferred an additional protection of 8 % [95 % CI: 0 %-16 %, p = 0.045] against symptomatic Omicron BA.5infection compared to the monovalent vaccines.

Emergence, spread and characterisation of the SARS-CoV-2 variant B.1.640 circulating in France, October 2021 to February 2022.

BackgroundSuccessive epidemic waves of COVID-19 illustrated the potential of SARS-CoV-2 variants to reshape the pandemic. Detecting and characterising emerging variants is essential to evaluate their public health impact and guide implementation of adapted control measures.AimTo describe the detection of emerging variant, B.1.640, in France through genomic surveillance and present investigations performed to inform public health decisions.MethodsIdentification and monitoring of SARS-CoV-2 variant B.1.640 was achieved through the French genomic surveillance system, producing 1,009 sequences. Additional investigation of 272 B.1.640-infected cases was performed between October 2021 and January 2022 using a standardised questionnaire and comparing with Omicron variant-infected cases.ResultsB.1.640 was identified in early October 2021 in a school cluster in Bretagne, later spreading throughout France. B.1.640 was detected at low levels at the end of SARS-CoV-2 Delta variant's dominance and progressively disappeared after the emergence of the Omicron (BA.1) variant. A high proportion of investigated B.1.640 cases were children aged under 14 (14%) and people over 60 (27%) years, because of large clusters in these age groups. B.1.640 cases reported previous SARS-CoV-2 infection (4%), anosmia (32%) and ageusia (34%), consistent with data on pre-Omicron SARS-CoV-2 variants. Eight percent of investigated B.1.640 cases were hospitalised, with an overrepresentation of individuals aged over 60 years and with risk factors.ConclusionEven though B.1.640 did not outcompete the Delta variant, its importation and continuous low-level spread raised concerns regarding its public health impact. The investigations informed public health decisions during the time that B.1.640 was circulating.

Effectiveness of second booster compared to first booster and protection conferred by previous SARS-CoV-2 infection against symptomatic Omicron BA.2 and BA.4/5 in France.

In face of evidence of rapid waning of vaccine effectiveness against Omicron and its sub-lineages, a second booster with mRNA vaccines was recommended for the most vulnerable in France. We used a test negative design to estimate the effectiveness of the second booster relative to the first booster and the protection conferred by a previous SARS-CoV-2 infection, against symptomatic Omicron BA.2 or BA.4/5. We included symptomatic ≥60 years old individuals tested for SARS-CoV-2 in March 21-October 30, 2022. Compared to a 181-210 days old first booster, a second booster restored protection with a relative effectiveness of 41% [95%CI: 39-42%], 7-30 days post-vaccination. This gain in protection was lower than the one observed with the first booster, at equal time points since vaccination. High levels of protection were associated to previous SARS-CoV-2 infection, especially when the infection was recent and occurred when an antigenic-related variant was dominant.

Analysis of the HbpA Protein from Corynebacterium diphtheriae Clinical Isolates and Identification of a Putative Hemoglobin-Binding Site on HbpA.

The Corynebacterium diphtheriae hemoglobin-binding protein HbpA is critical for the acquisition of iron from the hemoglobin-haptoglobin complex (Hb-Hp). Previous studies using C. diphtheriae strain 1737 showed that large aggregates formed by HbpA are associated with iron transport activity and enhanced binding to Hb-Hp; however, specific regions within HbpA required for Hb-Hp binding or iron uptake have not been identified. In this study, we characterized two clinical isolates from Austria, designated 07-18 and 09-15, which express HbpA proteins that share only 53% and 44% sequence identity, respectively, to the strain 1737 HbpA protein. The HbpA proteins expressed by the Austrian strains had functional and structural properties similar to those of the HbpA protein in strain 1737 despite the limited sequence similarity. These shared characteristics between the HbpA proteins included similar cellular localization, aggregate formation, and Hb and Hb-Hp binding. Additionally, the Austrian strains were able to acquire iron from Hb and Hb-Hp, and deletion of the hbpA gene from these two clinical isolates reduced their ability to use Hb-Hp as an iron source. A sequence comparison between the HbpA proteins from 1737 and the Austrian strains assisted in the identification of a putative Hb-binding site that shared similar characteristics with the Hb-binding regions in Staphylococcus aureus NEAT domains. Amino acid substitutions within this conserved Hb-binding region significantly reduced Hb and Hb-Hp binding and diminished the hemin-iron uptake function of HbpA. These findings represent important advances in our understanding of the interaction of HbpA with human hemoproteins. IMPORTANCE Hemoglobin (Hb) is the primary source of iron in humans, and the acquisition of hemin-iron from Hb is critical for many bacterial pathogens to infect and survive in the human host. In this study, we have examined the C. diphtheriae Hb-binding protein HbpA in two clinical isolates and show that these proteins, despite limited sequence similarity, are functionally equivalent to the previously described HbpA protein in strain 1737. A sequence comparison between these three strains led to the identification of a conserved Hb-binding site, which will further our understanding of how this novel protein functions in hemin-iron transport and, more generally, will expand our knowledge on how Hb interacts with proteins.

Rapid investigation of BA.4/BA.5 cases in France.

Aim: We aimed to describe the characteristics of individuals infected by BA.4 or BA.5 in France in comparison to BA.1, and analyze the factors associated with hospitalization among BA.4 and BA.5 cases. Methods: A standardized questionnaire was used to collect information on confirmed and probable Omicron cases. Hospitalization risk factors among BA.4/BA.5 cases were analyzed using Poisson regression. Variables with a p-value below 0.2 in the univariate analysis and a priori confounders were included in the multivariable regression model. Results: The median age of the 301 cases investigated was 47 years and 97% of cases were symptomatic. The most common clinical signs were asthenia/fatigue (75.7%), cough (58.3%), fever (58.3%), headache (52.1%) and rhinorrhea (50.7%). Twelve cases were hospitalized, and 27.1% reported risk factors. No admissions to intensive care and no deaths were reported. Vaccination status was available for 292 cases, 20.9% were unvaccinated, 1.4% had received one dose, 38.3% two doses and 39.4% three doses. Cases presenting at least one risk factor were almost seventeen times more likely to be hospitalized than those with no risk factors (aRR = 16.72 [95% CI2.59-326.86]). Conclusion: Despite the longer duration of and the differences in symptoms and their possible immune escape, BA.4/BA.5 Omicron sub-lineages globally showed no severe clinical presentation. The presence of at least one risk factor for severe disease significantly increased the risk of hospitalization for those infected with BA.4 or BA.5.

Association of Phylogenomic Relatedness among Neisseria gonorrhoeae Strains with Antimicrobial Resistance, Austria, 2016-2020.

We investigated genomic determinants of antimicrobial resistance in 1,318 Neisseria gonorrhoeae strains isolated in Austria during 2016-2020. Sequence type (ST) 9363 and ST11422 isolates had high rates of azithromycin resistance, and ST7363 isolates correlated with cephalosporin resistance. These results underline the benefit of genomic surveillance for antimicrobial resistance monitoring.

Rifampicin Resistance Associated with rpoB Mutations in Neisseria gonorrhoeae Clinical Strains Isolated in Austria, 2016 to 2020.

Due to increasing rates of antimicrobial resistance (AMR) in Neisseria gonorrhoeae, alternative treatments should be considered. To assess rifampicin's potential as a gonorrhea treatment, we used rpoB mutations to estimate rifampicin resistance in Austrian N. gonorrhoeae isolates. We found 30% of resistant isolates clustering in three main phylogenomic branches. Rifampicin resistance was associated with resistance to other antibiotics. Therefore, rifampicin cannot be recommended as an alternative gonorrhea treatment in Austria, even in combination therapy. IMPORTANCE Gonorrhea, caused by Neisseria gonorrhoeae, is one of the most common bacterial sexually transmitted infections. It is treated with antibiotics, but an increasing number of N. gonorrhoeae strains are resistant to currently used treatments. In this study, we explored the potential of rifampicin, another antibiotic, as a treatment option for gonorrhea. However, around 30% of Austrian N. gonorrhoeae strains investigated were already resistant to rifampicin, which would limit its benefit as a gonorrhea treatment.

Evidence of Transmission and Circulation of Deltacron XD Recombinant Severe Acute Respiratory Syndrome Coronavirus 2 in Northwest France.

In February 2022, samples collected in northwest France showed discordant molecular results. After virological and epidemiological investigations, 17 cases of Deltacron XD recombinant severe acute respiratory syndrome coronavirus 2 were confirmed by sequencing or suspected due to epidemiological links, showing evidence of an extended transmission event and circulation of this form, with low clinical severity.

Severe hospital events following symptomatic infection with Sars-CoV-2 Omicron and Delta variants in France, December 2021-January 2022: A retrospective, population-based, matched cohort study.

Background: A rapid increase in incidence of the SARS-CoV-2 Omicron variant (sub-lineage BA.1) occurred in France in December 2021, while the Delta variant was prevailing since July 2021. We aimed to determine whether the risk of a severe hospital event following symptomatic SARS-CoV-2 infection differs for Omicron versus Delta. Methods: We conducted a retrospective cohort study to compare severe hospital events (admission to intensive care unit or death) between Omicron and Delta symptomatic cases matched according to week of virological diagnosis and age. The analysis was adjusted for age, sex, vaccination status, presence of comorbidities and region of residence, using Cox proportional hazards model. Findings: Between 06/12/2021-28/01/2022, 184 364 cases were included, of which 931 had a severe hospital event (822 Delta, 109 Omicron). The risk of severe event was lower among Omicron versus Delta cases; the difference in severity between the two variants decreased with age (adjusted Hazard Ratio (aHR)=0·13 95%CI: 0·08-0·20 among 40-64 years, aHR=0·50 95%CI: 0·26-0.98 among 80+ years). The risk of severe event increased with the presence of comorbidities (for very-high-risk comorbidity, aHR=4·15 95%CI: 2·86-6·01 among 40-64 years) and in males (aHR=2·28 95%CI: 1·82-2·85among 40-64 years) and was higher in unvaccinated compared to primo-vaccinated (aHR=7·29 95%CI: 5·58-9·54 among 40-64 years). A booster dose reduced the risk of severe hospital event in 80+ years infected with Omicron (aHR=0·29; 95%CI: 0·12-0·69). Interpretation: This study confirms the lower severity of Omicron compared to Delta. However, the difference in disease severity is less marked in the elderly. Further studies are needed to better understand the interactions between age and severity of variants. Funding: The study was performed as part of routine work at Public Health France.

Multiplexed detection of SARS-CoV-2 and other respiratory infections in high throughput by SARSeq.

The COVID-19 pandemic has demonstrated the need for massively-parallel, cost-effective tests monitoring viral spread. Here we present SARSeq, saliva analysis by RNA sequencing, a method to detect SARS-CoV-2 and other respiratory viruses on tens of thousands of samples in parallel. SARSeq relies on next generation sequencing of multiple amplicons generated in a multiplexed RT-PCR reaction. Two-dimensional, unique dual indexing, using four indices per sample, enables unambiguous and scalable assignment of reads to individual samples. We calibrate SARSeq on SARS-CoV-2 synthetic RNA, virions, and hundreds of human samples of various types. Robustness and sensitivity were virtually identical to quantitative RT-PCR. Double-blinded benchmarking to gold standard quantitative-RT-PCR performed by human diagnostics laboratories confirms this high sensitivity. SARSeq can be used to detect Influenza A and B viruses and human rhinovirus in parallel, and can be expanded for detection of other pathogens. Thus, SARSeq is ideally suited for differential diagnostic of infections during a pandemic.

Tracking the Origin of Austrian Human Brucellosis Cases Using Whole Genome Sequencing.

Brucellosis is a zoonotic disease caused by Brucella spp. and a major concern for livestock. Most human cases are caused by B. melitensis and clinical presentation is usually a mild febrile illness. However, treatment failure is frequent and more severe complications can occur. In Austria, every human brucellosis is investigated to determine whether it was imported from endemic areas or is the sign of an undetected autochthonous transmission. For this study, 21 B. melitensis strains isolated in Austria between 2005 and 2019 were collected, 17 strains from 15 different patients and four strains from cattle. Whole genome sequencing combined with core-genome MLST analysis was used to characterize these strains. A cluster of seven isolates from 2018 (three human and four cattle isolates) was identified, with fewer than two allelic differences. They corresponded to the only Austrian B. melitensis outbreak that happened over the past 15 years. The other 12 Austrian brucellosis cases were single cases, and geographical origins were available for 8/12. Genomic data was used to locate probable geographical origins and compared with the results of the epidemiological investigations. Austrian strains were compared with 67 published B. melitensis sequences available on NCBI. The result of genomic analysis matched for 7/8 cases with documented conclusion of the epidemiological investigation. Genome analysis also pointed to the geographical origin for three of the four cases with missing epidemiological data. Strains from six cases were grouped together (<40 allelic differences) with 4/6 cases imported from the Balkans. Additional B. melitensis isolates from Serbian animals were analyzed and grouped with this branch, suggesting frequent importation from Balkan countries to Austria. Overall, this study highlights the specificities of human brucellosis in Austria. It also underlines the value of whole genome sequencing as a tool to investigate brucellosis cases, allowing to identify and investigate outbreaks but also to support epidemiological investigation of imported cases. However, the reliability of such methods depends on the number of strains for comparison, which can be challenging in low incidence countries. Increasing the availability of published sequences with documented geographical origins would help establishing genomic-based methods for investigating brucellosis cases.

Lassa fever outcomes and prognostic factors in Nigeria (LASCOPE): a prospective cohort study.

BACKGROUND: Lassa fever is a viral haemorrhagic fever endemic in parts of west Africa. New treatments are needed to decrease mortality, but pretrial reference data on the disease characteristics are scarce. We aimed to document baseline characteristics and outcomes for patients hospitalised with Lassa fever in Nigeria. METHODS: We did a prospective cohort study (LASCOPE) at the Federal Medical Centre in Owo, Nigeria. All patients admitted with confirmed Lassa fever were invited to participate and asked to give informed consent. Patients of all ages, including newborn infants, were eligible for inclusion, as were pregnant women. All participants received standard supportive care and intravenous ribavirin according to Nigeria Centre for Disease Control guidelines and underwent systematic biological monitoring for 30 days. Patients' characteristics, care received, mortality, and associated factors were recorded using standard WHO forms. We used univariable and multivariable logistic regression models to investigate an association between baseline characteristics and mortality at day 30. FINDINGS: Between April 5, 2018, and March 15, 2020, 534 patients with confirmed Lassa fever were admitted to hospital, of whom 510 (96%) gave consent and were included in the analysis. The cohort included 258 (51%) male patients, 252 (49%) female patients, 426 (84%) adults, and 84 (16%) children (younger than 18 years). The median time between first symptoms and hospital admission was 8 days (IQR 7-13). At baseline, 176 (38%) of 466 patients had a Lassa fever RT-PCR cycle threshold (Ct) lower than 30. From admission to end of follow-up, 120 (25%) of 484 reached a National Early Warning Score (second version; NEWS2) of 7 or higher, 67 (14%) of 495 reached a Kidney Disease-Improving Global Outcome (KDIGO) stage of 2 or higher, and 41 (8%) of 510 underwent dialysis. All patients received ribavirin for a median of 10 days (IQR 9-13). 62 (12%) patients died (57 [13%] adults and five [6%] children). The median time to death was 3 days (1-6). The baseline factors independently associated with mortality were the following: age 45 years or older (adjusted odds ratio 16·30, 95% CI 5·31-50·30), NEWS2 of 7 or higher (4·79, 1·75-13·10), KDIGO grade 2 or higher (7·52, 2·66-21·20), plasma alanine aminotransferase 3 or more times the upper limit of normal (4·96, 1·69-14·60), and Lassa fever RT-PCR Ct value lower than 30 (4·65, 1·50-14·50). INTERPRETATION: Our findings comprehensively document clinical and biological characteristics of patients with Lassa fever and their relationship with mortality, providing prospective estimates that could be useful for designing future therapeutic trials. Such trials comparing new Lassa fever treatments to a standard of care should take no more than 15% as the reference mortality rate and consider adopting a combination of mortality and need for dialysis as the primary endpoint. FUNDING: Institut National de la Santé et de la Recherche Médicale, University of Oxford, EU, UK Department for International Development, Wellcome Trust, French Ministry of Foreign Affairs, Agence Nationale de Recherches sur le SIDA et les hépatites virales, French National Research Institute for Sustainable Development.

Systemic viral spreading and defective host responses are associated with fatal Lassa fever in macaques.

Lassa virus (LASV) is endemic in West Africa and induces a viral hemorrhagic fever (VHF) with up to 30% lethality among clinical cases. The mechanisms involved in control of Lassa fever or, in contrast, the ensuing catastrophic illness and death are poorly understood. We used the cynomolgus monkey model to reproduce the human disease with asymptomatic to mild or fatal disease. After initial replication at the inoculation site, LASV reached the secondary lymphoid organs. LASV did not spread further in nonfatal disease and was rapidly controlled by balanced innate and T-cell responses. Systemic viral dissemination occurred during severe disease. Massive replication, a cytokine/chemokine storm, defective T-cell responses, and multiorgan failure were observed. Clinical, biological, immunological, and transcriptomic parameters resembled those observed during septic-shock syndrome, suggesting that similar pathogenesis is induced during Lassa fever. The outcome appears to be determined early, as differentially expressed genes in PBMCs were associated with fatal and non-fatal Lassa fever outcome very early after infection. These results provide a full characterization and important insights into Lassa fever pathogenesis and could help to develop early diagnostic tools.

Assessing the Genetic Diversity of Austrian Corynebacterium diphtheriae Clinical Isolates, 2011 to 2019.

Diphtheria is a vaccine-preventable disease with a high potential for reemergence. One of its causative agents is Corynebacterium diphtheriae, with some strains producing diphtheria toxin. From 2011 to 2019, 57 clinical C. diphtheriae strains were isolated in Austria, either from the respiratory tract or from skin infections. The aim of this study was to investigate the genetic diversity of these C. diphtheriae isolates using whole-genome sequencing. Isolates were characterized by genome-wide comparisons using single nucleotide polymorphism analysis or core genome multilocus sequence typing and by searching sequence data for antimicrobial resistance genes and genes involved in diphtheria toxin production. The genetic diversity among the isolates was high, with no clear distribution over time or place. Corynebacterium belfantii isolates were separated from other strains and were strongly associated with respiratory infections (odds ratio [OR] = 57). Two clusters, limited in time and space, were identified. Almost 40% of strains carried resistance genes against tetracycline or sulfonamides, mostly from skin infections. Microbiological tests showed that 55% of isolates were resistant to penicillin but did not carry genes conferring ß-lactam resistance. A diphtheria toxin gene with no nonsynonymous mutation was found in three isolates only. This study showed that sequencing can provide valuable information complementing routine microbiological and epidemiological investigations. It allowed us to identify unknown clusters, evaluate antimicrobial resistance more broadly, and support toxigenicity results obtained by PCR. For these reasons, C. diphtheriae surveillance could strongly benefit from the routine implementation of whole-genome sequencing.

Draft Genome Sequences of Six Corynebacterium ulcerans Strains Isolated from Humans and Animals in Austria, 2013 to 2019.

Corynebacterium ulcerans is an emerging pathogen responsible for severe diseases in humans and animals. Here, we present the draft genome of six C. ulcerans strains isolated in Austria. These draft genomes have 2,446,822 to 2,551,141 bp encoding 57 to 60 RNAs.

Lassa fever clinical course and setting a standard of care for future randomized trials: A protocol for a cohort study of Lassa-infected patients in Nigeria (LASCOPE).

BACKGROUND: Lassa Fever (LF), is a severe viral disease prevalent in Western Africa. It is classified as a priority disease by the World Health Organization (WHO). Ribavirin is the recommended therapy despite weak evidence of its efficacy. Promising therapeutic agents are becoming available for evaluation in human. Before launching therapeutic trials, we need data on the evolution of the disease under the best possible conditions of care. METHODS: We have initiated a prospective study in Nigeria to better understand the clinical course and prognostic factors of LF while implementing high quality standardized care. Inclusion criteria are: suspected or confirmed LF and informed consent. Participants are followed 60 days from admission and receive free of charge standardized supportive care and biological monitoring, as well as intravenous ribavirin for those with confirmed LF. Data are collected using standardized case report forms (CRF). Primary and secondary outcomes are fatality and severe morbidity, with special focus on acute kidney dysfunction and pregnancy complications. Factors associated with outcomes will be investigated. RESULTS: The cohort is planned for 3 years. Inclusions started in April 2018 at the Federal Medical Center Owo in Ondo State. A second site will open in Nigeria in 2020 and discussions are underway to open a site in Benin. 150 to 200 new participants are expected per year. CONCLUSIONS: This cohort will: provide evidence to standardize LF case management; provide key inputs to design future clinical trials of novel therapeutics; and establish clinical research teams capable of conducting such trials in LF-endemic areas. STUDY REGISTRATION: The LASCOPE study was registered on ClinicalTrial.gov (NCT03655561).

Vaccines inducing immunity to Lassa virus glycoprotein and nucleoprotein protect macaques after a single shot.

Lassa fever is a major threat in Western Africa. The large number of people living at risk for this disease calls for the development of a vaccine against Lassa virus (LASV). We generated live-attenuated LASV vaccines based on measles virus and Mopeia virus platforms and expressing different LASV antigens, with the aim to develop a vaccine able to protect after a single shot. We compared the efficacy of these vaccines against LASV in cynomolgus monkeys. The vaccines were well tolerated and protected the animals from LASV infection and disease after a single immunization but with varying efficacy. Analysis of the immune responses showed that complete protection was associated with robust secondary T cell and antibody responses against LASV. Transcriptomic and proteomic analyses showed an early activation of innate immunity and T cell priming after immunization with the most effective vaccines, with changes detectable as early as 2 days after immunization. The most efficacious vaccine candidate, a measles vector simultaneously expressing LASV glycoprotein and nucleoprotein, has been selected for further clinical evaluation.

Non-Pathogenic Mopeia Virus Induces More Robust Activation of Plasmacytoid Dendritic Cells than Lassa Virus.

Lassa virus (LASV) causes a viral haemorrhagic fever in humans and is a major public health concern in West Africa. An efficient immune response to LASV appears to rely on type I interferon (IFN-I) production and T-cell activation. We evaluated the response of plasmacytoid dendritic cells (pDC) to LASV, as they are an important and early source of IFN-I. We compared the response of primary human pDCs to LASV and Mopeia virus (MOPV), which is very closely related to LASV, but non-pathogenic. We showed that pDCs are not productively infected by either MOPV or LASV, but produce IFN-I. However, the activation of pDCs was more robust in response to MOPV than LASV. In vivo, pDC activation may support the control of viral replication through IFN-I production, but also improve the induction of a global immune response. Therefore, pDC activation could play a role in the control of LASV infection.

Immune parameters and outcomes during Ebola virus disease.

BACKGROUND: The West African Ebola virus epidemic from 2014-2016 highlighted the lack of knowledge about the pathogenicity of the virus and the factors responsible for outcome. A performant and rapid diagnosis is of crucial importance, as is overcoming the difficulty of providing high-quality patient management during such an extensive outbreak. Here, we propose to study the role of the immune mediators during Ebola virus disease and to define some molecules of importance in the outcome. METHODS: Plasma from Guinean patients sampled during the outbreak were analyzed using RT-qPCR, magnetic bead assay, ELISA, and high-quality statistical analyses. We also performed a transcriptomic analysis in leukocytes samples. Therefore, we deeply characterized the immune responses involved in Ebola virus disease. RESULTS: We evaluated the immune patterns depending on the outcome of the disease. Survivors presented an efficient and well-balanced immune response, whereas fatalities were characterized by an intense inflammatory response, overexpression of multiple cytokines, and a "chemokine storm." The plasma concentration of most of the parameters tested increased until death. Statistical analyses also allowed us to define a panel of markers highly predictive of outcome. CONCLUSION: The immune response observed in fatalities was highly similar to that characterizing septic shock syndrome. Our results suggest that immune responses can play a major pathogenic role during severe Ebola virus infection and argue in favor of therapeutic approaches that act on both viral replication and the induction of shock syndrome. FUNDING: French Ministry of Foreign Affairs, the Agence Française de Développement, and the Institut Pasteur.