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Abstract A recent study reported exaggerated false positives by popular differential expression methods when analyzing large population samples. We reproduce the differential expression analysis simulation results and identify a caveat in the data generation process. Data not truly generated under the null hypothesis led to incorrect comparisons of benchmark methods. We provide corrected simulation results that demonstrate the good performance of dearseq and argue against the superiority of the Wilcoxon rank-sum test as suggested in the previous study.

Abstract Background We assessed the prognostic value of serological humoral markers measured one month after the last dose of the primary COVID-19 vaccine course for predicting the risk of severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 infection over the following six months in specific populations. Methods ANRS0001SCOV-POPART is a French nationwide multicenter prospective observational cohort study assessing the immune response to Covid-19 vaccines routinely administered to 11 subgroups of patients with chronic disease and a control group. Participants from the ANRS0001S COV-POPART were included if they received at least two doses of Covid-19 vaccine for the primary vaccine course, had measurements of anti-Spike, anti-receptor binding domain (RBD) IgG-specific or neutralizing antibodies one month after the end of the primary vaccine course, without being infected by SARS-CoV-2 before the measurement. SARS-CoV-2 infections defined by a positive PCR/antigenic test or seroconversion to detectable anti nucleocapsid antibodies were evaluated until the first COVID-19 booster injection. Cox proportional hazards models taking into account interval-censored data were implemented to estimate the association between each antibody level and the risk of SARS-CoV-2 infection. Predictive performances were evaluated by the area under the receiving operating characteristic curve (AUROC). Results Two thousand five hundred seventy adults from a specific population and 1,123 from the control group were included. The cumulative probabilities of SARS-CoV-2 infections at five months after serological measurement were 6.0% 95% confidence interval: [5.0; 7.9] and 10.1% 95% confidence interval: [8.3; 11.9], respectively. Higher levels of anti-Spike IgG antibody were associated with a lower risk of SARS-CoV-2 infections in the control group, but not in the specific populations. Among the specific populations, AUROC were 74.5%, 74.9%, and 72.4% for anti-Spike IgG, anti-RBD IgG, and neutralizing antibodies, respectively. AUROC were superior in the specific populations, 82.0%, 81.2%, and 81.4% for anti-Spike IgG, anti-RBD IgG, and neutralizing antibodies, respectively. Conclusions Vaccine-induced antibody response after the primary course of Covid-19 infection only moderately discriminated between participants developing a SARS-CoV-2 infection during the Omicron wave. Trial registration NCT04824651 (first posted: 2021-04-01).

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

In July 2023, the Center of Excellence in Respiratory Pathogens organized a two-day workshop on infectious diseases modelling and the lessons learnt from the Covid-19 pandemic. This report summarizes the rich discussions that occurred during the workshop.The workshop participants discussed multisource data integration and highlighted the benefits of combining traditional surveillance with more novel data sources like mobility data, social media, and wastewater monitoring. Significant advancements were noted in the development of predictive models, with examples from various countries showcasing the use of machine learning and artificial intelligence in detecting and monitoring disease trends. The role of open collaboration between various stakeholders in modelling was stressed, advocating for the continuation of such partnerships beyond the pandemic. A major gap identified was the absence of a common international framework for data sharing, which is crucial for global pandemic preparedness.Overall, the workshop underscored the need for robust, adaptable modelling frameworks and the integration of different data sources and collaboration across sectors, as key elements in enhancing future pandemic response and preparedness.

rVSVΔG-ZEBOV-GP and Ad26.ZEBOV, MVA-BN-Filo are WHO-prequalified vaccination regimens against Ebola virus disease (EVD). Challenges associated with measuring long-term clinical protection warrant the evaluation of immune response kinetics after vaccination.Data from a large phase 2 randomized double-blind clinical trial (PREVAC) were used to evaluate waning of anti-Ebola virus (EBOV) glycoprotein (GP1,2) antibody concentrations after rVSVΔG-ZEBOV-GP or Ad26.ZEBOV, MVA-BN-Filo vaccination with linear mixed-effect regression models.After a post-vaccination peak, each vaccination strategy was associated with a decrease of anti-EBOV GP1,2 antibody concentrations with distinct kinetics, highlighting a less-rapid decline in antibody levels after vaccination by rVSVΔG-ZEBOV-GP. One year after administration of the vaccine, antibody concentrations were higher in children compared to adults for both vaccines, although with different effect sizes: 1.74-fold higher concentrations (95% confidence interval [CI] [1.48; 2.02]) for children 12–17 years old to 3.10-fold higher concentrations (95% CI [2.58; 3.69]) for those 1–4 years old compared to adults for Ad26.ZEBOV, MVA-BN-Filo versus 1.36-fold (95% CI [1.12; 1.61]) to 1.41-fold (95% CI [1.21; 1.62]) higher at month 12 higher than these values for adults, with relatively small changes from one age category of children to another for rVSVΔG-ZEBOV-GP. Antibody concentrations also differed according to geographical location, pre-vaccination antibody concentration, and sex.In combination with knowledge on memory response, characterization of the major determinants of immune response durability of both vaccinations may guide future EVD control protocols.Trial registration: ClinicalTrials.gov identifier: NCT02876328..

BackgroundThe exposure to parasites may influence the immune response to vaccines in endemic African countries. In this study, we aimed to assess the association between helminth exposure to the most prevalent parasitic infections, schistosomiasis, soil transmitted helminths infection and filariasis, and the Ebola virus glycoprotein (EBOV GP) antibody concentration in response to vaccination with the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen in African and European participants using samples obtained from three international clinical trials.Methods/principal findingsWe conducted a study in a subset of participants in the EBL2001, EBL2002 and EBL3001 clinical trials that evaluated the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen against EVD in children, adolescents and adults from the United Kingdom, France, Burkina Faso, Cote d'Ivoire, Kenya, Uganda and Sierra Leone. Immune markers of helminth exposure at baseline were evaluated by ELISA with three commercial kits which detect IgG antibodies against schistosome, filarial and Strongyloides antigens. Luminex technology was used to measure inflammatory and activation markers, and Th1/Th2/Th17 cytokines at baseline. The association between binding IgG antibodies specific to EBOV GP (measured on day 21 post-dose 2 and on Day 365 after the first dose respectively), and helminth exposure at baseline was evaluated using a multivariable linear regression model adjusted for age and study group. Seventy-eight (21.3%) of the 367 participants included in the study had at least one helminth positive ELISA test at baseline, with differences of prevalence between studies and an increased prevalence with age. The most frequently detected antibodies were those to Schistosoma mansoni (10.9%), followed by Acanthocheilonema viteae (9%) and then Strongyloides ratti (7.9%). Among the 41 immunological analytes tested, five were significantly (p < .003) lower in participants with at least one positive helminth ELISA test result: CCL2/MCP1, FGFbasic, IL-7, IL-13 and CCL11/Eotaxin compared to participants with negative helminth ELISA tests. No significant association was found with EBOV-GP specific antibody concentration at 21 days post-dose 2, or at 365 days post-dose 1, adjusted for age group, study, and the presence of any helminth antibodies at baseline.Conclusions/significanceNo clear association was found between immune markers of helminth exposure as measured by ELISA and post-vaccination response to the Ebola Ad26.ZEBOV/ MVA-BN-Filo vaccine regimen.Trial registrationNCT02416453, NCT02564523, NCT02509494. ClinicalTrials.gov.

Background: Non-pharmaceutical interventions (NPIs) and vaccines have been widely used to manage the COVID-19 pandemic. However, uncertainty persists regarding the effectiveness of these interventions due to data quality issues, methodological challenges, and differing contextual factors. Accurate estimation of their effects is crucial for future epidemic preparedness. Methods: To address this, we developed a population-based mechanistic model that includes the impact of NPIs and vaccines on SARS-CoV-2 transmission and hospitalization rates. Our statistical approach estimated all parameters in one step, accurately propagating uncertainty. We fitted the model to comprehensive epidemiological data in France from March 2020 to October 2021. With the same model, we simulated scenarios of vaccine rollout. Results: The first lockdown was the most effective, reducing transmission by 84 % (95 % confidence interval (CI) 83–85). Subsequent lockdowns had diminished effectiveness (reduction of 74 % (69–77) and 11 % (9–18), respectively). A 6 pm curfew was more effective than one at 8 pm (68 % (66–69) vs. 48 % (45–49) reduction), while school closures reduced transmission by 15 % (12–18). In a scenario without vaccines before November 2021, we predicted 159,000 or 168 % (95 % prediction interval (PI) 70-315) more deaths and 1,488,000 or 300 % (133-492) more hospitalizations. If a vaccine had been available after 100 days, over 71,000 deaths (16,507–204,249) and 384,000 (88,579–1,020,386) hospitalizations could have been averted. Conclusion: Our results highlight the substantial impact of NPIs, including lockdowns and curfews, in controlling the COVID-19 pandemic. We also demonstrate the value of the 100 days objective of the Coalition for Epidemic Preparedness Innovations (CEPI) initiative for vaccine availability.

Abstract The persistence of the long-term immune response induced by the heterologous Ad26.ZEBOV, MVA-BN-Filo two-dose vaccination regimen against Ebola has been investigated in several clinical trials. Longitudinal data on IgG-binding antibody concentrations were analyzed from 487 participants enrolled in six Phase I and Phase II clinical trials conducted by the EBOVAC1 and EBOVAC2 consortia. A model based on ordinary differential equations describing the dynamics of antibodies and short- and long-lived antibody-secreting cells (ASCs) was used to model the humoral response from 7 days after the second vaccination to a follow-up period of 2 years. Using a population-based approach, we first assessed the robustness of the model, which was originally estimated based on Phase I data, against all data. Then we assessed the longevity of the humoral response and identified factors that influence these dynamics. We estimated a half-life of the long-lived ASC of at least 15 years and found an influence of geographic region, sex, and age on the humoral response dynamics, with longer antibody persistence in Europeans and women and higher production of antibodies in younger participants.

Because SARS-CoV-2 constantly mutates to escape from the immune response, there is a reduction of neutralizing capacity of antibodies initially targeting the historical strain against emerging Variants of Concern (VoC)s. That is why the measure of the protection conferred by vaccination cannot solely rely on the antibody levels, but also requires to measure their neutralization capacity. Here we used a mathematical model to follow the humoral response in 26 individuals that received up to three vaccination doses of Bnt162b2 vaccine, and for whom both anti-S IgG and neutralization capacity was measured longitudinally against all main VoCs. Our model could identify two independent mechanisms that led to a marked increase in measured humoral response over the successive vaccination doses. In addition to the already known increase in IgG levels after each dose, we identified that the neutralization capacity was significantly increased after the third vaccine administration against all VoCs, despite large inter-individual variability. Consequently, the model projects that the mean duration of detectable neutralizing capacity against non-Omicron VoC is between 348 days (Beta variant, 95% Prediction Intervals PI [307; 389]) and 587 days (Alpha variant, 95% PI [537; 636]). Despite the low neutralization levels after three doses, the mean duration of detectable neutralizing capacity against Omicron variants varies between 173 days (BA.5 variant, 95% PI [142; 200]) and 256 days (BA.1 variant, 95% PI [227; 286]). Our model shows the benefit of incorporating the neutralization capacity in the follow-up of patients to better inform on their level of protection against the different SARS-CoV-2 variants. Trial registration: This clinical trial is registered with ClinicalTrials.gov, Trial IDs NCT04750720 and NCT05315583.

Abstract Background While there seems to be a consensus that a decrease in gut microbiome diversity is related to a decline in health status, the associations between respiratory microbiome diversity and chronic lung disease remain a matter of debate. We provide a systematic review and meta-analysis of studies examining lung microbiota alpha-diversity in patients with asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) or bronchiectasis (NCFB), in which a control group based on disease status or healthy subjects is provided for comparison. Results We reviewed 351 articles on title and abstract, of which 27 met our inclusion criteria for systematic review. Data from 24 of these studies were used in the meta-analysis. We observed a trend that CF patients have a less diverse respiratory microbiota than healthy individuals. However, substantial heterogeneity was present and detailed using random-effects models, which limits the comparison between studies. Conclusions Knowledge on respiratory microbiota is under construction, and for the moment, it seems that alpha-diversity measurements are not enough documented to fully understand the link between microbiota and health, excepted in CF context which represents the most studied chronic respiratory disease with consistent published data to link alpha-diversity and lung function. Whether differences in respiratory microbiota profiles have an impact on chronic respiratory disease symptoms and/or evolution deserves further exploration.

Summary: 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

Abstract Background The capacity to use data linkage and artificial intelligence to estimate and predict health indicators varies across European countries. However, the estimation of health indicators from linked administrative data is challenging due to several reasons such as variability in data sources and data collection methods resulting in reduced interoperability at various levels and timeliness, availability of a large number of variables, lack of skills and capacity to link and analyze big data. The main objective of this study is to develop the methodological guidelines calculating population-based health indicators to guide European countries using linked data and/or machine learning (ML) techniques with new methods. Method We have performed the following step-wise approach systematically to develop the methodological guidelines: i. Scientific literature review, ii. Identification of inspiring examples from European countries, and iii. Developing the checklist of guidelines contents. Results We have developed the methodological guidelines, which provide a systematic approach for studies using linked data and/or ML-techniques to produce population-based health indicators. These guidelines include a detailed checklist of the following items: rationale and objective of the study (i.e., research question), study design, linked data sources, study population/sample size, study outcomes, data preparation, data analysis (i.e., statistical techniques, sensitivity analysis and potential issues during data analysis) and study limitations. Conclusions This is the first study to develop the methodological guidelines for studies focused on population health using linked data and/or machine learning techniques. These guidelines would support researchers to adopt and develop a systematic approach for high-quality research methods. There is a need for high-quality research methodologies using more linked data and ML-techniques to develop a structured cross-disciplinary approach for improving the population health information and thereby the population health.

In this study, Marlin et al. provide insights into the potential use of subunit vaccines that induce a high level of protection against SARS-CoV-2 in animal models.

BackgroundRobust and flexible infectious disease surveillance is crucial for public health. Event-based surveillance (EBS) was developed to allow timely detection of infectious disease outbreaks by using mostly web-based data. Despite its widespread use, EBS has not been evaluated systematically on a global scale in terms of outbreak detection performance. ObjectiveThe aim of this study was to assess the variation in the timing and frequency of EBS reports compared to true outbreaks and to identify the determinants of variability by using the example of seasonal influenza epidemic in 24 countries. MethodsWe obtained influenza-related reports between January 2013 and December 2019 from 2 EBS systems, that is, HealthMap and the World Health Organization Epidemic Intelligence from Open Sources (EIOS), and weekly virological influenza counts for the same period from FluNet as the gold standard. Influenza epidemic periods were detected based on report frequency by using Bayesian change point analysis. Timely sensitivity, that is, outbreak detection within the first 2 weeks before or after an outbreak onset was calculated along with sensitivity, specificity, positive predictive value, and timeliness of detection. Linear regressions were performed to assess the influence of country-specific factors on EBS performance. ResultsOverall, while monitoring the frequency of EBS reports over 7 years in 24 countries, we detected 175 out of 238 outbreaks (73.5%) but only 22 out of 238 (9.2%) within 2 weeks before or after an outbreak onset; in the best case, while monitoring the frequency of health-related reports, we identified 2 out of 6 outbreaks (33%) within 2 weeks of onset. The positive predictive value varied between 9% and 100% for HealthMap and from 0 to 100% for EIOS, and timeliness of detection ranged from 13% to 94% for HealthMap and from 0% to 92% for EIOS, whereas system specificity was generally high (59%-100%). The number of EBS reports available within a country, the human development index, and the country’s geographical location partially explained the high variability in system performance across countries. ConclusionsWe documented the global variation of EBS performance and demonstrated that monitoring the report frequency alone in EBS may be insufficient for the timely detection of outbreaks. In particular, in low- and middle-income countries, low data quality and report frequency impair the sensitivity and timeliness of disease surveillance through EBS. Therefore, advances in the development and evaluation and EBS are needed, particularly in low-resource settings.

Abstract Suicidal thoughts and behaviours are prevalent among college students. Yet little is known about screening tools to identify students at higher risk. We aimed to develop a risk algorithm to identify the main predictors of suicidal thoughts and behaviours among college students within one-year of baseline assessment. We used data collected in 2013–2019 from the French i-Share cohort, a longitudinal population-based study including 5066 volunteer students. To predict suicidal thoughts and behaviours at follow-up, we used random forests models with 70 potential predictors measured at baseline, including sociodemographic and familial characteristics, mental health and substance use. Model performance was measured using the area under the receiver operating curve (AUC), sensitivity, and positive predictive value. At follow-up, 17.4% of girls and 16.8% of boys reported suicidal thoughts and behaviours. The models achieved good predictive performance: AUC, 0.8; sensitivity, 79% for girls, 81% for boys; and positive predictive value, 40% for girls and 36% for boys. Among the 70 potential predictors, four showed the highest predictive power: 12-month suicidal thoughts, trait anxiety, depression symptoms, and self-esteem. We identified a parsimonious set of mental health indicators that accurately predicted one-year suicidal thoughts and behaviours in a community sample of college students.

The definition of correlates of protection is critical for the development of next-generation SARS-CoV-2 vaccine platforms. Here, we propose a model-based approach for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication.

Summary: Background: There is an urgent need of a new generation of vaccine that are able to enhance protection against SARS-CoV-2 and related variants of concern (VOC) and emerging coronaviruses. Methods: We identified conserved T- and B-cell epitopes from Spike (S) and Nucleocapsid (N) highly homologous to 38 sarbecoviruses, including SARS-CoV-2 VOCs, to design a protein subunit vaccine targeting antigens to Dendritic Cells (DC) via CD40 surface receptor (CD40.CoV2). Findings: CD40.CoV2 immunization elicited high levels of cross-neutralizing antibodies against SARS-CoV-2, VOCs, and SARS-CoV-1 in K18-hACE2 transgenic mice, associated with viral control and survival after SARS-CoV-2 challenge. A direct comparison of CD40.CoV2 with the mRNA BNT162b2 vaccine showed that the two vaccines were equally immunogenic in mice. We demonstrated the potency of CD40.CoV2 to recall in vitro human multi-epitope, functional, and cytotoxic SARS-CoV-2 S- and N-specific T-cell responses that are unaffected by VOC mutations and cross-reactive with SARS-CoV-1 and, to a lesser extent, MERS epitopes. Interpretation: We report the immunogenicity and antiviral efficacy of the CD40.CoV2 vaccine in a preclinical model providing a framework for a pan-sarbecovirus vaccine. Fundings: This work was supported by INSERM and the Investissements d'Avenir program, Vaccine Research Institute (VRI), managed by the ANR and the CARE project funded from the Innovative Medicines Initiative 2 Joint Undertaking (JU).

Abstract Background Weight gain (mainly gain of fat mass) occurs quickly after successful kidney transplantation and is associated with metabolic complications (alterations of glycaemic control, hyperlipidaemia). Determinants of weight gain are multifactorial and are mainly related to the transplant procedure itself (glucocorticoid use, increased appetite). In the modern era of transplantation, one challenge is to limit these metabolic alterations by promoting gain of muscle mass rather than fat mass. This prospective study was performed to assess determinants of fat mass, fat-free mass and body cell mass changes after kidney transplantation with a focus on physical activity and nutritional behaviour before and after transplantation. Methods Patients were included at the time of listing for deceased donor kidney transplantation. Body composition was determined using dual X-ray absorptiometry and bioimpedance spectroscopy to assess fat mass, fat-free mass and body cell mass (= fat-free mass − extracellular water) at the time of inclusion, 12 months later, and 1, 6, 12 and 24 months after transplantation. Recall dietary data and physical activity level were also collected. Results Eighty patients were included between 2007 and 2010. Sixty-five had a complete 24-month follow-up after kidney transplantation. Fat mass, fat-free mass and body cell mass decreased during the waiting period and early after kidney transplantation. The nadirs of body cell mass and fat-free mass occurred at 1 month and the nadir for fat mass occurred at 6 months. Maximum levels of all parameters of body composition were seen at 12 months, after which body cell mass and fat-free mass decreased, while fat mass remained stable. In multivariate analysis, male recipients, higher physical activity level and lower corticosteroid dose were significantly associated with better body cell mass recovery after kidney transplantation. Conclusions Lifestyle factors, such as physical activity level, together with low dose of corticosteroids seem to influence body composition evolution following kidney transplantation with recovery of body cell mass. Specific strategies to promote physical activity in kidney transplant recipients should be provided before and after kidney transplantation.

Abstract Natural killer (NK) cells are implicated among immune effectors after vaccination against viral pathogens, including Ebola virus. The two-dose heterologous Ebola virus vaccine regimen, adenovirus type 26.ZEBOV followed by modified vaccinia Ankara-BN-Filo (EBOVAC2 consortium, EU Innovative Medicines Initiative), induces NK cell activation and anti-Ebola glycoprotein (GP) antibody-dependent NK cell activation post-dose 1, which is further elevated post-dose 2. Here, in a multicentre, phase 2 clinical trial (EBL2001), we demonstrate durable ex vivo NK cell activation 180 days after dose 2, with responses enriched in CD56bright NK cells. In vitro antibody-dependent responses to immobilised Ebola GP increased after dose 1, and remained elevated compared to pre-vaccination levels in serum collected 180 days later. Peak NK cell responses were observed post-dose 2 and NK cell IFN-γ responses remained significantly elevated at 180 days post-dose 2. Individual variation in NK cell responses were influenced by both anti-Ebola GP antibody concentrations and intrinsic interindividual differences in NK cell functional capacity. In summary, this study demonstrates durable NK cell responses after Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccination and could inform the immunological evaluation of future iterations of the vaccine regimen and vaccination schedules.

Patients who have recovered from Ebola virus can have ongoing health problems. Here, the authors show that 35 Guinean survivors of the last West African Ebola epidemic have a chronic disease with high inflammatory cytokine expression and other markers of immune activation as well as evidence of intestinal tissue damage nearly two years after their release from hospital.

Background Reoccurring Ebola outbreaks in West and Central Africa have led to serious illness and death in thousands of adults and children. The objective of this study was to assess safety, tolerability, and immunogenicity of the heterologous 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in adolescents and children in Africa. Methods and findings In this multicentre, randomised, observer-blind, placebo-controlled Phase II study, 131 adolescents (12 to 17 years old) and 132 children (4 to 11 years old) were enrolled from Eastern and Western Africa and randomised 5:1 to receive study vaccines or placebo. Vaccine groups received intramuscular injections of Ad26.ZEBOV (5 × 1010 viral particles) and MVA-BN-Filo (1 × 108 infectious units) 28 or 56 days apart; placebo recipients received saline. Primary outcomes were safety and tolerability. Solicited adverse events (AEs) were recorded until 7 days after each vaccination and serious AEs (SAEs) throughout the study. Secondary and exploratory outcomes were humoral immune responses (binding and neutralising Ebola virus [EBOV] glycoprotein [GP]-specific antibodies), up to 1 year after the first dose. Enrolment began on February 26, 2016, and the date of last participant last visit was November 28, 2018. Of the 263 participants enrolled, 217 (109 adolescents, 108 children) received the 2-dose regimen, and 43 (20 adolescents, 23 children) received 2 placebo doses. Median age was 14.0 (range 11 to 17) and 7.0 (range 4 to 11) years for adolescents and children, respectively. Fifty-four percent of the adolescents and 51% of the children were male. All participants were Africans, and, although there was a slight male preponderance overall, the groups were well balanced. No vaccine-related SAEs were reported; solicited AEs were mostly mild/moderate. Twenty-one days post-MVA-BN-Filo vaccination, binding antibody responses against EBOV GP were observed in 100% of vaccinees (106 adolescents, 104 children). Geometric mean concentrations tended to be higher after the 56-day interval (adolescents 13,532 ELISA units [EU]/mL, children 17,388 EU/mL) than the 28-day interval (adolescents 6,993 EU/mL, children 8,007 EU/mL). Humoral responses persisted at least up to Day 365. A limitation of the study is that the follow-up period was limited to 365 days for the majority of the participants, and so it was not possible to determine whether immune responses persisted beyond this time period. Additionally, formal statistical comparisons were not preplanned but were only performed post hoc. Conclusions The heterologous 2-dose vaccination was well tolerated in African adolescents and children with no vaccine-related SAEs. All vaccinees displayed anti-EBOV GP antibodies after the 2-dose regimen, with higher responses in the 56-day interval groups. The frequency of pyrexia after vaccine or placebo was higher in children than in adolescents. These data supported the prophylactic indication against EBOV disease in a paediatric population, as licenced in the EU. Trial registration ClinicalTrials.govNCT02564523. Zacchaeus Anywaine and co-workers study safety and immunogenicity of an Ebola vaccine among children and adolescents across four African countries. Author summary Why was the study done? There have been larger and more extensive Ebola virus disease (EVD) outbreaks in Africa in the past decade with no licenced treatments available. As such, there is an unmet medical need for prophylactic Ebola vaccines. This study was performed to evaluate whether a 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination was safe and immunogenic in healthy African children. What did the researchers do and find? In this randomised, placebo-controlled, Phase II clinical trial, the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination regimen was administered to African participants in 2 age cohorts (12 to 17 and 4 to 11 years). No vaccine-related serious adverse events were reported, and robust immune responses were induced in both adolescents and children after receiving the active 2-dose regimen. What do these findings mean? These data support the use of the Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in African adolescents and children at risk of Ebola infection. Although vaccination according to a 28-day regimen may lead to protection against EVD in a shorter time frame, vaccination according to a 56-day regimen results in higher EBOV GP binding and neutralising antibody responses. The observation that Ad26 preexisting immunity in the majority of participants does not affect the EBOV GP-specific antibody responses postvaccination augurs well for the use of this vaccine regimen even in regions with a high prevalence of preexisting Ad26 seropositivity.

Background We investigated safety, tolerability, and immunogenicity of the heterologous 2-dose Ebola vaccination regimen in healthy and HIV-infected adults with different intervals between Ebola vaccinations. Methods and findings In this randomised, observer-blind, placebo-controlled Phase II trial, 668 healthy 18- to 70-year-olds and 142 HIV-infected 18- to 50-year-olds were enrolled from 1 site in Kenya and 2 sites each in Burkina Faso, Cote d’Ivoire, and Uganda. Participants received intramuscular Ad26.ZEBOV followed by MVA-BN-Filo at 28-, 56-, or 84-day intervals, or saline. Females represented 31.4% of the healthy adult cohort in contrast to 69.7% of the HIV-infected cohort. A subset of healthy adults received booster vaccination with Ad26.ZEBOV or saline at Day 365. Following vaccinations, adverse events (AEs) were collected until 42 days post last vaccination and serious AEs (SAEs) were recorded from signing of the ICF until the end of the study. The primary endpoint was safety, and the secondary endpoint was immunogenicity. Anti-Ebola virus glycoprotein (EBOV GP) binding and neutralising antibodies were measured at baseline and at predefined time points throughout the study. The first participant was enrolled on 9 November 2015, and the date of last participant’s last visit was 12 February 2019. No vaccine-related SAEs and mainly mild-to-moderate AEs were observed among the participants. The most frequent solicited AEs were injection-site pain (local), and fatigue, headache, and myalgia (systemic), respectively. Twenty-one days post-MVA-BN-Filo vaccination, geometric mean concentrations (GMCs) with 95% confidence intervals (CIs) of EBOV GP binding antibodies in healthy adults in 28-, 56-, and 84-day interval groups were 3,085 EU/mL (2,648 to 3,594), 7,518 EU/mL (6,468 to 8,740), and 7,300 EU/mL (5,116 to 10,417), respectively. In HIV-infected adults in 28- and 56-day interval groups, GMCs were 4,207 EU/mL (3,233 to 5,474) and 5,283 EU/mL (4,094 to 6,817), respectively. Antibody responses were observed until Day 365. Ad26.ZEBOV booster vaccination after 1 year induced an anamnestic response. Study limitations include that some healthy adult participants either did not receive dose 2 or received dose 2 outside of their protocol-defined interval and that the follow-up period was limited to 365 days for most participants. Conclusions Ad26.ZEBOV, MVA-BN-Filo vaccination was well tolerated and immunogenic in healthy and HIV-infected African adults. Increasing the interval between vaccinations from 28 to 56 days improved the magnitude of humoral immune responses. Antibody levels persisted to at least 1 year, and Ad26.ZEBOV booster vaccination demonstrated the presence of vaccination-induced immune memory. These data supported the approval by the European Union for prophylaxis against EBOV disease in adults and children ≥1 year of age. Trial registration ClinicalTrials.govNCT02564523 Houreratou Barry and co-workers report on safety and immunogenicity of an Ebola vaccine in adults across four African countries. Author summary Why was this study done? With Ebola outbreaks increasing, there is an unmet medical need for a prophylactic vaccine to prevent and mitigate Ebola outbreaks. To address the urgent medical need during the 2014 to 2016 outbreak, the clinical development of the 2-dose vaccine regimen comprising of Ad26.ZEBOV and MVA-BN-Filo was accelerated. This Phase II study was part of this accelerated program, evaluating the safety and immunogenicity of the 2-dose vaccine regimen in healthy and HIV-infected African adults, with 28-, 56-, and 84-day intervals between doses. The study was amended to evaluate safety and immunogenicity of a booster vaccination with Ad26.ZEBOV, administered approximately 1 year after the first vaccination, in healthy adults. What did the researchers do and find? We conducted a randomised trial to assess the safety and the immunogenicity of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen in 3 different vaccination intervals in healthy and HIV-infected adults. The vaccine regimen was well tolerated and induced marked immune responses; the highest humoral responses were observed after vaccination with 56-day and 84-day intervals. Anamnestic responses were observed in all healthy participants receiving Ad26.ZEBOV as booster at 1 year after the first dose. What do these findings mean? Our results demonstrate that the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen is safe and immunogenic in healthy and HIV-infected adults and induces immune memory that can rapidly be reactivated. Our findings support the prophylactic use of the 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccine regimen against Ebola infection in African adult populations. The 2-dose vaccine regimen comprising of Ad26.ZEBOV and MVA-BN-Filo has received marketing authorisation under exceptional circumstances for prophylactic use against EVD in adults and children ≥1 year old within the European Union.

Summary: The identification of patients with coronavirus disease 2019 and high risk of severe disease is a challenge in routine care. We performed cell phenotypic, serum, and RNA sequencing gene expression analyses in severe hospitalized patients (n = 61). Relative to healthy donors, results showed abnormalities of 27 cell populations and an elevation of 42 cytokines, neutrophil chemo-attractants, and inflammatory components in patients. Supervised and unsupervised analyses revealed a high abundance of CD177, a specific neutrophil activation marker, contributing to the clustering of severe patients. Gene abundance correlated with high serum levels of CD177 in severe patients. Higher levels were confirmed in a second cohort and in intensive care unit (ICU) than non-ICU patients (P < 0.001). Longitudinal measurements discriminated between patients with the worst prognosis, leading to death, and those who recovered (P = 0.01). These results highlight neutrophil activation as a hallmark of severe disease and CD177 assessment as a reliable prognostic marker for routine care.

Abstract Objectives To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. Trial design Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. Participants Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate 5.5 mmol/L or

Abstract Background Older adults with cancer experience negative long‐term functional effects of both cancer and treatments. Exercise may minimize their age‐related and cancer‐related functional decline. Methods We conducted a multicentre open‐label 12 month randomized clinical trial with two parallel arms including participants aged ≥70 years with lymphoma or carcinoma requiring curative treatment. The study started at the beginning of any phase of cancer treatment (surgery, chemotherapy, or radiotherapy). The usual care group (UCG) received the current national recommendations in physical activity (a guideline without specific counselling). The intervention group (IG) received 1 year phoned physical activity advice individually adapted to physical assessment (twice a month during the first 6 months and then monthly). The primary outcome was the proportion of subjects with a 1 year decreased short physical performance battery (SPPB) score of 1 point or more. Physical, cognitive, and clinical secondary outcomes were also investigated. Results We allocated 301 participants (age 76.7 ± 5.0, female 60.6%) to each group. At baseline, the median SPPB was 10/12 in both groups. Breast was the most frequent tumour site (35.7%). After 1 year, 14.0% of participants in the UCG and 18.7% in the IG had a decrease in SPPB score of 1 point or more (P = 0.772). At 2 years, there was no difference in SPPB, gait speed, International Physical Activity Questionnaire score, and verbal fluency. Subgroup analyses after 2 years showed a decline in SPPB for 29.8% of UCG and 5.0% of IG breast cancer participants (P = 0.006), in 21.7% of UCG and 6.2% of IG female participants (P = 0.019), and in 24.5% of UCG and 11.1% of IG normal nutritional status participants (P = 0.009). Falls, hospitalization, institutionalization, and death rates were similar in both groups. Conclusions Personalized phoned physical activity advice had not reduced functional decline at 1 year but provided preliminary evidence that may prevent physical performance decline at 2 years in older adults with breast cancer.

Abstract Background Biological assays for the quantification of markers may suffer from a lack of sensitivity and thus from an analytical detection limit. This is the case of human immunodeficiency virus (HIV) viral load. Below this threshold the exact value is unknown and values are consequently left-censored. Statistical methods have been proposed to deal with left-censoring but few are adapted in the context of high-dimensional data. Methods We propose to reverse the Buckley-James least squares algorithm to handle left-censored data enhanced with a Lasso regularization to accommodate high-dimensional predictors. We present a Lasso-regularized Buckley-James least squares method with both non-parametric imputation using Kaplan-Meier and parametric imputation based on the Gaussian distribution, which is typically assumed for HIV viral load data after logarithmic transformation. Cross-validation for parameter-tuning is based on an appropriate loss function that takes into account the different contributions of censored and uncensored observations. We specify how these techniques can be easily implemented using available R packages. The Lasso-regularized Buckley-James least square method was compared to simple imputation strategies to predict the response to antiretroviral therapy measured by HIV viral load according to the HIV genotypic mutations. We used a dataset composed of several clinical trials and cohorts from the Forum for Collaborative HIV Research (HIV Med. 2008;7:27-40). The proposed methods were also assessed on simulated data mimicking the observed data. Results Approaches accounting for left-censoring outperformed simple imputation methods in a high-dimensional setting. The Gaussian Buckley-James method with cross-validation based on the appropriate loss function showed the lowest prediction error on simulated data and, using real data, the most valid results according to the current literature on HIV mutations. Conclusions The proposed approach deals with high-dimensional predictors and left-censored outcomes and has shown its interest for predicting HIV viral load according to HIV mutations.

Natural killer cells play an important role in the control of viral infections both by regulating acquired immune responses and as potent innate or antibody-mediated cytotoxic effector cells. NK cells have been implicated in control of Ebola virus infections and our previous studies in European trial participants have demonstrated durable activation, proliferation and antibody-dependent NK cell activation after heterologous two-dose Ebola vaccination with adenovirus type 26.ZEBOV followed by modified vaccinia Ankara-BN-Filo. Regional variation in immunity and environmental exposure to pathogens, in particular human cytomegalovirus, have profound impacts on NK cell functional capacity. We therefore assessed the NK cell phenotype and function in African trial participants with universal exposure to HCMV. We demonstrate a significant redistribution of NK cell subsets after vaccine dose two, involving the enrichment of less differentiated CD56dimCD57− and CD56dimFcεR1γ+ (canonical) cells and the increased proliferation of these subsets. Sera taken after vaccine dose two support robust antibody-dependent NK cell activation in a standard NK cell readout; these responses correlate strongly with the concentration of anti-Ebola glycoprotein specific antibodies. These sera also promote comparable IFN-γ production in autologous NK cells taken at baseline and post-vaccine dose two. However, degranulation responses of post-vaccination NK cells were reduced compared to baseline NK cells and these effects could not be directly attributed to alterations in NK cell phenotype after vaccination. These studies demonstrate consistent changes in NK cell phenotypic composition and robust antibody-dependent NK cell function and reveal novel characteristics of these responses after heterologous two dose Ebola vaccination in African individuals.

HIV-2 infection is characterized by low viremia and slow disease progression as compared to HIV-1 infection. Circulating CD14++CD16+ monocytes were found to accumulate and CD11c+ conventional dendritic cells (cDC) to be depleted in a Portuguese cohort of people living with HIV-2 (PLWHIV-2), compared to blood bank healthy donors (HD). We studied more precisely classical monocytes; CD16+ inflammatory (intermediate, non-classical and slan+ monocytes, known to accumulate during viremic HIV-1 infection); cDC1, important for cross-presentation, and cDC2, both depleted during HIV-1 infection. We analyzed by flow cytometry these PBMC subsets from Paris area residents: 29 asymptomatic, untreated PLWHIV-2 from the IMMUNOVIR-2 study, part of the ANRS-CO5 HIV-2 cohort: 19 long-term non-progressors (LTNP; infection ≥8 years, undetectable viral load, stable CD4 counts≥500/μL; 17 of West-African origin -WA), and 10 non-LTNP (P; progressive infection; 9 WA); and 30 age-and sex-matched controls: 16 blood bank HD with unknown geographical origin, and 10 HD of WA origin (GeoHD). We measured plasma bacterial translocation markers by ELISA. Non-classical monocyte counts were higher in GeoHD than in HD (54 vs. 32 cells/μL, p = 0.0002). Slan+ monocyte counts were twice as high in GeoHD than in HD (WA: 28 vs. 13 cells/μL, p = 0.0002). Thus cell counts were compared only between participants of WA origin. They were similar in LTNP, P and GeoHD, indicating that there were no HIV-2 related differences. cDC counts did not show major differences between the groups. Interestingly, inflammatory monocyte counts correlated with plasma sCD14 and LBP only in PLWHIV-2, especially LTNP, and not in GeoHD. In conclusion, in LTNP PLWHIV-2, inflammatory monocyte counts correlated with LBP or sCD14 plasma levels, indicating a potential innate immune response to subclinical bacterial translocation. As GeoHD had higher inflammatory monocyte counts than HD, our data also show that specific controls are important to refine innate immunity studies.

DNA vectors have been widely used as a priming of poxvirus vaccine in prime/boost regimens. Whether the number of DNA impacts qualitatively or quantitatively the immune response is not fully explored. With the aim to reinforce T-cell responses by optimizing the prime-boost regimen, the multicentric EV03/ANRS VAC20 phase I/II trial, randomized 147 HIV-negative volunteers to either 3xDNA plus 1xNYVAC (weeks 0, 4, 8 plus 24; n = 74) or to 2xDNA plus 2xNYVAC (weeks 0, 4 plus 20, 24; n = 73) groups. T-cell responses (IFN-γ ELISPOT) to at least one peptide pool were higher in the 3xDNA than the 2xDNA groups (91% and 80% of vaccinees) (P = 0.049). In the 3xDNA arm, 26 (37%) recipients developed a broader T-cell response (Env plus at least to one of the Gag, Pol, Nef pools) than in the 2xDNA (15; 22%) arms (primary endpoint; P = 0.047) with a higher magnitude against Env (at week 26) (P

The low pathogenicity and replicative potential of HIV-2 are still poorly understood. We investigated whether HIV-2 reservoirs might follow the peculiar distribution reported in models of attenuated HIV-1/SIV infections, i.e. limited infection of central-memory CD4 T lymphocytes (TCM). Antiretroviral-naive HIV-2 infected individuals from the ANRS-CO5 (12 non-progressors, 2 progressors) were prospectively included. Peripheral blood mononuclear cells (PBMCs) were sorted into monocytes and resting CD4 T-cell subsets (naive [TN], central- [TCM], transitional- [TTM] and effector-memory [TEM]). Reactivation of HIV-2 was tested in 30-day cultures of CD8-depleted PBMCs. HIV-2 DNA was quantified by real-time PCR. Cell surface markers, co-receptors and restriction factors were analyzed by flow-cytometry and multiplex transcriptomic study. HIV-2 DNA was undetectable in monocytes from all individuals and was quantifiable in TTM from 4 individuals (median: 2.25 log10 copies/106 cells [IQR: 1.99-2.94]) but in TCM from only 1 individual (1.75 log10 copies/106 cells). HIV-2 DNA levels in PBMCs (median: 1.94 log10 copies/106 PBMC [IQR = 1.53-2.13]) positively correlated with those in TTM (r = 0.66, p = 0.01) but not TCM. HIV-2 reactivation was observed in the cells from only 3 individuals. The CCR5 co-receptor was distributed similarly in cell populations from individuals and donors. TCM had a lower expression of CXCR6 transcripts (p = 0.002) than TTM confirmed by FACS analysis, and a higher expression of TRIM5 transcripts (p = 0.004). Thus the low HIV-2 reservoirs differ from HIV-1 reservoirs by the lack of monocytic infection and a limited infection of TCM associated to a lower expression of a potential alternative HIV-2 co-receptor, CXCR6 and a higher expression of a restriction factor, TRIM5. These findings shed new light on the low pathogenicity of HIV-2 infection suggesting mechanisms close to those reported in other models of attenuated HIV/SIV infection models.

The goal of HIV therapeutic vaccination is to induce HIV-specific immune response able to control HIV replication. We previously reported that vaccination with ex vivo generated Dendritic Cells (DC) loaded with HIV-lipopeptides in HIV-infected patients (n = 19) on antiretroviral therapy (ART) was well-tolerated and immunogenic. Vaccine-elicited HIV-specific T cell responses were associated with improved control of viral replication following antiretroviral interruption (ATI from w24 to w48). We show an inverse relationship between HIV-specific responses (production of IL-2, IL-13, IL-21, IFN-g, CD4 polyfunctionality, i.e., production of at least two cytokines) and the peak of viral load during ATI. Here we have performed an integrative systems vaccinology analysis including: (i) post vaccination (w16) immune responses assessed by cytometry, cytokine secretion, and Interferon-γ ELISPOT assays; (ii) whole blood and cellular gene expression measured during vaccination; and (iii) viral parameters following ATI, with the objective to disentangle the relationships between these markers and to identify vaccine signatures. During vaccination, 69 gene expression modules out of 260 varied significantly including (by order of significance) modules related to inflammation (Chaussabel Modules M3.2, M4.13, M4.6, M5.7, M7.1, M4.2), plasma cells (M4.11) and T cells (M4.1, 4.15). Cellular immune responses were positively correlated to genes belonging to T cell functional modules (M4.1, M4.15) at w16 and negatively correlated to genes belonging to inflammation modules (M7.1, M5.7, M3.2, M4.13, M4.2). More specifically, we show that prolonged increased abundance of inflammatory gene pathways related to toll-like receptor signaling (especially TLR4) are associated with both lower vaccine immune responses and control of viral replication post ATI. Further comparison of DC vaccine gene signatures with previously reported non-HIV vaccine signatures, such as flu and pneumococcal vaccines, revealed common pathways across vaccines. Overall, these results show that too long duration and too high intensity of vaccine inflammatory responses hamper the magnitude of effector responses.

An amendment to this paper has been published and can be accessed via the original article.

MOTIVATION:The recent revolution in new sequencing technologies, as a part of the continuous process of adopting new innovative protocols has strongly impacted the interpretation of relations between phenotype and genotype. Thus, understanding the resulting gene sets has become a bottleneck that needs to be addressed. Automatic methods have been proposed to facilitate the interpretation of gene sets. While statistical functional enrichment analyses are currently well known, they tend to focus on well-known genes and to ignore new information from less-studied genes. To address such issues, applying semantic similarity measures is logical if the knowledge source used to annotate the gene sets is hierarchically structured. In this work, we propose a new method for analyzing the impact of different semantic similarity measures on gene set annotations. RESULTS:We evaluated the impact of each measure by taking into consideration the two following features that correspond to relevant criteria for a "good" synthetic gene set annotation: (i) the number of annotation terms has to be drastically reduced and the representative terms must be retained while annotating the gene set, and (ii) the number of genes described by the selected terms should be as large as possible. Thus, we analyzed nine semantic similarity measures to identify the best possible compromise between both features while maintaining a sufficient level of details. Using Gene Ontology to annotate the gene sets, we obtained better results with node-based measures that use the terms' characteristics than with measures based on edges that link the terms. The annotation of the gene sets achieved with the node-based measures did not exhibit major differences regardless of the characteristics of terms used.

To unravel the complex relationships between cytomegalovirus-induced-, autoimmune-induced responses, microbial translocation and chronic immune activation (CIA) in successfully treated HIV-infected patients and to explore the mediating role of alpha-interferon in these processes.Cross-sectional study nested in the ANRS CO3 Aquitaine Cohort, a prospective hospital-based cohort of HIV-1-infected patients in South-Western France.Patients initiated antiretroviral therapy between 2005 and 2008 and were treated with sustained virological suppression for at least two years. CIA was defined by the percentage of HLA-DR+/CD38+ among CD8+T-cells. Integrative analyses were performed using structural equation modelling (SEM).The main analysis was performed in 57 HLA-A*0201 positive patients, due to availability of percentages of actin-, vimentin-, lamin-specific CD8+T-cells (HLA-A2-restricted tests) to further characterize autoimmune response. Cytomegalovirus-induced response was assessed by Quantiferon and pp-65 ELISPOT. SEM revealed a direct effect of cytomegalovirus-induced response on CIA (standardized estimate βstd = 0.56, p-value = 0.0004). The effect of autoimmune-induced response on CIA was indirect through alpha-interferon pathway, assessed by expression levels of 5 alpha-interferon-stimulated genes ADAR, ISG15, IFIT1, Mx1 and OAS1 (effect of autoimmune response on alpha-interferon: βstd = 0.36, p-value = 0.0401; effect of alpha-interferon on CIA: βstd = 0.39, p-value = 0.0044). There was no direct effect of autoimmune-induced response on CIA (p-value = 0.3169). Microbial translocation as measured by 16SrDNA and sCD14 in plasma was not associated with CIA. Results were consistent in 142 patients in whom cytomegalovirus and auto-immunity responses were measured by Quantiferon and anti-nuclear antibodies, respectively. All analyses performed in HLA-A*0201 positive patients and in the overall population revealed a significant effect of IFN-α latent variable on CIA.The role of cytomegalovirus-induced response on CIA was confirmed as well as the involvement of alpha-interferon on CIA. The indirect effect of auto-immunity response on CIA revealed through the alpha-interferon pathway requires further investigation to confirm the potential role of auto-immunity for CIA in HIV-infected patients.