A dose-dependent plasma signature of the safety and immunogenicity of the rVSV-Ebola vaccine in Europe and Africa.

The 2014-2015 Ebola epidemic affected several African countries, claiming more than 11,000 lives and leaving thousands with ongoing sequelae. Safe and effective vaccines could prevent or limit future outbreaks. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSV-ZEBOV) vaccine has shown marked immunogenicity and efficacy in humans but is reactogenic at higher doses. To understand its effects, we examined plasma samples from 115 healthy volunteers from Geneva who received low-dose (LD) or high-dose (HD) vaccine or placebo. Fifteen plasma chemokines/cytokines were assessed at baseline and on days 1, 2 to 3, and 7 after injection. Significant increases in monocyte-mediated MCP-1/CCL2, MIP-1β/CCL4, IL-6, TNF-α, IL-1Ra, and IL-10 occurred on day 1. A signature explaining 68% of cytokine/chemokine vaccine-response variability was identified. Its score was higher in HD versus LD vaccinees and was associated positively with vaccine viremia and negatively with cytopenia. It was higher in vaccinees with injection-site pain, fever, myalgia, chills, and headache; higher scores reflected increasing severity. In contrast, HD vaccinees who subsequently developed arthritis had lower day 1 scores than other HD vaccinees. Vaccine dose did not influence the signature despite its influence on specific outcomes. The Geneva-derived signature associated strongly (ρ = 0.97) with that of a cohort of 75 vaccinees from a parallel trial in Lambaréné, Gabon. Its score in Geneva HD vaccinees with subsequent arthritis was significantly lower than that in Lambaréné HD vaccinees, none of whom experienced arthritis. This signature, which reveals monocytes' critical role in rVSV-ZEBOV immunogenicity and safety across doses and continents, should prove useful in assessments of other vaccines

Cross-cultural psychometric assessment of an appetite questionnaire for patients with cancer

Objective: To evaluate the psychometric properties, along with cross-cultural invariance analysis, of the Cancer Appetite and Symptom Questionnaire (CASQ). Method: Data from 555 United Kingdom (UK) cancer patients were used to evaluate the psychometric properties of the CASQ. Construct validity was assessed through factorial and convergent validity. We conducted a confirmatory factor analysis using as indices the chi-square ratio by degrees of freedom (χ2/df), the comparative fit index (CFI), the goodness of fit index (GFI), and the root mean square error of approximation (RMSEA). Convergent validity was estimated by the items’ average variance extracted (AVE). Reliability was estimated by composite reliability and internal consistency. Factorial invariance analysis of the CASQ was evaluated by multigroup analysis (∆χ2) using the UK and Brazilian samples. Results: All items showed adequate psychometric sensitivity in the UK sample. One item was removed and four correlations were included between errors with an appropriate fit of the model (χ2/df = 2.674, CFI = 0.966, GFI = 0.964, RMSEA = 0.055). The reliability of the CASQ was adequate and the convergent validity was low. The factorial structure of the CASQ differed across countries, and a lack of measurement invariance for the two countries was observed (λ: ∆χ2 = 64.008, p < 0.001; i: ∆χ2 = 3515.047, p < 0.001; Res: ∆χ2 = 4452.504, p < 0.001). Conclusion: The CASQ showed adequate psychometric properties in the UK sample. The ability to estimate loss of appetite and the presence of symptoms was different between UK and Brazilian patients

European enhanced surveillance of invasive pneumococcal disease in 2010: data from 26 European countries in the post-heptavalent conjugate vaccine era.

Streptococcus pneumoniae is a leading cause of severe infectious diseases worldwide. This paper presents the results from the first European invasive pneumococcal disease (IPD) enhanced surveillance where additional and valuable data were reported and analysed. Following its authorisation in Europe in 2001 for use in children aged between two months and five years, the heptavalent pneumococcal conjugate vaccine (PCV7) was progressively introduced in the European Union (EU)/European Economic Area (EEA) countries, albeit with different schemes and policies. In mid-2010 European countries started to switch to a higher valency vaccine (PCV10/PCV13), still without a significant impact by the time of this surveillance. Therefore, this surveillance provides an overview of baseline data from the transition period between the introduction of PCV7 and the implementation of PCV10/PCV13. In 2010, 26 EU/EEA countries reported 21 565 cases of IPD to The European Surveillance System (TESSy) applying the EU 2008 case definition. Serotype was determined in 9946/21565 (46.1%) cases. The most common serotypes were 19A, 1, 7F, 3, 14, 22F, 8, 4, 12F and 19F, accounting for 5949/9946 (59.8%) of the serotyped isolates. Data on antimicrobial susceptibility testing (AST) in the form of minimum inhibitory concentrations (MIC) were submitted for penicillin 5384/21565 (25.0%), erythromycin 4031/21565 (18.7%) and cefotaxime 5252/21565 (24.4%). Non-susceptibility to erythromycin was highest at 17.6% followed by penicillin at 8.9%. PCV7 serotype coverage among children &lt;5 years in Europe, was 19.2%; for the same age group, the serotype coverage for PCV10 and PCV13 were 46.1% and 73.1%, respectively. In the era of pneumococcal conjugate vaccines, the monitoring of changing trends in antimicrobial resistance and serotype distribution are essential in assessing the impact of vaccines and antibiotic use control programmes across European countries

European enhanced surveillance of invasive pneumococcal disease in 2010: data from 26 European countries in the post-heptavalent conjugate vaccine era.

Streptococcus pneumoniae is a leading cause of severe infectious diseases worldwide. This paper presents the results from the first European invasive pneumococcal disease (IPD) enhanced surveillance where additional and valuable data were reported and analysed. Following its authorisation in Europe in 2001 for use in children aged between two months and five years, the heptavalent pneumococcal conjugate vaccine (PCV7) was progressively introduced in the European Union (EU)/European Economic Area (EEA) countries, albeit with different schemes and policies. In mid-2010 European countries started to switch to a higher valency vaccine (PCV10/PCV13), still without a significant impact by the time of this surveillance. Therefore, this surveillance provides an overview of baseline data from the transition period between the introduction of PCV7 and the implementation of PCV10/PCV13. In 2010, 26 EU/EEA countries reported 21 565 cases of IPD to The European Surveillance System (TESSy) applying the EU 2008 case definition. Serotype was determined in 9946/21565 (46.1%) cases. The most common serotypes were 19A, 1, 7F, 3, 14, 22F, 8, 4, 12F and 19F, accounting for 5949/9946 (59.8%) of the serotyped isolates. Data on antimicrobial susceptibility testing (AST) in the form of minimum inhibitory concentrations (MIC) were submitted for penicillin 5384/21565 (25.0%), erythromycin 4031/21565 (18.7%) and cefotaxime 5252/21565 (24.4%). Non-susceptibility to erythromycin was highest at 17.6% followed by penicillin at 8.9%. PCV7 serotype coverage among children <5 years in Europe, was 19.2%; for the same age group, the serotype coverage for PCV10 and PCV13 were 46.1% and 73.1%, respectively. In the era of pneumococcal conjugate vaccines, the monitoring of changing trends in antimicrobial resistance and serotype distribution are essential in assessing the impact of vaccines and antibiotic use control programmes across European countries

Transcriptomic signatures induced by the Ebola virus vaccine rVSVΔG-ZEBOV-GP in adult cohorts in Europe, Africa, and North America: a molecular biomarker study

Background A recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP) vaccine has been reported as safe, immunogenic, and highly protective in a ring vaccination trial. We aimed to identify transcriptomic immune response biomarker signatures induced by vaccination and associated signatures with its immunogenicity and reactogenicity to better understand the potential mechanisms of action of the vaccine. Methods 354 healthy adult volunteers were vaccinated in randomised, double-blind, placebo-controlled trials in Europe (Geneva, Switzerland [November, 2014, to January, 2015]) and North America (USA [Dec 5, 2014, to June 23, 2015]), and dose-escalation trials in Africa (Lambaréné, Gabon [November, 2014, to January, 2015], and Kilifi, Kenya [December, 2014, to January, 2015]) using different doses of the recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP; 3 × 105 to 1 × 108 plaque-forming units [pfu]). Longitudinal transcriptomic responses (days 0, 1, 2, 3, 7, 14, and 28) were measured in whole blood using a targeted gene expression profiling platform (dual-colour reverse-transcriptase multiplex ligation-dependent probe amplification) focusing on 144 immune-related genes. The effect of time and dose on transcriptomic response was also assessed. Logistic regression with lasso regularisation was applied to identify host signatures with optimal discriminatory capability of vaccination at day 1 or day 7 versus baseline, whereas random-effects models and recursive feature elimination combined with regularised logistic regression were used to associate signatures with immunogenicity and reactogenicity. Findings Our results indicated that perturbation of gene expression peaked on day 1 and returned to baseline levels between day 7 and day 28. The magnitude of the response was dose-dependent, with vaccinees receiving a high dose (≥9 × 106 pfu) of rVSVΔG-ZEBOV-GP exhibiting the largest amplitude. The most differentially expressed genes that were significantly upregulated following vaccination consisted of type I and II interferon-related genes and myeloid cell-associated markers, whereas T cell, natural killer cell, and cytotoxicity-associated genes were downregulated. A gene signature associated with immunogenicity (common to all four cohorts) was identified correlating gene expression profiles with ZEBOV-GP antibody titres and a gene signatures associated with reactogenicity (Geneva cohort) was identified correlating gene expression profiles with an adverse event (ie, arthritis). Interpretation Collectively, our results identify and cross-validate immune-related transcriptomic signatures induced by rVSVΔG-ZEBOV-GP vaccination in four cohorts of adult participants from different genetic and geographical backgrounds. These signatures will aid in the rational development, testing, and evaluation of novel vaccines and will allow evaluation of the effect of host factors such as age, co-infection, and comorbidity on responses to vaccines

Transcriptomic signatures induced by the Ebola virus vaccine rVSVΔG-ZEBOV-GP in adult cohorts in Europe, Africa, and North America: a molecular biomarker study

Background A recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP) vaccine has been reported as safe, immunogenic, and highly protective in a ring vaccination trial. We aimed to identify transcriptomic immune response biomarker signatures induced by vaccination and associated signatures with its immunogenicity and reactogenicity to better understand the potential mechanisms of action of the vaccine. Methods 354 healthy adult volunteers were vaccinated in randomised, double-blind, placebo-controlled trials in Europe (Geneva, Switzerland [November, 2014, to January, 2015]) and North America (USA [Dec 5, 2014, to June 23, 2015]), and dose-escalation trials in Africa (Lambaréné, Gabon [November, 2014, to January, 2015], and Kilifi, Kenya [December, 2014, to January, 2015]) using different doses of the recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP; 3 × 105 to 1 × 108 plaque-forming units [pfu]). Longitudinal transcriptomic responses (days 0, 1, 2, 3, 7, 14, and 28) were measured in whole blood using a targeted gene expression profiling platform (dual-colour reverse-transcriptase multiplex ligation-dependent probe amplification) focusing on 144 immune-related genes. The effect of time and dose on transcriptomic response was also assessed. Logistic regression with lasso regularisation was applied to identify host signatures with optimal discriminatory capability of vaccination at day 1 or day 7 versus baseline, whereas random-effects models and recursive feature elimination combined with regularised logistic regression were used to associate signatures with immunogenicity and reactogenicity. Findings Our results indicated that perturbation of gene expression peaked on day 1 and returned to baseline levels between day 7 and day 28. The magnitude of the response was dose-dependent, with vaccinees receiving a high dose (≥9 × 106 pfu) of rVSVΔG-ZEBOV-GP exhibiting the largest amplitude. The most differentially expressed genes that were significantly upregulated following vaccination consisted of type I and II interferon-related genes and myeloid cell-associated markers, whereas T cell, natural killer cell, and cytotoxicity-associated genes were downregulated. A gene signature associated with immunogenicity (common to all four cohorts) was identified correlating gene expression profiles with ZEBOV-GP antibody titres and a gene signatures associated with reactogenicity (Geneva cohort) was identified correlating gene expression profiles with an adverse event (ie, arthritis). Interpretation Collectively, our results identify and cross-validate immune-related transcriptomic signatures induced by rVSVΔG-ZEBOV-GP vaccination in four cohorts of adult participants from different genetic and geographical backgrounds. These signatures will aid in the rational development, testing, and evaluation of novel vaccines and will allow evaluation of the effect of host factors such as age, co-infection, and comorbidity on responses to vaccines