Assessment of the clinical and analytical performance of three Seegene Allplex SARS-CoV-2 assays within the VALCOR framework.

The coronavirus disease 2019 (COVID-19) pandemic demonstrated the need for accurate diagnostic testing for the early detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the pandemic has ended, accurate assays are still needed to monitor viral spread at national levels and beyond through population and wastewater surveillance. To enhance early detection, SARS-CoV-2 assays should have high diagnostic accuracy and should be validated to assure accurate results. Three distinct SARS-CoV-2 assays were evaluated with clinical samples using the VALCOR (VALidation of SARS-CORona Virus-2 assays) framework, with the TaqPath COVID-19 assay (ThermoFisher Scientific, USA) as a comparator. We evaluated clinical sensitivity, specificity, limit of detection (LOD), and overall concordance between comparator and three index Allplex SARS-CoV-2 assays (Seegene, South Korea): Allplex-SC2, Allplex-SC2Fast (Fast PCR), and Allplex-SC2FabR (SARS-CoV-2/FluA/FluB/respiratory syncytial virus). Analytical performance and LOD of index assays were assessed using a dilution series of three synthetic SARS-CoV-2 sequence reference materials (RMs). Ninety SARS-CoV-2 positives and 90 SARS-CoV-2 negatives were tested. All Allplex assays had 100.0% sensitivity (95%CI = 95.9%-100.0%). Allplex-SC2 and Allplex-SC2Fast assays had 97.8% specificity (95%CI = 92.3%-99.7%) and 98.9% overall concordance [κ = 0.978 (95%CI = 0.947-1.000)]. Allplex-SC2FabR assay showed 100.0% specificity (95%CI = 95.9%-100.0%) and 100.0% overall concordance [κ = 1.000 (95%CI = 1.000-1.000)]. LOD assessment of index assays revealed detection down to 2.61 × 102 copies/mL in clinical samples, while the analytical LOD was 9.00 × 102 copies/mL. In conclusion, the evaluation of the three Seegene Allplex SARS-CoV-2 assays showed high sensitivity and specificity and an overall good assay concordance with the comparator. The assays showed low analytical LOD using RM and even a slightly lower LOD in clinical samples. Non-overlapping target gene sequences between SARS-CoV-2 assays and RMs emphasize the need for aligning targeted sequences of diagnostic assays and RMs.IMPORTANCEThe coronavirus disease 2019 pandemic has a significant impact on global public health, economies, and societies. As shown through the first phases of the pandemic, accurate and timely diagnosis is crucial for disease control, prevention, and monitoring. Though the pandemic phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has concluded, diagnostic assays remain in demand to monitor SARS-CoV-2 at the individual patient level, regionally, and nationally, as well as to remain an infectious disease preparedness instrument to monitor any new SARS-CoV-2 dissemination across borders using population and wastewater surveillance. The anticipation by WHO and central health care policy entities such as the Center for Disease Control, EMA, and multiple national health authorities is that SARS-CoV-2 will reside as an endemic respiratory disease for years to come. The key strategic consideration is hence shifting from combating a pandemic situation with a high number of patients to instead allowing precise diagnostics of suspected patients with the intention of correct management in a low-prevalence setting.

Public health impact and return on investment of Belgium's pediatric immunization program.

Objective: We evaluated the public health impact and return on investment of Belgium's pediatric immunization program (PIP) from both healthcare-sector and societal perspectives. Methods: We developed a decision analytic model for 6 vaccines routinely administered in Belgium for children aged 0-10 years: DTaP-IPV-HepB-Hib, DTaP-IPV, MMR, PCV, rotavirus, and meningococcal type C. We used separate decision trees to model each of the 11 vaccine-preventable pathogens: diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type b, measles, mumps, rubella, Streptococcus pneumoniae, rotavirus, and meningococcal type C; hepatitis B was excluded because of surveillance limitations. The 2018 birth cohort was followed over its lifetime. The model projected and compared health outcomes and costs with and without immunization (based on vaccine-era and pre-vaccine era disease incidence estimates, respectively), assuming that observed reductions in disease incidence were fully attributable to vaccination. For the societal perspective, the model included productivity loss costs associated with immunization and disease in addition to direct medical costs. The model estimated discounted cases averted, disease-related deaths averted, life-years gained, quality-adjusted life-years gained, costs (2020 euros), and an overall benefit-cost ratio. Scenario analyses considered alternate assumptions for key model inputs. Results: Across all 11 pathogens, we estimated that the PIP prevented 226,000 cases of infections and 200 deaths, as well as the loss of 7,000 life-years and 8,000 quality-adjusted life-years over the lifetime of a birth cohort of 118,000 children. The PIP was associated with discounted vaccination costs of €91 million from the healthcare-sector perspective and €122 million from the societal perspective. However, vaccination costs were more than fully offset by disease-related costs averted, with the latter amounting to a discounted €126 million and €390 million from the healthcare-sector and societal perspectives, respectively. As a result, pediatric immunization was associated with overall discounted savings of €35 million and €268 million from the healthcare-sector and societal perspectives, respectively; every €1 invested in childhood immunization resulted in approximately €1.4 in disease-related cost savings to the health system and €3.2 in cost savings from a societal perspective for Belgium's PIP. Estimates of the value of the PIP were most sensitive to changes in input assumptions for disease incidence, productivity losses due to disease-related mortality, and direct medical disease costs. Conclusion: Belgium's PIP, which previously had not been systematically assessed, provides large-scale prevention of disease-related morbidity and premature mortality, and is associated with net savings to health system and society. Continued investment in the PIP is warranted to sustain its positive public health and financial impact.

Assessment of the clinical and analytical performance of the Aptima SARS-CoV-2 assay using the VALCOR protocol.

BACKGROUND: The COVID-19 pandemic highlighted the importance of diagnostic testing against curbing the spread of SARS-CoV-2. The urgent need and scale for diagnostic tools resulted in manufacturers of SARS-CoV-2 assays receiving emergency authorization that lacked robust analytical or clinical evaluation. As it is highly likely that testing for SARS-CoV-2 will continue to play a central role in public health, the performance characteristics of assays should be evaluated to ensure reliable diagnostic outcomes are achieved. METHODS: VALCOR or "VALidation of SARS-CORona Virus-2 assays" is a study protocol designed to set up a framework for test validation of SARS-CoV-2 virus assays. Using clinical samples collated from VALCOR, the performance of Aptima SARS-CoV-2 assay was assessed against a standard comparator assay. Diagnostic test parameters such as sensitivity, specificity and overall per cent agreement were calculated for the clinical performance of Aptima SARS-CoV-2 assay. RESULTS: A total of 180 clinical samples were tested with an addition of 40 diluted clinical specimens to determine the limit of detection. When compared to the standard comparator assay Aptima had a sensitivity of 100.0% [95% CI 95.9-100.0] and specificity of 96.7% [95% CI 90.8-99.3]. The overall percent agreement was 98.3% with an excellent Cohen's coefficient of κ = 0.967 [95% CI 0.929-1.000]. For the limit of detection, Aptima was able to detect all of the diluted clinical samples. CONCLUSION: In conclusion. validation of Aptima SARS-CoV-2 assay using clinical samples collated through the VALCOR protocol showed excellent test performance. Additionally, Aptima demonstrated high analytical sensitivity by detecting all diluted clinical samples corresponding to a low limit of detection.

A Novel Dynamic Model for Health Economic Analysis of Influenza Vaccination in the Elderly.

INTRODUCTION: New vaccines are being developed to improve the efficacy of seasonal influenza immunization in elderly persons aged ≥65 years. These products require clinical and economic evaluation to aid policy decisions. METHODS: To address this need, a two-part model has been developed, which we have applied to examine the potential clinical and economic impact of vaccinating elderly persons with adjuvanted trivalent inactivated influenza vaccine (aTIV) relative to conventional trivalent (TIV) and quadrivalent (QIV) vaccines. We compared outcomes in the US population for (1) aTIV in persons aged ≥65 years and QIV in all other age cohorts; (2) QIV in all cohorts; (3) TIV in all cohorts. Low, average, and high intensity seasons with low, average, and high vaccine match scenarios were compared. Probabilistic sensitivity analysis was conducted within each discrete scenario to explore the impact of variation in model inputs on potential outcomes. RESULTS: Assuming current vaccination coverage rates in the US population with (a) 25% better efficacy of adjuvanted versus non-adjuvanted vaccine against any strain and (b) 35% better efficacy of non-adjuvanted vaccine against matched B versus mismatched B strains, use of aTIV in persons aged ≥65 years and QIV in persons <65 years could reduce influenza cases by 11,166-1,329,200, hospitalizations by 1365-43,674, and deaths by 421-11,320 versus use of QIV in all cohorts. These outcomes are reflected in a corresponding increase in quality-adjusted life-years (QALYs) of 3003-94,084. If the prevalence of mismatched influenza B was >54.5% of all circulating strains, use of QIV in all cohorts would offset the clinical benefits of aTIV. Elderly aTIV or QIV vaccination was associated with improved outcomes over non-adjuvanted TIV in many of the scenarios, particularly in low match seasons of any intensity. Total cost savings (including direct and indirect healthcare costs plus productivity impacts) with aTIV in the elderly versus QIV in the whole population ranged from $27 million (low intensity, low match) to $934 million (high intensity, high match). Univariate sensitivity analysis of relative vaccine prices in the average intensity, average match scenario indicated that aTIV could be marginally cost saving relative to QIV at the currently published Medicare price for influenza vaccines offering enhanced efficacy in the elderly. Elderly vaccination with aTIV was associated with a higher overall cost compared with TIV in only two scenarios (low intensity with average or high match); the incremental cost/QALY relative to TIV was $9980 in the average match scenario and $28,800 in the high match scenario. CONCLUSIONS: Vaccination of persons aged ≥65 years with aTIV has the potential to provide clinical and economic benefit relative to QIV and TIV. The new model allows the assessment of various alternative strategies for available influenza vaccines. FUNDING: Novartis Vaccines.

Complete genome characterization of recent and ancient Belgian pig group A rotaviruses and assessment of their evolutionary relationship with human rotaviruses.

UNLABELLED: Group A rotaviruses (RVAs) are an important cause of diarrhea in young pigs and children. An evolutionary relationship has been suggested to exist between pig and human RVAs. This hypothesis was further investigated by phylogenetic analysis of the complete genomes of six recent (G2P[27], G3P[6], G4P[7], G5P[7], G9P[13], and G9P[23]) and one historic (G1P[7]) Belgian pig RVA strains and of all completely characterized pig RVAs from around the globe. In contrast to the large diversity of genotypes found for the outer capsid proteins VP4 and VP7, a relatively conserved genotype constellation (I5-R1-C1-M1-A8-N1-T7-E1-H1) was found for the other 9 genes in most pig RVA strains. VP1, VP2, VP3, NSP2, NSP4, and NSP5 genes of porcine RVAs belonged to genotype 1, which is shared with human Wa-like RVAs. However, for most of these gene segments, pig strains clustered distantly from human Wa-like RVAs, indicating that viruses from both species have entered different evolutionary paths. However, VP1, VP2, and NSP3 genes of some archival human strains were moderately related to pig strains. Phylogenetic analysis of the VP6, NSP1, and NSP3 genes, as well as amino acid analysis of the antigenic regions of VP7, further confirmed this evolutionary segregation. The present results also indicate that the species barrier is less strict for pig P[6] strains but that chances for successful spread of these strains in the human population are hampered by the better adaptation of pig RVAs to pig enterocytes. However, future surveillance of pig and human RVA strains is warranted. IMPORTANCE: Rotaviruses are an important cause of diarrhea in many species, including pigs and humans. Our understanding of the evolutionary relationship between rotaviruses from both species is limited by the lack of genomic data on pig strains. In this study, recent and ancient Belgian pig rotavirus isolates were sequenced, and their evolutionary relationship with human Wa-like strains was investigated. Our data show that Wa-like human and pig strains have entered different evolutionary paths. Our data indicate that pig P[6] strains form the most considerable risk for interspecies transmission to humans. However, efficient spread of pig strains in the human population is most likely hampered by the adaptation of some crucial viral proteins to the cellular machinery of pig enterocytes. These data allow a better understanding of the risk for direct interspecies transmission events and the emergence of pig rotaviruses or pig-human reassortants in the human population.

Effectiveness of rotavirus vaccination in prevention of hospital admissions for rotavirus gastroenteritis among young children in Belgium: case-control study.

OBJECTIVE: To evaluate the effectiveness of rotavirus vaccination among young children in Belgium. DESIGN: Prospective case-control study. SETTING: Random sample of 39 Belgian hospitals, February 2008 to June 2010. PARTICIPANTS: 215 children admitted to hospital with rotavirus gastroenteritis confirmed by polymerase chain reaction and 276 age and hospital matched controls. All children were of an eligible age to have received rotavirus vaccination (that is, born after 1 October 2006 and aged ≥ 14 weeks). MAIN OUTCOME MEASURE: Vaccination status of children admitted to hospital with rotavirus gastroenteritis and matched controls. RESULTS: 99 children (48%) admitted with rotavirus gastroenteritis and 244 (91%) controls had received at least one dose of any rotavirus vaccine (P<0.001). The monovalent rotavirus vaccine accounted for 92% (n=594) of all rotavirus vaccine doses. With hospital admission as the outcome, the unadjusted effectiveness of two doses of the monovalent rotavirus vaccine was 90% (95% confidence interval 81% to 95%) overall, 91% (75% to 97%) in children aged 3-11 months, and 90% (76% to 96%) in those aged ≥ 12 months. The G2P[4] genotype accounted for 52% of cases confirmed by polymerase chain reaction with eligible matched controls. Vaccine effectiveness was 85% (64% to 94%) against G2P[4] and 95% (78% to 99%) against G1P[8]. In 25% of cases confirmed by polymerase chain reaction with eligible matched controls, there was reported co-infection with adenovirus, astrovirus and/or norovirus. Vaccine effectiveness against co-infected cases was 86% (52% to 96%). Effectiveness of at least one dose of any rotavirus vaccine (intention to vaccinate analysis) was 91% (82% to 95%). CONCLUSIONS: Rotavirus vaccination is effective for the prevention of admission to hospital for rotavirus gastroenteritis among young children in Belgium, despite the high prevalence of G2P[4] and viral co-infection.

Estimating the incidence of symptomatic rotavirus infections: a systematic review and meta-analysis.

BACKGROUND: We conducted for the first time a systematic review, including a meta-analysis, of the incidence of symptomatic rotavirus (RV) infections, because (1) it was shown to be an influential factor in estimating the cost-effectiveness of RV vaccination, (2) multiple community-based studies assessed it prospectively, (3) previous studies indicated, inconclusively, it might be similar around the world. METHODOLOGY: Pubmed (which includes Medline) was searched for surveys assessing prospectively symptomatic (diarrheal) episodes in a general population and situation, which also reported on the number of the episodes being tested RV+ and on the persons and the time period observed. A bias assessment tool was developed and used according to Cochrane guidelines by 4 researchers with different backgrounds. Heterogeneity was explored graphically and by comparing fits of study-homogenous 'fixed effects' and -heterogeneous 'random effects' models. Data were synthesized using these models. Sensitivity analysis for uncertainty regarding data abstraction, bias assessment and included studies was performed. PRINCIPAL FINDINGS: Variability between the incidences obtained from 20 studies is unlikely to be due to study groups living in different environments (tropical versus temperate climate, slums versus middle-class suburban populations), nor due to the year the study was conducted (from 1967 to 2003). A random effects model was used to incorporate unexplained heterogeneity and resulted in a global incidence estimate of 0.31 [0.19; 0.50] symptomatic RV infections per personyear of observation for children below 2 years of age, and of 0.24 [0.17; 0.34] when excluding the extreme high value of 0.84 reported for Mayan Indians in Guatemala. Apart from the inclusion/exclusion of the latter study, results were robust. CONCLUSIONS/SIGNIFICANCE: Rather than assumptions based on an ad-hoc selection of one or two studies, these pooled estimates (together with the measure for variability between populations) should be used as an input in future cost-effectiveness analyses of RV vaccination.

The health and economic burden of rotavirus disease in Belgium.

For health economic evaluations of rotavirus vaccination, estimates of the health and cost burden of rotavirus are required. Due to differences in health care systems and surveillance organisations, this is difficult to achieve by imputing estimates from one country to others. This study aimed to estimate the burden of rotavirus disease in Belgium. In children younger than 7 years of age, rotavirus is predicted to account annually for about 5,600 hospitalisations (676:100,000 children); 26,800 outpatient, general practitioner and paediatrician visits; and about 44,600 episodes for which no medical care is sought. This burden is estimated to represent direct costs of 7.7 million Euro and indirect costs of 12.8 million Euro. Rotavirus disease causes a substantial health and economic burden in Belgium.

Early prediction of major depression in chronic hepatitis C patients during peg-interferon alpha-2b treatment by assessment of vegetative-depressive symptoms after four weeks.

AIM: To study the predictive value of the vegetative-depressive symptoms of the Zung Depression Rating Scale for the occurrence of depression during treatment with peg-interferon alpha-2b of chronic hepatitis C (CHC) patients. METHODS: The predictive value of vegetative-depressive symptoms at 4 wk of treatment for the occurrence of a subsequent diagnosis of major depressive disorder (MDD) was studied in CHC patients infected after substance use in a prospective, multi-center treatment trial in Belgium. The presence of vegetative-depressive symptoms was assessed using the Zung Scale before and 4 wk after the start of antiviral treatment. RESULTS: Out of 49 eligible patients, 19 (39%) developed MDD. The area under the ROC curve of the vegetative Zung subscale was 0.73, P = 0.004. The sensitivity at a cut-point of > 15/35 was 95% (95% CI: 74-100). The positive predictive value equalled 44% (95% CI: 29-60). CONCLUSION: In this group of Belgian CHC patients infected after substance use, antiviral treatment caused a considerable risk of depression. Seven vegetative-depressive symptoms of the Zung scale at wk 4 of treatment predicted 95% of all emerging depressions, at a price of 56% false positive test results.