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Background Methodologically rigorous studies on Covid-19 vaccine effectiveness (VE) in preventing SARS-CoV-2 infection are critically needed to inform national and global policy on Covid-19 vaccine use. In Israel, healthcare personnel (HCP) were initially prioritized for Covid-19 vaccination, creating an ideal setting to evaluate early real-world VE in a closely monitored population. Methods We conducted a prospective study among HCP in 6 hospitals to estimate the effectiveness of the BNT162b2 mRNA Covid-19 vaccine in preventing SARS-CoV-2 infection. Participants filled out weekly symptom questionnaires, provided weekly nasal specimens, and three serology samples – at enrollment, 30 days and 90 days. We estimated VE against PCR-confirmed SARS-CoV-2 infection using the Cox Proportional Hazards model and against a combined PCR/serology endpoint using Fisher’s exact test. Results Of the 1567 HCP enrolled between December 27, 2020 and February 15, 2021, 1250 previously uninfected participants were included in the primary analysis; 998 (79.8%) were vaccinated with their first dose prior to or at enrollment, all with Pfizer BNT162b2 mRNA vaccine. There were four PCR-positive events among vaccinated participants, and nine among unvaccinated participants. Adjusted two-dose VE against any PCR-confirmed infection was 94.5% (95% CI: 82.6%-98.2%); adjusted two-dose VE against a combined endpoint of PCR and seroconversion for a 60-day follow-up period was 94.5% (95% CI: 63.0%-99.0%). Five PCR-positive samples from study participants were sequenced; all were alpha variant. Conclusions Our prospective VE study of HCP in Israel with rigorous weekly surveillance found very high VE for two doses of Pfizer BNT162b2 mRNA vaccine against SARS-CoV-2 infection in recently vaccinated HCP during a period of predominant alpha variant circulation. Funding Clalit Health Services.

Background The incidence of invasive pneumococcal disease (IPD) declined during the COVID-19 pandemic. Previous studies hypothesized that this was due to reduced pneumococcal transmission resulting from nonpharmaceutical interventions. We used multiple ongoing cohort surveillance projects in children Methods The first SARS-CoV-2 cases were detected in February 2020, resulting in a full lockdown, followed by several partial restrictions. Data from ongoing surveillance projects captured the incidence dynamics of community-acquired alveolar pneumonia (CAAP), nonalveolar lower respiratory infections necessitating chest X-rays (NA-LRIs), nasopharyngeal pneumococcal carriage in nonrespiratory visits, nasopharyngeal respiratory virus detection (by polymerase chain reaction), and nationwide IPD. Monthly rates (January 2020 through February 2021 vs mean monthly rates 2016–2019 [expected rates]) adjusted for age and ethnicity were compared. Results CAAP and bacteremic pneumococcal pneumonia were strongly reduced (incidence rate ratios [IRRs]: .07 and .19, respectively); NA-LRIs and nonpneumonia IPD were also reduced by a lesser magnitude (IRRs: .46 and .42, respectively). In contrast, pneumococcal carriage prevalence was only slightly reduced, and density of colonization and pneumococcal serotype distributions were similar to previous years. The decline in pneumococcus-associated disease was temporally associated with a full suppression of respiratory syncytial virus, influenza viruses, and human metapneumovirus, often implicated as co-pathogens with pneumococcus. In contrast, adenovirus, rhinovirus, and parainfluenza activities were within or above expected levels. Conclusions Reductions in pneumococcal and pneumococcus-associated diseases occurring during the COVID-19 pandemic in Israel were not predominantly related to reduced pneumococcal carriage and density but were strongly associated with the disappearance of specific respiratory viruses.

The SARS-CoV-2 pandemic led to unprecedented testing demands, causing significant testing delays globally. One strategy used for increasing testing capacity was pooled-testing, using a two-stage technique first introduced during WWII. Here we report the development, validation and clinical application of P-BEST - a single-stage pooled-testing strategy that was approved for clinical use in Israel. P-BEST was clinically evaluated using 3,636 side-by-side tests and was able to correctly detect all positive samples and accurately estimate their Ct value. P-BEST was then used to clinically test 837,138 samples using 270,095 PCR tests - a 3.1 fold reduction in the number of tests. Importantly, P-BEST was also used during the Alpha and Delta waves, when positivity rates exceeded 10%, rendering traditional pooling non-practical. We also describe a tablet-based solution that allows performing manual single-stage pooling in settings where liquid dispensing robots are not available. Our data provides a proof-of-concept for large-scale clinical implementation of single-stage pooled-testing for continuous surveillance of multiple pathogens with reduced test costs, and as an important tool for increasing testing efficiency during pandemic outbreaks.

Background During the early Covid-19 pandemic, we observed a close-to-full disappearance of the activity of 4 respiratory viruses (RSV, hMPV, influenza, and parainfluenza), followed by an off-season sequential re-emergence in 2021. Surprisingly, a striking similarity between the dynamics of pneumococcus-associated disease (PAD; namely community-acquired alveolar pneumonia [CAAP; often considered pneumococcal] and bacteremic-pneumococcal pneumonia [IPD-Pneumonia]), was also observed. In contrast, adenovirus and rhinovirus activities did not change during COVID-19. We examined the association between PAD and RSV, hMPV, influenza, and parainfluenza (PAD-viruses). Methods Surveillance of CAAP and IPD-Pneumonia incidences and viral activity in children < 5 years was described in detail previously [Danino D. et al. Clin Infect Dis. 2022, https://doi.org/10.1093/cid/ciab1014]. We extended the observations until December 2021, to capture the sequential re-emergence of the 4 PAD-viruses. A hierarchical linear regression model was used to quantify the association between PAD-viruses (each virus individually and combined), adenovirus and PAD. After fitting the models, the contribution of each virus was estimated. Results The Figure shows striking similarities in the dynamics of CAAP, IPD-Pneumonia, and PAD-viruses both before and during the COVID-19 pandemic. During the expected peak season (Oct 2020 – Apr 2021) PAD episodes were extremely low. However, off-season peaks were seen during May – Dec 2021. Overall, 78% and 25% of all CAAP and IPD-Pneumonia episodes, respectively, were attributable to these viruses in children < 5 (Table). In CAAP, cases were attributable to each of the 4 PAD-viruses individually throughout the first 5 years of life: RSV and hMPV combined contributed 80%, 63%, and 42% of all CAAP episodes in children aged < 1, 1, and 2-4 years, respectively. The respective figures for influenza and parainfluenza combined were 13%, 21%, and 22%. Only RSV significantly contributed to IPD-Pneumonia (19%). Adenovirus did not contribute to PAD episodes. Conclusion Our model suggests an important causative association between RSV, hMPV, influenza, and parainfluenza viruses and CAAP, and between RSV and IPD-Pneumonia. Disclosures All Authors: No reported disclosures.

Background Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) and to a lesser extent, parainfluenza and influenza viruses have been associated with pneumonia in young children. In contrast, adenovirus (AdV) and rhinovirus (RhV) are usually not associated with pneumonia. We aimed to evaluate the involvement of the four pneumonia associated viruses (grouped as PAV) in pediatric CAAP, before and during the COVID-19 pandemic. Methods CAAP incidence and viral activity surveillance in southern Israel in children < 5y and virological detection methods were described previously (Danino. CID 2022, https://doi.org/10.1093/cid/ciab1014). We reviewed the period of Jan 2016 - Mar 2022. Most cases of COVID-19 in children < 5y occurred during Dec 2021 - Mar 2022 (Figure 1); Over 95% of children admitted for respiratory disease were tested for COVID-19 (PCR). Since AdV and RhV activity was previously not associated with CAAP and tended to be equally involved in mixed and single infections, the current analysis was done for the four PAV only. Results CAAP incidence dynamics closely resembled the four PAV (grouped) activity dynamics (Figure 2A, 2B) with very low activity during the expected peak in winter 2020-2021, but with an off-season resurgence from spring 2021. Even though most CAAP episodes during the pandemic coincided with peak COVID-19 rates, only 9 CAAP episodes were COVID-19 positive (7 in 2022, of which 5 were RSV positive). Out of 3,430 CAAP episodes 55% were tested for PAV, of which 61% were positive, with similar rates before and during the pandemic. RSV was the most common involved virus, followed by hMPV. The virus distribution in CAAP during the entire period reflected their activity in the community (Figure 2C). Unlike pre-pandemic years where all four PAV appeared almost simultaneously, in 2021 PAV resurged sequentially, resulting in successive involvement in CAAP episodes, suggesting a causative association. Conclusion 1. SARS-CoV-2 was only rarely involved in CAAP in young children. 2. PAV were involved in 61% of CAAP episodes in children < 5y with predominance of RSV and hMPV. 3. The atypical dynamics imposed by the COVID-19 pandemic suggests a causative association between PAV and CAAP. Disclosures All Authors: No reported disclosures.

SummaryBACKGROUNDIn young children, rates of lower respiratory infections (LRI) and invasive pneumococcal disease (IPD) have been associated with respiratory syncytial virus (RSV), human metapneumovirus (hMPV), influenza (flu), and parainfluenza (PIV) (collectively termed here as pneumonia and pneumococcal disease-associated viruses [PDA-viruses]). However, their contribution to the pathogenesis of these disease endpoints has not yet been elucidated. The COVID-19 pandemic provided a unique opportunity to examine the question.METHODSThis prospective study comprised all children FINDINGSDuring 2016 through 2021, 3,204, 26,695, 257, and 619 episodes of CAAP, non-CAAP LRI, pneumococcal bacteremic pneumonia and non-pneumonia IPD, respectively, were reported. Compared to 2016-2019, broad declines in the disease endpoints were observed shortly after the pandemic surge, coincident with a complete disappearance of all PDA-viruses and continued circulation of rhinovirus (RhV) and adenovirus (AdV). From April 2021, off-season and abrupt surges of all disease endpoints occurred, associated with similar dynamics among the PDA-viruses, which re-emerged sequentially. Using our model fit to the entire 2016-2021 period, 82% (95% CI, 75-88%) of CAAP episodes in 2021 were attributable to the common respiratory viruses, as were 22%-31% of the other disease endpoints. Virus-specific contributions to CAAP were: RSV, 49% (95% CI, 43-55%); hMPV, 13% (10-17%); PIV, 11% (7-15%); flu, 7% (1-13%). RhV and AdV did not contribute. RSV was the main contributor in all endpoints, especially in infants. Pneumococcal carriage prevalence remained largely stable throughout the study.INTERPRETATIONRSV and hMPV play a critical role in the burden of CAAP and pneumococcal disease in children. Interventions targeting these viruses could have a secondary effect on the burden of disease typically attributed to bacteria.FUNDINGThere was no funding for this study.Research in ContextEvidence before this studyLower respiratory infections (LRI) and invasive pneumococcal disease (IPD) in young children, have often been associated with specific respiratory viruses, namely respiratory syncytial virus (RSV), human metapneumovirus (hMPV) influenza viruses (flu), and parainfluenza viruses (PIV) (termed in the current article pneumonia and pneumococcal disease-associated viruses [PDA-viruses]). However, their causative role as co-pathogens has not yet been fully elucidated. There is already ample evidence that bacteria and viruses interact to cause severe disease. This could be seen after the introduction of pneumococcal conjugate vaccines (PCVs), when there was a significant reduction in hospitalisation for viral lower respiratory infections (LRIs). This suggests that viral-pneumococcal coinfections are common and play a role in the pathogenesis of pneumococcal respiratory infections. To demonstrate the contribution of viruses to the burden of pneumococcal disease specifically, and pneumonia in general, it would be necessary to eliminate one or more of the respiratory viruses. Shortly after the start of the COVID-19 pandemic, multiple reports demonstrated reduced IPD and LRI rates among young children, coincident with dramatically reduced rates of the PDA-viruses globally. Initially, the reduced rates of pneumococcal disease were attributed to non-pharmaceutical interventions that might reduce pneumococcal transmission in the community. However, continuous, virtually unchanged pneumococcal carriage rates were reported in multiple studies, strongly suggesting the reduced circulation ofS. pneumoniaewas not significantly contributing to disease reduction. Surprisingly, pneumococcus-associated diseases and PDA-viruses simultaneously re-emerged in 2021 during the off-season. In contrast to PDA-viruses, other viruses, such as adenovirus and rhinovirus did not show any of the patterns discussed above. We searched PubMed on June 1st, 2022, for studies since 2020 using the following terms: (“COVID-19” or “SARS-Cov-2”) and (“S. pneumoniae” or “pneumococcus” or “IPD” or “respiratory virus” or respiratory syncytial virus” or “hMPV” or “influenza” or “parainfluenza” or “adenovirus” or “rhinovirus” or “lower respiratory infection”). The search was for English literature and unrestricted by date.Added value of this studyThree unique characteristics of the COVID-19 pandemic-induced abnormal dynamics, coupled with multiple ongoing cohort studies in young children, contributed to the historic opportunity to model and quantify the attributable role of the various common respiratory viruses to four pneumococcus-associated disease endpoints (in particular community-acquired alveolar pneumonia (CAAP), non-CAAP LRIs, pneumococcal bacteremic pneumonia and non-pneumonia IPD): First, the full seasonal disappearance of all PDA-viruses shortly after the start of the pandemic, in the presence of continuous, uninterrupted pneumococcal carriage and continuous unchanged rhinovirus and adenovirus activity. Second, the off-season resurgence of the PDA-viruses in 2021. Third, the sequential, rather than simultaneous, re-emergence of the PDA-viruses. The analysis in this study suggests that several of the respiratory viruses, particularly RSV and hMPV, play an important causative role in the pathogenesis of pneumococcal diseases and other respiratory infections. Furthermore, the proportion attributable to each of the PDA-viruses for each of the four studied disease endpoints, and each of the age groups (Implication of all the available findingsOur findings add evidence about the absolute and relative contribution of common respiratory viruses to the burden of pneumonia and pneumococcal diseases and related conditions in young children. The strong contribution of RSV to disease burden compared to other viruses in all studied disease endpoints suggests that interventions that target viruses could have secondary effects on the burden of diseases typically attributed to bacteria.

Variants of concern (VOC) of SARS-CoV2 and waning immunity pose a serious global problem. Overall, vaccination and prior infection provide significant protection, but some individuals remain susceptible to infection and severe disease. Rigorously identifying correlates of protection (COP) is necessary to identify these susceptible populations. We conducted a multicenter prospective study assessing the association between serological profiles and the risk for SARS-CoV-2 infection, comparing those vaccinated with three to four doses of Pfizer BNT162b2 vaccine. We identified several IgG and IgA binding markers that were COPs. The strongest COP was reduced IgG levels to RBD mutants and IgA levels to VOCs (three-dose-group HR=6.34, p=0.008; four-dose-group HR=8.14, p=0.018). Most importantly, we identified a subset of vaccinated individuals with low antibody levels that generated a significant boost in neutralizing antibody titers after a fourth dose, but were still at significantly increased susceptibility to infection.

Background Immunomodulators and anti tumor-necrosis-α antibodies (anti-TNFs) have been implicated in increased risk of Epstein–Barr virus (EBV)–driven B-cell lymphoproliferative disorders in inflammatory bowel disease (IBD) patients. However, the underlying mechanisms are poorly understood. Methods An in-vitro model of lymphoblastoid cell line (LCL) was established by co-incubation of EBV-infected human peripheral blood mononuclear cells (PBMC) with Cyclosporin-A (CSA). After 4 weeks, the resultant LCLs were analyzed by flow cytometry, telomerase activity assay, and next generation sequencing. Subsequently, LCLs were explored in the presence of therapeutic agents for IBD (anti-TNFs, vedolizumab, 6-Mercaptopurine [6MP], methotrexate). Epstein–Barr virus titers were quantitated by real-time polymerase chain reaction. Results In cultures of PBMC with EBV and CSA, LCLs were characterized as an expanded, long lived population of CD58+CD23hi B-cells with high telomerase activity and clonal expansion. Upon addition to the cell cultures, LCL percentages were higher with infliximab (median 19.21%, P = 0.011), adalimumab (median 19.85%, P = 0.003), and early washed-out 6MP (median 30.57%, P = 0.043) compared with PBMC with EBV alone (median 9.61%). However, vedolizumab had no such effect (median 8.97%; P = 0.435). Additionally, LCL expansion was accompanied by increase in intracellular, rather than extracellular, EBV viral copies. Compared with PBMC with EBV alone, high levels of LCL were subsequently observed after triple depletion of NK cells, CD4+ T cells, and CD8+ T cells (median 52.8% vs 16.4%; P = 0.046) but also in cultures depleted solely of CD4+ T cells (median 30.7%, P = 0.046). Conclusions These results suggest that both anti-TNFs and 6MP, but not vedolizumab, propagate EBV-driven lymphoblastoid transformation in an in vitro model of lymphoma. This model may prove useful for studying mechanisms underlying proneoplastic viral immune interactions of novel drugs in IBD therapy.

BackgroundMethodologically rigorous studies on Covid-19 vaccine effectiveness (VE) in preventing SARS-CoV-2 infection are critically needed to inform national and global policy on Covid-19 vaccine use. In Israel, healthcare personnel (HCP) were initially prioritized for Covid-19 vaccination, creating an ideal setting to evaluate real-world VE in a closely monitored population.MethodsWe conducted a prospective study among HCP in 6 hospitals to estimate the effectiveness of the BNT162b2 mRNA Covid-19 vaccine in preventing SARS-CoV-2 infection. Participants filled out weekly symptom questionnaires, provided weekly nasal specimens, and three serology samples – at enrollment, 30 days and 90 days. We estimated VE against PCR-confirmed SARS-CoV-2 infection using the Cox Proportional Hazards model and against a combined PCR/serology endpoint using Fisher’s exact test.FindingsOf the 1,567 HCP enrolled between December 27, 2020 and February 15, 2021, 1,250 previously uninfected participants were included in the primary analysis; 998 (79.8%) were vaccinated with their first dose prior to or at enrollment, all with Pfizer BNT162b2 mRNA vaccine. There were four PCR-positive events among vaccinated participants, and nine among unvaccinated participants. Adjusted two-dose VE against any PCR- confirmed infection was 94.5% (95% CI: 82.6%-98.2%); adjusted two-dose VE against a combined endpoint of PCR and seroconversion for a 60-day follow-up period was 94.5% (95% CI: 63.0%-99.0%). Five PCR-positive samples from study participants were sequenced; all were alpha variant.InterpretationOur prospective VE study of HCP in Israel with rigorous weekly surveillance found very high VE for two doses of Pfizer BNT162b2 mRNA vaccine against SARS-CoV-2 during a period of predominant alpha variant circulation.FundingClalit Health Services

BackgroundInvasive pneumococcal disease (IPD) declined during the COVID-19 pandemic. Previous studies hypothesized that this was due to reduced pneumococcal transmission resulting from non-pharmacological interventions. We used multiple ongoing cohort surveillance projects in children MethodsThe first SARS-CoV-2 cases were detected in February-2020, resulting in a full lockdown, followed by several partial restrictions. Data from ongoing surveillance projects captured the incidence dynamics of community-acquired alveolar pneumonia (CAAP), non-alveolar lower respiratory infections necessitating chest X-rays (NA-LRI), nasopharyngeal pneumococcal carriage in non-respiratory visits, nasopharyngeal respiratory virus detection (by PCR), and nationwide invasive pneumococcal disease (IPD). Monthly rates (January-2020 through February-2021 vs. mean monthly rates 2016-2019 [expected rates]) adjusted for age and ethnicity, were compared.FindingsCAAP and bacteremic pneumococcal pneumonia were strongly reduced (incidence rate ratios, [IRRs] 0η07 and 0η19, respectively); NA-LRI and non-pneumonia IPD were also reduced, with a lesser magnitude (IRRs, 0η46 and 0η42, respectively). In contrast, pneumococcal carriage prevalence was only slightly reduced and density of colonization and pneumococcal serotype distributions were similar to previous years. The pneumococcus-associated disease decline was temporally associated with a full suppression of RSV, influenza viruses, and hMPV, often implicated as co-pathogens with pneumococcus. In contrast, adenovirus, rhinovirus, and parainfluenza activities were within or above expected levels.InterpretationReductions in pneumococcal and pneumococcus-associated diseases occurring during the COVID-19 pandemic were not predominantly related to reduced pneumococcal transmission and carriage but were strongly associated with the complete disappearance of specific respiratory viruses.FundingPartially funded by Pfizer, Inc.

SummaryThe SARS-CoV-2 pandemic has been raging for over a year, creating global detrimental impact. The BNT162b2 mRNA vaccine has demonstrated high protection levels, yet apprehension exists that several variants of concerns (VOCs) can surmount the immune defenses generated by the vaccines. Neutralization assays have revealed some reduction in neutralization of VOCs B.1.1.7 and B.1.351, but the relevance of these assays in real life remains unclear. We performed a case-control study that examined the distribution of SARS-CoV-2 variants observed in infections of vaccinated individuals (“breakthrough cases”) and matched infections of unvaccinated individuals. We hypothesized that if there is lower vaccine effectiveness against one of the VOCs, its proportion among the breakthrough cases should be higher than among unvaccinated cases. Our results show that vaccinees that tested positive at least a week after the second dose were indeed disproportionally infected with B.1.351, as compared with unvaccinated individuals (odds ratio of 8:1). Those who tested positive between two weeks after the first dose and one week after the second dose, were disproportionally infected by B.1.1.7 (odds ratio of 26:10), suggesting reduced vaccine effectiveness against both VOCs at particular time windows following vaccination. Nevertheless, the B.1.351 incidence in Israel to-date remains low and vaccine effectiveness remains high among those fully vaccinated. These results overall suggest that vaccine breakthrough infection may be more frequent with both VOCs, yet a combination of mass-vaccination with two doses coupled with non-pharmaceutical interventions control and contain their spread.

Toward eradicating the COVID-19 pandemic, vaccines that induce high humoral and cellular immune responses are essential. However, SARS-CoV-2 variants have begun to emerge and raise concerns, as they may potentially compromise vaccine efficiency. Here, we monitored neutralization potency of convalescent or Pfizer-BTN162b2 post-vaccination sera against pseudoviruses displaying spike proteins derived from wild-type SARS-CoV-2, or its UK-B.1.1.7 and SA-B.1.351 variants. Compared to convalescent sera, vaccination induces high titers of neutralizing antibodies, which exhibit efficient neutralization potential against pseudovirus carrying wild-type SARS-CoV-2. However, while wild-type and UK-N501Y pseudoviruses were similarly neutralized, those displaying SA-N501Y/K417N/E484K spike mutations moderately resist neutralization. Contribution of single or combined spike mutations to neutralization and infectivity were monitored, highlighting mechanisms by which viral infectivity and neutralization resistance are enhanced by N501Y or E484K/K417N mutations. Our study validates the importance of the Pfizer vaccine but raises concerns regarding its efficacy against specific SARS-CoV-2 circulating variants., Graphical abstract, Kuzmina and colleagues monitored the neutralization potential of convalescent sera or sera from Pfizer-vaccinated individuals against pseudoviruses displaying wild-type, B.1.1.7, or B.1.351 SARS-CoV-2 spike proteins. While vaccine sera comparably neutralizes wild-type and B.1.1.7 pseudoviruses, the B.1.351 variant moderately resists vaccine-mediated neutralization, highlighting the importance of monitoring the emergence of variants.

SUMMARYTowards eradicating COVID19, developing vaccines that induce high levels of neutralizing antibodies is a main goal. As counter measurements, viral escape mutants rapidly emerge and potentially compromise vaccine efficiency. Herein we monitored ability of convalescent or Pfizer-BTN162b2 post-vaccination sera to neutralize wide-type SARS-CoV2 or its UK-B.1.1.7 and SA-B.1.351 variants. Relative to convalescent sera, post-vaccination sera exhibited higher levels of neutralizing antibodies against wild-type or mutated viruses. However, while SARS-CoV2 wild-type and UK-N501Y were similarly neutralized by tested sera, the SA-N501Y/K417N/E484K variant moderately escaped neutralization. Significant contribution to infectivity and sensitivity to neutralization was attributed to each of the variants and their single or combined mutations, highlighting alternative mechanisms by which prevalent variants with either N501Y or E484K/K417N mutations spread. Our study validates the clinical significance of currently administered vaccines, but emphasizes that their efficacy may be compromised by circulated variants, urging the development of new ones with broader neutralization functions.

Background There are limited data on influenza vaccine effectiveness (IVE) in preventing laboratory-confirmed influenza illness among healthcare personnel (HCP). Methods HCP with direct patient contact working full-time in hospitals were followed during three influenza seasons in Israel (2016–2017 to 2018–2019) and Peru (2016 to 2018). Trivalent influenza vaccines were available at all sites, except during 2018–2019 when Israel used quadrivalent vaccines; vaccination was documented by electronic medical records, vaccine registries, and/or self-report (for vaccinations outside the hospital). Twice-weekly active surveillance identified acute respiratory symptoms or febrile illness (ARFI); self-collected respiratory specimens were tested by real-time reverse transcription polymerase chain reaction (PCR) assay. IVE was 100 × 1-hazard ratio (adjusted for sex, age, occupation, and hospital). Results Among 5,489 HCP who contributed 10,041 person-seasons, influenza vaccination coverage was 47% in Israel and 32% in Peru. Of 3,056 ARFIs in Israel and 3,538 in Peru, A or B influenza virus infections were identified in 205 (7%) in Israel and 87 (2.5%) in Peru. IVE against all viruses across seasons was 1% (95% confidence interval [CI] = −30%, 25%) in Israel and 12% (95% CI = −61%, 52%) in Peru. Conclusion Estimates of IVE were null using person-time models during six study seasons in Israel and Peru.

The BNT162b2 mRNA vaccine is highly effective against SARS-CoV-2. However, apprehension exists that variants of concern (VOCs) may evade vaccine protection, due to evidence of reduced neutralization of the VOCs B.1.1.7 and B.1.351 by vaccine sera in laboratory assays. We performed a matched cohort study to examine the distribution of VOCs in infections of BNT162b2 mRNA vaccinees from Clalit Health Services (Israel) using viral genomic sequencing, and hypothesized that if vaccine effectiveness against a VOC is reduced, its proportion among breakthrough cases would be higher than in unvaccinated controls. Analyzing 813 viral genome sequences from nasopharyngeal swabs, we showed that vaccinees who tested positive at least 7 days after the second dose were disproportionally infected with B.1.351, compared with controls. Those who tested positive between 2 weeks after the first dose and 6 days after the second dose were disproportionally infected by B.1.1.7. These findings suggest reduced vaccine effectiveness against both VOCs within particular time windows. Our results emphasize the importance of rigorously tracking viral variants, and of increasing vaccination to prevent the spread of VOCs., At early time points after vaccination with a single dose or two doses of the BNT162b2 mRNA COVID-19 vaccine, breakthrough SARS-CoV-2 infections can be disproportionately caused by the B.1.1.7 or B.1.351 variants of concern, underlining the need to ensure rapid and complete vaccination.

Full genome sequences are increasingly used to track the geographic spread and transmission dynamics of viral pathogens. Here, with a focus on Israel, we sequence 212 SARS-CoV-2 sequences and use them to perform a comprehensive analysis to trace the origins and spread of the virus. We find that travelers returning from the United States of America significantly contributed to viral spread in Israel, more than their proportion in incoming infected travelers. Using phylodynamic analysis, we estimate that the basic reproduction number of the virus was initially around 2.5, dropping by more than two-thirds following the implementation of social distancing measures. We further report high levels of transmission heterogeneity in SARS-CoV-2 spread, with between 2-10% of infected individuals resulting in 80% of secondary infections. Overall, our findings demonstrate the effectiveness of social distancing measures for reducing viral spread., In this study, Adi Stern and colleagues use full genome sequences of SARS-CoV-2 to look at the rate of infections in Israel. They report that social distancing had a significant effect on minimising the rate of transmission, and find evidence for transmission heterogeneity (superspreading events).

The advent of direct-acting antivirals (DAAs) has transformed the landscape of hepatitis C virus (HCV) management. We aimed to prospectively (real-time) evaluate the feasibility of using a response-guided therapy approach, based on mathematical modeling of early viral kinetics, to reduce the duration of DAAs therapy. Patients were treated with DAAs according to the physicians’ preference. HCV was measured at baseline and at day 2 and weeks 1, 2 and 4 after treatment initiation. The primary endpoint was the proportion of patients with sustained-virological response (SVR) at 12 and/or 24 weeks post-treatment. Twenty-nine patients (mean age 54 ± 16, 44% females, 73% with HCV genotype 1), were enrolled and all completed therapy. Treatment duration was shortened in 11 of the 29 patients (38%). SVR was achieved in 28 of the 29 patients (97%). Relapse occurred post treatment in a single case of a non-cirrhotic male with genotype 3, who was treated with sofosbuvir/velpatasvir for 6 weeks. Virus sequencing did not identify baseline or treatment emergent resistance associated substitutions. Real-time mathematical modeling of early HCV kinetics can be utilized for shortening DAAs duration in approximately 40% of patients without compromising treatment efficacy.Clinical trial registration: ClinicalTrials.gov Identifier: NCT03603327.

Background An Israeli national taskforce performed a multi-center clinical and analytical validation of seven serology assays to determine their utility and limitations for SARS-CoV-2 diagnosis. Methods Serology assays from Roche, Abbott, Diasorin, BioMerieux, Beckman-Coulter, Siemens, and Mt.-Sinai ELISA were included. Negative samples from 2391 individuals representative of the Israeli population, and 698 SARS-CoV-2 PCR positive patients, collected between March and May 2020, were analyzed Findings Immunoassays sensitivities between 81.5%-89.4% and specificities between 97.7%-100% resulted in a profound impact on the expected Positive Predictive Value (PPV) in low (

Single-stage group testing uses compressed sensing for efficient high-throughput SARS-CoV-2 testing., Recent reports suggest that 10 to 30% of severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infected patients are asymptomatic and that viral shedding may occur before symptom onset. Therefore, there is an urgent need to increase diagnostic testing capabilities to prevent disease spread. We developed P-BEST, a method for Pooling-Based Efficient SARS-CoV-2 Testing, which identifies all positive subjects within a set of samples using a single round of testing. Each sample is assigned into multiple pools using a combinatorial pooling strategy based on compressed sensing. We pooled sets of 384 samples into 48 pools, providing both an eightfold increase in testing efficiency and an eightfold reduction in test costs, while identifying up to five positive carriers. We then used P-BEST to screen 1115 health care workers using 144 tests. P- BEST provides an efficient and easy-to-implement solution for increasing testing capacity that can be easily integrated into diagnostic laboratories.

Background: The aims of this study were to evaluate the incidence of congenital cytomegalovirus (CMV) in term and near-term infants who fail hearing screen (target screening), the incidence of cong...

Adherence to treatment of chronic Hepatitis B Virus (HBV) is an important issue and can affect the complication rate. Nucleos(t)ide analogue as oral treatments are used for patients with necro-inflammatory activity and high viral load, with the goal of decline the complication rate such cirrhosis and hepatic cancer. We aimed to investigate the adherence to chronic HBV treatment. Chronic HBV patients with dispensing medication rates (DMR) of at least 80% were defined as high adherence group (HAG) and those who dispensed less than 80% as low adherence group (LAG). The study included 273 patients. 90 patients (33%) were in the LAG and 183 (67%) in the HAG. The All-cause mortality in the LAG was 15.6%, and 8.7% among the HAG (p-value = 0.09). 185 patients were of Jewish origin (mean age of 52.96 &plusmn, 14.6 years, 30% women) and 88 patients of Arab Bedouin (AB) origin (mean age of 40.86 &plusmn, 13.96 years (p-value &lt, 0.001), 42% women). The proportion of Jewish patients with high adherence was 71% (131 patients) versus 59% (52 patients) in AB patients (p-value = 0.054). The all-causes mortality was 14.6% among Jewish origin and 3.4% of AB (p-value = 0.01). We conclude that, two third of HBV carriers are with high level adherence to treatment in southern Israel, with lower but marginally significant all-cause mortality. No-significant differences in adherence patterns were noted between Arab Bedouin and Jews.

The COVID-19 pandemic is rapidly spreading throughout the world. Recent reports suggest that 10-30% of SARS-CoV-2 infected patients are asymptomatic. Other studies report that some subjects have significant viral shedding prior to symptom onset. Since both asymptomatic and pre-symptomatic subjects can spread the disease, identifying such individuals is critical for effective control of the SARS-CoV-2 pandemic. Therefore, there is an urgent need to increase diagnostic testing capabilities in order to also screen asymptomatic carriers. In fact, such tests will be routinely required until a vaccine is developed. Yet, a major bottleneck of managing the COVID-19 pandemic in many countries is diagnostic testing, due to limited laboratory capabilities as well as limited access to genome-extraction and Polymerase Chain Reaction (PCR) reagents. We developed P-BEST - a method for Pooling-Based Efficient SARS-CoV-2 Testing, using a non-adaptive group-testing approach, which significantly reduces the number of tests required to identify all positive subjects within a large set of samples. Instead of testing each sample separately, samples are pooled into groups and each pool is tested for SARS-CoV-2 using the standard clinically approved PCR-based diagnostic assay. Each sample is part of multiple pools, using a combinatorial pooling strategy based on compressed sensing designed for maximizing the ability to identify all positive individuals. We evaluated P-BEST using leftover samples that were previously clinically tested for COVID-19. In our current proof-of-concept study we pooled 384 patient samples into 48 pools providing an 8-fold increase in testing efficiency. Five sets of 384 samples, containing 1-5 positive carriers were screened and all positive carriers in each set were correctly identified. P-BEST provides an efficient and easy-to-implement solution for increasing testing capacity that will work with any clinically approved genome-extraction and PCR-based diagnostic methodologies.

Social restrictions intended to limit the transmission of SARS-CoV-2 may have also been associated with decreased rates of other communicable diseases. Evidence suggests that infection incidence rates (IRs) are rebounding after easing of social restrictions (eg, mask mandates). The reemergence of infectious disease complicates efforts to manage the ongoing COVID-19 pandemic.To examine IRs of frequently occurring infectious diseases after a successful SARS-CoV-2 vaccination campaign in Israel and cessation of social restrictions.This cross-sectional study was conducted using records for respiratory and gastrointestinal infectious diseases at 209 community clinics in southern Israel from 2017 to 2021. Included patients attended community clinics from January 1, 2017, to June 30, 2021.Incidence of infectious diseases was estimated in the first 3 months after the easing of social restrictions (ie, April-June 2021) across age groups.Age-specific and disease-specific weekly IRs per 100 000 population for April to June were compared between 2017 and 2021 and expected current IR was estimated using segmented linear regression. Growth rates of respiratory infections across years and weekly diagnoses detected by real-time polymerase chain reaction testing were also compared.Among 386 711 patients with a total of 1 221 568 visits to community clinics, the mean (SD) age was 27.29 (23.93) years, and there were 202 494 (52.3%) male patients and 184 217 (47.7%) female patients. Children aged 0 to 3 years had significantly increased rates of respiratory and gastrointestinal infection diagnoses (IR ratio, 2.64; 95% CI, 2:30-2.91; P .001). In addition, incidence of non-SARS-CoV-2 respiratory infections were significantly increased across age groups (IR ratio, 1.74; 95% CI, 1.56-1.94; P .001).These morbidity trends observed in Israel suggest that similar trends could occur in coming months in other countries after easing of COVID-19-related restrictions, particularly with the ongoing challenges of SARS-CoV-2 variants.

Background Characteristics of hepatitis B (HBV) and delta (HDV) coinfection in various geographical regions, including Israel, remain unclear. Here we studied HDV seroprevalence in Israel, assessed HDV/HBV viral loads, circulating genotypes and hepatitis delta antigen (HDAg) conservation. Methods Serological anti HDV IgG results from 8969 HBsAg positive individuals tested in 2010-2015 were retrospectively analyzed to determine HDV seroprevalence. In a cohort of HBV/HDV coinfected (n=58) and HBV monoinfected (n=27) patients, quantitative real-time PCR (qRT-PCR) and sequencing were performed to determine viral loads, genotypes and hepatitis delta antigen (HDAg) protein sequence. Results 6.5% (587/8969) of the HBsAg positive patients were positive for anti HDV antibodies. HDV viral load was >2 log copies/ml higher than HBV viral load in most of the coinfected patients with detectable HDV RNA (86%, 50/58). HDV genotype 1 was identified in all patients, most of whom did not express HBV. While 66.6% (4/6) of the HBV/HDV co-expressing patients carried HBV-D2 only 18.5% (5/27) of the HBV monoinfections had HBV-D2 (p=0.03). Higher genetic variability in the HDAg protein sequence was associated with higher HDV viral load. Conclusions The overall significant prevalence of HDV (6.5%) mandates HDV RNA testing for all coinfected patients. Patients positive for HDV RNA (characterized by low HBV DNA blood levels) carried HDV genotype 1. Taken together, the significant HDV seroprevalence and the lack of effective anti-HDV therapy, necessitates strict clinical surveillance especially in patients with higher HDV viral loads and increased viral evolution.

In this study, we found that the measles virus (MV) can infect human-induced pluripotent stem cells (hiPSCs). Wild-type MV strains generally use human signaling lymphocyte activation molecule (SLAM; CD150) as a cellular receptor, while vaccine strains such as the Edmonston strain can use both CD150 and CD46 as receptors. It is not yet known how early in the embryonal differentiation stages these receptors are expressed. We established two hiPSCs (BGU-iPSCs and EMF-iPSCs) which express CD46 and CD150. Both cell types can be infected by MV to form persistent, noncytopathic cell lines that release infectious MV particles. Following MV persistent infection, BGU-iPSCs and EMF-iPSCs remain pluripotent and can differentiate in vitro into the three germ layers. This includes cells expressing the neuronal differentiation markers: NF68 and miRNA-124. Since the MV does not integrate into the cell's genome, it can be utilized as a vehicle to systematically introduce genes into iPSC, to dissect and to define factors regulating lineage differentiation.

Background: The advent of direct-acting antivirals (DAAs) has transformed the landscape of hepatitis C virus (HCV) management. However, the high cost of DAAs therapy has become a major barrier to HCV elimination. We aimed to prospectively evaluate the efficacy and safety of reducing the duration of DAAs therapy using response-guided therapy approach based on mathematical modeling of viral kinetics. Methods: Patients were treated with DAAs according to the physicians’ preference. HCV was measured at baseline and at day 2 and weeks 1, 2 and 4 after treatment initiation. The primary endpoint was the proportion of patients with sustained-virological response (SVR) at 12 and/or 24 weeks post-treatment. Findings: Twenty-nine patients (mean age 54±16, 44% females, 73% with HCV genotype 1), were enrolled and all completed therapy. Sofosbuvir/velpatasvir, elbasvir/grazoprevir, sofosbuvir/ledipasvir and glecaprevir/pibrentasvir, were administered in 38%, 27%, 21% and 14% of patients, respectively. Treatment duration was shortened in 11 of the 29 patients (38%). SVR was achieved in 28 of the 29 patients (97%). Relapse occurred post treatment in a single case of a non-cirrhotic male with genotype 3, who was treated with sofosbuvir/velpatasvir for 6 weeks. Virus sequencing did not identify baseline or treatment emergent resistance associated substitutions. Interpretation: Real-time modeling can be utilized for shortening DAAs duration in approximately 40% of patients without compromising treatment efficacy. Implementation of this model on a wider scale may lead to significant cost-saving and to improved access to anti-HCV care. Trial Registration: ClinicalTrials.gov Identifier: NCT03603327. Funding Statement: This research was supported in part by Clalit Health Services and the National Institutes of Health (NIH) and extramural NIH grants R01-AI078881 and R01GM121600. Declaration of Interests: OE has consulted for Gilead and Abbvie and received lecture fees from Gilead, Abbvie and MSD. HD has consulted for CoCrystal Inc. None of the other authors has any financial interest or conflict of interest related to this research. Ethics Approval Statement: The study was approved by the institutional review boards of Soroka and Rabin Medical Centers and was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulatory requirements. All patients provided written informed consent.

Human coronaviruses (HCoVs) cause mild to severe respiratory diseases. Six types of HCoVs have been discovered, the most recent one termed the Middle East respiratory syndrome coronavirus (MERS-CoV). The aim of this study is to monitor the circulation of HCoV types in the population during 2015&ndash, 2016 in Israel. HCoVs were detected by real-time PCR analysis in 1910 respiratory samples, collected from influenza-like illness (ILI) patients during the winter sentinel influenza survey across Israel. Moreover, 195 HCoV-positive samples from hospitalized patients were detected during one year at Soroka University Medical Center. While no MERS-CoV infections were detected, 10.36% of patients in the survey were infected with HCoV-OC43 (43.43%), HCoV-NL63 (44.95%), and HCoV-229E (11.62%) viruses. The HCoVs were shown to co-circulate with respiratory syncytial virus (RSV) and to appear prior to influenza virus infections. HCoV clinical symptoms were more severe than those of RSV infections but milder than influenza symptoms. Hospitalized patients had similar HCoV types percentages. However, while it was absent from the public winter survey, 22.6% of the patients were HCoV-HKU1 positives, mainly during the spring-summer period.

Background Influenza vaccine effectiveness (VE) varies by season, circulating influenza strain, age, and geographic location. There have been few studies of influenza VE among hospitalized children, particularly in Europe and the Middle East. Methods We estimated VE against influenza hospitalization among children aged 6 months to 8 years at Clalit Health Services hospitals in Israel in the 2015-2016, 2016-2017, and 2017-2018 influenza seasons, using the test-negative design. Estimates were computed for full and partial vaccination. Results We included 326 influenza-positive case patients and 2821 influenza-negative controls (140 case patients and 971 controls from 2015-2016, 36 case patients and 1069 controls from 2016-2017, and 150 case patients and 781 controls from 2017-2018). Over all seasons, VE was 53.9% for full vaccination (95% confidence interval [CI], 38.6%-68.3%), and 25.6% for partial vaccination (-3% to 47%). In 2015-2016, most viruses were influenza A(H1N1) and vaccine lineage-mismatched influenza B/Victoria; the VE for fully vaccinated children was statistically significant for influenza A (80.7%; 95% CI, 40.3%-96.1%) but not B (23.0%; -38.5% to 59.4%). During 2016-2017, influenza A(H3N2) predominated, and VE was (70.8%; 95% CI, 17.4%-92.4%). In 2017-2018, influenza A(H3N2), H1N1 and lineage-mismatched influenza B/Yamagata cocirculated; VE was statistically significant for influenza B (63.0%; 95% CI, 24.2%-83.7%) but not influenza A (46.3%; -7.2% to 75.3%). Conclusions Influenza vaccine was effective in preventing hospitalizations among fully vaccinated Israeli children over 3 influenza seasons, but not among partially vaccinated children. There was cross-lineage protection in a season where the vaccine contained B/Victoria and the circulating strain was B/Yamagata, but not in a season with the opposite vaccine-circulating strain distribution.

Background The Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI) prospectively follows a cohort of healthcare personnel (HCP) in two hospitals in Israel. SHIRI will describe the frequency of influenza virus infections among HCP, identify predictors of vaccine acceptance, examine how repeated influenza vaccination may modify immunogenicity, and evaluate influenza vaccine effectiveness in preventing influenza illness and missed work. Methods Cohort enrollment began in October, 2016; a second year of the study and a second wave of cohort enrollment began in June 2017. The study will run for at least 3 years and will follow approximately 2000 HCP (who are both employees and members of Clalit Health Services [CHS]) with routine direct patient contact. Eligible HCP are recruited using a stratified sampling strategy. After informed consent, participants complete a brief enrollment survey with questions about occupational responsibilities and knowledge, attitudes, and practices about influenza vaccines. Blood samples are collected at enrollment and at the end of influenza season; HCP who choose to be vaccinated contribute additional blood one month after vaccination. During the influenza season, participants receive twice-weekly short message service (SMS) messages asking them if they have acute respiratory illness or febrile illness (ARFI) symptoms. Ill participants receive follow-up SMS messages to confirm illness symptoms and duration and are asked to self-collect a nasal swab. Information on socio-economic characteristics, current and past medical conditions, medical care utilization and vaccination history is extracted from the CHS database. Information about missed work due to illness is obtained by self-report and from employee records. Respiratory specimens from self-collected nasal swabs are tested for influenza A and B viruses, respiratory syncytial virus, human metapneumovirus, and coronaviruses using validated multiplex quantitative real-time reverse transcription polymerase chain reaction assays. The hemagglutination inhibition assay will be used to detect the presence of neutralizing influenza antibodies in serum. Discussion SHIRI will expand our knowledge of the burden of respiratory viral infections among HCP and the effectiveness of current and repeated annual influenza vaccination in preventing influenza illness, medical utilization, and missed workdays among HCP who are in direct contact with patients. Trial registration NCT03331991. Registered on November 6, 2017. Electronic supplementary material The online version of this article (10.1186/s12879-018-3444-7) contains supplementary material, which is available to authorized users.

Background Mobile phones are commonly used by healthcare workers (HCW) in the working environment, as they allow instant communication and endless resource utilisation. Studies suggest that mobile phones have been implicated as reservoirs of bacterial pathogens, with the potential to cause nosocomial infection. This study aimed to investigate the presence of Respiratory Syncytial Virus, Adenovirus and Influenza Virus on HCWs mobile phones and to identify risk factors implied by HCWs practice of mobile phones in a clinical paediatric environment. Methods Fifty HCWs' mobile phones were swabbed over both sides of the mobile phone, for testing of viral contamination during 8 days in January 2015. During the same period, a questionnaire investigating usage of mobile phones was given to 101 HCWs. Results Ten per cent of sampled phones were contaminated with viral pathogens tested for. A total of 91% of sampled individuals by questionnaire used their mobile phone within the workplace, where 37% used their phone at least every hour. Eighty-nine (88%) responders were aware that mobile phones could be a source of contamination, yet only 13 (13%) disinfect their cell phone regularly. Conclusion Mobile phones in clinical practice may be contaminated with viral pathogenic viruses. HCWs use their mobile phone regularly while working and, although the majority are aware of contamination, they do not disinfect their phones.

Viral encoded microRNAs play key roles in regulating gene expression and the life cycle of human herpes viruses. Latency is one of the hallmarks of the human cytomegalovirus (HCMV or HHV5) life cycle, and its control may have immense practical applications. The present study aims to identify HCMV encoded microRNAs during the latency phase of the virus. We used a highly sensitive real time PCR (RTPCR) assay that involves a pre-amplification step before RTPCR. It can detect HCMV encoded microRNAs (miRNAs) during latency in purified monocytes and PBMCs from HCMV IgG positive donors and in latently infected monocytic THP-1 cell lines. During the latency phase, only eight HCMV encoded microRNAs were detected in PBMCs, monocytes and in the THP-1 cells. Five originated from the UL region of the virus genome and three from the US region. Reactivation of the virus from latency, in monocytes obtained from the same donor, using dexamethasone restored the expression of all known HCMV encoded miRNAs including those that were absent during latency. We observed a shift in the abundance of the two arms of mir-US29 between the productive and latency stages of the viral life cycle, suggesting that the star "passenger" form of this microRNA is preferentially expressed during latency. As a whole, our study demonstrates that HCMV expresses during the latency phase, both in vivo and in vitro, only a subset of its microRNAs, which may indicate that they play an important role in maintenance and reactivation of latency.

Background Use of nucleic acid amplification techniques has increased the identification of respiratory viruses (RVs) in adult patients with community-acquired pneumonia (CAP). The objectives of the present study were to identify RV in patients with CAP using three different sampling methods and to compare CAP virus proportions and types with two comparison groups. Methods The study population included 183 adult patients with CAP, 450 control subjects, and 201 patients with nonpneumonic lower respiratory tract infection (NPLRTI). Each participant was sampled by oropharyngeal swab, nasopharyngeal swab, and nasopharyngeal washing, and the samples were tested for detection of 12 RVs by multiplex TaqMan Hydrolysis probe-based real-time polymerase chain reaction (Integrated DNA Technology; Coralville, IA). Results At least one RV was identified in 58 patients with CAP (31.7%) compared with 32 (7.1%) in control subjects and 104 (51.7%) in patients with NPLRTI (P < .01 and P < .01, respectively). Coronaviruses were identified in 24 (13.1%) patients with CAP, compared with 17 (3.8%) in control subjects, and 21 (10.4%) patients with NPLRTI. Respiratory syncytial virus was identified in 13 (7.1%), four (0.9%), and seven (3.5%); rhinovirus in nine (4.9%), nine (2.0%), and 15 (7.5%); and influenza virus in eight (4.4%), two (0.4%), and 63 (31.3%) patients with CAP, control subjects, and patients with NPLRTI, respectively. Conclusions The proportion of RV involvement in CAP is higher than previously reported. The proportion of RV identified in healthy subjects is significantly lower than in CAP, but it is not zero and should be weighed when interpreting corresponding proportions among patients.

Respiratory infections (RI) can be viral or bacterial in origin. In either case, the invasion of the pathogen results in production and release of various volatile organic compounds (VOCs). The present study examines the VOCs released from cultures of five viruses (influenza A, influenza B, adenovirus, respiratory syncitial virus and parainfluenza 1 virus), three bacteria (Moraxella catarrhalis, Haemophilus influenzae and Legionella pneumophila) and Mycoplasma pneumoniae isolated colonies. Our results demonstrate the involvement of inflammation-induced VOCs. Two significant VOCs were identified as associated with infectious bacterial activity, heptane and methylcyclohexane. These two VOCs have been linked in previous studies to oxidative stress effects. In order to distinguish between bacterial and viral positive cultures, we performed principal component analysis including peak identity (retention time) and VOC concentration (i.e. area under the peak) revealing 1-hexanol and 1-heptadecene to be good predictors.

Description of additional terms and methods used in the Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel. (DOCX 77 kb)

We assessed the seasonality of viral lower respiratory tract infections (V-LRI), bacteremic pneumonia, nonbacteremic pneumonia and nonpneumonia invasive pneumococcal diseases (IPD) in the pre-PCV era. Both bacteremic and nonbacteremic pneumonia seasonality peaked in winter, coinciding with V-LRI seasonality, whereas non-pneumonia IPD peaked in autumn before V-LRI increase, suggesting different pathogenesis.

Many viruses can establish non-cytolytic, chronic infections in host cells. Beyond the intrinsically interesting questions of how this long-term parasitism is achieved, persistently infected cells can be useful to study virus-host interactions. MicroRNAs (miRNAs) are a class of noncoding RNAs transcribed from the genomes of all multicellular organisms and some viruses. Individual miRNAs may regulate several hundred genes. In this research we have studied the expression of a selective group of host-cell encoded miRNAs, as expressed in a Respiratory Syncytial Virus (RSV) persistently infected HEp-2 cell line (HEp-2 + RSV-GFP). The RSV is a virus that does not encode miRNAs in its genome. Our study shows that Dicer is down regulated, miRNA’s 146a-5p is strongly up-regulated and miRNAs 345-5p, let-7c-5p and miRNA’s-221 are down-regulated in HEp-2 + RSV-GFP cells. Correspondingly, changes in the miRNA 146a-5p and he sequences of the reference genes are miRNA 345-5p respective miRNAs target proteins: HSP-70 and p21, were observed. Thus, RSV persistent viral infection induces unique patterns of miRNA’s expression with relevance to how the virus regulates the host cell response to infection.

Measles virus (MV) infects a variety of lymphoid and non-lymphoid peripheral organs. However, in rare cases, the virus can persistently infect cells within the central nervous system. Although some of the factors that allow MV to persist are known, the contribution of host cell-encoded microRNAs (miRNA) have not been described. MiRNAs are a class of noncoding RNAs transcribed from genomes of all multicellular organisms and some viruses, which regulate gene expression in a sequence-specific manner. We have studied the contribution of host cell-encoded miRNAs to the establishment of MV persistent infection in human neuroblastoma cells. Persistent MV infection was accompanied by differences in the expression profile and levels of several host cell-encoded microRNAs as compared to uninfected cells. MV persistence infection of a human neuroblastoma cell line (UKF-NB-MV), exhibit high miRNA-124 expression, and reduced expression of cyclin dependent kinase 6 (CDK6), a known target of miRNA-124, resulting in slower cell division but not cell death. By contrast, acute MV infection of UKF-NB cells did not result in increased miRNA-124 levels or CDK6 reduction. Ectopic overexpression of miRNA-124 affected cell viability only in UKF-NB-MV cells, causing cell death; implying that miRNA-124 over expression can sensitize cells to death only in the presence of MV persistent infection. To determine if miRNA-124 directly contributes to the establishment of MV persistence, UKF-NB cells overexpressing miRNA-124 were acutely infected, resulting in establishment of persistently infected colonies. We propose that miRNA-124 triggers a CDK6-dependent decrease in cell proliferation, which facilitates the establishment of MV persistence in neuroblastoma cells. To our knowledge, this is the first report to describe the role of a specific miRNA in MV persistence.