SARS-CoV-2 spike IgG titres up to 137 days following Comirnaty mRNA COVID-19 vaccination, Israel, February to May 2021.

BackgroundData regarding the long-term protection afforded by vaccination for the SARS-CoV-2 infection are essential for allocation of scarce vaccination resources worldwide.MethodsWe conducted a retrospective cohort study aimed at studying the kinetics of IgG antibodies against SARS-CoV-2 in COVID-19-naïve patients fully vaccinated with two doses of Comirnaty mRNA COVID-19 vaccine. Geometric mean concentrations (GMCs) of antibody levels were reported. Linear models were used to assess antibody levels after full vaccination and their decline over time.ResultsThe study included 4,740 patients and 5,719 serological tests. Unadjusted GMCs peaked 28-41 days after the first dose at 10,174 AU/mL (95% CI: 9,211-11,237) and gradually decreased but remained well above the positivity cut-off. After adjusting for baseline characteristics and repeated measurements, the antibodies half-life time was 34.1 days (95% CI: 33.1-35.2), and females aged 16-39 years with no comorbidities had antibody levels of 20,613 AU/mL (95% CI: 18,526-22,934) on day 28 post-first-dose. Antibody levels were lower among males (0.736 of the level measured in females; 95% CI: 0.672-0.806), people aged 40-59 (0.729; 95% CI: 0.649-0.818) and ≥ 60 years (0.452; 95% CI: 0.398-0.513), and patients having haematological (0.241; 95% CI: 0.190-0.306) or solid malignancies (0.757; 95% CI: 0.650-0.881), chronic kidney disease with glomerular filtration rate (GFR) ≥ 30 (0.434; 95% CI: 0.354-0.532) or with GFR < 30 mL/min (0.176; 95% CI: 0.109-0.287), and immunosuppression (0.273; 95% CI: 0.235-0.317). Body mass index, cardiovascular disease, congestive heart failure, chronic obstructive pulmonary disease, diabetes and inflammatory bowel diseases were not associated with antibody levels.ConclusionsVaccination with two doses resulted in persistently high levels of antibodies (≥ cut-off of 50 AU/mL) up to 137 days post-first-dose. Risk factors for lower antibody levels were identified.

Robust antibody response after a third BNT162b2 vaccine compared to the second among immunocompromised and healthy individuals, a prospective longitudinal cohort study.

PURPOSE: As protection from COVID-19 following two doses of the BNT162b2 vaccine showed a time dependent waning, a third (booster) dose was administrated. This study aims to compare the antibody response following the third dose versus the second and to evaluate post-booster seroconversion. METHODS: A prospective observational study conducted in Maccabi Healthcare Services. Serial SARS-CoV-2 Spike IgG tests, 1,2,3 and 6 months following the second vaccine dose and one month following the third were obtained. Neutralizing antibody levels were measured in a subset of participants. Per individual SARS-CoV-2 Spike IgG titer ratios were calculated one month after the booster administration compared to titers one month following the second dose and prior to booster. RESULTS: Among 110 participants,56 (51%) were women. Mean age was 61.7 ± 1.9 years and 66 (60%) were immunocompromised. One month after third dose, IgG titers were induced 7.83 (95 %CI 5.25-11.67) folds and 2.40 (95 %CI 1.90-3.03) folds compared to one month after the second, in the immunocompromised and immunocompetent groups, respectively. Of the 17 immunocompromised participants who were seronegative after the second dose, 4 (24%) became seropositive following the third. Comparing the titers prior to the third dose, an increase of 50.7 (95 %CI 32.5-79.1) fold in the immunocompromised group and 25.7 (95 %CI 19.1-34.7) fold in and immunocompetent group, was observed. CONCLUSION: A third BNT162b2 vaccine elicited robust humoral response, superior to the response observed following the second, among immunocompetent and immunocompromised individuals.

Screening for non-classic congenital adrenal hyperplasia in women: New insights using different immunoassays.

Context: The 250µg-cosyntropin stimulation test (CST) is used to diagnose non-classic congenital adrenal hyperplasia (NCCAH). The current recommendation is to perform CST when follicular 17-hydroxyprogesterone (17OHP) is 6-30 nmol/L, a cutoff derived from radioimmunoassay (RIA). Recently, enzyme-linked immunosorbent assay (ELISA) has replaced RIA. Objectives: We aimed to (1) determine the RIA and ELISA-based 17OHP cutoffs at which CST should be performed, (2) identify predictors of NCCAH. Methods: A retrospective study at an Israeli Health Maintenance Organization. Data were retrieved from women with suspected NCCAH, referred for CST during 2001-2020. NCCAH was defined as a stimulated 17OHP >30 nmol/L. Serum 17OHP levels were assayed by RIA from 1/2000-3/2015, and by ELISA from 4/2015-12/2020. ROC curves were generated and optimal 17OHP thresholds were determined. Multivariate analysis was performed. Results: CST was performed in 2409 women (1564 in RIA, 845 in ELISA). NCCAH was diagnosed in 4.7% of the RIA group and 7.5% of the ELISA group. The optimal basal 17OHP cutoff values predicting NCCAH were 6.1 nmol/L in RIA (sensitivity=93.2%, specificity=91.7%) and 8.2 nmol/L in ELISA (sensitivity=93.7%, specificity=92.3%). In multivariate analysis, higher basal 17OHP, lower LH: FSH ratio, and oligomenorrhea were predictors of NCCAH in RIA. Higher basal 17OHP, androstenedione, and total testosterone were predictors of NCCAH in ELISA. A lower LH: FSH ratio showed similar trend in ELISA. Conclusions: Optimal RIA-based basal 17OHP cutoff was comparable with that recommended in guidelines. The results suggest adopting a higher 17OHP cutoff when using ELISA. LH : FSH ratio improves the negative predictive value of basal 17OHP.

Effectiveness of mRNA BNT162b2 Vaccine 6 Months after Vaccination among Patients in Large Health Maintenance Organization, Israel.

Israel experienced a new wave of coronavirus disease during June 2021, six months after implementing a national vaccination campaign. We conducted 3 discrete analyses using data from a large health maintenance organization in Israel to determine whether IgG levels of fully vaccinated persons decrease over time, describe the relationship between IgG titer and subsequent PCR-confirmed infection, and compare PCR-confirmed infection rates by period of vaccination. Mean IgG levels steadily decreased over the 6-month period in the total tested population and in all age groups. An inverse relationship was found between IgG titer and subsequent PCR-positive infection. Persons vaccinated during the first 2 months of the campaign were more likely to become infected than those subsequently vaccinated. The vaccinated group >60 years of age had lower initial IgG levels and were at greater risk for infection. The findings support the decision to add a booster vaccine for persons >60 years of age.

Comparison of Covid-19 antibody status after vaccination between residents in long-term geriatric care and residents assisted-living facilities.

OBJECTIVE: To compare 2 CoV-SARS-2 ('anti-s') antibody levels after vaccination between residents in long-term geriatric care (LTGC) and residents in assisted-living facilities who had received two doses of the BNT162b2 vaccine. SARS-CoV-2 serology was tested with Quant II IgG CoV-SARS-2. Blood samples were collected 3-4 months after administration of the second vaccine dose. RESULTS: Anti-s ≥ 50 AU/ml was found in 85.4% of 90 residents in LTGC (median 498 AU/ml) and 94.9% of 214 residents in assisted living (median 728 AU/ml). p = .006. Factors associated with anti-s < 300 AU/ml were multi-morbidity, diabetes mellitus and cancer.

Kinetics of SARS-CoV-2 anti-S IgG after BNT162b2 vaccination.

Deployment of the BNT162b2 mRNA Covid-19 Vaccine in Israel began in December 2020. This is a retrospective analysis of serological data, showing SARS-CoV-2 anti-S IgG kinetics in 116 Israeli health care workers receiving BNT162b2. Sero-conversion occurred in 14 days in all study participants, with IgG levels peaking approximately 30 days after initiation of the vaccination series. A statistically significant difference was observed in IgG levels between subjects younger than 50 years and older participants, although in all cases, IgG levels were well above the level considered reactive by the test's manufacturer. The importance of this difference needs to be studied further, but a potential difference in vaccine efficacy and vaccine effect length could possibly be present between these two groups.

Increased incidence of coeliac disease autoimmunity rate in Israel: a 9-year analysis of population-based data.

BACKGROUND: Incidence rate and temporal trends in coeliac disease and coeliac disease autoimmunity incidence vary worldwide with most data available from North American and European countries. AIMS: To explore temporal trends in incidence of coeliac disease autoimmunity and their relation to increase in screening tests in Israel. METHODS: A large retrospective population-based study was conducted in Maccabi Healthcare Services, a 2.3-million-member health maintenance organisation operating in Israel. The cohort included all patients with newly diagnosed coeliac disease autoimmunity based on first positive anti-tissue transglutaminase type 2 IgA antibodies. Data were analysed for the years 2007-2015. RESULTS: During the study period (17.3 million person-years), a total of 403 283 patients were tested for coeliac disease autoimmunity, of whom 6444 were positive, representing an average incidence rate of 36.64 per 100 000 person-years (95% CI: 35.74-37.55). Incidence of coeliac disease autoimmunity increased from 25.4 per 100 000 in 2007 to 52.3 per 100 000 person-years in 2015 (Incidence rate ratio of 2.06, 95% CI 1.81-2.26). Coeliac disease autoimmunity incidence was highest in the paediatric age groups, especially in children aged 0-5, and was 4 times higher than the incidence in adults aged 26-55 (Incidence rate ratio of 0.24, 95% CI (0.22-0.26). The increase in incidence surpassed the increase in testing for new patients. Positive trends in incidence were highest in small children, whereas the incidence in adults was stable over the years. CONCLUSIONS: There was a steady increase in coeliac disease autoimmunity incidence in our cohort between the years 2007-2015. The paediatric population was the only contributor to this trend.

Multi-center nationwide comparison of seven serology assays reveals a SARS-CoV-2 non-responding seronegative subpopulation.

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 an in-house RBD 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 (<15%) prevalence scenarios. No meaningful increase was detected in the false positive rate in children compared to adults. A positive correlation between disease severity and antibody titers, and no decrease in antibody titers in the first 8 weeks after PCR positivity was observed. We identified a subgroup of symptomatic SARS-CoV-2 positive patients (~5% of patients), who remained seronegative across a wide range of antigens, isotypes, and technologies. INTERPRETATION: The commercially available automated immunoassays exhibit significant differences in performance and expected PPV in low prevalence scenarios. The low false-positivity rate in under 20's suggests that cross-reactive immunity from previous CoV strains is unlikely to explain the milder disease course in children. Finding no decrease in antibody titers in the first 8 weeks is in contrast to some reports of short half-life for SARS-CoV-2 antibodies. The ~5% who were seronegative non-responders, using multiple assays in a population-wide manner, represents the proportion of patients that may be at risk for re-infection. FUNDING: Israel Ministry of Health.

Cervical Pap screening among Israeli women, 2005-2010.

PURPOSE: This study describes the distribution and the trends of cervical abnormalities in Israel, based on Pap smear results. METHODS: A retrospective analysis of cervical smears received by the Central Pathology Laboratory of Maccabi Healthcare Services between January 2005 and December 2010. RESULTS: In total, 711,541 Pap smears were screened in the study period. Cytological abnormalities were observed in 4.78% of the total smears screened. An increase was observed in the rate of positive results from 2.63% in 2005 to 6.78% in 2010 (p = 0.0026). The cervical abnormalities in the study period distributed as follows: atypical squamous cell (ASC)-2.72%, low-grade squamous intraepithelial lesion (LSIL)-1.54%, high-grade squamous intraepithelial lesion (HSIL)-0.34%, squamous cell carcinoma-0.01%, atypical glandular cells (AGC)-0.10%, adenocarcinoma in situ (AIS)-0.06% and invasive adenocarcinoma-0.01%. The increase was statistically significant for ASC (p = 0.0028), LSIL (p = 0.0069) and for HSIL (p = 0.0260). The mean ages at diagnosis of women with ASCUS, LSIL, HSIL, squamous cell carcinoma, AGC, AIS and adenocarcinoma were 37.8, 33.2, 38.6, 55.4, 41.1, 49.9 and 57.1 years, respectively. CONCLUSIONS: The increase in the rate of squamous cell abnormalities demonstrated in this study emphasizes the need of implementing an education and a screening program among Israeli women. HPV vaccine, sexual behavior, cytology performance and HPV test are primary and secondary prevention tools which may reduce morbidity and mortality in the future. In addition, based on the age at diagnosis of the different pathologies, the age group in which Pap test is performed in Israel should be expanded from 35-54 to 25-65 years.

Geldanamycin-associated inhibition of intracellular trafficking is attributed to a co-purified activity.

Geldanamycin, an ansamycin antibiotic that specifically inhibits heat-shock protein-90 (HSP90) and its endoplasmic reticulum homologue, glucose-regulated protein-94 (GRP94), accelerates the degradation of selected cellular proteins. We showed previously that geldanamycin inhibits maturation and transport of the epidermal growth factor receptor in addition to accelerating its degradation (Supino-Rosin, L., Yoshimura, A., Yarden, Y., Elazar, Z., and Neumann, D. (2000) J. Biol. Chem. 275, 21850-21855). Here we demonstrate that the additional activities of geldanamycin on intracellular transport and protein maturation are related to its supply source. By combining chemical separation of Streptomyces hygroscopicus var. geldanus extracts and biological screens, we show that the geldanamycin-associated effects on intracellular transport and protein maturation are not mediated by geldanamycin itself but are due to the presence of an additional component(s). Chromatography of S. hygroscopicus var. geldanus extracts on a silica-gel column allowed separation between the inhibition of intracellular trafficking and geldanamycin-mediated degradation. One fraction that was devoid of geldanamycin blocked secretion of a soluble form of the erythropoietin receptor, retarded maturation of the epidermal growth factor receptor without enhancing its degradation, and blocked anterograde transport of a temperature-sensitive mutant of the vesicular stomatitis virus G protein (VSVGtsO45) from the early Golgi cisternae. This fraction was enriched (>95%) in 17-demethylgeldanamycin. However, as synthetically derived 17-demethylgeldanamycin did not inhibit intracellular trafficking, we concluded that 17-demethylgeldanamycin is not the active component. We thus propose that a compound(s) that co-purifies with benzoquinone ansamycins inhibits intracellular transport. Taken together, our data demonstrate that the inhibitory effects on protein maturation and intracellular trafficking, previously attributed to geldanamycin, are mediated by another distinct moiety.