Twenty-five years of sentinel laboratory-based surveillance of shigellosis in a high-income country endemic for the disease, Israel, 1998 to 2022.

BackgroundShigella is a leading cause of moderate-to-severe diarrhoea worldwide and diarrhoeal deaths in children in low- and-middle-income countries.AimWe investigated trends and characteristics of shigellosis and antimicrobial resistance of Shigella sonnei in Israel.MethodsWe analysed data generated by the Sentinel Laboratory-Based Surveillance Network for Enteric Pathogens that systematically collects data on detection of Shigella at sentinel laboratories, along with the characterisation of the isolates at the Shigella National Reference Laboratory. Trends in the shigellosis incidence were assessed using Joinpoint regression and interrupted time-series analyses.ResultsThe average incidence of culture-confirmed shigellosis in Israel declined from 114 per 100,000 population (95% confidence interval (CI): 112-115) 1998-2004 to 80 per 100,000 population (95% CI: 79-82) 2005-2011. This rate remained stable 2012-2019, being 18-32 times higher than that reported from the United States or European high-income countries. After decreasing to its lowest values during the COVID-19 pandemic years (19/100,000 in 2020 and 5/100,000 in 2021), the incidence of culture-confirmed shigellosis increased to 39 per 100,000 population in 2022. Shigella sonnei is the most common serogroup, responsible for a cyclic occurrence of propagated epidemics, and the proportion of Shigella flexneri has decreased. Simultaneous resistance of S. sonnei to ceftriaxone, ampicillin and sulphamethoxazole-trimethoprim increased from 8.5% (34/402) in 2020 to 92.0% (801/876) in 2022.ConclusionsThese findings reinforce the need for continuous laboratory-based surveillance and inform the primary and secondary prevention strategies for shigellosis in Israel and other endemic high-income countries or communities.

Lower Serologic Response to COVID-19 mRNA Vaccine in Patients With Inflammatory Bowel Diseases Treated With Anti-TNFα.

BACKGROUND & AIM: Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor necrosis factor (TNF)α biologics, are at high risk for vaccine-preventable infections. Their ability to mount adequate vaccine responses is unclear. The aim of the study was to assess serologic responses to messenger RNA-Coronavirus Disease 2019 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared with healthy controls (HCs). METHODS: Prospective, controlled, multicenter Israeli study. Subjects enrolled received 2 BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibody levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinally. RESULTS: Overall, 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HCs. After the first vaccine dose, all HCs were seropositive, whereas ∼7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose, all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFα treated compared with non-anti-TNFα treated patients, and HCs (both P < .001). Neutralizing and inhibitory functions were both lower in anti-TNFα treated compared with non-anti-TNFα treated patients, and HCs (P < .03; P < .0001, respectively). Anti-TNFα drug levels and vaccine responses did not affect anti-spike levels. Infection rate (∼2%) and AEs were comparable in all groups. IBD activity was unaffected by BNT162b2. CONCLUSIONS: In this prospective study in patients with IBD stratified according to treatment, all patients mounted serologic response to 2 doses of BNT162b2; however, its magnitude was significantly lower in patients treated with anti-TNFα, regardless of administration timing and drug levels. Vaccine was safe. As vaccine serologic response longevity in this group may be limited, vaccine booster dose should be considered.

The effect of age at immigration on cervical cancer incidence: a population-based cohort study of 1 486 438 Israeli women.

OBJECTIVE: To clarify the effect of mass migration from a high-risk area (former Soviet Union) to a low-risk area (Israel) on cervical cancer incidence and mortality in Israel and the modifying effect of age at immigration. METHODS: All women who immigrated to Israel from the former Soviet Union between January 1, 1990 and December 31, 2000 (N=345 202) and all Jewish Israeli-born women who were 0-80 years old on January 1, 1990 (N=1 141 236) were included. Follow-up ended at December 31, 2010 or date of death or date of cervical cancer diagnosis, whatever occurred earlier. Crossing data from the computerized population registry of the Ministry of Interior, the Israel National Cancer Registry and the Central Bureau of Statistics, cervical cancer incidence and mortality and adjusted hazard ratios (aHR) with 95% confidence intervals (95% CI) were calculated. RESULTS: 1595 new cases (crude incidence rate 29.71: 100 000 person years) of cervical cancer were diagnosed in immigrants as compared with 6159 cases (crude incidence rate 27.21: 100 000 person years) diagnosed in Israel-born Jewish women. Immigration at an age older than 12 years was hazardous (aHR 1.27, 95% CI 1.19 to 1.35; P<0.001) while immigration at a younger age was protective (aHR 0.62, 95% CI 0.51 to 0.75; P<0.001) for cervical cancer incidence compared with native Israeli women. Cervical cancer mortality was also significantly higher in immigrants compared with Israel-born women with incidence density rates of 1.15 and 0.35 per 100 person years, respectively (P<0.0001). CONCLUSIONS: Factors related to the acquired causes of the disease at the country of origin are probably at the root of the low incidence of cervical cancer in Israel. Adult immigrants from the former Soviet Union should be managed as a high-risk group.

Helicobacter pylori Infection in Early Childhood and Growth at School Age.

BACKGROUND: There are conflicting results regarding the role of H. pylori in children's growth. We examined differences in growth indices at school age according to H. pylori infection acquisition in preschool age. MATERIALS AND METHODS: A prospective study was undertaken between 2004 and 2009, in which of healthy children (N = 139, ages 3-5 years at baseline) were tested for the presence of H. pylori antigen in their stool using enzyme-linked immunoassay and followed-up till age 6-9 years (median follow-up time 45 months). Height, weight, and hemoglobin levels were measured, and socioeconomic data were obtained. Z scores of height for age, weight for age, and body mass index for age at baseline and follow-up were calculated using the 2000 Center for Disease Control and Prevention growth reference curves. Growth velocity (cm/month) between preschool and school age was compared between H. pylori-infected and uninfected children using mixed models. RESULTS: Fifty-three percent of the children were H. pylori positive at baseline, and all except one child tested positive at follow-up. The adjusted mean Z score of height for age at follow-up was significantly lower among H. pylori-infected children than uninfected ones: 0.15 (95% confidence intervals (CIs) 0.02, 0.29) and 0.45 (95% CI 0.29, 0.60), respectively (p = .002). Growth velocity was slower in the former group -0.0264 cm/month (95% CI -0.047, -0.005) (p = .014), after adjusting for baseline height and age. H. pylori infection was not associated with body weight. CONCLUSIONS: Helicobacter pylori infection acquired in early childhood may have long-term adverse influence on linear growth at school age.

Change in incidence of clinic visits for all-cause and rotavirus gastroenteritis in young children following the introduction of universal rotavirus vaccination in Israel.

Both rotavirus vaccines RotaTeq and Rotarix were efficacious against severe rotavirus gastroenteritis in clinical trials; yet real-world data on the effect of rotavirus vaccines on mild to moderate disease are limited. We used a large computerised database of Maccabi Health Services Health Maintenance Organisation (HMO), the second largest HMO in Israel covering 25% of the Israeli population, to compare the incidence of acute gastroenteritis (AGE) clinic visits in community settings (n=302,445) before (2005-10) and after (2011-13) the introduction of universal rotavirus immunisation in Israel. We retrieved laboratory results of rotavirus antigen tests (n=18,133) and using a weighted analysis, we estimated the impact of rotavirus immunisation on the disease burden of rotavirus AGE clinic visits. Following the introduction of universal rotavirus immunisation, the typical winter peaks of rotavirus AGE were substantially lower and significant reductions of 14.8% (95% confidence interval (CI): 13.5-16.1) in all-cause AGE clinic visits and of 59.7% (95% CI: 59.8-62.6) in rotavirus AGE clinic visits were observed. The decrease was observed in all age groups, but it was greater in children aged 0 to 23 months than those aged 24 to 59 months. Continued rotavirus laboratory surveillance is warranted to monitor the sustainability of these changes.

Incidence and risk factors for intussusception among children in northern Israel from 1992 to 2009: a retrospective study.

BACKGROUND: Determining the background incidence of intussusception is important in countries implementing rotavirus immunization. Rotavirus immunization was introduced into the routine infant immunization program in Israel during late 2010. Incidence and risk factors for intussusception were examined in children aged less than five years between 1992 and 2009. METHODS: Data were collected from medical records of children hospitalized due to intussusception (N = 190), and from control children (N = 295), at Carmel and Hillel Yaffe hospitals in northern Israel. RESULTS: The average annual incidence of intussusception in Jewish and Arab children aged less than five years was estimated at 36.1 (95% CI 17.0-76.5) vs. 23.2 per 100,000 (95% CI 9.3-57.9); for infants less than 12 months of age- 128.1 (95% CI 53.0-309.6) vs. 80.1 (95% CI 29.1-242.6) per 100,000. The risk of intussusception was higher in infants aged 3-5 months: OR 5.30 (95% CI 2.11-13.31) and 6-11 months: OR 2.53 (95% CI 1.13-5.62) when compared to infants aged less than 3 months; in those living in low vs high socioeconomic communities: OR 2.81 (95% CI 1.45-5.43), and in children with recent gastroenteritis: OR 19.90 (95% CI 2.35-168.32) vs children without recent gastroenteritis. Surgical reduction was required in 23.2%. The likelihood of surgery was significantly increased in patients presenting with bloody stool, in Arabs and those who were admitted to Hillel Yaffe Hospital. CONCLUSIONS: The incidence of intussusception prior to universal rotavirus immunization was documented in northern Israel. Despite the lower incidence, Arab patients underwent surgery more often, suggesting delayed hospital admission of Arab as opposed to Jewish patients.

IgG Serum Antibodies to Shigella sonnei Lipopolysaccharide Are Inversely Associated with the Incidence of Culture-Proven S. sonnei Shigellosis in Israeli Children and Adolescents.

BACKGROUND: Shigella is a leading cause of moderate-to-severe diarrhea globally, with young children most affected. The burden of shigellosis drops increasingly with age, inferring the acquisition of natural immunity. We tested the hypothesis that IgG antibodies elicited against Shigella O-specific polysaccharide (O-SP) are correlates of age-acquired immunity. OBJECTIVES: We examined levels and determinants of serum IgG to S. sonnei LPS and the association with the incidence of S. sonnei shigellosis in Israeli children and adolescents. METHODS: We analyzed 1096 serum samples from 0- to 19-year-olds collected in 2008-2015 for IgG anti-S. sonnei LPS levels by ELISA. Corresponding age-specific incidences of culture-proven S. sonnei shigellosis from 2008 to 2015 were obtained. We compared ecologically IgG levels, prevalence above a proposed protective threshold, and S. sonnei shigellosis incidence. RESULTS: In a multivariable analysis model, children aged 1-4, 5-14, and 15-19 years were 6.71, 27.68, and 48.62 times more likely to have IgG anti-S. sonnei LPS above the threshold than those aged < 1 year, respectively (p < 0.001). Infants 0-3 months old had relatively high IgG anti-S. sonnei LPS levels of maternal origin that dropped thereafter. Children of low socioeconomic status had a 2.73 times higher likelihood of having IgG anti-S. sonnei LPS above the threshold (p < 0.001). A significant inverse correlation between age-specific IgG anti-S. sonnei LPS levels and S. sonnei shigellosis incidence was observed (Spearman rho= -0.76, p = 0.028). CONCLUSIONS: The study results support anti-S. sonnei LPS antibodies as correlates of protection that can inform Shigella vaccine development.

A Shigella flexneri 2a synthetic glycan-based vaccine induces a long-lasting immune response in adults.

Shigella is a leading cause of moderate to severe diarrhea worldwide and of diarrhea-associated deaths in children under 5 years of age in low-and middle-income countries. A vaccine against shigellosis is in high demand. SF2a-TT15, a synthetic carbohydrate-based conjugate vaccine candidate against Shigella flexneri 2a (SF2a) was found safe and strongly immunogenic in adult volunteers. Here, SF2a-TT15 at 10 µg oligosaccharide (OS) vaccine dose is shown to induce a sustained immune response in magnitude and functionality in the majority of volunteers followed up 2 and 3 years post-vaccination. High levels of either one of the humoral parameters as well as the number of specific-IgG memory B-cells determined 3 months after vaccination were good predictors of the durability of the immune response. This study is the first to examine the long-term durability of antibody functionality and memory B-cell response induced by a Shigella vaccine candidate.

Threshold protective levels of serum IgG to Shigella lipopolysaccharide: re-analysis of Shigella vaccine trials data.

OBJECTIVES: Establishing a correlate of protection is essential for the development and licensure of Shigella vaccines. We examined potential threshold levels of serum IgG to Shigella lipopolysaccharide (LPS) that could predict protection against shigellosis. METHODS: We performed new analyses of serologic and vaccine efficacy (VE) data from two randomized vaccine-controlled trials of the Shigella sonnei-Pseudomonas aeruginosa recombinant exoprotein A (rEPA) conjugate conducted in young adults and children aged 1-4 years in Israel. Adults received either S. sonnei-rEPA (n = 183) or control vaccines (n = 277). Children received the S. sonnei-rEPA conjugate (n = 1384) or S. flexneri 2a-rEPA conjugate (n = 1315). VE against culture-proven shigellosis was determined. Sera were tested for IgG anti-S. sonnei LPS antibodies. We assessed the association of various levels of IgG anti-S. sonnei LPS antibodies with S. sonnei shigellosis risk using logistic regression models and the reverse cumulative distribution of IgG levels. RESULTS: Among adults, four vaccinees and 23 controls developed S. sonnei shigellosis; the VE was 74% (95% CI, 28-100%). A threshold of ≥1:1600 IgG anti-S. sonnei LPS titre was associated with a reduced risk of S. sonnei shigellosis and a predicted VE of 73.6% (95% CI, 65-80%). The IgG anti-S. sonnei LPS correlated with serum bactericidal titres. In children, a population-based level of 4.5 ELISA Units (EU) corresponding to 1:1072 titre, predicted VE of 63%, versus 71% observed VE in children aged 3-4 years. The predicted VE in children aged 2-4 years was 49%, consistent with the 52% observed VE. CONCLUSION: Serum IgG anti-S. sonnei LPS threshold levels can predict the degree of VE and can be used for the evaluation of new vaccine candidates.

Predictors of reinfection with pre-Omicron and Omicron variants of concern among individuals who recovered from COVID-19 in the first year of the pandemic.

OBJECTIVES: The predictors of SARS-CoV-2 reinfection are unclear. We examined predictors of reinfection with pre-Omicron and Omicron variants among COVID-19-recovered individuals. METHODS: Randomly selected COVID-19-recovered patients (N = 1004) who donated convalescent plasma during 2020 were interviewed between August 2021 and March 2022 regarding COVID-19 vaccination and laboratory-proven reinfection. The sera from 224 (22.3%) participants were tested for antispike (anti-S) immunoglobulin G and neutralizing antibodies. RESULTS: The participants' median age was 31.1 years (78.6% males). The overall reinfection incidence rate was 12.8%; 2.7% versus 21.6% for the pre-Omicron (mostly Delta) versus Omicron variants. Negative associations were found between fever during the first illness and pre-Omicron reinfection: relative risk 0.29 (95% confidence interval 0.09-0.94), high anti-N level at first illness and Omicron reinfection: 0.53 (0.33-0.85), and overall reinfection: 0.56 (0.37-0.84), as well as between subsequent COVID-19 vaccination with the BNT162b2 vaccine and pre-Omicron 0.15 (0.07-0.32), Omicron 0.48 (0.25-0.45), and overall reinfections 0.38 (0.25-0.58). These variables significantly correlated with immunoglobulin G anti-S follow-up levels. High pre-existing anti-S binding and neutralizing antibody levels against the SARS-CoV-2 Wuhan and Alpha strains predicted protection against Omicron reinfections. CONCLUSION: Strong immune responses after the first COVID-19 infection and subsequent vaccination with the BNT162b2 vaccine provided cross-protection against reinfections with the Delta and Omicron variants.

Serologic Response and Safety after a Third Dose of the COVID-19 BNT162b2 Vaccine in Patients with Inflammatory Bowel Diseases.

Vaccines are pivotal for control of the coronavirus disease (COVID-19) pandemic. Patients with inflammatory bowel diseases (IBDs) treated with antitumor necrosis factor (TNF)-α have lower serologic response after two COVID-19 vaccine doses. Data regarding a third vaccine dose are scarce. An Israeli multicenter prospective observational study recruited 319 subjects: 220 with IBD (79 treated with anti-TNFα) and 99 healthy control (HC) participants. All patients received two mRNA-BNT162b2 vaccines (Pfizer/BioNTech), 80% of whom received a third vaccine dose. Evaluation included disease activity, anti-spike (S) and nucleocapsid (N) antibody levels, anti-TNFα drug levels, and adverse events (AEs). All participants showed significant serologic response one month after receiving a third dose. However, three months later, the anti-S levels decreased significantly in patients treated with anti-TNFα compared with the non-anti-TNFα and HC groups. A correlation between serologic response to the third vaccine dose and anti-TNF drug levels was not found. No significant AE or IBD exacerbation was observed. Importantly, lower serologic response after the third vaccine dose predicted infection. A third dose of BNT162b2 is effective and safe in patients with IBD. Lower serologic response predicted infection, even in seropositive subjects. Lower serologic responses and their rapid decline suggest a fourth vaccine dose in this patient population.

Incidence, age of acquisition and risk factors of Helicobacter pylori infection among Israeli Arab infants.

We examined the age of acquisition of Helicobacter pylori infection in a prospective study that was conducted among 231 Israeli Arab children. Helicobacter pylori was identified in stool specimens collected at ages 2, 4, 6, 8, 12 and 18 months, using a monoclonal stool antigen immunoassay. Information on household characteristics, breastfeeding, antibiotic use and hygiene practices was obtained. The incidence of H. pylori infection was 33.3%. The estimated mean age of H. pylori infection acquisition was 14 months. The determinants of H. pylori infection were living in a low socioeconomic status (SES) village: OR 9.60 (95% CI 2.91-31.68, p < 0.001); low paternal education: OR 3.35 (95% CI 1.21-9.29, p = 0.02); and boiling feeding bottles and nipples at low frequency: OR 7.12 (95% CI 1.82-27.86, p = 0.005). In conclusion, H. pylori infection is acquired at a higher rate in low SES settings. Parental education and hygiene play an important role in H. pylori acquisition in infancy.

Pentraxin 3 and Shigella LPS and IpaB Antibodies Interplay to Defeat Shigellosis.

Shigella causes moderate to severe diarrhea or dysentery after invading the colon mucosa. Long Pentraxin 3 (PTX3) is recognized as the humoral component of the innate immune response to bacterial pathogens. We examined the interplay between levels of PTX3 and levels of anti-Shigella lipopolysaccharide (LPS) and anti-Shigella type 3 secretion system protein-IpaB antibodies in children during acute shigellosis and after recovery. PTX3 concentrations in serum and stool extracts were determined by sandwich ELISA using commercial anti-PTX3 antibodies. Serum IgG, IgM, and IgA anti-S. sonnei LPS or anti-S. sonnei IpaB were measured using in house ELISA. Children with acute shigellosis (n = 60) had elevated PTX3 levels in serum and stools as compared with recovered subjects (9.6 ng/mL versus 4.7 ng/mL, p < 0.009 in serum and 16.3 ng/g versus 1.1 ng/g in stool, p = 0.011). Very low levels of PTX3 were detected in stools of healthy children (0.3 ng/g). Increased serum levels of PTX3 correlated with high fever accompanied by bloody or numerous diarrheal stools characteristic of more severe shigellosis while short pentraxin; C-Reactive Protein (CRP) did not show such a correlation. PTX3 decreased in convalescence while anti-Shigella antibodies increased, switching the response from innate to adaptive toward the eradication of the invasive organism. These data can inform the development of Shigella vaccines and treatment options.

SARS-CoV-2 IgG Antibody Levels in Women with IBD Vaccinated during Pregnancy.

INTRODUCTION: Regulatory agencies supported vaccination of pregnant women with SARS-CoV-2 mRNA vaccines, including patients with IBD. No data exist regarding these vaccines in IBD during pregnancy. AIM: To assess the serologic response to two doses of the mRNA SARS-CoV-2 BNT162b2 vaccine in pregnant women with IBD vaccinated during pregnancy, compared to that of pregnant women without IBD, and non-pregnant women with IBD. METHODS: Anti-spike antibody levels were assessed in all women and in cord blood of consenting women. RESULTS: From December 2020 to December 2021, 139 women were assessed: pregnant with IBD-36, pregnant without IBD-61, and not pregnant with IBD-42. Antibodies were assessed in cords of two and nine newborns of women with and without IBD, respectively. Mean gestational ages at administration of the second vaccine doses were 22.0 weeks in IBD and 23.2 weeks in non-IBD, respectively. Mean (SD) duration from the second vaccine dose to serology analysis in pregnant women with IBD, without IBD, and in non-pregnant women with IBD was 10.6 (4.9), 16.4 (6.3), and 4.3 (1.0) weeks, respectively. All women mounted a serologic response. In multivariable analysis, no correlation was found between the specific group and antibody levels. In both pregnancy groups, an inverse correlation between antibody levels and the interval from the second vaccine dose was demonstrated. Cord blood antibody levels exceeded maternal levels in women with and without IBD. CONCLUSION: All patients with IBD mounted a serologic response. The interval between vaccine administration to serology assessment was the most important factor determining antibody levels. A third vaccine dose should be considered in pregnant women with IBD vaccinated at early stages of pregnancy.

Anti-TNFα Treatment Impairs Long-Term Immune Responses to COVID-19 mRNA Vaccine in Patients with Inflammatory Bowel Diseases.

Patients with inflammatory bowel disease (IBD) treated with anti-tumor-necrosis factor-alpha (TNFα) exhibited lower serologic responses one-month following the second dose of the COVID-19 BNT162b2 vaccine compared to those not treated with anti-TNFα (non-anti-TNFα) or to healthy controls (HCs). We comprehensively analyzed long-term humoral responses, including anti-spike (S) antibodies, serum inhibition, neutralization, cross-reactivity and circulating B cell six months post BNT162b2, in patients with IBD stratified by therapy compared to HCs. Subjects enrolled in a prospective, controlled, multi-center Israeli study received two BNT162b2 doses. Anti-S levels, functional activity, specific B cells, antigen cross-reactivity, anti-nucleocapsid levels, adverse events and IBD disease score were detected longitudinally. In total, 240 subjects, 151 with IBD (94 not treated with anti-TNFα and 57 treated with anti-TNFα) and 89 HCs participated. Six months after vaccination, patients with IBD treated with anti-TNFα had significantly impaired BNT162b2 responses, specifically, more seronegativity, decreased specific circulating B cells and cross-reactivity compared to patients untreated with anti-TNFα. Importantly, all seronegative subjects were patients with IBD; of those, >90% were treated with anti-TNFα. Finally, IBD activity was unaffected by BNT162b2. Altogether these data support the earlier booster dose administration in these patients.

Interaction among ethnicity, socioeconomic status, and Helicobacter pylori seroprevalence in Israeli children and adolescents.

OBJECTIVES: The aim of the study was to examine the prevalence of Helicobacter pylori infection among Israeli children from different backgrounds and to assess potential interactions between ethnicity, socioeconomic status (SES), and H pylori seroprevalence. PATIENTS AND METHODS: The present sero-epidemiologic study was conducted among 0- to 20-year-old children seeking medical attention, not specifically gastrointestinal symptoms, using sera collected between 2000 and 2001 from 575 Israeli Arab children, 584 Jewish children from the general population, and sera that were obtained between 1997 and 2007 from 464 children of an ultraorthodox Jewish community. An enzyme-linked immunosorbent assay was used to measure H pylori serum immunoglobulin G antibodies and seropositivity to H pylori CagA strains. RESULTS: H pylori seropositivity was 22.9% (95% confidence interval [CI] 19.7-26.5) among Jewish children from the general population, 25.2% (95% CI 21.5-29.4) among ultraorthodox Jewish children, and 45.6% (95% CI 41.5-49.7) among Arab children. H pylori seroprevalence increased significantly with age in the 3 study groups, but it was consistently higher in Arab children. Compared with Jewish participants from high SES and controlling for age and sex, the odds ratio for H pylori seropositivity was 2.03 (95% CI 1.31-3.12) in Jewish children from intermediate SES, 2.42 (95% CI 1.29-4.53) in Arab children from intermediate SES, 2.26 (95% CI 1.52-3.36) in Jewish children from low SES, and 5.72 (95% CI 3.89-8.42) in Arab children from low SES. CagA seropositivity was 40.8% and 45.0% among Jewish and Arab children, respectively (P =0.59), and it was highest among subjects of lower SES. CONCLUSIONS: Socioeconomic factors may not totally explain the ethnic differences in H pylori prevalence.

Differences in glycated hemoglobin levels and cholesterol levels in individuals with diabetes according to Helicobacter pylori infection.

This study examined differences in glycated hemoglobin (HbA1c), fasting plasma glucose and cholesterol levels between H. pylori infected and uninfected persons with diabetes. Anonymized data of Maccabi Healthcare Services in Israel were analyzed, of 12,207 individuals (50.0% H. pylori positive) aged 25-95 years who underwent the urea breath test. The data included HbA1c, fasting plasma glucose and cholesterol levels. The inverse probability of treatment weighting approach was used to account for confounders. Differences between individuals who were H. pylori positive and negative, in HbA1c (> or ≤ 7.0%) and in cholesterol levels were assessed using weighted generalized estimating equations. For men, but not women, the likelihood of having HbA1c > 7.0% was increased in those infected than uninfected with H. pylori: prevalence ratio 1.11 (95% CI 1.00, 1.24), P = 0.04. For both sexes, total cholesterol (P = 0.004) and low-density lipoprotein (LDL) levels (P = 0.006) were higher among those infected than uninfected with H. pylori. No significant differences were found in glucose and HDL levels according to H. pylori infection. The results were consistent in unweighted multivariable analyses. In conclusion, H. pylori infection might be related to worse glycemic control in men, and higher total cholesterol and LDL cholesterol levels in both sexes.

Convulsions in children hospitalized for acute gastroenteritis.

The study aim was to examine possible correlates of convulsions in children hospitalized for acute gastroenteritis (AGE). Data collected in a prospective study of AGE hospitalizations in children aged 0-59 months in 3 hospitals in Israel during 2008-2015 were analyzed. Stool samples were tested for rotavirus using immunochromatography and stool culture was performed for the detection of Salmonella, Shigella and Campylobacter We compared clinical and demographic characteristics of children hospitalized for AGE who had convulsions (n = 68, cases) with children hospitalized for AGE without convulsions (n = 3505, controls). Age differed between children with and without convulsions (p = 0.005); the former were mostly toddlers aged 12-23 months (51%) compared to 30% of the control group. A higher percentage of cases tested positive for Shigella (11% vs. 4%, p = 0.002), the opposite was found for rotavirus (2% vs. 30% p < 0.001). A multivariable model showed that body temperature (OR 2.91 [95% CI 1.78-4.76], p < 0.001) and high blood glucose level (> 120 mg/dL) (OR 5.71 [95% CI 1.27-25.58] p = 0.023) were positively related to convulsions in children with AGE, while severe AGE (Vesikari score ≥ 11) was inversely related with convulsions (OR 0.09 [95% CI 0.03-0.24], p < 0.001). Conclusion: Elevated body temperature is associated with convulsions in children with AGE, but not severity of AGE, while hyperglycemia might reflect a neuroendocrine stress reaction to convulsions, AGE or both.

A nationwide analysis of population group differences in the COVID-19 epidemic in Israel, February 2020-February 2021.

BACKGROUND: Social inequalities affect the COVID-19 burden and vaccine uptake. The aim of this study was to explore inequalities in the incidence and mortality rate of SARS-CoV-2 infection and vaccine uptake in various sociodemographic and population group strata in Israel. METHODS: We analysed nationwide publicly available, aggregated data on PCR-confirmed SARS-CoV-2 infections and COVID-19 deaths between March 2020 and February 2021, as well as the first three months of COVID-19 immunisation according to sociodemographics, including population group and residential socioeconomic status (SES). We computed incidence and mortality rates of COVID-19. Comparisons between towns with predominantly Arab, ultra-Orthodox Jewish (the minorities), general Jewish populations, and according to SES, were conducted using generalised linear models with negative binomial distribution. FINDINGS: Overall, 774,030 individuals had SARS-CoV-2 infection (cumulative incidence 84•5 per 1,000 persons) and 5687 COVID-19 patients had died (mortality rate 62•8 per 100,000 persons). The highest mortality rate was found amongst the elderly. Most (>75%) individuals aged 60 years or above have been vaccinated with BNT162b2 vaccine. The risk of SARS-CoV-2 infection was higher in towns with predominantly Arab and ultra-Orthodox Jewish populations than in the general Jewish population, and in low SES communities. COVID-19 mortality rate was highest amongst Arabs. Conversely, vaccine uptake was lower amongst Arab and ultra-Orthodox Jewish populations and low SES communities. INTERPRETATION: Ethnic and religious minorities and low SES communities experience substantial COVID-19 burden, and have lower vaccine uptake, even in a society with universal accessibility to healthcare. Quantifying these inequalities is fundamental towards reducing these gaps, which imposes a designated apportion of resources to adequately control the pandemic. FUNDING: No external funding was available for this study.

Safety and immunogenicity of a synthetic carbohydrate conjugate vaccine against Shigella flexneri 2a in healthy adult volunteers: a phase 1, dose-escalating, single-blind, randomised, placebo-controlled study.

BACKGROUND: Shigella remains in the top four pathogens responsible for moderate to severe diarrhoea in children below 5 years of age. The shigella O-specific polysaccharide (O-SP) is a promising vaccine target. We developed a conjugate vaccine prototype incorporating a unique well defined synthetic oligosaccharide hapten, chemically designed for optimal antigenic, conformational, structural, and functional mimicry of the O-SP from Shigella flexneri 2a (SF2a). We aimed to assess the safety, tolerability, and immunogenicity of this original synthetic oligosaccharide-based vaccine candidate, SF2a-TT15, conceived to drive the antibody response towards the key protective determinants of the native lipopolysaccharide antigen, in a first-in-human phase 1 study. METHODS: We did a first-in-human, dose-escalating, single-blind, observer-masked, randomised, placebo-controlled study at the Clinical Research Center of Tel Aviv Sourasky Medical Center (Israel). Participants were healthy adults aged 18-45 years with low titres of serum SF2a-specific IgG antibodies. 64 eligible participants were assigned to one of two cohorts. 32 participants in each of the two cohorts were randomly assigned via computer-generated algorithm in a stepwise manner to receive the 2 µg (cohort 1) and 10 µg oligosaccharide dose (cohort 2) of the SF2a-TT15 vaccine candidate non-adjuvanted or adjuvanted with aluminium hydroxide (alum) or matching placebos. The vaccine was administered as three single intramuscular injections into the arm, 28 days apart. The primary outcome was the incidence and severity of adverse events, which were assessed in the intention-to-treat safety population analysis including all participants who were randomly assigned and received at least one vaccine or placebo injection. The immunogenicity endpoints were secondary outcomes and were analysed in all participants who were randomly assigned, received all of the assigned injections before the time of the immunogenicity assessment, and provided blood samples for immunological follow-up (per-protocol immunogenicity analysis). The study is registered with ClinicalStudies.gov, NCT02797236 and is completed. FINDINGS: Of 203 volunteers initially screened, 64 participants were enrolled between Sept 20, 2016, and Sept 26, 2017. In each of the two cohorts, 12 participants received the adjuvanted vaccine, 12 received the non-adjuvanted vaccine and eight received the matching placebo (four each). The SF2a-TT15 glycoconjugate was well tolerated at both doses. No serious or severe adverse events occurred. Overall, seven (88%) of eight to 12 (100%) of 12 in each group of volunteers had one adverse event or more after receiving the study agents with the majority of adverse events, 300 (98%) of 307, considered mild in intensity. Of the seven adverse events defined as moderate in severity, one (nausea) was suspected to be related to the vaccine candidate. At all post-immunisation days and for both oligosaccharide doses, whether adjuvanted or not, SF2a-TT15 induced significantly higher serum IgG anti-SF2a lipopolysaccharide geometric mean titres (GMTs) as compared with baseline or with the corresponding GMTs in placebo recipients (p<0·01). After one injection, the non-adjuvanted 10 µg oligosaccharide dose induced a 27-times increase in IgG GMT (5080 vs 189) and the non-adjuvanted 2 µg oligosaccharide dose induced a five-times increase (1411 vs 283), compared with baseline. Alum enhanced the specific IgG response at 2 µg oligosaccharide dose after the third injection (GMTs 3200 vs 1176, p=0.045). INTERPRETATION: SF2a-TT15 was safe and well tolerated and induced high titres of anti-SF2a LPS IgG antibodies. These results support further evaluation of this original synthetic oligosaccharide-protein conjugate vaccine candidate for safety, immunogenicity, and protective efficacy in target populations. FUNDING: The European Union Seventh Framework Programme.