Search

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.

Background 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. Aim To assess serologic responses to mRNA-COVID-19 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared to healthy controls (HC). Methods Prospective, controlled, multi-center Israeli study. Subjects enrolled received two BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibodies levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinaly. Results Overall 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HC. After the first vaccine dose all HC were seropositive, while ∼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 to non-anti-TNFα treated patients, and HC (both P, Graphical abstract

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.

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.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.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.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.

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.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.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 (p0·01). 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).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.The European Union Seventh Framework Programme.

BackgroundPatients 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.Aimto assess immune responses to mRNA-COVID-19 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared to healthy controls (HC).MethodsProspective, controlled, multi-center Israeli study. Subjects enrolled received two BNT162b2 (Pfizer/BioNTech) doses. Anti-spike (S) antibodies levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinaly.ResultsOverall 258 subjects: 185 IBD (67 treated with anti-TNFα), and 73 HC. After the first vaccine dose all HC were seropositive, while some patients with IBD, regardless of treatment, remained seronegative. After the second dose all subjects were seropositive, however anti-S levels were significantly lower in anti-TNFα treated compared to untreated patients, and HC (pConclusionsIn this prospective study in patients with IBD stratified according to treatment all patients mounted an immune response to two 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 immune response longevity in this group may be limited, vaccine booster dose should be considered.

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 p 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 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.

Summary 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.

Objectives: This study aims to examine the prevalence and risk factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sero-positivity in health care workers (HCWs), a main risk group, and assess the sero-incidence of SARS-CoV-2 infection between the first and second waves of coronavirus disease 2019 (COVID-19) in Israel.Methods: A longitudinal study was conducted among 874 HCWs from nine hospitals. Demographics, health information, and blood samples were obtained at baseline (first wave—April–May 2020) and at follow-up (n = 373) (second wave—September–November 2020). Sero-positivity was determined based on the detection of total antibodies to the nucleocapsid antigen of SARS-CoV-2, using electro-chemiluminescence immunoassay (Elecsys® Anti-SARS-CoV-2, Roche Diagnostics, Rotkreuz, Switzerland).Results: The sero-prevalence of SARS-CoV-2 antibodies was 1.1% [95% confidence intervals (CI) 0.6–2.1] at baseline and 8.3% (95% CI 5.9–11.6) at follow-up. The sero-conversion of SARS-CoV-2 serum antibody was 6.9% (95% CI 4.7–9.9) during the study period. The increase in SARS-CoV-2 sero-prevalence paralleled the rise in PCR-confirmed SARS-CoV-2 infections among the HCWs across the country. The likelihood of SARS-CoV-2 sero-prevalence was higher in males vs. females [odds ratio (OR) 2.52 (95% CI 1.05–6.06)] and in nurses vs. physicians [OR 4.26 (95% CI 1.08–16.77)] and was associated with being quarantined due to exposure to COVID-19 patients [OR 3.54 (95% CI 1.58–7.89)] and having a positive PCR result [OR 109.5 (95% CI 23.88–502.12)].Conclusions: A significant increase in the risk of SARS-CoV-2 infection was found among HCWs between the first and second waves of COVID-19 in Israel. Nonetheless, the sero-prevalence of SARS-CoV-2 antibodies remains low, similar to the general population. Our findings reinforce the rigorous infection control policy, including quarantine, and utilization of personal protective equipment that should be continued together with COVID-19 immunization in HCWs and the general population.

Background Gastroesophageal reflux disease (GERD) is associated with high utilization of health care services. Diagnostic tests usually are not required to establish GERD diagnosis, but endoscopy is recommended for patients with alarm symptoms such as dysphagia and unintentional weight loss, and those whose symptoms are not relieved by proton pump inhibitors (PPIs) therapy. Evidence on the correlates of utilization of gastroenterology health services among GERD patients is limited. The study aim was to examine associations of patient and physician’s characteristics with high utilization of gastroenterology services. Methods In a cross-sectional study using the database of the second largest integrated care organization in Israel, data of all adult GERD patients (N = 75,219) in 2012–2015 were analyzed. High utilization of services was assessed using two dependent variables analyzed separately: undergoing two or more gastroscopies or having six or more visits to a gastroenterology consultant during the study-period. Results Overall, 11,261 (15.0%) patients had two or more gastroscopies and 23,703 (31.5%) had six or more visits to a gastroenterology consultant. The likelihood of high utilization of gastroscopy increased with age; in immigrants from the Former Soviet Union versus patients who were born in Israel; residents of Jerusalem, the south, the north and Haifa districts versus the center district; in patients with high PPI purchases, and in patients who belonged to clinics in which the physician-manger had no board certification. The correlates were similar for visits to a gastroenterology consultant. Conclusions Patient and physician’s characteristics were related to high utilization of gastroenterology services among GERD patients. The associations with age and country of birth might reflect more severe disease. The regional differences warrant further research and interventions at the district level. Training in gastroenterology of primary care physicians without a board certification is warranted. Electronic supplementary material The online version of this article (10.1186/s13584-019-0335-3) contains supplementary material, which is available to authorized users.

Shigella is a leading cause of diarrhea among children globally and of diarrheal deaths among children under 5 years of age in low- and middle-income countries. To date, no licensed Shigella vaccin...

Objectives: Ultraorthodox Jewish populations living in towns with good sanitary infrastructure but with conditions of crowding have been the epicenter of Shigella sonnei shigellosis outbreaks. In this study, the incidence and risk factors of S. sonnei shigellosis in children living in an ultraorthodox community were determined. Methods: Data for the years 2000–2013 for all reported culture-proven S. sonnei shigellosis cases in children aged 0–59 months in the city of Elad were compared with data for the rest of the sub-district. Environmental factors obtained through parental interviews were evaluated for 78 incident cases of S. sonnei shigellosis and 141 community controls, matched by age, sex, and neighborhood. Conditional logistic regression models were performed. Results: Cyclic epidemics of S. sonnei shigellosis occurred every 2 years. The mean annual incidence was 10.0 per 1000 children in Elad (95% confidence interval 7.9–12.6) vs. 3.8 per 1000 children (95% confidence interval 3.3–4.4) in the sub-district (p

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.

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.

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.

The role of the humoral immune response to Clostridium difficile in modulating the severity of C. difficile infection (CDI) is unclear. We compared the levels of serum immunoglobulin G (IgG) and immunoglobulin A (IgA) against toxin A (TcdA) and toxin B (TcdB) of C. difficile between CDI and control patients and according to disease severity. The levels of IgG and IgA antibodies against TcdA and TcdB were measured in sera from patients with CDI (n = 50, 19 had severe CDI) and control patients (n = 52), using ELISA. Patients with CDI had higher levels of IgG antibodies against TcdA and TcdB than controls (p = 0.001 and p = 0.04, respectively). Higher IgG levels against TcdA and TcdB were found in patients with mild vs. severe CDI 7&ndash, 14 days after the diagnosis (p = 0.004 and 0.036, respectively). A factor analysis included both IgA and IgG levels against both toxins into one composite variable, which was of higher values in patients with mild vs. severe CDI (p = 0.026). In conclusion, the systemic humoral immune responses against TcdA and TcdB might modulate the severity of CDI. These preliminary findings provide a basis for future large-scale studies and support the development and evaluation of active and passive immunotherapies for CDI management.

The few published studies on the relationship between Helicobacter pylori infection and metabolic homeostasis were relatively small and yielded inconsistent results. We examined the prevalence of metabolic syndrome in relation to H. pylori infection and its symptoms in a large and unselected population. Coded data from the computerised database of a large health maintenance organisation in Israel were accessed for 147,936 individuals 25–95 years of age who performed the urea breath test during 2002–2012. The classification of metabolic syndrome followed a modified definition of the international diabetes federation. Prevalences of H. pylori infection and metabolic syndrome were 52.0% and 11.4% respectively. H. pylori infected patients had increased likelihood of metabolic syndrome: adjusted odds ratio (aOR) 1.15 (95% confidence intervals (CI) 1.10–1.19), as did patients with gastric ulcer: aOR 1.15 (95% CI 1.03–1.28) vs patients without these conditions. Duodenal ulcer was associated with metabolic syndrome only in persons aged 25–34 years: aOR 1.59 (95% CI 1.19-2.13), but not in older persons (P = 0.001 for heterogeneity). In conclusion, the likelihood of metabolic syndrome appeared significantly increased in relation to H. pylori infection and gastric and duodenal ulcers. These findings suggest that H. pylori long-term gastric inflammation might play a role in metabolic homeostasis.

Shigella is a leading cause of diarrhea among children globally and of diarrheal deaths among children under 5 years of age in low- and middle-income countries. To date, no licensed Shigella vaccine exists. We review evidence that serum IgG antibodies to Shigella LPS represent a good correlate of protection against shigellosis; this could support the process of development and evaluation of Shigella vaccine candidates. Case-control and cohort studies conducted among Israeli soldiers serving under field conditions showed significant serotype-specific inverse associations between pre-exposure serum IgG antibodies to Shigella LPS and shigellosis incidence. The same serum IgG fraction showed a dose–response relationship with the protective efficacy attained by vaccine candidates tested in phase III trials of young adults and children aged 1–4 years and in Controlled Human Infection Model studies and exhibited mechanistic protective capabilities. Identifying a threshold level of these antibodies associated with protection can promote the development of an efficacious vaccine for infants and young children.

Following the introduction of universal immunization against rotavirus, concerns were raised regarding pathogen-replacement of rotavirus by norovirus. The study aim was to examine the incidence and characteristics and norovirus gastroenteritis before and after the introduction of universal rotavirus immunization in Israel. We studied 1179 stool samples collected between November 2007 and December 2014 for a prospective hospital-based surveillance study of children aged 0–59 months hospitalized for gastroenteritis. A real-time RT-PCR assay was used to identify genogroup II (GII) norovirus in extracted fecal RNA samples. Overall, the weighted percentage of norovirus positive patients was 10.9%. Norovirus positivity was similar in the pre-universal rotavirus immunisation years (2008–2010) and the universal years (2011–2014), the respective average annual incidence of norovirus gastroenteritis was 1.6 (95% CI 0.6–2.3) per 1000 and 1.1 (95% CI 0.8–1.4) per 1000 children. Rotavirus was detected in 36.8% and 19.6% of the patients in the pre-vaccine years and the universal vaccine years, with an estimated incidence of 5.5 (95% CI 3.4–7.6) per 1000 and 2.1 (95% CI 1.6–2.7) per 1000 children, respectively. Most patients (59.1%) with norovirus gastroenteritis were infants aged 0–11 months. Norovirus was detected all year round with a significant 3-month peak from September through November. In conclusion, norovirus continues to be a leading cause of acute gastroenteritis associated with hospitalizations in young children. Future norovirus vaccines should target young infants. There was no evidence of pathogen-replacement by norovirus following the introduction of universal rotavirus immunization in Israel.

ObjectiveTo 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.MethodsAll 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.Results1595 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; PConclusionsFactors 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.

Shigellosis or bacillary dysentery is endemic worldwide and is a significant cause of death in children less than five years of age in developing countries. There are no licensed Shigella vaccines and glycoconjugates are among the leading candidate vaccines against shigellosis today. We used whole genome sequence analysis (WGA) to find out whether immunization, with an investigational Shigella sonnei glycoconjugate, could induce selective pressure leading to changes in the genome of S. sonnei. An outbreak of culture-proven S. sonnei shigellosis which occurred immediately after vaccination in one of the cohorts of volunteers participating in a phase III trial of the vaccine in Israel created a unique condition in which the epidemic agent "co-existed" with the developing immune responses induced by the vaccine and natural infection among vaccinees who developed S. sonnei shigellosis. By comparing the whole genomes of S. sonnei isolated from vaccinees and from volunteers in the control group, we show at a very high sensitivity that a potent S. sonnei glycoconjugate that conferred 74% protective efficacy against the homologous disease did not induce changes in the genome of S. sonnei and in particular on the O-antigen gene cluster.

Background Helicobacter pylori causes peptic ulcer disease and gastric cancer only in a subset of infected persons. Sex differences were shown in results of urea breath test (UBT), a commonly used test for the diagnosis of H. pylori infection. However, factors that might explain these differences, or affect UBT values, are not fully understood. We examined differences in UBT values between H. pylori-infected men and women while adjusting for background characteristics such as age, body mass index (BMI), and smoking. Methods A cross-sectional study was undertaken using coded data from the computerized database of Maccabi Health Services in Israel. Included were adults examined for UBT during 2002–2012 and were found H. pylori positive (UBT > 3.5‰). Multivariable linear mixed models were performed to assess the relationship between sex and UBT quantitative results, while adjusting for background characteristics. Results A total of 76,403 patients were included (52% of examined patients during the study period). Adjusted mean UBT value was significantly higher in women 33.8‰ (95% CI 33.4, 34.1) than in men 24.9‰ (95% CI 24.5, 25.3). A significant (P

The use of rotavirus pentavalent vaccine (RotaTeqA test-negative case-control study included age-eligible children for universal RotaTeq immunization (aged 2-59 months, born in 2011-2015). Cases (n = 98) were patients who tested positive for rotavirus by immunochromatography; those who tested negative (n = 628) comprised the control group. Information on rotavirus immunization history was obtained through linkage with a national immunization registry. Vaccination status was compared between cases and controls, adjusted odds ratios (aORs) were obtained from logistic regression models, and vaccine effectiveness calculated as (1 - aOR)*100.Immunization with RotaTeq was less frequent in RVGE cases (73.5%) than in controls (90.1%), p 0.001; this association persisted after controlling for potential confounders. Effectiveness of the complete vaccine series was estimated at 77% (95% confidence interval (CI): 49-90) in children aged 6-59 months, and 86% (95% CI: 65-94) in children aged 6-23 months; whereas for the incomplete series, the respective estimates were 72% (95% CI: 28-89) and 75% (95% CI: 30-91). Vaccine effectiveness was estimated at 79% (95% CI: 45-92) against G1P[8]-associated RVGE hospitalizations and 69% (95% CI: 11-89) against other genotype-RVGE hospitalizations.High effectiveness of RotaTeq as the sole rotavirus vaccine in a universal immunization programme was demonstrated in a high-income country. Although partial vaccination conferred protection, completing the vaccine series is warranted to maximize the benefit.

SUMMARYWe provide an update on the epidemiology of shigellosis in Israel using data generated by a sentinel laboratory-based surveillance network for the period 1998–2012. The average annual incidence of culture-proven shigellosis was 97/100 000. We estimated that each case of shigellosis accounted for 25 cases in the community indicating the high burden of disease. Orthodox Jewish communities, living in highly crowded conditions and with a high number of children aged S. sonneishigellosis.S. flexneriwas the leadingShigellaserogroup in Israeli Arabs.S. flexneri2a andS. flexneri6 alternated as the most common serotypes. BothS. sonneiandS. flexneriisolates showed high rates of resistance to ampicillin and trimethoprim/sulfamethoxazole and very low rates of resistance to quinolones and third-generation cephalosporins. Shigellosis due toS. sonneiconferred 81% (95% confidence interval 69–89) protection against the homologousShigellaserotype when epidemic exposure re-occurred 2 years later. These data are of value in the process ofShigellavaccine development.

Background Uncertainty exists about the sustainability of the reduction in rotavirus gastroenteritis (RVGE) following the introduction of rotavirus vaccines into national immunization programs, and on its potential impact on circulating genotypes. RotaTeq was introduced into the Israeli national immunization program in December 2010, and vaccination coverage is around 80%. Aims To examine the change in incidence of RVGE hospitalization and rotavirus genotypes, during the five years after introduction of RotaTeq into the Israeli national immunization program. Methods Data were obtained prospectively on hospitalization of children aged 0–59 months due to acute gastroenteritis (N = 7346) from three hospitals in northern Israel. Stool samples were tested for rotavirus by immunochromatography. Rotavirus was genotyped (N = 506) by RT-PCR and/or sequencing. Results The average incidence of RVGE hospitalization declined by 61.0% (95% CI 49.0–73.4%), from 5.6 per 1000 (95% CI 5.0–6.2) in the pre-universal immunization period (2008–2010) to 2.2 per 1000 (95% CI 1.8–2.5) during the universal immunization period (2012–2015), but yearly fluctuations were still observed. The most common genotypes in the pre-universal immunization period were G1P[8] (35.3%) followed by G2P[4] (15.5%), G3P[8] (8.8%), G4P[8] (4.3%) and G9P[8] (4.3%), and 19.5% were mixed infections. The dominance of G1P[8] continued into the universal immunization period (48.6%), followed by G3P[8] (21.5%), G9P[8] (15.9%) and G12P[8] (4.7%), while mixed rotavirus infections were no longer detected. Conclusions Universal immunization with RotaTeq in Israel was associated a sustained reduction in RVGE hospitalization. It is unclear whether changes in the circulating rotavirus genotypes are due to vaccine-induced selective pressure. Assessment of the long-term impact of rotavirus vaccination on the incidence of rotavirus gastroenteritis and continued strain surveillance is warranted.

The association between rotavirus gastroenteritis (RVGE)-associated hospitalization and rotavirus vaccine receipt was examined, and vaccine effectiveness was estimated in a case-control study conducted between 11/2007 and 12/2009 among Israeli children age eligible for rotavirus vaccination. Cases (n=111) were hospitalized children with diarrhea testing positive for rotavirus by immunochromatography. Controls (n=216) were hospitalized children with diarrhea testing negative for rotavirus. Among controls 36 (16.7%) children were vaccinated against rotavirus compared with two children (1.8%) among cases (p0.001). Rotavirus immunization was associated with lower risk of RVGE-associated hospitalization; adjusted OR 0.106 (95% CI 0.024, 0.481), yielding a vaccine effectiveness of 89.4% (95% CI 51.9%, 97.6%) in preventing hospitalization. These data demonstrate high effectiveness of rotavirus vaccines in a high income country.

BACKGROUND Limited data exist on the epidemiology and burden of rotavirus gastroenteritis in Israel. Objectives. Our objective was to examine the incidence, characteristics, and economic burden of rotavirus gastroenteritis associated with hospitalization of children

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.

Universal rotavirus vaccination with RotaTeq was introduced in Israel in December 2010. We examined hospitalization rates of children under 5 years of age due to all-cause and rotavirus gastroenteritis, both before and 3 years after universal introduction of the vaccination. An ongoing hospital-based surveillance network that was established in November 2007, accessed information regarding hospitalization of children due to gastroenteritis (n = 6205) in 3 hospitals in northern Israel, with an annual average of about 60,000 children under 5 years of age living in the catchment area of these hospitals. Stool samples were tested for rotavirus by immunochromatography. Compared to the period preceding implementation of the universal rotavirus vaccination (2008–2010), hospitalizations due to rotavirus gastroenteritis in children

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 enzymelinked 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.

The incidence of sporadic GII norovirus gastroenteritis associated with hospitalization was examined among 515 children aged

Background The risk factors of underutilization of childhood vaccines in populations with high access to health services are not fully understood. Objectives To determine vaccination coverage and factors associated with underutilization of childhood vaccines in a population with sub-optimal vaccination compliance, despite a high health care access. Methods The study was conducted among 430 children from ultraorthodox Jewish communities in the Bnei Brak city and Jerusalem district. Data on immunization status, socio-demographic factors and on parents’ attitudes regarding vaccines were obtained from medical records and through parents’ interviews. Results The proportion of fully vaccinated children was 65% in 2- to 5-year-old ultraorthodox children from Jerusalem district, and 86% in 2.5-year-old children from Bnei Brak city. The factors that were significantly associated with vaccines underutilization in Bnei Brak were having >6 siblings, maternal academic education, parental religious beliefs against vaccination, perceived risk of vaccine preventable diseases as low, and mistrust in the Ministry of Health (MOH). Similarly, in Jerusalem, religious beliefs against vaccination, and the perceived low risk of vaccine preventable diseases significantly increased the likelihood of under-immunization, while having a complementary health insurance was inversely related with vaccines underutilization. Conclusions The risk factors of under-immunization are in part modifiable, by means of health education on the risks of vaccine preventable diseases and by improving the trust in the MOH. The leaders of the ultraorthodox communities could play an important role in such interventions.

Summary 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 ¼ 0.02); and boiling feeding bottles and nipples at low frequency: OR 7.12 (95% CI 1.82– 27.86, p ¼ 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.

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 generalpopulation,andserathatwereobtainedbetween1997and2007from 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 ¼0.59), and it was highest among subjects of lower SES. Conclusions: Socioeconomic factors may not totally explain the ethnic differences in H pylori prevalence.

We examined the uptake of rotavirus vaccine and its effectiveness in preventing acute gastroenteritis (AGE) in the community. Data on rotavirus vaccines purchases and AGE were extracted from the computerized database of a large health maintenance organization in Israel. The incidence of AGE requiring a physician visit during 2008–09 rotavirus season among vaccinated and non-vaccinated children were compared, and vaccine effectiveness was calculated as: (1 − Relative Risk) × 100. During the study period, the uptake of rotavirus vaccine (mostly monovalent) reached 55.1% (N = 19,108) of the studied cohort. The risk of AGE requiring a physician visit was 23.2% and 46.4% among vaccinated and unvaccinated children, respectively, yielding an effectiveness of 50.1% (95% CI: 47.5%, 52.6%). Rotavirus monovalent vaccine was highly effective in preventing AGE in the community.

This study was undertaken to estimate the magnitude of Bordetella pertussis infections in a highly vaccinated population in Israel in order to evaluate the relationship between clinical notification data and serology-based evidence of infection. A cross-sectional survey was conducted on a total of 1982 serum samples from the National Serum Bank, collected from January 2000 through December 2001, in order to monitor high levels of pertussis toxin (PT) IgG antibody indicative of recent B. pertussis infection, by standardized methods. The estimation yielded an infection incidence rate of 2448 per 100,000 population (≥3 years of age) for the year 2000 compared to an annual incidence of reported pertussis of 5.6 per 100,000 for the same period. The peaks of estimated incidence of infection were found in the groups of 15–19-year olds (5245 per 100,000) and older than 60 years (6469 per 100,000), whereas the majority of clinical pertussis cases were reported for the 10–14-year olds (20.5 per 100,000). The findings clearly show that despite a high vaccination coverage rate (>93%), there is still a considerable circulation of B. pertussis , particularly in adolescents and elderly. Population-based serosurveillance for pertussis offers the potential to assist interpretation of trends independent of notification and diagnostic bias.

353 — Poster Session Cervical cancer epidemiology in former Soviet Union immigrants to Israel: A step towards solving the enigma Y. Raz, D. Grisaru, L. Boker-Keinan, D. Cohen, S. Goren. Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, Tel-Aviv University, Tel-Aviv, Israel, Gertner institute, Ministry of Health, Sheba Medical Center, Tel Hashomer, Israel, Haifa University, Heifa, Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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.