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.