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IMPORTANCE: The administration of a fourth BNT162b2 COVID-19 vaccine dose was approved in Israel in December 2021 for individuals 60 years or older who were vaccinated with a third dose 4 months previously or earlier to control the substantial surge of the SARS-CoV-2 Omicron variant. Nonetheless, the association between receipt of the fourth dose and protection against infection remains elusive. OBJECTIVE: To determine the association of the fourth BNT162b2 dose with protection against SARS-CoV-2–related infections, hospitalizations, and deaths during the Omicron surge in long-term care facility (LTCF) residents. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study was conducted in Israel between January 10 and March 31, 2022 and included LTCF residents 60 years or older. EXPOSURES: Vaccination with the fourth dose of BNT162b2 vs 3 doses that were administered 4 months previously or earlier. MAIN OUTCOMES AND MEASURES: Cumulative incidences of SARS-CoV-2 infections, hospitalizations, and deaths during the Omicron surge. The follow-up was initiated more than 7 days after receipt of the fourth dose, which was matched to the follow-up initiation date of those who had received 3 doses of vaccine in each facility. We obtained hazard ratios and 95% confidence intervals from multivariable Cox regression models. RESULTS: The data of 43 775 residents (mean [SD] age, 80.1 [9.4] years; 29 679 women [67.8%]) were analyzed, of whom 24 088 (55.0%) and 19 687 (45.0%) received the fourth and third dose (4 months previously or earlier), respectively. The median follow-up time was 73 days (4-dose group: IQR, 6 days; 3-dose group: IQR, 56 days). More than 7 days postvaccination with the fourth dose, SARS-CoV-2 infection was detected among 4058 fourth-dose vs 4370 third-dose recipients (cumulative incidence, 17.6% vs 24.9%). The corresponding incidences of hospitalizations for mild-to-moderate COVID-19, severe illness, and mortality were 0.9% and 2.8%, 0.5% and 1.5%, and 0.2% and 0.5%, respectively. The adjusted protections were 34% (95% CI, 30%-37%), 64% (95% CI, 56%-71%), and 67% (95% CI, 57%-75%) against overall infection, hospitalizations for mild-to-moderate illness, and severe illness, respectively, and 72% (95% CI, 57%-83%) against related deaths. CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that receipt of a fourth BNT162b2 dose conferred high protection against COVID-19 hospitalizations and deaths among LTCF residents during a substantial Omicron variant surge, but protection was modest against infection. These findings are relevant to the control of COVID-19 pandemic globally, especially among the population of LTCFs.

Background It is unknown whether convalescent immunoglobulins (cIgG) are better than convalescent plasma (CP) for COVID-19 patients. Methods In this randomized trial we assigned high risk COVID-19 with ≤10 days of symptoms, to receive cIgG or CP. The primary endpoint was improvement on day 14 according to the WHO scale. Secondary endpoints were survival on day 14, and improvement, survival, and percent of ventilated patients on day 28 and treatment response in unvaccinated and vaccinated patients. Results 319 patients were included; 166 received cIgG, and 153 CP. Median age was 64-66 years. 112 patients (67.5%) in the cIgG and 103 patients (67.3%) in the CP group reached the primary endpoint. Difference between groups was 0.1 (95%CI -10.1-10.4, p=0.026), failing to reach non-inferiority. More patients receiving cIgG improved by day 28 [136 patients (81.9%) and 108 patients (70.6%), respectively, 95% CI 1.9-20.7, p Conclusions cIgG failed to reach the primary non-inferiority endpoint on day 14 but was superior to CP on day 28. Survival and improvement by day 28 in unvaccinated patients treated with cIgG were better. In the face of new variants, cIgG is a viable option for treating COVID-19. Trial registration number My Trials MOH_2021-01-14_009667

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

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 We assessed vaccine effectiveness (VE) of BNT162b2 mRNA coronavirus disease 2019 (COVID-19) vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) acquisition among healthcare workers (HCWs) of long-term care facilities (LTCFs). Methods This prospective study, in the framework of the “Senior Shield” program in Israel, included routine weekly nasopharyngeal SARS-CoV-2 RT-PCR testing from all LTCF HCWs since July 2020. All residents and 75% of HCWs were immunized between December 2020 and January 2021. The analysis was limited to HCWs adhering to routine testing. Fully vaccinated (14+ days after second dose; n = 6960) and unvaccinated (n = 2202) HCWs were simultaneously followed until SARS-CoV-2 acquisition or end of follow-up, 11 April 2021. Hazard ratios (HRs) for vaccination versus no vaccination were calculated (Cox proportional hazards regression models, adjusting for sociodemographics and residential-area COVID-19 incidence). VE was calculated as (1– HR) × 100. RT-PCR cycle threshold (Ct) values were compared between vaccinated and unvaccinated HCWs. Results At >14 days post–second dose, 40 vaccinated HCWs acquired SARS-CoV-2 (median follow-up, 66 days; cumulative incidence, 0.6%) versus 84 unvaccinated HCWs (median follow-up, 43 days; cumulative incidence, 5.1%) (HR, .11; 95% CI, .07–.17; unadjusted VE, 89%; 95% CI, 83–93%). Adjusted VE >7 and >14 days post–second dose were similar. The median PCR Ct targeting the ORF1ab gene among 20 vaccinated and 40 unvaccinated HCWs was 32.0 versus 26.7, respectively (P value = .008). Conclusions VE following 2 doses of BNT162b2 against SARS-CoV-2 acquisition in LTCF HCWs was high. The lower viral loads among SARS-CoV-2–positive HCWs suggest further reduction in transmission.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerged in Israel in February 2020 and spread from then. In December 2020, the FDA approved an emergency use authorization of the Pfizer-BioNTech vaccine, and on 20 December, an immunization campaign began among adults in Israel. We characterized seropositivity for IgG anti-spike antibodies against SARS-CoV-2 between January 2020 and July 2021, before and after the introduction of the vaccine in Israel among adults. We tested 9520 serum samples, collected between January 2020 and July 2021. Between January and August 2020, seropositivity rates were lower than 5.0%; this rate increased from September 2020 (6.3%) to April 2021 (84.9%) and reached 79.1% in July 2021. Between January and December 2020, low socio-economic rank was an independent, significant correlate for seropositivity. Between January and July 2021, the 40.00–64.99-year-old age group, Jews and others, and residents of the Northern district were significantly more likely to be seropositive. Our findings indicate a slow, non-significant increase in the seropositivity rate to SARS-CoV-2 between January and December 2020. Following the introduction of the Pfizer-BioNTech vaccine in Israel, a significant increase in seropositivity was observed from January until April 2021, with stable rates thereafter, up to July 2021.

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.

Non-typhoidal salmonellosis (NTS) is one of the most common foodborne diseases worldwide. In this study, we aimed to analyze trends in the epidemiology of NTS in the last decade in Israel. Laboratory-confirmed cases of NTS at eight sentinel laboratories were reported to the Israel Sentinel Laboratory-Based Surveillance Network, integrated with the serotype identification performed at the Salmonella National Reference Laboratory of the Ministry of Health. The decrease in NTS incidence since 1999 continued between 2010 and 2014 (16.1 per 100,000 in 2014) and was interrupted by a rise between 2015 and 2017 (39.1 per 100,000 in 2017) associated with outbreaks of Salmonella Enteritidis. The incidence of NTS dropped again thereafter (21.4 per 100,000 in 2021). The 0–4 age group was the most affected by NTS (55.5% of the cases) throughout the surveillance period. The age-adjusted incidence rates were consistently high in the summer months (June-September) and low in the winter months (December–February). The overall decrease in the incidence of NTS in Israel since 1999 was temporarily interrupted in the last decade by country-wide outbreaks involving emerging or re-emerging Salmonella serotypes. Control measures should be enhanced for all risk points of food chain transmission of Salmonella spp. to further reduce the NTS morbidity in Israel.

Despite ongoing efforts to characterize the host response toward SARS-CoV-2, a major gap in our knowledge still exists regarding the magnitude and duration of the humoral response. Analysis of the antibody response in mild versus moderate/severe patients, using our new developed quantitative electrochemiluminescent assay for detecting IgM/IgA/IgG antibodies toward SARS-CoV-2 antigens, revealed a rapid onset of IgG/IgA antibodies, specifically in moderate/severe patients. IgM antibodies against the viral receptor binding domain, but not against nucleocapsid protein, were detected at early stages of the disease. Furthermore, we observed a marked reduction in IgM/IgA antibodies over-time. Adapting our assay for ACE2 binding-competition, demonstrated that the presence of potentially neutralizing antibodies is corelated with IgG/IgA. Finally, analysis of the cytokine profile in COVID-19 patients revealed unique correlation of an IL-12p70/IL33 and IgG seroconversion, which correlated with disease severity. In summary, our comprehensive analysis has major implications on the understanding and monitoring of SARS-CoV-2 infections.

Mumps and rubella are vaccine-preventable viral diseases through the measles-mumps-rubella-varicella (MMRV) vaccine, administered at 12 months and again at 6 years. We assessed the sero-prevalence of mumps and rubella, identified factors associated with sero-negativity, and evaluated concordance between mumps and rubella sero-positivity. A national cross-sectional sero-survey was conducted on samples collected in 2015 by the Israel National Sera Bank. Samples were tested for mumps and rubella IgG antibodies using an enzyme-linked immunosorbent assay. Of 3131 samples tested for mumps IgG, 84.8% (95%CI: 83.5–86.0%) were sero-positive. Sero-negativity for mumps was significantly associated with age (high odds ratios observed in infants younger than 4 years and 20–29 years old subjects). Of 3169 samples tested for rubella IgG antibodies, 95.2% (95%CI: 94.4–95.9%) were sero-positive. Rubella sero-negativity was significantly associated with age (high odds ratios observed in children younger than 4 years old and adults older than 30 years), males, Jews, and others. Concordant sero-positivity for both mumps and rubella viruses was observed in 83.9% of the tested samples. The Israeli population was sufficiently protected against rubella but not against mumps. Since both components are administered in the MMRV vaccine simultaneously, the mumps component has a lower uptake than rubella and quicker waning.

Vaccination against brucellosis using live attenuated strains is the primary approach in protecting livestock against the disease through a strong cellular immune response. Attenuated vaccine strains also induce serum anti-Brucella antibodies, mostly against Brucella O-polysaccharide, but their role in protection against the disease remains unclear. In this study, we show that Brucella OPS serum antibodies after vaccination or natural infection could kill Brucella in vitro as shown by the serum bactericidal activity (SBA) assay. We used serum samples of Rev. 1 vaccinated sheep that were negative or positive for Brucella OPS antibodies by either one of complement fixation test (CFT), microplate agglutination test (MAT) and ELISA, or sera of naturally infected sheep positive by CFT. We found a significant increase in the killing ability of sera 30 days after intraocular vaccination with Rev. 1 as compared with pre-vaccination. SBA was significantly higher in sera containing Brucella OPS IgG antibodies in comparison with sera lacking such antibodies (p < 0.001 against 16M & Rev. 1 strains). All 10 sera of convalescent sheep demonstrated significant killing ability against the 16M B. melitensis field strain. Specific OPS antibodies participate in the in vitro complement mediated Brucella killing suggesting a potential role in protection against the disease through this mechanism and relevance of developing OPS-based Brucella vaccines.

Background Waning of protection against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) conferred by 2 doses of the BNT162b2 vaccine begins shortly after inoculation and becomes substantial within 4 months. With that, the impact of prior infection on incident SARS-CoV-2 reinfection is unclear. Therefore, we examined the long-term protection of naturally acquired immunity (protection conferred by previous infection) compared to vaccine-induced immunity. Methods A retrospective observational study of 124 500 persons, compared 2 groups: (1) SARS-CoV-2-naive individuals who received a 2-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 vaccine, and (2) previously infected individuals who have not been vaccinated. Two multivariate logistic regression models were applied, evaluating four SARS-CoV-2-related outcomes—infection, symptomatic disease (coronavirus disease 2019 [COVID-19]), hospitalization, and death—between 1 June and 14 August 2021, when the Delta variant was dominant in Israel. Results SARS-CoV-2-naive vaccinees had a 13.06-fold (95% confidence interval [CI], 8.08–21.11) increased risk for breakthrough infection with the Delta variant compared to unvaccinated-previously-infected individuals, when the first event (infection or vaccination) occurred during January and February of 2021. The increased risk was significant for symptomatic disease as well. When allowing the infection to occur at any time between March 2020 and February 2021, evidence of waning naturally acquired immunity was demonstrated, although SARS-CoV-2 naive vaccinees still had a 5.96-fold (95% CI: 4.85–7.33) increased risk for breakthrough infection and a 7.13-fold (95% CI: 5.51–9.21) increased risk for symptomatic disease. Conclusions Naturally acquired immunity confers stronger protection against infection and symptomatic disease caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 2-dose vaccine-indued immunity.

Background: Antimicrobial resistance (AMR) in Gram-negative bacteria-causing bloodstream infections (BSIs), such as Klebsiella pneumoniae and non-typhoidal Salmonella (NTS), is a major public health concern. Nonetheless, AMR surveillance remains scarce in sub-Saharan Africa, where BSI treatment is largely empirical. The aim of the study was to determine the distribution and AMR patterns of BSI-causing NTS, K. pneumoniae, and other Gram-negative bacteria in Ghana. Methods: A cross-sectional study was conducted between April and December 2021 at eleven sentinel health facilities across Ghana as part of a pilot study on the feasibility and implementation of the human sector AMR surveillance harmonized protocol in sub-Saharan Africa. Gram-negative bacteria recovered from blood specimens of febrile patients were identified using MALDI-TOF and evaluated for antimicrobial resistance using the BD Phoenix M50 analyzer and Kirby-Bauer disc diffusion. The Department of Medical Microbiology at the University of Ghana served as the reference laboratory. Results: Out of 334 Gram-negative blood isolates, there were 18 (5.4%) NTS, 85 (25.5%) K. pneumoniae, 88 (26.4%) Escherichia coli, 40 (12.0%) Acinetobacter baumannii, 25 (7.5%) Pseudomonas aeruginosa, and 77 (23.1%) other Gram-negative bacteria. As a composite, the isolates displayed high resistance to the antibiotics tested—amoxicillin (89.3%), tetracycline (76.1%), trimethoprim-sulfamethoxazole (71.5%), and chloramphenicol (59.7%). Resistance to third-generation cephalosporins [ceftriaxone (73.7%), cefotaxime (77.8%), and ceftazidime (56.3%)] and fluoroquinolones [ciprofloxacin (55.3%)] was also high; 88% of the isolates were multidrug resistant, and the rate of extended-spectrum beta-lactamase (ESBL) production was 44.6%. Antibiotic resistance in K. pneumoniae followed the pattern of all Gram-negative isolates. Antibiotic resistance was lower in NTS blood isolates, ranging between 16.7–38.9% resistance to the tested antibiotics. Resistance rates of 38.9%, 22.2%, and 27.8% were found for cefotaxime, ceftriaxone, and ceftazidime, respectively, and 27.8% and 23.8% for ciprofloxacin and azithromycin, respectively, which are used in the treatment of invasive NTS. The prevalence of multidrug resistance in NTS isolates was 38.9%. Conclusions: Multicenter AMR surveillance of Gram-negative blood isolates from febrile patients was well-received in Ghana, and the implementation of a harmonized protocol was feasible. High resistance and multidrug resistance to first- or second-choice antibiotics, including penicillins, third-generation cephalosporins, and fluoroquinolones, were found, implying that these antibiotics might have limited effectiveness in BSI treatment in the country. Continuation of AMR surveillance in Gram-negative blood isolates is essential for a better understanding of the extent of AMR in these pathogens and to guide clinical practice and policymaking.

Vaccination against brucellosis using live attenuated strains is the primary approach in protecting livestock against the disease through a strong cellular immune response. Attenuated vaccine strains also induce serum anti

Advancing new O-antigen-based Shigella vaccines is critically dependent on development of an international standard serum and harmonized ELISA, demonstration of field efficacy in young children in low- and middle-income countries, and early engagement with regulators and policy makers.

Background Helicobacter pylori (H. pylori) infection is acquired during childhood and causes chronic gastritis that remains asymptomatic in most infected people. H. pylori alters the gastric microbiota and causes peptic ulcer disease. Evidence on the relationship between asymptomatic H. pylori infection and children's gut microbiota remains elusive. Aim We characterized the relationship between H. pylori infection and the intestinal microbiome of healthy children, adjusting for known inter-personal and environmental exposures. Materials and methods This cross-sectional study included stool samples obtained from 163 Israeli Arab children aged 6-9 years from different socioeconomic strata. Sociodemographic information was collected through maternal interviews. H. pylori infection was determined using monoclonal antigen detection stool enzyme immunoassay. The gut microbiome was characterized by implementing 16S rRNA gene sequencing of the V4 region and a multivariate downstream analysis. Results Overall, 57% of the participants were positive for H. pylori infection and it was significantly associated with low socioeconomic status. There was no significant association between H. pylori infection and bacterial richness of fecal microbiome. H. pylori infection was significantly associated with intestinal bacterial composition, including a strong association with Prevotella copri and Eubacterium biforme. Moreover, socioeconomic status was strongly associated with bacterial composition. Discussion and conclusions H. pylori infection in healthy children was significantly associated with altered intestinal microbiome structure. Socioeconomic determinants exhibit a strong effect, related to both H. pylori infection and intestinal diversity and composition in childhood. These findings are clinically important to the understanding of the role of H. pylori infection and other intestinal microbes in health and disease.

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.

BackgroundReports of waning vaccine-induced immunity against COVID-19 have begun to surface. With that, the comparable long-term protection conferred by previous infection with SARS-CoV-2 remains unclear.MethodsWe conducted a retrospective observational study comparing three groups: (1)SARS-CoV-2-naïve individuals who received a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 vaccine, (2)previously infected individuals who have not been vaccinated, and (3)previously infectedandsingle dose vaccinated individuals. Three multivariate logistic regression models were applied. In all models we evaluated four outcomes: SARS-CoV-2 infection, symptomatic disease, COVID-19-related hospitalization and death. The follow-up period of June 1 to August 14, 2021, when the Delta variant was dominant in Israel.ResultsSARS-CoV-2-naïve vaccinees had a 13.06-fold (95% CI, 8.08 to 21.11) increased risk for breakthrough infection with the Delta variant compared to those previously infected, when the first event (infection or vaccination) occurred during January and February of 2021. The increased risk was significant (PConclusionsThis study demonstrated that natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced immunity. Individuals who were both previously infected with SARS-CoV-2 and given a single dose of the vaccine gained additional protection against the Delta variant.

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.

Diarrheal diseases remain a leading cause of mortality globally.1 Recent estimates of the Global Burden Disease study showed that nearly 1.65 million diarrheal diseases deaths occurred in 2016 in a...

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

BACKGROUND The introduction of rotavirus vaccines into national immunization programs necessitates vaccine effectiveness evaluations. Parental report of vaccination status is a simple and accessible source of information; however, its validity is unclear. AIMS To validate parental reports of rotavirus immunization compared to documentation of vaccination in national immunization registry, and to assess vaccine effectiveness by each method. METHODS Parents of 1272 children aged 2-59 months from northern Israel hospitalized for gastroenteritis in 2011-2015 were interviewed on the sociodemographics and rotavirus vaccination status of their child. Rotavirus immunization status based on parental report was compared to that documented in the national immunization registry, which was considered the gold standard. Stool samples collected from patients were tested for rotavirus antigen by immunochromotgraphy. In a rotavirus test-negative case-control study, vaccination history was compared between children found positive for rotavirus and those who tested negative. Vaccine effectiveness for ≥ 1 dose vs. zero doses was calculated as: (1-adjusted odds ratio) * 100. RESULTS The sensitivity and specificity of parental report of their child's immunization with a rotavirus vaccine were 97% (95% CI 96-98), and 75% (95% CI 65-82), respectively. Kappa coefficient was 0.69 (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.

COVID-19 vaccine might be less immunogenic and effective among residents of long-term care facilities (LTCFs).To examine the association of BNT162b2 third dose (first booster dose) with overall SARS-CoV-2 infection, COVID-19 hospitalizations, and mortality among LTCF residents during a nationwide surge of the Delta variant in Israel.This observational cohort study conducted nationwide COVID-19 surveillance in LTCFs in Israel between August and October 2021. Participants were residents of LTCFs aged 60 years or older.Vaccination with the third dose of BNT162b2 vaccine vs receipt of 2 doses at least 5 months earlier, based on self-preference and choice.The cumulative incidences of reverse transcription-polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infection, COVID-19 hospitalizations, and COVID-19-related deaths more than 7 days after vaccination with the third dose were compared between the groups using Kaplan-Meier curves. Hazard ratios (HRs) and 95% CIs were obtained using multivariable Cox regression models.Among 18 611 residents included in the analysis, 12 715 (68.3%) were female, 463 (2.5%) were from the Arab population, 16 976 (91.2%) were from the general Jewish population, and 618 (3.3%) were from the ultraorthodox Jewish population; the mean (SD) age was 81.1 (9.2) years; 16 082 residents received their first booster dose (third dose) and 2529 were vaccinated with 2 doses at least 5 months earlier. The median (IQR) follow-up durations were 66 (60-70) days among 3-dose recipients and 56 (53-62) days among 2-dose-only recipients; 107 residents had SARS-CoV-2 infection after 7 days following vaccination with the booster dose compared with 185 among the 2-dose only group (cumulative incidence: 0.7% vs 7.5%; adjusted HR, 0.11 [95% CI, 0.07-0.15]). The respective adjusted HRs were 0.07 (95% CI, 0.03-0.14) and 0.10 (95% CI, 0.04-0.24) for the associations of vaccination with the third dose with hospitalization for mild-to-moderate COVID-19 and severe illness. Five COVID-19-related deaths occurred among the third dose vaccinees during the follow-up period compared with 22 among the 2-dose-only vaccinees (cumulative rate: 0.04% vs 0.9%; adjusted HR, 0.04 [95% CI, 0.009-0.16]).This cohort study found significant inverse associations between vaccination with the third dose of the BNT162b2 vaccine with overall SARS-CoV-2 infection, COVID-19 hospitalizations, severe disease, and COVID-19-related deaths among LTCF residents during a massive surge caused by the Delta variant in Israel.

Initial reports on the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the aetiological cause of coronavirus disease 2019 (COVID-19), were published in December 2019. Since then, COVID-19 has resulted in substantial morbidity and mortality globally [1]. From December 2020 through the beginning of 2021, several COVID-19 vaccines received regulatory authorization in many countries. The population of Israel includes more than nine million people. Approximately 74% are Jews (of which nearly 12% are ultraorthodox (religious)), 21% are Arabs and 5% are of other religions and ethnicities [2]. The healthcare system in Israel is characterized by universal health insurance. Under the regulation of the Ministry of Health (MoH), a broad basket of health services is provided to all citizens through four health maintenance organizations (sick funds). Each citizen must be a member of one of these sick funds that supply primary care services via community clinics. Inpatient services are generally provided by public hospitals, with associated costs covered by the sick funds [3]. All sick funds maintain electronic health records and have well developed physical and virtual infrastructure and paths of communication with their members. Centralized management of the COVID-19 epidemic in Israel was led by the MoH, and operationalized by sick funds and hospitals. Operational assistance was provided by the military, civilian organizations, and local municipalities. Before COVID-19 vaccines became available, non-pharmaceutical preventive measures were implemented in Israel to control the epidemic, including limitations on international travel, school closures, social and physical distancing, obligatory face masks in public spaces (enforced by law), cancellation of mass gatherings, and several prolonged near-complete lockdowns [4]. In addition, a large-scale programme of contact tracing and isolation was implemented through epidemiological investigations and digital tracking, with widespread RT-PCR testing among contacts of confirmed COVID-19 patients [4]. These measures were associated with a reduced risk of SARS-CoV-2 transmission [5]. Nonetheless, maintaining strict public compliance with non-pharmaceutical preventive measures was challenging, and disease surges that occurred after lockdowns were lifted suggested that such measures may be effective only for short-term reduction of viral transmission and disease burden. On 19th December 2020, Israel introduced mass vaccination with the BNT162b2 mRNA vaccine (Pfizer-BioNTech) [6]. Herein we describe the Israeli experience and perspective on COVID-19 immunization.

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.

Key Points Question Is 1 dose of the BNT162b2 COVID-19 mRNA vaccine associated with protection against infection with SARS-CoV-2 and symptomatic COVID-19 in real-world settings? Findings In this comparative effectiveness study of 503 875 individuals who received 1 dose of the BNT162b2 vaccine, the first dose of the vaccine was associated with an approximately 51% reduction in the risk of SARS-CoV-2 infections at 13 to 24 days after immunization compared with 1 to 12 days after vaccination. The first dose was associated with 54% effectiveness against symptomatic COVID-19. Meaning The results of this study agree with vaccine efficacy as reported in the phase III randomized clinical trial after 1 dose., This comparative effectiveness study examines the effectiveness associated with 1 dose of the BNT162b2 COVID-19 vaccine in a real-world setting., Importance The BNT162b2 vaccine showed high efficacy against COVID-19 in a phase III randomized clinical trial. A vaccine effectiveness evaluation in a real-world setting is needed. Objective To assess the short-term effectiveness of the first dose of the BNT162b2-vaccine against SARS-CoV-2 infection 13 to 24 days after immunization in a real-world setting. Design, Setting, and Participants This comparative effectiveness study used data from a 2.6 million-member state-mandated health care system in Israel. Participants included all individuals aged 16 years and older who received 1 dose of the BNT162b2 vaccine between December 19, 2020, and January 15, 2021. Data were analyzed in March 2021. Exposure Receipt of 1 dose of the BNT162b2 vaccine. Main Outcomes and Measures Information was collected regarding medical history and positive SARS-CoV-2 polymerase chain reaction test and COVID-19 symptoms from 1 day after first vaccine to January 17, 2021. Daily and cumulative infection rates in days 13 to 24 were compared with days 1 to 12 after the first dose using Kaplan-Meier survival analysis and generalized linear models. Results Data for 503 875 individuals (mean [SD] age, 59.7 [14.7] years; 263 228 [52.4%] women) were analyzed, of whom 351 897 had follow-up data for days 13 to 24. The cumulative incidence of SARS-CoV-2 infection was 2484 individuals (0.57%) during days 1 through 12 and 614 individuals (0.27%) in days 13 through 24. The weighted mean (SE) daily incidence of SARS-CoV-2 infection in days 1 through 12 was 43.41 (12.07) infections per 100 000 population and 21.08 (6.16) infections per 100 000 population in days 13 through 24, a relative risk reduction (RRR) of 51.4% (95% CI, 16.3%-71.8%). The decrease in incidence was evident from day 18 after the first dose. Similar RRRs were calculated in individuals aged 60 years or older (44.5%; 95% CI, 4.1%-67.9%), those younger than 60 years (50.2%; 95% CI, 14.1%-71.2%), women (50.0%; 95% CI, 13.5%-71.0%), and men (52.1%; 95% CI, 17.3%-72.2%). Findings were similar in subpopulations (eg, ultraorthodox Jewish: RRR, 53.5% [95% CI, 19.2%-73.2%]) and patients with various comorbidities (eg, cardiovascular diseases: RRR, 47.2% [95% CI, 7.8%-69.8%]). Vaccine effectiveness against symptomatic COVID-19 was 54.4% (95% CI, 21.4%-73.6%). Conclusions and Relevance In this comparative effectiveness study of a single dose of the BNT162b2 vaccine, results were comparable to that of the phase III randomized clinical trial.

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 Coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines were shown to be highly efficacious in preventing the disease in randomized controlled trials; nonetheless, evidence on the real-world effectiveness of this vaccine is limited. Study objective was to evaluate the effectiveness of BNT162b2 vaccine in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19-related hospitalization and mortality. Methods This historical cohort study included members of a large health provider in Israel that were vaccinated with at least 1 dose of BNT162b2. The primary outcome was incidence rate of a SARS-CoV-2 infection confirmed with real-time polymerase chain reaction (rt-PCR), between 7 and 27 days after second dose (protection-period), as compared to days 1–7 after the first dose, where no protection by the vaccine is assumed (reference-period). Results Data of 1 178 597 individuals vaccinated with BNT162b2 were analyzed (mean age 47.7 years [SD = 18.1], 48.4% males) of whom 872 454 (74.0%) reached the protection period. Overall, 4514 infections occurred during the reference period compared to 728 during the protection period, yielding a weighted mean daily incidence of 54.8 per 100 000 (95% confidence interval [CI]: 26.1–115.0 per 100 000) and 5.4 per 100 000 (95% CI: 3.5–8.4 per 100 000), respectively. The vaccine effectiveness in preventing infection was 90% (95% CI: 79%–95%) and 94% (95% CI: 88%–97%) against COVID-19. Among immunosuppressed patients, vaccine effectiveness against infection was 71% (95% CI: 37%–87%). The adjusted hazard ratios for hospitalization in those infected were 0.82 (95% CI: .36–1.88), 0.45 (95% CI: .23–.90), and 0.56 (95% CI: .36–.89) in the age groups 16–44, 45–64. and ≥75 years, respectively. Conclusions The effectiveness of the BNT162b2 vaccine is comparable to the one reported in the phase III clinical trial.

The development of the gut microbiome occurs mainly during the first years of life; however, little is known on the role of environmental and socioeconomic exposures, particularly within the household, in shaping the microbial ecology through childhood. We characterized differences in the gut microbiome of school-age healthy children, in association with socioeconomic disparities and household crowding. Stool samples were analyzed from 176 Israeli Arab children aged six to nine years from three villages of different socioeconomic status (SES). Sociodemographic data were collected through interviews with the mothers. We used 16 S rRNA gene sequencing to characterize the gut microbiome, including an inferred analysis of metabolic pathways. Differential analysis was performed using the analysis of the composition of microbiomes (ANCOM), with adjustment for covariates. An analysis of inferred metagenome functions was performed implementing PICRUSt2. Gut microbiome composition differed across the villages, with the largest difference attributed to socioeconomic disparities, with household crowding index being a significant explanatory variable. Living in a low SES village and high household crowding were associated with increased bacterial richness and compositional differences, including an over-representation of Prevotella copri and depleted Bifidobacterium. Secondary bile acid synthesis, d-glutamine and d-glutamate metabolism and Biotin metabolism were decreased in the lower SES village. In summary, residential SES is a strong determinant of the gut microbiome in healthy school-age children, mediated by household crowding and characterized by increased bacterial richness and substantial taxonomic and metabolic differences. Further research is necessary to explore possible implications of SES-related microbiome differences on children’s health and development.

The Israel National Sera Bank (INSB) was established in 1997 in the Israel Center for Disease Control. The purpose of the INSB was to provide policymakers with data on the immunity status of the Israeli population against vaccine-preventable diseases, and on the extent and characteristics of exposure to emerging and re-emerging infectious diseases. The aim of this paper is to describe the methods, representativeness, and challenges in maintaining the INSB. The INSB comprises residual sera collected in six laboratories. By the end of 2019, 138,898 samples had been deposited in the INSB. These include samples from four community laboratories: 30.7% from the National Blood Service, 22.2% from Haifa and the Western Galilee, 21.7% from Soroka, and 0.7% from Jerusalem, and from two medical center laboratories: 18.6% from Schneider and 6.1% from Mayanei Hayeshua. The demographic characteristics of the sample at the end of 2019 closely resembled those of the general population. The main challenges addressed in maintaining the INSB relate to its representativeness, the possibility of repeated donors, costs, stability of antibody levels after long-term storage, ethical aspects, and the data available for each sample. The INSB is a unique, powerful, and necessary tool for assessing population immunity levels, based on serum samples collected over a long period of time.

BackgroundBNT162b2 vaccines showed high efficacy against COVID-19 in a randomised controlled phase-III trial. A vaccine effectiveness evaluation in real life settings is urgently needed, especially given the global disease surge. Hence, we assessed the short-term effectiveness of the first dose of BNT162b2-vaccine against SARS-CoV-2 infection. Given the BNT162b2 Phase-III results, we hypothesized that the cumulative incidence of SARS-CoV-2 infection among vaccinees will decline after 12 days following immunization compared to the incidence during the preceding days.MethodsWe conducted a retrospective cohort study using data from 2·6 million-member state-mandated health provider in Israel. Study population consisted of all members aged 16 or above years who were vaccinated with BNT162b2-vaccine between December/19/2020 and January/15/2021. We collected information regarding medical history and positive SARS-CoV-2 polymerase chain reaction test from days after first dose to January/17/2021. Daily and cumulative infection rates in days 13-24 were compared to days 1-12 after first dose using Kaplan-Meier survival analysis and generalized linear models.FindingsData of 503,875 individuals (mean age 59·7 years SD=14·7, 47·8% males) were analysed, of whom 351,897 had 13-24 days of follow-up. The cumulative incidence of SARS-CoV-2 infection was 0·57% (n=2484) during days 1-12 and 0·27% (n=614) in days 13-24. A 51·4% relative risk reduction (RRR) was calculated in weighted-average daily incidence of SARS-CoV-2 infection from 43·41-per-100,000(SE=12·07) in days 1-12 to 21·08-per-100,000(SE=6·16) in days 13-24 following immunization. The decrement in incidence was evident from day 18 after first dose. Similar RRRs were calculated in individuals aged 60 or above (44.5%), younger individuals (50.2%), females (50.0%) and males (52.1%). Findings were similar in sub-populations and patients with various comorbidities.ConclusionsWe demonstrated an effectiveness of 51% of BNT162b2 vaccine against SARS-CoV-2 infection 13-24 days after immunization with the first dose. Immunization with the second dose should be continued to attain the anticipated protection.Research in contextEvidence before this studyWe searched PubMed for follow-up studies regarding the effectiveness of BNT162b2 mRNA Covid-19 Vaccine without any language restrictions. The search terms were (BNT162b2 OR mRNA Covid-19 Vaccine) AND (effectiveness OR real-world OR phase IV) until Jan 15, 2021. We found no relevant observational studies among humans. We also assessed Phase II and Phase III clinical trials with BNT162b2 mRNA vaccine.Added value of this studyTo our knowledge, this is the first and largest phase IV study on the effectiveness of the BNT162b2 mRNA COVID-19 vaccine in real-world settings. Our findings showed that the first dose of the vaccine is associated with an approximately 51% reduction in the incidence of PCR-confirmed SARS-CoV-2 infections at 13 to 24 days after immunization compared to the rate during the first 12 days. Similar levels of effectiveness were found across age groups, sex, as well as among individuals residing in Arab or ultra-orthodox Jewish communities that display an increased COVID-19 risk.Implications of all the available evidenceThe study results indicate that in real life the first dose of the new BNT162b2 mRNA COVID-19 vaccine confers around 50% protection against overall SARS-CoV-2 infections (symptomatic or asymptomatic). Together our findings and the 95% efficacy shown in the phase III trial, suggest that the BNT162b2 vaccine should be administered in two doses to achieve maximum protection and impact in terms of disease burden reduction and possibly reducing SARS-CoV-2 transmission. COVID-19 vaccines should be urgently deployed globally.

Background: We assessed vaccine effectiveness (VE) of BNT162b2 mRNA COVID-19 vaccine against SARS-CoV-2 acquisition among health care workers (HCWs) of long-term care facilities (LTCFs). Methods: This prospective study, in the framework of "Senior Shield" program in Israel, included routine, weekly nasopharyngeal SARS-CoV-2 RT-PCR testing from all LTCF HCWs since July 2020. All residents and 75% of HCWs were immunized between December 2020 and January 2021. The analysis was limited to HCWs adhering to routine testing. Fully vaccinated (14+ days after second dose; n=6960) and unvaccinated HCWs (n=2202) were simultaneously followed until SARS-CoV-2 acquisition, or end of follow-up, April 11, 2021. Hazard ratios (HR) for vaccination vs. no vaccination were calculated (Cox proportional hazards regression models, adjusting for socio-demographics and residential-area COVID-19 incidence). VE was calculated as [(1– HR)×100]. RT-PCR cycle threshold values (Cts) were compared between vaccinated and unvaccinated HCWs. Findings: At >14 days post second dose, 40 vaccinated HCWs acquired SARS-CoV-2 (median follow-up, 66 days; cumulative incidence 0·6%) vs. 84 unvaccinated HCWs (median follow-up 43 days; cumulative incidence, 5·1%); HR=0·11 (95% CI 0·07, 0.17), unadjusted VE=89% (95% CI 83%, 93%). Adjusted VE beyond seven days and >14 days post second dose were similar. The median PCR Cts targeting ORF1ab gene among 20 vaccinated and 40 unvaccinated HCWs was 32·0 vs. 26·7, respectively, p=0·008. Interpretation: VE following two doses of BNT162b2 against SARS-CoV-2 acquisition in LTCF HCWs was high. The lower viral loads among SARS-CoV-2 positive HCWs suggests further reduction in transmission. Funding Information: The current study did not have external funding sources. Declaration of Interests: None. Ethics Approval Statement: The study protocol was approved by the institutional review board of the Soroka University Medical Center, Beer-Sheva, Israel.

Background: BNT162b2 vaccines showed high efficacy against COVID-19 in a randomised controlled phase-III trial. A vaccine effectiveness evaluation in real life settings is urgently needed, especially given the global disease surge. Hence, we assessed the short-term effectiveness of the first dose of BNT162b2-vaccine against SARS-CoV-2 infection. Given the BNT162b2 Phase-III results, we hypothesized that the cumulative incidence of SARS-CoV-2 infection among vaccinees will decline after 12 days following immunization compared to the incidence during the preceding days. Methods: We conducted a retrospective cohort study using data from 2·6 million-member state-mandated health provider in Israel. Study population consisted of all members aged 16 or above years who were vaccinated with BNT162b2-vaccine between December/19/2020 and January/15/2021. We collected information regarding medical history and positive SARS-CoV-2 polymerase chain reaction test from days after first dose to January/17/2021. Daily and cumulative infection rates in days 13-24 were compared to days 1-12 after first dose using Kaplan-Meier survival analysis and generalized linear models. Findings: Data of 503,875 individuals (mean age 59·7 years SD=14·7, 47·8% males) were analysed, of whom 351,897 had 13-24 days of follow-up. The cumulative incidence of SARS-CoV-2 infection was 0·57% (n=2484) during days 1-12 and 0·27% (n=614) in days 13-24. A 51·4% relative risk reduction (RRR) was calculated in weighted-average daily incidence of SARS-CoV-2 infection from 43·41-per-100,000(SE=12·07) in days 1-12 to 21·08-per-100,000(SE=6·16) in days 13-24 following immunization. The decrement in incidence was evident from day 18 after first dose. Similar RRRs were calculated in individuals aged 60 or above (44.5%), younger individuals (50.2%), females (50.0%) and males (52.1%). Findings were similar in sub-populations and patients with various comorbidities. Interpretation: We demonstrated an effectiveness of 51% of BNT162b2 vaccine against SARS-CoV-2 infection 13-24 days after immunization with the first dose. Immunization with the second dose should be continued to attain the anticipated protection. Funding: No external funding was available for this study. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: We obtained ethical approval from Maccabi Healthcare Services Ethics Committee.

Shigella is the second most common cause of moderate to severe diarrhea among children worldwide and of diarrheal disease-associated mortality in young children in low-and middle-income countries. In spite of many years of attempts to develop Shigella vaccines, no licensed vaccines are yet available. Injectable conjugate vaccines made of the detoxified lipopolysaccharide (LPS) of S. flexneri 2a, S. sonnei, and S. dysenteriae type 1 covalently bound to protein carriers were developed in the early 1990s by John B. Robbins and Rachel Schneerson at the US National Institutes of Health. This approach was novel for a disease of the gut mucosa, at a time when live, rationally attenuated oral vaccine strains that intended to mimic Shigella infection and induce a protective local immune response were extensively investigated. Of keystone support to Shigella glycoconjugates development were the findings of a strong association between pre-existent serum IgG antibodies to S. sonnei or S. flexneri 2a LPS and a lower risk of infection with the homologous Shigella serotypes among Israeli soldiers serving in field units. In view of these findings and of the successful development of the pioneering Haemophilus influenzae type b conjugate vaccines, it was hypothesized that protective immunity may be conferred by serum IgG antibodies to the O-Specific Polysaccharide (O-SP) following parenteral delivery of the conjugates. S. sonnei and S. flexneri 2a glycoconjugates induced high levels of serum IgG against the homologous LPS in phase I and II studies in healthy volunteers. The protective efficacy of a S. sonnei detoxified LPS-conjugate was further demonstrated in field trials in young adults (74%) and in children older than three years of age (71%), but not in younger ones. The evaluation of the Shigella conjugates confirmed that IgG antibodies to Shigella LPS are correlates of protection and provided solid basis for the development of a new generation of glycoconjugates and other injectable LPS-based vaccines that are currently in advanced stages of clinical evaluation.

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.

To estimate the rate and identified risk factors for recurrent Clostridium difficile infection (rCDI) in Israel. We conducted a retro-prospective case-control study of all adult (age ≥ 18 years) patients with an initial episode of CDI (iCDI) at Tel Aviv Sourasky Medical Center from January 1, 2012 to December 31, 2014. We collected demographic, clinical, and epidemiological information for patients who were classified as recurrent (cases) and non-recurrent (control) groups. In total, 648 patients with iCDI were identified in the study. During the 36-month study period, 82 (12.7%) patients had at least one rCDI identified. We identified several factors as independent variables significantly associated with recurrent CDI: functional disability, severity of the initial infection, continuous non-Clostridium difficile antibiotic treatment with third-generation cephalosporins or clindamycin, and iCDI treatment with metronidazole and vancomycin; however, neutropenia had high measure of effect as a predictor for rCDI (adjusted odds ratio, 7.9; 95% confidence interval, 1.27-49.58; p = 0.026). The identification of the main modifiable risk factors for recurrent CDI, continuous non-Clostridium difficile antibiotics after diagnosis of the initial infection, and antibiotic treatment with third-generation cephalosporins or clindamycin are critical in reducing the spread of recurrent infection with Clostridium difficile in hospital.

OBJECTIVESTo estimate the incidence and identified risk factors for community-acquired (CA) and hospital-acquired (HA) Clostridium difficile infection (CDI)METHODSWe conducted 2 parallel case-control studies at Tel Aviv Sourasky Medical Center from January 1, 2011, to December 31, 2014. We identified persons with CDI, determined whether infection was community or hospital acquired, and calculated incidence rates from 2007 to 2014. We collected demographic, clinical, and epidemiological information for CDI cases and hospitalized control cases and estimated the odds ratio with 95% confidence interval using conditional logistic regression.RESULTSIn total, 1,563 CDI cases were identified in the study. The incidence rate of CA-CDI and HA-CDI increased by 1.6-fold and 1.2-fold, respectively, during 2012–2014. However, the incidence rate of CA-CDI was 0.84 per 100,000 (95% CI, 0.52–1.30), the rate for HA-CDI was 4.7 per 10,000 patient days (95% CI, 4.08–5.38), respectively, in 2014. We identified several factors as independent variables significantly associated with HA-CDI: functional disability, presence of nasogastric tube, antibiotic use, chemotherapy, infection by extended-spectrum β-lactamases, and mean of albumin values. Risk factors independently associated with CA-CDI were close contact with a family member who had been hospitalized in the previous 6 months, inflammatory bowel disease, and home density index (adjusted odds ratio, 25.7; 95% confidence interval, 3.99–165.54; P=.001).CONCLUSIONSThe identification of the main modifiable risk factors for HA-CDI (antibiotic exposure and hypoalbuminemia) and for CA-CDI (close contact with a family member who had been hospitalized in the previous 6 months) is likely to optimize prevention efforts; these factors are critical in preventing the spread of CDI.Infect Control Hosp Epidemiol 2017;38:912–920

Moderate to severe diarrhea caused by Shigella is a global health concern due to its substantial contribution to morbidity and mortality in children aged

Background Persistent infections that induce prolonged inflammation might negatively affect the leukocyte telomere length (LTL); however, the role in LTL of Helicobacter pylori (H. pylori) infection, which persistently colonizes the stomach, remains unknown. The study objective was to examine associations of sero-prevalence of H. pylori immunoglobulin G (IgG) antibody and serum pepsinogens (PGs), as markers of atrophic gastritis, with LTL. A cross-sectional study was performed among 934 Arab residents of East Jerusalem, aged 27–78 years, randomly selected from Israel’s national population registry. Sera were tested for H. pylori IgG and PG levels by ELISA. LTL was measured by southern blots. Multiple linear regression models were fitted to adjust for sociodemographic and lifestyle factors. Results LTL decreased significantly with age (p < 0.001) and was shorter in men than women (p = 0.032). The mean LTL was longer in H. pylori sero-positive persons than negative ones: mean difference 0.13 kb (95% CI 0.02, 0.24), p = 0.016. Participants with atrophic gastritis (PGI < 30 μg/L or a PGI: PGII < 3.0) had shorter LTL than did those without: mean difference − 0.18 (95% CI − 0.32, − 0.04). The difference was of larger magnitude between persons who had past H. pylori infection (sero-negative to H. pylori IgG antibody) and atrophic gastritis, compared to those who were H. pylori sero-negative and did not have atrophic gastritis: mean difference − 0.32 kb (95% CI − 0.55, − 0.10). This association remained significant after adjustment for age, sex, and religiosity: beta coefficient − 0.21 kb (95% CI − 0.41, − 0.001), p = 0.049. The results were similar after further adjustment for lifestyle factors. In bivariate analysis, mean LTL was longer in physically active persons than non-active ones, and shorter in persons with than without obesity; however, these differences were diminished and were not significant in the multivariable model. Conclusions H. pylori IgG sero-positivity per se was not related to reduced LTL. However, persons with past H. pylori infection (i.e., lacking H. pylori IgG serum antibody) and with serological evidence of atrophic gastritis, had a significantly shorter LTL than did those without atrophic gastritis. Electronic supplementary material The online version of this article (10.1186/s40246-019-0217-3) contains supplementary material, which is available to authorized users.

Background Helicobacter pylori inhabits the stomach and causes persistent inflammation, with changes in gastric acidity. However, it is unclear whether the presence of H pylori plays a role in Clostridium difficile-associated disease (CDAD). The study's aim was to examine relationships of H pylori seroprevalence and serum pepsinogens (PGs), as markers of gastric inflammation, with CDAD. Materials and methods A case-control study was conducted among 49 CDAD cases and 54 controls (median age 82 years). Using enzyme-linked immunosorbent assays, sera were tested for H pylori IgG antibody, and PGI and PGII levels. Helicobacter pylori-positive samples were tested for IgG antibody to recombinant cytotoxin-associated gene A (CagA) virulent protein. Logistic regression models were fitted. Results Cases and controls were comparable in age (P = .5) and sex distribution (females 62% vs 57%, P = .6). Helicobacter pylori IgG seroprevalence was 47%, of whom 23% were CagA seropositives. Among cases compared to controls, 43% vs 28% were H pylori seropositive but lacking CagA IgG antibody: adjusted odd ratio (OR) 3.43 (95% confidence intervals [CI] 1.29-9.10); 18% vs 4% were positive for CagA phenotype: adjusted OR 9.32 (95% CI 1.61-53.76). This association was not affected by PG levels. Conclusions Helicobacter pylori infection, especially with CagA virulent phenotype, might predispose to C difficile infection in elderly patients.