The carbon isotope ratio of breath is elevated by short-term and long-term added sugar and animal protein intake in a controlled feeding study.

BACKGROUND: The breath carbon isotope ratio (CIR) was recently identified as a noninvasive candidate biomarker of short-term added sugars (AS) intake. OBJECTIVES: This study aimed to better understand the potential of the breath CIR as a dietary biomarker. We evaluated the effects of short-term and long-term intakes of AS, animal protein (AP), and related variables on breath CIR, in the context of typical dietary intake patterns. METHODS: We conducted a 15-d controlled feeding study of 100 adults (age 18-70 y, 55% females) in Phoenix, AZ. Participants were provided individualized diets that approximated habitual food intakes and recorded the timing of food consumption. Three breath samples (fasting, midday, and evening) were collected on each of 3 nonconsecutive study days. We modeled the effects of dietary intake in each of 8 h preceding collection of the breath sample on breath CIR with a linear mixed model, which also included 15-d mean intakes, sex, age, and BMI. RESULTS: Median (IQR) intakes of AS and AP in our study were 65 (38) and 67 (33) g/d, respectively. Midday and evening breath CIRs correlated strongly with each other (0.80) and with fasting breath CIR (0.77 and 0.68, respectively). In our linear mixed models, breath CIR increased by AS consumed 1-4 h before sample collection, AP consumed 3-6 h before sample collection, and 15-d intakes of AS and AP, all with similar effect sizes. The breath CIR was also inversely associated with 15-d intakes of intrinsic sugars and plant protein; thus, associations with 15-d intakes were particularly strong when expressed proportionally as the AS ratio (added sugars/total sugars) and AP ratio (animal protein/total protein). CONCLUSIONS: The breath CIR is a promising measure of long-term intakes of AS and AP, especially as proportional intakes. Approaches to increase specificity would benefit the further development of this biomarker.

Causes and predictors of recurrent unplanned hospital admissions in heart failure patients: a cohort study.

Despite progress in therapy, heart failure (HF) inflicts a heavy burden of hospital admissions. In this study, we identified among 1360 community-dwelling HF patients (mean age 70.7 ± 11.3 years, 72.5% men) subgroups sharing similar profiles of unplanned hospital admissions, based on the admission causes and frequency of each cause. Hospital discharge summaries were reviewed for the main admission cause. Patient subgroups were identified via cluster analysis. We investigated baseline predictors associated with these subgroups, using multinomial logistic models. During 3421 patient-years, there were 5192 hospital admissions, of which 4252 (82%) were unplanned. We identified five patient subgroups (clusters 1-5) with distinctive hospitalization profiles. HF accounted for approximately one-third of admissions in the first patient cluster (23% of the patient sample). In contrast, patients in the second cluster (39% of the patient sample) were hospitalized for various reasons, with no single prominent admission cause identified. The other three clusters, comprising 16% of the patient sample, accounted for 42% of all unplanned hospitalizations. While patients in the third cluster were hospitalized mainly due to ischemic heart disease and arrhythmia, patients in the fourth and fifth clusters shared a high burden of recurrent HF admissions. The five patient clusters differed by baseline predictors, including age, functional capacity, comorbidity burden, hemoglobin, and cause of HF. HF patients differ significantly in the causes and overall burden of unplanned hospitalizations. The patient subgroups identified and predictors for these subgroups may guide personalized interventions to reduce the burden of unplanned hospitalizations among HF patients. Trial registration: ClinicalTrials.gov, NCT00533013. Registered 20 September 2007. https://clinicaltrials.gov/study/NCT00533013 .

Methodology and challenges for harmonization of nutritional data from seven historical studies.

BACKGROUND: Collection of detailed dietary data is labor intensive and expensive, harmonization of existing data sets has been proposed as an effective tool for research questions in which individual studies are underpowered. METHODS: In this paper, we describe the methodology used to retrospectively harmonize nutritional data from multiple sources, based on the individual participant data of all available studies, which collected nutritional data in Israel between 1963 and 2014. This collaboration was established in order to study the association of red and processed meat with colorectal cancer. Two types of nutritional questionnaires, the Food Frequency Questionnaires (FFQ) and the 24-h dietary recall (24HR recall), and different food composition tables, were used by the participating studies. The main exposure of interest included type of meat (total meat, red meat, and poultry) and level of processing. RESULTS: A total of 29,560 Israeli men and women were enrolled. In studies using FFQ,the weighted mean intakes of total, red, processed meat, and poultry were 95, 27, 37 and 58 gr/day and 92, 25, 10, and 66 gr/day in studies using 24HR recall, respectively.. Despite several methodological challenges, we successfully harmonized nutritional data from the different studies. CONCLUSIONS: This paper emphasizes the significance and feasibility of harmonization of previously collected nutritional data, offering an opportunity to examine associations between a range of dietary exposures and the outcome of interest, while minimizing costs and time in epidemiological studies.

A historical cohort study with 27,754 individuals on the association between meat consumption and gastrointestinal tract and colorectal cancer incidence.

In order to explore the association between meat consumption and gastrointestinal/colorectal cancer (CRC) risk and to estimate the Israeli population attributable fraction (PAF), we conducted a collaborative historical cohort study using the individual participant data of seven nutritional studies from the past 6 decades. We included healthy adult men and women who underwent a nutritional interview. Dietary assessment data, using food-frequency or 24-h recall questionnaires, were harmonized. The study file was linked to the National Cancer and death registries. Among 27,754 participants, 1216 (4.4%) were diagnosed with gastrointestinal cancers and 839 (3.0%) with CRC by the end of 2016. Using meta-analysis methods applied to Cox proportional hazard models (adjusted for daily energy intake, sex, age, ethnic origin, education and smoking),100 g/day increments in beef, red meat and poultry consumption, and 50 g/day increment in processed meat consumption were associated with hazard ratios (HRs) and 95% confidence intervals of 1.46 (1.06-2.02), 1.15 (0.87-1.52), 1.06 (0.89-1.26), and 0.93 (0.76-1.12), respectively, for CRC. Similar results were obtained for gastrointestinal cancer, although red meat consumption reached statistical significance (HR = 1.27; 95%CI: 1.02-1.58). The PAFs associated with a reduction to a maximum of 50 g/day in the consumption of red meat were 2.7% (95%CI: -1.9 to 12.0) and 5.2% (0.3-13.9) for CRC and gastrointestinal cancers, respectively. Reduction of beef consumption to a maximum of 50 g/day will result in a CRC PAF reduction of 7.5% (0.7%-24.3%). While beef consumption was associated with gastrointestinal/CRC excess risk, poultry consumption was not. A substantial part of processed meat consumption in Israel is processed poultry, perhaps explaining the lack of association with CRC.

Celiac plexus radiosurgery for pain management in advanced cancer: a multicentre, single-arm, phase 2 trial.

BACKGROUND: Refractory upper abdominal pain or lower back pain (retroperitoneal pain syndrome) related to celiac plexus involvement characterises pancreatic and other upper gastrointestinal malignancies and is an unmet need. We hypothesised that ablative radiation delivered to the celiac plexus would decrease pain. METHODS: This multicentre, single-arm, phase 2 study was done at eight hospitals in five countries (Israel, Poland, Canada, the USA, and Portugal). Eligible patients aged 18 years or older with an average pain level of 5-10 on the Brief Pain Inventory short form (BPI-SF), an Eastern Cooperative Oncology Group performance status score of 0-2, and either pancreatic cancer or other tumours involving the celiac axis, received a single fraction of 25 Gy of external-beam photons to the celiac plexus. The primary endpoint was complete or partial pain response based on a reduction of the BPI-SF average pain score of 2 points or more from baseline to 3 weeks after treatment. All evaluable patients with stable pain scores were included in response assessment. The trial is registered with ClinicalTrials.gov, NCT03323489, and is complete. FINDINGS: Between Jan 3, 2018, and Dec 28, 2021, 125 patients were treated, 90 of whom were evaluable. Patients were followed up until death. Median age was 65·5 years (IQR 58·3-71·8), 50 (56%) were female and 40 (44%) were male, 83 (92%) had pancreatic cancer, and 77 (86%) had metastatic disease. Median baseline BPI-SF average pain score was 6 (IQR 5-7). Of the 90 evaluable patients at 3 weeks, 48 (53%; 95% CI 42-64) had at least a partial pain response. The most common grade 3-4 adverse events, irrespective of attribution, were abdominal pain (35 [28%] of 125) and fatigue (23 [18%]). 11 serious adverse events of grade 3 or worse were recorded. Two grade 3 serious adverse events were probably attributed to treatment by the local investigators (abdominal pain [n=1] and nausea [n=1]), and nine were possibly attributed to treatment (seven were grade 3: blood bilirubin increased [n=1], duodenal haemorrhage [n=2], abdominal pain [n=2], and progressive disease [n=2]; and two were grade 5: gastrointestinal bleed from suspected varices 24 days after treatment [n=1] and progressive disease [advanced pancreatic cancer] 89 days after treatment [n=1]). INTERPRETATION: Celiac plexus radiosurgery could potentially be a non-invasive palliative option for patients with retroperitoneal pain syndrome. Further investigation by means of a randomised comparison with conventional celiac block or neurolysis is warranted. FUNDING: Gateway for Cancer Research and the Israel Cancer Association.

Can sodium and potassium measured in timed voids be used as reference instruments for validating self-report instruments? Results from a urine calibration study.

BACKGROUND: Sodium and potassium measured in 24-h urine collections are often used as reference measurements to validate self-reported dietary intake instruments. OBJECTIVES: To evaluate whether collection and analysis of a limited number of urine voids at specified times during the day ("timed voids") can provide alternative reference measurements, and to identify their optimal number and timing. METHODS: We used data from a urine calibration study among 441 adults aged 18-39 y. Participants collected each urine void in a separate container for 24 h and recorded the collection time. For the same day, they reported dietary intake using a 24-h recall. Urinary sodium and potassium were analyzed in a 24-h composite sample and in 4 timed voids (morning, afternoon, evening, and overnight). Linear regression models were used to develop equations predicting log-transformed 24-h urinary sodium or potassium levels using each of the 4 single timed voids, 6 pairs, and 4 triples. The equations also included age, sex, race, BMI (kg/m2), and log creatinine. Optimal combinations minimizing the mean squared prediction error were selected, and the observed and predicted 24-h levels were then used as reference measures to estimate the group bias and attenuation factors of the 24-h dietary recall. These estimates were compared. RESULTS: Optimal combinations found were as follows: single voids-evening; paired voids-afternoon + overnight (sodium) and morning + evening (potassium); and triple voids-morning + evening + overnight (sodium) and morning + afternoon + evening (potassium). Predicted 24-h urinary levels estimated 24-h recall group biases and attenuation factors without apparent bias, but with less precision than observed 24-h urinary levels. To recover lost precision, it was estimated that sample sizes need to be increased by ∼2.6-2.7 times for a single void, 1.7-2.1 times for paired voids, and 1.5-1.6 times for triple voids. CONCLUSIONS: Our results provide the basis for further development of new reference biomarkers based on timed voids. CLINICAL TRIAL REGISTRY: clinicaltrials.gov as NCT01631240.

Glucagon-Like Peptide-1 Receptor Agonists and Pancreatic Cancer Risk in Patients With Type 2 Diabetes.

Importance: Concerns have been raised that glucagon-like peptide-1 receptor agonists (GLP-1RA) may increase the risk of pancreatic cancer. Objective: To investigate the association of GLP-1RA treatment with pancreatic cancer incidence over 9 years of follow-up. Design, Setting, and Participants: In this population-based historical cohort study, adult patients (aged 21 to 89 years) with type 2 diabetes insured by Clalit Healthcare Services, the largest state-mandated health organization in Israel, were followed up from 2009, when GLP-1RA became available in Israel, until pancreatic cancer diagnosis, death, reaching age 90 years, or end of follow-up (December 2017). Data were analyzed from June 2022 to November 2023. Exposures: Treatment with GLP-1RA was compared with basal insulin. Main Outcome and Measures: Pancreatic cancer incidence was compared according to weighted cumulative exposures to GLP-1RA and to basal insulin in a Cox model implemented in discrete time, with time origin at 2 years after diabetes diagnosis, adjusting for confounding. In sensitivity analyses, propensity score-matched pair new-user design and prevalent new-user design were used for the comparison. Because of risk for reverse-causation bias, results in the fifth to seventh year after medication were emphasized. Results: During a cumulative follow-up of 3 290 439 person-years of 543 595 adults with a mean (SD) age of 59.9 (12.8) years (277 502 women [51%]) with incident diabetes, 1665 patients received pancreatic cancer diagnoses. In total, 33 377 patients (6.1%) used GLP-1RA and 106 849 (19.7%) used basal insulin. The estimated hazard ratio (HR) for pancreatic cancer associated with incremental use of 1 defined daily dose per day of GLP-1RA compared with basal insulin in the fifth to seventh year previously (all other characteristics, including age, sex, ethnic background, sociodemographic status, baseline body mass index, smoking history, history of pancreatitis, other glucose-lowering medications treatment history, and length of diabetes, being equal) was 0.50 (95% CI, 0.15-1.71). The new-user and prevalent new-user designs showed HRs from the fifth year onwards following initiation of GLP-1RA vs basal insulin of 0.52 (95 % CI, 0.19-1.41) and 0.75 (95 % CI, 0.37-1.53), respectively. Conclusions and Relevance: In this historical cohort study of adults with type 2 diabetes, no support for an increased pancreatic cancer incidence over 7 years following start of GLP-1RA treatment was found. However, monitoring for pancreatic cancer risk beyond 7 years following initiation of therapy is still required. Trial Registration: ClinicalTrials.gov Identifier: NCT02072902.

Measuring vaccine protection when the population is mostly vaccinated.

OBJECTIVES: This study aims to address limitations in assessing vaccine protection using the classical vaccine effectiveness (VE) measure, especially in contexts where a significant portion of the population is already vaccinated or infected. STUDY DESIGN AND SETTING: We propose using the adjusted number of cases (ANC) as a building block for deriving vaccine effectiveness measures. This approach accounts for biases arising from small and unrepresentative unvaccinated reference groups with incomplete data. We demonstrate the use of these measures for assessing the protection conferred by a booster dose against severe COVID-19 using data from Israel. RESULTS: The use of ANC and the derived measures reveals a more comprehensive understanding of the complex immunity landscape compared to traditional VE measures. This approach enables meaningful comparisons between different vaccination categories and provides insights to inform policy decisions. CONCLUSION: In situations with widespread vaccination and prior infections, traditional VE measures can be limited in their informative value. Using the ANC offers a more robust and insightful assessment of vaccine effectiveness. A demonstration of the evaluation of booster dose protection against severe COVID-19 in Israel underscores the importance of adopting complementary measures to guide public health strategies.

Reverse causation biases weighted cumulative exposure model estimates, but can be investigated in sensitivity analyses.

OBJECTIVES: To examine the effects of reverse causation on estimates from the weighted cumulative exposure (WCE) model that is used in pharmacoepidemiology to explore drug-health outcome associations, and to identify sensitivity analyses for revealing such effects. STUDY DESIGN AND SETTING: 314,099 patients with diabetes under Clalit Health Services, Israel, were followed over 2002-2012. The association between metformin and pancreatic cancer (PC) was explored using a WCE model within the framework of discrete-time Cox regression. We used computer simulations to explore the effects of reverse causation on estimates of a WCE model and to examine sensitivity analyses for revealing and adjusting for reverse causation. We then applied those sensitivity analyses to our data. RESULTS: Simulation demonstrated bias in the weighted cumulative exposure model and showed that sensitivity analysis could reveal and adjust for these biases. In our data, a positive association was observed (hazard ratio (HR) = 3.24, 95% confidence interval (CI): 2.24-4.73) with metformin exposure in the previous 2 years. After applying sensitivity analysis, assuming reverse causation operated up to 4 years before cancer diagnosis, the association between metformin and PC was no longer apparent. CONCLUSION: Reverse causation can cause substantial bias in the WCE model. When suspected, sensitivity analyses based on causal analysis are advocated.

Longitudinal bidirectional link between socioeconomic position and health: a national panel survey analysis.

BACKGROUND: Health inequities can stem from socioeconomic position (SEP) leading to poor health (social causation) or poor health resulting in lower SEP (health selection). We aimed to examine the longitudinal bidirectional SEP-health associations and identify inequity risk factors. METHODS: Longitudinal Household Israeli Panel survey participants (waves 1-4), age ≥25 years, were included (N=11 461; median follow-up=3 years). Health rated on a 4-point scale was dichotomised as excellent/good and fair/poor. Predictors included SEP parameters (education, income, employment), immigration, language proficiency and population group. Mixed models accounting for survey method and household ties were used. RESULTS: Examining social causation, male sex (adjusted OR 1.4; 95% CI 1.1 to 1.8), being unmarried, Arab minority (OR 2.4; 95% CI 1.6 to 3.7, vs Jewish), immigration (OR 2.5; 95% CI 1.5 to 4.2, reference=native) and less than complete language proficiency (OR 2.22; 95% CI 1.50 to 3.28) were associated with fair/poor health. Higher education and income were protective, with 60% lower odds of subsequently reporting fair/poor health and 50% lower disability likelihood. Accounting for baseline health, higher education and income were associated with lower likelihood of health deterioration, while Arab minority, immigration and limited language proficiency were associated with higher likelihood. Regarding health selection, longitudinal income was lower among participants reporting poor baseline health (85%; 95% CI 73% to 100%, reference=excellent), disability (94%; 95% CI 88% to 100%), limited language proficiency (86%; 95% CI 81% to 91%, reference=full/excellent), being single (91%; 95% CI 87% to 95%, reference=married), or Arab (88%; 95% CI 83% to 92%, reference=Jews/other). CONCLUSION: Policy aimed at reducing health inequity should address both social causation (language, cultural, economic and social barriers to good health) and health selection (protecting income during illness and disability).

Factors Associated With Protection From SARS-CoV-2 Omicron Variant Infection and Disease Among Vaccinated Health Care Workers in Israel.

Importance: A correlation between antibody levels and risk of infection has been demonstrated for the wild-type, Alpha, and Delta SARS-COV-2 variants. High rates of breakthrough infections by the Omicron variant emphasized the need to investigate whether the humoral response elicited by mRNA vaccines is also associated with reduced risk of Omicron infection and disease. Objective: To investigate whether the high antibody levels in individuals who have received at least 3 doses of an mRNA vaccine are associated with reduced risk of Omicron infection and disease. Design, Setting, and Participants: This prospective cohort study used serial real time-polymerase chain reaction (RT-PCR) and serological test data from January and May 2022 to assess the association of preinfection immunoglobin G (IgG) and neutralizing antibody titers with incidence of Omicron variant infection, incidence of symptomatic disease, and infectivity. Participants included health care workers who had received 3 or 4 doses of an mRNA COVID-19 vaccine. Data were analyzed from May to August 2022. Exposures: Levels of SARS-CoV-2 anti-receptor binding domain IgG and neutralizing antibodies. Main Outcomes and Measures: The main outcomes were incidence of Omicron infection, incidence of symptomatic disease, and infectivity. Outcomes were measured using SARS-COV-2 PCR and antigen testing and daily online surveys regarding symptomatic disease. Results: This study included 3 cohorts for 3 different analyses: 2310 participants were included in the protection from infection analysis (4689 exposure events; median [IQR] age, 50 [40-60] years; 3590 [76.6%] among female health care workers), 667 participants (median [IQR] age, 46.28 (37.44,54.8); 516 [77.4%] female) in the symptomatic disease analysis, and 532 participants (median [IQR] age, 48 [39-56] years; 403 [75.8%] female) in the infectivity analysis. Lower odds of infection were observed for each 10-fold increase in preinfection IgG (odds ratio [OR], 0.71; 95% CI, 0.56-0.90) and for each 2-fold increase in neutralizing antibody titers (OR, 0.89; 95% CI, 0.83-0.95). The odds of substantial symptomatic disease were reduced for each 10-fold increase in IgG levels (OR, 0.48; 95% CI, 0.29-0.78) and for each 2-fold increase in neutralizing antibodies levels (OR, 0.86; 95% CI, 0.76-0.96). Infectivity, assessed by mean cycle threshold value, was not significantly decreased with increasing IgG or neutralizing antibodies titers. Conclusions and Relevance: In this cohort study of vaccinated health care workers, IgG and neutralizing antibody titer levels were associated with protection against infection with the Omicron variant and against symptomatic disease.

Issues in Implementing Regression Calibration Analyses.

Regression calibration is a popular approach for correcting biases in estimated regression parameters when exposure variables are measured with error. This approach involves building a calibration equation to estimate the value of the unknown true exposure given the error-prone measurement and other covariates. The estimated, or calibrated, exposure is then substituted for the unknown true exposure in the health outcome regression model. When used properly, regression calibration can greatly reduce the bias induced by exposure measurement error. Here, we first provide an overview of the statistical framework for regression calibration, specifically discussing how a special type of error, called Berkson error, arises in the estimated exposure. We then present practical issues to consider when applying regression calibration, including: 1) how to develop the calibration equation and which covariates to include; 2) valid ways to calculate standard errors of estimated regression coefficients; and 3) problems arising if one of the covariates in the calibration model is a mediator of the relationship between the exposure and outcome. Throughout, we provide illustrative examples using data from the Hispanic Community Health Study/Study of Latinos (United States, 2008-2011) and simulations. We conclude with recommendations for how to perform regression calibration.

Urinary Sucrose and Fructose From Spot Urine May Be Used as a Predictive Biomarker of Total Sugar Intake-Findings From a Controlled Feeding Study.

BACKGROUND: Recently, we confirmed 24-h urinary sucrose plus fructose (24 uSF) as a predictive biomarker of total sugar intake. However, the collection of 24-h urine samples has limited feasibility in population studies. OBJECTIVE: We investigated the utility of the urinary sucrose plus fructose (uSF) biomarker measured in spot urine as a measure of 24 uSF biomarker and total sugar intake. METHODS: Hundred participants, 18-70 y of age, from the Phoenix Metropolitan Area completed a 15-d feeding study. For 2 of the 8 collected 24-h urine samples, each spot urine sample was collected in a separate container. We considered 4 timed voids of the day [morning (AM) void: first void 08:30-12:30; afternoon (PM) void: first void 12:31-17:30; evening (EVE) void: first void 17:31-12:00; and next-day (ND) void: first void 04:00-12:00]. We investigated the performance of uSF from 1 void, and uSF combined from 2 and 3 voids as a measure of 24 uSF and sugar intake. RESULTS: The biomarker averaged from PM/EVE void strongly correlated with 24 uSF (partial r = 0.75). The 24 uSF predicted from the PM/EVE combination was significantly associated with observed sugar intake and was selected for building the calibrated biomarker equation (marginal R2 = 0.36). Spot urine-based calibrated biomarker, ie, biomarker-estimated sugar intake was moderately correlated with the 15-d mean-observed sugar intake (r = 0.50). CONCLUSIONS: uSF measured from a PM and EVE void may be used to generate biomarker-based sugar intake estimate when collecting 24-h urine samples is not feasible, pending external validation.

Protection against Omicron BA.1/BA.2 severe disease 0-7 months after BNT162b2 booster.

Following evidence of waning immunity against both infection and severe disease after 2 doses of the BNT162b2 vaccine, Israel began administering a 3rd BNT162b2 dose (booster) in July 2021. Recent studies showed that the 3rd dose provides a much lower protection against infection with the Omicron variant compared to the Delta variant and that this protection wanes quickly. However, there is little evidence regarding the protection of the 3rd dose against Omicron (BA.1/BA.2) severe disease. In this study, we estimate the preservation of immunity from severe disease up to 7 months after receiving the booster dose. We calculate rates of severe SARS-CoV-2 disease between groups of individuals aged 60 and above, comparing those who received two doses at least 4 months previously to those who received the 3rd dose (stratified by the time from vaccination), and to those who received a 4th dose. The analysis shows that protection conferred by the 3rd dose against Omicron severe disease did not wane over a 7-month period. Moreover, a 4th dose further improved protection, with a severe disease rate approximately 3-fold lower than in the 3-dose cohorts.

The Association Between Prebooster Vaccination Antibody Levels and the Risk of Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

The correlation between anti-severe acute respiratory syndrome coronavirus 2 antibody levels and infection was reported. Here, we estimated the role of pre-fourth dose levels using data from 1098 healthcare workers. The risk of infection was reduced by 46% (95% confidence interval, 29%-59%) for each 10-fold increase in prebooster levels. Prebooster antibody levels could be used to optimally time boosters.

Initial protection against SARS-CoV-2 omicron lineage infection in children and adolescents by BNT162b2 in Israel: an observational study.

BACKGROUND: The BNT162b2 (Pfizer-BioNTech) two-dose vaccine regiment for children and the BNT162b2 third dose for adolescents were approved shortly before the SARS-CoV-2 omicron (B.1.1.529) outbreak in Israel. We aimed to estimate the effects of these vaccines on the rates of confirmed infection against the omicron variant in children and adolescents. METHODS: In this observational cohort study, we extracted data for the omicron-dominated (sublineage BA.1) period. We compared rates of confirmed SARS-CoV-2 infection between children aged 5-10 years 14-35 days after receiving the second vaccine dose with an internal control group of children 3-7 days after receiving the first dose (when the vaccine is not yet effective). Similarly, we compared confirmed infection rates in adolescents aged 12-15 years 14-60 days after receiving a booster dose with an internal control group of adolescents 3-7 days after receiving the booster dose. We used Poisson regression, adjusting for age, sex, socioeconomic status, calendar week, and exposure. FINDINGS: Between Dec 26, 2021, and Jan 8, 2022, we included 1 158 289 participants. In children aged 5-10 years, the adjusted rate of confirmed infection was 2·3 times (95% CI 2·0-2·5) lower in children who received a second dose than in the internal control group. The adjusted infection rate in children who received a second dose was 102 infections per 100 000 risk-days (94-110) compared with 231 infections per 100 000 risk-days (215-248) in the corresponding internal control cohort. In adolescents aged 12-15 years, the booster dose decreased confirmed infection rates by 3·3 times (2·8-4·0) compared with in the internal control group. The adjusted infection rate of the booster cohort was 70 per 100 000 risk-days (60-81) compared with 232 per 100 000 risk-days (212-254) in the internal control cohort. INTERPRETATION: A recent two-dose vaccination regimen with BNT162b2 and a recent booster dose in adolescents substantially reduced the rate of confirmed infection compared with the internal control groups. Future studies are needed to assess the duration of this protection and protection against other outcomes such as paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 and long-COVID. FUNDING: None.

Immunogenicity and efficacy of fourth BNT162b2 and mRNA1273 COVID-19 vaccine doses; three months follow-up.

Booster doses for the ongoing COVID-19 pandemic are under consideration in many countries. We report a three-month follow-up of 700 participants in a fourth vaccine dose study, comparing BNT162b2 and mRNA1273, administered four months after a third BNT162b2 dose. The primary outcomes are the levels of IgG, neutralizing antibodies, and microneutralization and the secondary outcomes are the levels of IgA and T cell activation, and clinical outcomes of SARS-CoV-2 infection and substantial symptomatic disease. Waning of the immune response is evident during follow-up, with an 11% (ß = 0.89, 95% CI, 0.88-0.9) and 21% (ß = 0.79, 95% CI, 0.76-0.82) multiplicative decay per week of IgG and neutralizing antibodies, respectively, in the mRNA1273 group, and of 14% (ß = 0.86, 95% CI, 0.86-0.87) and 26% (ß = 0.74, 95% CI, 0.72-0.76), respectively, in the BNT162b2 group. Direct neutralization of Omicron variants is low relative to ancestral strains. Cumulatively over the study period, both vaccines show little efficacy against infection but were highly efficacious against substantial symptomatic disease [89% [(IRR 0.11, 95% CI, 0.02-0.37) and 71% (IRR 0.29, 95% CI, 0.13-0.57) for mRNA1273 and BNT162b2, respectively]. These results are informative for further boosting policy-making. Trial registration numbers (clinicaltrials.gov): NCT05231005 and NCT05230953.