Elizabeth Tacket Rogawski McQuade

Background: Effective vaccines against Shigella , the leading bacterial cause of diarrheal disease globally, could prevent morbidity and mortality from shigellosis as well as limit antibiotic resistance. Several Shigella vaccine candidates are in late stages of development, and the design of large Phase 3 trials in target populations is underway. In high incidence settings, children are expected to rapidly accrue natural immunity such that after repeated pathogen exposure, unvaccinated infants may have similar levels of immunity as vaccinated infants. For this reason, in these settings estimates of vaccine efficacy (VE) may underestimate expected efficacy in a fully naïve population. To set expectations and support optimal planning of future Shigella vaccine trials, we aimed to quantify the potential impact of this phenomenon on VE estimates under different surveillance strategies and assumptions about Shigella immunity. Methods and findings: We simulated Shigella vaccine trials in low-, medium-, and high-burden settings under different assumptions about vaccine- and infection-conferred immunity. We estimated VE against severe, Shigella -attributable disease and any Shigella -attributable diarrhea under six trial designs: active surveillance for Shigella infection or symptom-based reporting paired with single-outcome, stratified recurrent outcome, or crude recurrent-outcome Cox proportional hazards models. In each scenario, we evaluated bias, 95% confidence interval (CI) coverage, and the false negative rate. Only the trial design using active surveillance for infection and single outcome models was consistently unbiased across all examined scenarios. The other five designs underestimated VE by up to an absolute 20%, with a single outcome model paired with symptom-based reporting performing least poorly. Bias generally was worse at higher-burden sites. For realistically sized trials, the 95% CI coverage and false negative rate were also worse at higher-burden sites. The results were sensitive to input parameters which depended on assumptions about Shigella natural history based on limited published data. Conclusions: The observed VE in Shigella vaccine trials is likely to underestimate true VE, though the magnitude of underestimation described here is conditional on the simulation’s inputs and assumptions. Careful trial design is needed to minimize this underestimation.

Background: Frequent enteric infections can damage the small intestine causing inflammation and malabsorption, leading to environmental enteric dysfunction. We aimed to characterize the association between intestinal inflammation and enteric pathogens among children in low- and middle-income countries (LMICs) who presented to care with diarrhea. Methodology/principle findings: We conducted a cross-sectional analysis within the Enterics for Global Health - Shigella surveillance study at six LMIC sites: Bangladesh, Kenya, Malawi, Pakistan, Peru, and The Gambia. From August 2022 to July 2024, rectal swabs and whole stool samples were collected from 4,903 children with medically attended diarrhea aged 6–35 months (44.4% females, n = 2178/4903; mean age: 15.4 months ± 7.4 months) and were analyzed for Shigella and four fecal inflammatory biomarkers: hemoglobin, lipocalin-2, myeloperoxidase, and calprotectin via Enzyme Linked Immunosorbent Assays. Caregivers and clinicians demonstrated moderate accuracy in identifying blood in stool compared to fecal hemoglobin (area under the curve (AUC)=0.70). Among 10 pathogens evaluated, Shigella -attributable diarrhea had the highest concentrations of calprotectin, hemoglobin, and myeloperoxidase. Shigella culture-/PCR+ episodes had intermediate levels of inflammation between culture-/PCR- and culture+ episodes. In multivariable models restricted to Shigella episodes, dysentery was positively associated and vomiting was negatively associated with biomarker concentrations, with the strongest associations observed for hemoglobin (dysentery geometric mean ratio: 12.82 (95% CI: 7.21, 22.77) and vomiting geometric mean ratio: 0.45 (95% CI: 0.23, 0.86)). Age, sex, and both acute and chronic malnutrition were not associated with inflammatory biomarker concentrations. Conclusions/significance: Hemoglobin appeared to be a more sensitive marker of blood in stool than visual observation. While Shigella was associated with heightened levels of all inflammatory biomarkers, hemoglobin was most strongly associated with Shigella , especially among attributable and culture positive episodes. The distinct clinical characteristics of Shigella were most closely associated with elevated hemoglobin concentrations.

The objective of this study was to examine if height at 2 years, 5 years, and 6–8 years of age was related to school-age cognitive development in low resource settings. Some studies report improved scores in those who catch up, while others found no improvement. We hypothesize that persistent stunting will be negatively associated with cognition and that children who experienced catch-up growth would show improved cognition.Follow-up anthropometry and cognitive assessments at 6–8 years were completed in the Brazil, South Africa, and Tanzania MAL-ED cohorts. Semantic and phonemic fluency and reasoning skills were assessed with the Developmental NEuroPSYchological test and Raven Coloured Matrices, respectively. Stunting at 2, 5, and 6–8 years was used to categorize growth into persistently stunted, early catch-up, late catch-up, and never stunted. Multivariable linear regression was used to estimate relationships between linear growth, stunting, and catch-up growth and 6–8-year-old cognition.Stunting prevalence decreased with each follow-up assessment from 40.1% at 2 years to 13.4% at 6–8 years. Height at each age was negatively associated with cognition (Semantic Fluency: 0.2 z-scores, 95% CI: 0.1, 0.3). Persistent stunting was associated with decreased cognitive scores at 6–8 years (Semantic Fluency: -0.4 z-scores, 95% CI: -0.8, -0.03). Children with catch-up growth, both early (Semantic Fluency: -0.4 z-scores, 95% CI: -0.6, -0.1) and late (Semantic Fluency: -0.4 z-scores, 95% CI: -0.8, -0.1), did not have improved scores compared to those persistently stuntedLinear growth at 2 years remains an important indicator of cognitive development in late childhood. Efforts to reduce early stunting may continue as catch-up growth is not always associated with improved cognitive functioning.

Key points: Question: Among infants eligible to receive protection from maternal vaccination or infant long-acting monoclonal antibodies, what is the effectiveness RSV preventive strategies when accounting for real-world delays in administration? Findings: In this target trial emulation study of 120,586 mother-infant pairs from U.S. claims data, long-acting monoclonal antibody effectiveness was sensitive to implementation delays, rendering preventive strategies that protected infants at or close to birth more effective at preventing respiratory disease than a monoclonal antibody strategy that reflected real-world implementation. Meaning: Strategies, such as maternal vaccination or monoclonal antibodies provided within the first week of life, that protect infants at birth or close to birth are especially valuable in settings where delayed long-acting monoclonal antibody receipt is likely. Importance: Maternal vaccination and long-acting monoclonal antibodies are now available in the U.S. to prevent RSV. Long-acting monoclonal antibody administration in the U.S. commonly occurs after hospital discharge in outpatient settings, leaving some infants unprotected early in life when severe RSV risk is highest. Comparative effectiveness between the two interventions and whether delays affect effectiveness estimates have not been quantified. Objective: To evaluate the effectiveness of infant long-acting monoclonal antibody strategies and a maternal vaccination strategy, each compared to no intervention, and the comparative effectiveness of intervention strategies when accounting for real-world delays in monoclonal antibody receipt. Design: Cohort study using target trial emulation to compare four strategies for prevention of RSV-related outcomes. Setting: The U.S. between 2023 and 2025 using a nationwide database of employer-sponsored commercial insurance claims. Participants: 120,586 commercially insured mother-infants, whose infants were born in the U.S. during the 2023-2024 or 2024-2025 RSV season. Infants who could not be paired with their mother’s record, did not enroll in commercial insurance within 75 days from birth, received palivizumab, and had an implausible birth date were excluded. Interventions: Comparison of four RSV prevention strategies: (i) maternal RSVpreF; (ii) long-acting monoclonal antibody given within the first week of life (mAb as intended); (iii) long-acting monoclonal antibody given within a six-month grace period from birth (mAb within grace period); and (iv) a control. Main outcomes and measures: Effectiveness against first RSV-associated hospitalization and medically-attended RSV illness was summarized using adjusted hazard ratios (aHR) and estimated using an inverse propensity weighting approach, with weights accounting for maternal age, maternal comorbidities affecting pregnancy, obstetric and newborn complications, season, region, and birth timing relative to October 1. A weighted Kaplan Meier estimator was used to estimate strategy-specific cumulative incidence of RSV outcomes over time. Results: In the first five weeks of life, the mAb within grace period strategy doubled the hazard of RSV hospitalization (aHR: 2.0 [95% CI: 1.0-4.9]) and increased the hazard of medically-attended RSV (aHR: 1.6 [95% CI: 1.0-2.7]) compared to the maternal RSVpreF strategy. The hazard for RSV hospitalization was similar for the mAb as intended strategy compared to the maternal RSVpreF strategy (aHR = 0.9 [95% CI: 0.3-1.9]). Conclusions and relevance: RSVpreF and monoclonal antibodies were similarly effective when monoclonal antibodies were administered close to birth, but when accounting for real-world delays in monoclonal antibody receipt, the maternal RSVpreF strategy was more effective than the mAb within grace period strategy.

The naive approach to estimating the effects of a vaccine on asymptomatic infections, which compares the risk of asymptomatic infection among vaccinated and unvaccinated individuals, can be misleading because it comprises two effects: the vaccine preventing asymptomatic infections and the vaccine converting symptomatic to asymptomatic infections. When the latter effect is strong, vaccines can appear harmful with respect to asymptomatic infections. Using a causal principal stratification framework, we formalize an estimand, vaccine efficacy against naturally asymptomatic infection (VE _NAI ), that describes the efficacy of a vaccine in preventing asymptomatic infections among individuals who would naturally (i.e., in the absence of vaccine) be expected to be asymptomatic. This estimand excludes vaccine effects that convert symptomatic cases to asymptomatic infections, and we demonstrate how this makes it a more natural analogue of the usual vaccine efficacy estimands against infection and symptomatic disease. We describe the assumptions under which this estimand can be identified and estimated from randomized and observational studies. We further identify and estimate bounds that do not require cross-world independence assumptions and characterize sensitivity analyses around the main assumption needed for identification. Finally, we apply these methods to a randomized trial of the coronavirus disease 2019 mRNA-1273 vaccine. In this trial, VE _NAI was higher than standard estimates of efficacy against asymptomatic infections and was similar in magnitude to efficacy against any infection. Reporting VE _NAI in vaccine trials in addition to other vaccine effects would improve interpretability and could broaden understanding of vaccine impact on transmission, providing insights into immunological mechanisms.

Background: Live oral rotavirus vaccines were found to be less effective in low-income countries compared to high-income countries when using the same product and dosing schedule. We investigated whether altering dose timing may improve immune protection using a target trial emulation approach. Methods: We emulated a target trial with clone-censor weighting to compare the effectiveness of the recommended 2-dose rotavirus vaccine schedule with a delayed schedule among children under two years of age in Peru and Brazil. Secondary data from the Malnutrition and Enteric Disease Study (MAL-ED) birth cohort (2009-2014) were analyzed. Children were followed from the date of birth until the earliest occurrence of a rotavirus outcome (infection confirmed by PCR or enzyme immunoassay (EIA) or diarrhea confirmed by EIA), protocol nonadherence, loss to follow-up, or their second birthday. Results: We included 154 children in Brazil and 192 in Peru. At two years of follow-up, the risk ratio (RR) for PCR-confirmed infection, using the recommended schedule as the reference, was 1.00 (95% confidence interval [CI]: 0.73-1.37) in Peru and 0.85 (95% CI: 0.31-1.66) in Brazil. In Peru, the delayed schedule was associated with a higher cumulative risk of EIA-confirmed rotavirus diarrhea (RR at two years: 1.73; 95% CI: 1.02-2.77). Conclusions: Delaying the two-dose rotavirus vaccine schedule did not change the cumulative risk of rotavirus infection, but the delayed schedule was associated with a higher risk of rotavirus diarrhea in Peru, where rotavirus incidence was higher.

Background Quantifying the effect of Shigella diarrhea with and without antibiotic treatment on linear growth faltering is critical to understanding the potential impact of Shigella vaccines. Methods Using individual-level data from five multisite studies, we estimated the effect of Shigella diarrhea on length/height-for-age z-score (HAZ) 60-90 days after the episode compared to diarrhea episodes with no etiology identified and non-diarrheal controls. Effects were estimated under treatment with and without antibiotics using augmented inverse probability weighted estimators with ensemble machine learning. Findings Among 26,752 diarrhea episodes, 5,503 (20.6%) were attributed to Shigella and of those, 2,567 (46.6%) were treated with guideline recommended antibiotics. Compared to other diarrhea episodes, Shigella diarrhea without treatment with guideline recommended antibiotics was associated with small reductions in HAZ (HAZ difference: -0.03, 95% CI: -0.05, -0.01), but not when treated with guideline recommended antibiotics (HAZ difference: -0.01, 95% CI: -0.02, 0.01). Compared to non-diarrheal controls, Shigella diarrhea was associated with decrements in HAZ in the following 60-90 days regardless of antibiotic treatment (HAZ difference overall: -0.08, 95% CI: -0.10, -0.07). A larger impact of Shigella diarrhea was observed among younger children. Interpretation Shigella diarrhea was associated with short-term decrements in height. Treatment with guideline recommended antibiotics prevented the impact of Shigella on linear growth compared to other diarrhea episodes but not compared to non-diarrheal controls. These results suggest that improved recognition and treatment or prevention of Shigella could improve child growth.