Neutralizing antibody correlate of protection against severe-critical COVID-19 in the ENSEMBLE single-dose Ad26.COV2.S vaccine efficacy trial.

Assessment of immune correlates of severe COVID-19 has been hampered by the low numbers of severe cases in COVID-19 vaccine efficacy (VE) trials. We assess neutralizing and binding antibody levels at 4 weeks post-Ad26.COV2.

Omicron COVID-19 immune correlates analysis of a third dose of mRNA-1273 in the COVE trial.

In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.

Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study.

Background: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12.

Robust analysis of stepped wedge trials using composite likelihood models.

Stepped wedge trials (SWTs) are a type of cluster randomized trial that involve repeated measures on clusters and design-induced confounding between time and treatment. Although mixed models are commonly used to analyze SWTs, they are susceptible to misspecification particularly for cluster-longitudinal designs such as SWTs. Mixed model estimation leverages both "horizontal" or within-cluster information and "vertical" or between-cluster information.

Four statistical frameworks for assessing an immune correlate of protection (surrogate endpoint) from a randomized, controlled, vaccine efficacy trial.

A central goal of vaccine research is to characterize and validate immune correlates of protection (CoPs). In addition to helping elucidate immunological mechanisms, a CoP can serve as a valid surrogate endpoint for an infectious disease clinical outcome and thus qualifies as a primary endpoint for vaccine authorization or approval without requiring resource-intensive randomized, controlled phase 3 trials. Yet, it is challenging to persuasively validate a CoP, because a prognostic immune marker can fail as a reliable basis for predicting/inferring the level of vaccine efficacy against a clinical outcome, and because the statistical analysis of phase 3 trials only has limited capacity to disentangle association from cause.

Under-five mortality before and after implementation of the Liberia National Community Health Assistant (NCHA) program: A study protocol.

Between 2018 and 2022 the Liberian Government implemented the National Community Health Assistant (NCHA) program to improve provision of maternal and child health care to underserved rural areas of the country. Whereas the contributions of this and similar community health worker (CHW) based healthcare programs have been associated with improved process measures, the impact of a governmental CHW program at scale on child mortality has not been fully established. We will conduct a cluster sampled, community-based survey with landmark event calendars to retrospectively assess child births and deaths among all children born to women in the Grand Bassa District of Liberia.

A controlled effects approach to assessing immune correlates of protection.

An immune correlate of risk (CoR) is an immunologic biomarker in vaccine recipients associated with an infectious disease clinical endpoint. An immune correlate of protection (CoP) is a CoR that can be used to reliably predict vaccine efficacy (VE) against the clinical endpoint and hence is accepted as a surrogate endpoint that can be used for accelerated approval or guide use of vaccines. In randomized, placebo-controlled trials, CoR analysis is limited by not assessing a causal vaccine effect.

Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition.

Background: The phase 2b proof-of-concept Antibody Mediated Prevention (AMP) trials showed that VRC01, an anti-HIV-1 broadly neutralising antibody (bnAb), prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, we investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data.

Methods: The case-control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study.

Comparing antibody assays as correlates of protection against COVID-19 in the COVE mRNA-1273 vaccine efficacy trial.

The best assay or marker to define mRNA-1273 vaccine-induced antibodies as a correlate of protection (CoP) is unclear. In the COVE trial, participants received two doses of the mRNA-1273 COVID-19 vaccine or placebo. We previously assessed IgG binding antibodies to the spike protein (spike IgG) or receptor binding domain (RBD IgG) and pseudovirus neutralizing antibody 50 or 80% inhibitory dilution titer measured on day 29 or day 57, as correlates of risk (CoRs) and CoPs against symptomatic COVID-19 over 4 months after dose.

Immune correlates analysis of the ENSEMBLE single Ad26.COV2.S dose vaccine efficacy clinical trial.

Measuring immune correlates of disease acquisition and protection in the context of a clinical trial is a prerequisite for improved vaccine design. We analysed binding and neutralizing antibody measurements 4 weeks post vaccination as correlates of risk of moderate to severe-critical COVID-19 through 83 d post vaccination in the phase 3, double-blind placebo-controlled phase of ENSEMBLE, an international randomized efficacy trial of a single dose of Ad26.COV2.

A controlled effects approach to assessing immune correlates of protection.

An immune correlate of risk (CoR) is an immunologic biomarker in vaccine recipients associated with an infectious disease clinical endpoint. An immune correlate of protection (CoP) is a CoR that can be used to reliably predict vaccine efficacy (VE) against the clinical endpoint and hence is accepted as a surrogate endpoint that can be used for accelerated approval or guide use of vaccines. In randomized, placebo-controlled trials, CoR analysis is limited by not assessing a causal vaccine effect.

Adherence to Perioperative Antibiotic Prophylaxis Recommendations and Its Impact on Postoperative Surgical Site Infections.

Introduction Surgical site infections (SSIs) are common and carry a significant risk of morbidity and mortality and lead to increased healthcare costs. Perioperative antibiotic prophylaxis decreases the risk of SSIs. There are several guidelines on the use of perioperative antibiotic prophylaxis.

Analysis of stepped wedge cluster randomized trials in the presence of a time-varying treatment effect.

Stepped wedge cluster randomized controlled trials are typically analyzed using models that assume the full effect of the treatment is achieved instantaneously. We provide an analytical framework for scenarios in which the treatment effect varies as a function of exposure time (time since the start of treatment) and define the "effect curve" as the magnitude of the treatment effect on the linear predictor scale as a function of exposure time. The "time-averaged treatment effect" (TATE) and "long-term treatment effect" (LTE) are summaries of this curve.

Immune Correlates Analysis of a Single Ad26.COV2.S Dose in the ENSEMBLE COVID-19 Vaccine Efficacy Clinical Trial.

Anti-spike IgG binding antibody, anti-receptor binding domain IgG antibody, and pseudovirus neutralizing antibody measurements four weeks post-vaccination were assessed as correlates of risk of moderate to severe-critical COVID-19 outcomes through 83 days post-vaccination and as correlates of protection following a single dose of Ad26.COV2.S COVID-19 vaccine in the placebo-controlled phase of ENSEMBLE, an international, randomized efficacy trial.

Random effect misspecification in stepped wedge designs.

Stepped wedge cluster randomized trials are often analysed using linear mixed effects models that may include random effects for cluster, time and/or treatment. We investigate the impact of misspecification of the random effects structure of the model. Specifically, we considered two cases of misspecification of the random effects in a cross-sectional stepped wedge cluster randomized trials model - fit a linear mixed effects model with random time effects but the true model includes random treatment effects (case 1) or fit a linear mixed effects model with random treatment effect but the true model includes random time effects (case 2) - and derived the variance of the estimated treatment effect under misspecification.

Model misspecification in stepped wedge trials: Random effects for time or treatment.

Mixed models are commonly used to analyze stepped wedge trials (SWTs) to account for clustering and repeated measures on clusters. One critical issue researchers face is whether to include a random time effect or a random treatment effect. When the wrong model is chosen, inference on the treatment effect may be invalid.

Measuring Knowledge of Community Health Workers at the Last Mile in Liberia: Feasibility and Results of Clinical Vignette Assessments.

Introduction: Community health workers (CHWs) can provide lifesaving treatment for children in remote areas, but high-quality care is essential for effective delivery. Measuring the quality of community-based care in remote areas is logistically challenging. Clinical vignettes have been validated in facility settings as a proxy for competency.

Design and implementation of a mobile health electronic data capture platform that functions in fully-disconnected settings: a pilot study in rural Liberia.

Background: Mobile phones and personal digital assistants have been used for data collection in developing world settings for over three decades, and have become increasingly common. However, the use of electronic data capture (EDC) through mobile phones is limited in many areas by inconsistent network connectivity and poor access to electricity, which thwart data transmission and device usage. This is the case in rural Liberia, where many health workers live and work in areas without any access to cellular connectivity or reliable power.

Satellite images and machine learning can identify remote communities to facilitate access to health services.

Objective: Community health systems operating in remote areas require accurate information about where people live to efficiently provide services across large regions. We sought to determine whether a machine learning analyses of satellite imagery can be used to map remote communities to facilitate service delivery and planning.

Materials And Methods: We developed a method for mapping communities using a deep learning approach that excels at detecting objects within images.

A Community Health Worker Intervention to Increase Childhood Disease Treatment Coverage in Rural Liberia: A Controlled Before-and-After Evaluation.

Objectives: To assess a community health worker (CHW) program's impact on childhood illness treatment in rural Liberia.

Methods: We deployed CHWs in half of Rivercess County in August 2015 with the other half constituting a comparison group until July 2016. All CHWs were provided cash incentives, supply chain support, and monthly clinical supervision.

Validation Relaxation: A Quality Assurance Strategy for Electronic Data Collection.

Background: The use of mobile devices for data collection in developing world settings is becoming increasingly common and may offer advantages in data collection quality and efficiency relative to paper-based methods. However, mobile data collection systems can hamper many standard quality assurance techniques due to the lack of a hardcopy backup of data. Consequently, mobile health data collection platforms have the potential to generate datasets that appear valid, but are susceptible to unidentified database design flaws, areas of miscomprehension by enumerators, and data recording errors.

Implementation research on community health workers' provision of maternal and child health services in rural Liberia.

Objective: To assess changes in the use of essential maternal and child health services in Konobo, Liberia, after implementation of an enhanced community health worker (CHW) programme.

Methods: The Liberian Ministry of Health partnered with Last Mile Health, a nongovernmental organization, to implement a pilot CHW programme with enhanced recruitment, training, supervision and compensation. To assess changes in maternal and child health-care use, we conducted repeated cross-sectional cluster surveys before (2012) and after (2015) programme implementation.

Charting health system reconstruction in post-war Liberia: a comparison of rural vs. remote healthcare utilization.

Background: Despite a growing global emphasis on universal healthcare, access to basic primary care for remote populations in post-conflict countries remains a challenge. To better understand health sector recovery in post-conflict Liberia, this paper seeks to evaluate changes in utilization of health services among rural populations across a 5-year time span.

Methods: We assessed trends in healthcare utilization among the national rural population using the Liberian Demographic and Health Survey (DHS) from 2007 and 2013.

Facility-Based Delivery during the Ebola Virus Disease Epidemic in Rural Liberia: Analysis from a Cross-Sectional, Population-Based Household Survey.

Background: The Ebola virus disease (EVD) epidemic has threatened access to basic health services through facility closures, resource diversion, and decreased demand due to community fear and distrust. While modeling studies have attempted to estimate the impact of these disruptions, no studies have yet utilized population-based survey data.

Methods And Findings: We conducted a two-stage, cluster-sample household survey in Rivercess County, Liberia, in March-April 2015, which included a maternal and reproductive health module.