Systematic review of primary and booster COVID-19 sera neutralizing ability against SARS-CoV-2 omicron variant.

Virus neutralization data using post-vaccination sera are an important tool in informing vaccine use policy decisions, however, they often pose interpretive challenges. We systematically reviewed the pre-print and published literature for neutralization studies against Omicron using sera collected after both primary and booster vaccination. We found a high proportion of post-primary vaccination sera were not responding against Omicron but boosting increased both neutralizing activity and percent of responding sera. We recommend reporting percent of responders alongside neutralization data to portray vaccine neutralization ability more accurately.

An introduction to the Marburg virus vaccine consortium, MARVAC.

The emergence of Marburg virus (MARV) in Guinea and Ghana triggered the assembly of the MARV vaccine "MARVAC" consortium representing leaders in the field of vaccine research and development aiming to facilitate a rapid response to this infectious disease threat. Here, we discuss current progress, challenges, and future directions for MARV vaccines.

Lessons from the pandemic: Responding to emerging zoonotic viral diseases-a Keystone Symposia report.

The COVID-19 pandemic caught the world largely unprepared, including scientific and policy communities. On April 10-13, 2022, researchers across academia, industry, government, and nonprofit organizations met at the Keystone symposium "Lessons from the Pandemic: Responding to Emerging Zoonotic Viral Diseases" to discuss the successes and challenges of the COVID-19 pandemic and what lessons can be applied moving forward. Speakers focused on experiences not only from the COVID-19 pandemic but also from outbreaks of other pathogens, including the Ebola virus, Lassa virus, and Nipah virus. A general consensus was that investments made during the COVID-19 pandemic in infrastructure, collaborations, laboratory and manufacturing capacity, diagnostics, clinical trial networks, and regulatory enhancements-notably, in low-to-middle income countries-must be maintained and strengthened to enable quick, concerted responses to future threats, especially to zoonotic pathogens.

Bridging Animal and Human Data in Pursuit of Vaccine Licensure.

The FDA Animal Rule was devised to facilitate approval of candidate vaccines and therapeutics using animal survival data when human efficacy studies are not practical or ethical. This regulatory pathway is critical for candidates against pathogens with high case fatality rates that prohibit human challenge trials, as well as candidates with low and sporadic incidences of outbreaks that make human field trials difficult. Important components of a vaccine development plan for Animal Rule licensure are the identification of an immune correlate of protection and immunobridging to humans. The relationship of vaccine-induced immune responses to survival after vaccination and challenge must be established in validated animal models and then used to infer predictive vaccine efficacy in humans via immunobridging. The Sabin Vaccine Institute is pursuing licensure for candidate filovirus vaccines via the Animal Rule and has convened meetings of key opinion leaders and subject matter experts to define fundamental components for vaccine licensure in the absence of human efficacy data. Here, filoviruses are used as examples to review immune correlates of protection and immunobridging. The points presented herein reflect the presentations and discussions during the second meeting held in October 2021 and are intended to address important considerations for developing immunobridging strategies.

A U.S. Government-Coordinated Effort to Leverage Non-Human Primate Data to Facilitate Ebolavirus Vaccine Development.

A United States Government (USG) interagency group, the Filovirus Animal Non-Clinical Group (FANG), has been established to support the development of biodefense medical countermeasures (MCMs). As both vaccines and therapeutics are licensed using "non-traditional pathways", such as the U.S. Food and Drug Administration's (FDA) Animal Rule (AR), non-human primate (NHP) models and associated assays have been developed and standardized across BSL4 testing sites to evaluate candidate products. Vaccine candidates are evaluated using these NHP models, and through this public-private partnership, a meta-analysis of NHP control data has been conducted and submitted to the FDA as a master file. This is an example of how existing NHP control data can be leveraged in lieu of conducting separate natural history studies at multiple testing facilities to demonstrate the consistency of a standardized animal model for vaccine development. As a result, animal use can be minimized and the duplication of effort avoided, thus reducing the amount of time needed to conduct additional studies, as well as the cost of vaccine candidate development. This successful strategy may be applied to other pathogens of high consequence for vaccine development, and shows how strategic preparedness for biodefense can be leveraged in response to outbreaks and public health emergencies.

Advances and gaps in SARS-CoV-2 infection models.

The global response to Coronavirus Disease 2019 (COVID-19) is now facing new challenges such as vaccine inequity and the emergence of SARS-CoV-2 variants of concern (VOCs). Preclinical models of disease, in particular animal models, are essential to investigate VOC pathogenesis, vaccine correlates of protection and postexposure therapies. Here, we provide an update from the World Health Organization (WHO) COVID-19 modeling expert group (WHO-COM) assembled by WHO, regarding advances in preclinical models. In particular, we discuss how animal model research is playing a key role to evaluate VOC virulence, transmission and immune escape, and how animal models are being refined to recapitulate COVID-19 demographic variables such as comorbidities and age.

Status Report on COVID-19 Vaccines Development.

PURPOSE OF REVIEW: The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has affected lives of billions of individuals, globally. There is an urgent need to develop interventions including vaccines to control the ongoing pandemic. RECENT FINDINGS: Development of tools for fast-tracked testing including small and large animal models for vaccine efficacy analysis, assays for immunogenicity assessment, critical reagents, international biological standards, and data sharing allowed accelerated development of vaccines. More than 300 vaccines are under development and 9 of them are approved for emergency use in various countries, with impressive efficacy ranging from 50 to 95%. Recently, several new SARS-CoV-2 variants have emerged and are circulating globally, and preliminary findings imply that some of them may escape immune responses against previous variants and diminish efficacy of current vaccines. Most of these variants acquired new mutations in their surface protein (Spike) which is the antigen in most of the approved/under development vaccines. SUMMARY: In this review, we summarize novel and traditional approaches for COVID-19 vaccine development including inactivated, attenuated, nucleic acid, vector and protein based. Critical assessment of humoral and cell-mediated immune responses induced by vaccines has shown comparative immunogenicity profiles of various vaccines in clinical phases. Recent reports confirmed that some currently available vaccines provide partial to complete protection against emerging SARS-CoV-2 variants. If more mutated variants emerge, current vaccines might need to be updated accordingly either by developing vaccines matching the circulating strain or designing multivalent vaccines to extend the breadth.

Opportunities for Refinement of Non-Human Primate Vaccine Studies.

Non-human primates (NHPs) are used extensively in the development of vaccines and therapeutics for human disease. High standards in the design, conduct, and reporting of NHP vaccine studies are crucial for maximizing their scientific value and translation, and for making efficient use of precious resources. A key aspect is consideration of the 3Rs principles of replacement, reduction, and refinement. Funders of NHP research are placing increasing emphasis on the 3Rs, helping to ensure such studies are legitimate, ethical, and high-quality. The UK's National Centre for the 3Rs (NC3Rs) and the Coalition for Epidemic Preparedness Innovations (CEPI) have collaborated on a range of initiatives to support vaccine developers to implement the 3Rs, including hosting an international workshop in 2019. The workshop identified opportunities to refine NHP vaccine studies to minimize harm and improve welfare, which can yield better quality, more reproducible data. Careful animal selection, social housing, extensive environmental enrichment, training for cooperation with husbandry and procedures, provision of supportive care, and implementation of early humane endpoints are features of contemporary good practice that should and can be adopted more widely. The requirement for high-level biocontainment for some pathogens imposes challenges to implementing refinement but these are not insurmountable.

Organizational factors affecting successful physician-system integration: A qualitative study of Washington State health executives.

BACKGROUND: Health care delivery is moving toward a value-based environment, which calls for increased integration between physician groups and health systems. Health executives sit at a key nexus point for determining how and when physician-system integration occurs. PURPOSE: The objective of this study was to identify the organizational factors that health executives perceived to have made physician-system integration successful. METHODOLOGY/APPROACH: We used a multiple-case study research design. We conducted semistructured, qualitative interviews with 25 health executives in the roles of CEO, chief medical officer, chief financial officer and physician group chief executives from eight of Washington State's largest integrated delivery systems. To guide our analysis, we employed open systems theory and Porter's Value Chain to identify physician group and hospital factors that were integral to successful integration. RESULTS: Using the executives' perspectives, the factors grouped into three themes: (1) organizational structure-a mix of integration contracts united by common structural characteristics between physician groups and hospitals); (2) organizational culture-alignment of leadership between physician groups and hospitals; and (3) strategic resources-designated resources to establish and support care coordination activities. CONCLUSION: Our work indicates that health systems should focus on the pathway to integration success through the alignment of structure (not just the integration contract), culture, and resources and not on an end goal of the physician employment model. PRACTICE IMPLICATIONS: Health system executives are key drivers for when and how physician groups are integrated into health services organizations. This article provides executives with an evidence-based model to aid in formulating integration approaches that combine elements of organizational structure, organizational culture, and strategic resources.

Animal models for COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19), an emerging respiratory infection caused by the introduction of a novel coronavirus into humans late in 2019 (first detected in Hubei province, China). As of 18 September 2020, SARS-CoV-2 has spread to 215 countries, has infected more than 30 million people and has caused more than 950,000 deaths. As humans do not have pre-existing immunity to SARS-CoV-2, there is an urgent need to develop therapeutic agents and vaccines to mitigate the current pandemic and to prevent the re-emergence of COVID-19. In February 2020, the World Health Organization (WHO) assembled an international panel to develop animal models for COVID-19 to accelerate the testing of vaccines and therapeutic agents. Here we summarize the findings to date and provides relevant information for preclinical testing of vaccine candidates and therapeutic agents for COVID-19.

Kikwit Ebola Virus Disease Progression in the Rhesus Monkey Animal Model.

Ongoing Ebola virus disease outbreaks in the Democratic Republic of the Congo follow the largest recorded outbreak in Western Africa (2013-2016). To combat outbreaks, testing of medical countermeasures (therapeutics or vaccines) requires a well-defined, reproducible, animal model. Here we present Ebola virus disease kinetics in 24 Chinese-origin rhesus monkeys exposed intramuscularly to a highly characterized, commercially available Kikwit Ebola virus Filovirus Animal Non-Clinical Group (FANG) stock. Until reaching predetermined clinical disease endpoint criteria, six animals underwent anesthesia for repeated clinical sampling and were compared to six that did not. Groups of three animals were euthanized and necropsied on days 3, 4, 5, and 6 post-exposure, respectively. In addition, three uninfected animals served as controls. Here, we present detailed characterization of clinical and laboratory disease kinetics and complete blood counts, serum chemistries, Ebola virus titers, and disease kinetics for future medical countermeasure (MCM) study design and control data. We measured no statistical difference in hematology, chemistry values, or time to clinical endpoint in animals that were anesthetized for clinical sampling during the acute disease compared to those that were not.

Text Snippets to Corroborate Medical Relations: An Unsupervised Approach using a Knowledge Graph and Embeddings.

Knowledge graphs have been shown to significantly improve search results. Usually populated by subject matter experts, relations therein need to keep up to date with medical literature in order for search to remain relevant. Dynamically identifying text snippets in literature that confirm or deny knowledge graph triples is increasingly becoming the differentiator between trusted and untrusted medical decision support systems. This work describes our approach to mapping triples to medical text. A medical knowledge graph is used as a source of triples that are used to find matching sentences in reference text. Our unsupervised approach uses phrase embeddings and cosine similarity measures, and boosts candidate text snippets when certain key concepts exist. Using this approach, we can accurately map semantic relations within the medical knowledge graph to text snippets with a precision of 61.4% and recall of 86.3%. This method will be used to develop a novel application in the future to retrieve medical relations and corroborating snippets from medical text given a user query.

The Contribution of Physician-System Integrating Structure to Select Health System Outcomes.

Physician groups are increasingly being vertically integrated with hospitals and health systems; yet, the evidence on the impact of physician-system integration on health system outcomes is mixed. The objective of this study was to examine the impact of increased physician-system integration on select health system outcomes. We used a mixed-methods approach: (1) a fixed-effects multivariate mediation analysis; and (2) a qualitative analysis of interviews with health executives (n = 25). Our findings showed that hospitals spent $633 375.22 to $827 110.24 for each "level" increase in integration. This relationship was attenuated, however, by the presence of care coordination mechanisms.

In Vivo Activity of Amodiaquine against Ebola Virus Infection.

During the Ebola virus disease (EVD) epidemic in Western Africa (2013‒2016), antimalarial treatment was administered to EVD patients due to the high coexisting malaria burden in accordance with World Health Organization guidelines. In an Ebola treatment center in Liberia, EVD patients receiving the combination antimalarial artesunate-amodiaquine had a lower risk of death compared to those treated with artemether-lumefantrine. As artemether and artesunate are derivatives of artemisinin, the beneficial anti-Ebola virus (EBOV) effect observed could possibly be attributed to the change from lumefantrine to amodiaquine. Amodiaquine is a widely used antimalarial in the countries that experience outbreaks of EVD and, therefore, holds promise as an approved drug that could be repurposed for treating EBOV infections. We investigated the potential anti-EBOV effect of amodiaquine in a well-characterized nonhuman primate model of EVD. Using a similar 3-day antimalarial dosing strategy as for human patients, plasma concentrations of amodiaquine in healthy animals were similar to those found in humans. However, the treatment regimen did not result in a survival benefit or decrease of disease signs in EBOV-infected animals. While amodiaquine on its own failed to demonstrate efficacy, we cannot exclude potential therapeutic value of amodiaquine when used in combination with artesunate or another antiviral.

Challenges and Benefits of Repurposing Products for Use during a Radiation Public Health Emergency: Lessons Learned from Biological Threats and other Disease Treatments.

The risk of a radiological or nuclear public health emergency is a major growing concern of the U.S. government. To address a potential incident and ensure that the government is prepared to respond to any subsequent civilian or military casualties, the U.S. Department of Health and Human Services and the Department of Defense have been charged with the development of medical countermeasures (MCMs) to treat the acute and delayed injuries that can result from radiation exposure. Because of the limited budgets in research and development and the high costs associated with bring promising approaches from the bench through advanced product development activities, and ultimately, to regulatory approval, the U.S. government places a priority on repurposing products for which there already exists relevant safety and other important information concerning their use in humans. Generating human data can be a costly and time-consuming process; therefore, the U.S. government has interest in drugs for which such relevant information has been established (e.g., products for another indication), and in determining if they could be repurposed for use as MCMs to treat radiation injuries as well as chemical and biological insults. To explore these possibilities, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop including U.S. government, industry and academic subject matter experts, to discuss the challenges and benefits of repurposing products for a radiation indication. Topics covered included a discussion of U.S. government efforts (e.g. funding, stockpiling and making products available for study), as well unique regulatory and other challenges faced when repurposing patent protected or generic drugs. Other discussions involved lessons learned from industry on repurposing pre-license, pipeline products within drug development portfolios. This report reviews the information presented, as well as an overview of discussions from the meeting.

Five year results of the prospective randomized controlled prostatic urethral L.I.F.T. study.

INTRODUCTION: To report the five year results of a prospective, multi-center, randomized, blinded sham control trial of the Prostatic Urethral Lift (PUL) in men with bothersome lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: At 19 centers in North America and Australia, 206 subjects ≥ 50 years old with International Prostate Symptom Score (IPSS ) > 12, peak flow rate (Qmax) ≤ 12 mL/s, and prostate volume 30 cc-80 cc were randomized 2:1 to the PUL procedure or blinded sham control. In PUL permanent UroLift implants are placed to hold open the lateral lobes of the prostate to reduce urinary obstruction. After randomized comparison at 3 months and the only opportunity to add more PUL implants, PUL patients were followed to 5 years. LUTS severity (IPSS), quality of life (QOL), BPH Impact Index (BPHII), Qmax, sexual function, and adverse events were assessed throughout follow up. RESULTS: IPSS improvement after PUL was 88% greater than that of sham at 3 months. LUTS and QOL were significantly improved by 2 weeks with return to preoperative physical activity within 8.6 days. Improvement in IPSS, QOL, BPHII, and Qmax were durable through 5 years with improvements of 36%, 50%, 52%, and 44% respectively. No difference was seen between Intent to Treat and Per Protocol populations. Surgical retreatment was 13.6% over 5 years. Adverse events were mild to moderate and transient. Sexual function was stable over 5 years with no de novo, sustained erectile or ejaculatory dysfunction. CONCLUSIONS: PUL offers rapid improvement in symptoms, QOL and flow rate that is durable to 5 years. These improvements were achieved with minimal use of a postoperative urinary catheter, rapid return to normal, and preservation of both erectile and ejaculatory function. Symptom improvement was commensurate with patient satisfaction. PUL offers a minimally invasive option in the treatment of LUTS due to BPH.

Transforming growth factor ß1 (TGFß1) regulates CD44V6 expression and activity through extracellular signal-regulated kinase (ERK)-induced EGR1 in pulmonary fibrogenic fibroblasts.

The appearance of myofibroblasts is generally thought to be the underlying cause of the fibrotic changes that underlie idiopathic pulmonary fibrosis. However, the cellular/molecular mechanisms that account for the fibroblast-myofibroblast differentiation/activation in idiopathic pulmonary fibrosis remain poorly understood. We investigated the functional role of hyaluronan receptor CD44V6 (CD44 containing variable exon 6 (v6)) for differentiation of lung fibroblast to myofibroblast phenotype. Increased hyaluronan synthesis and CD44 expression have been detected in numerous fibrotic organs. Previously, we found that the TGFß1/CD44V6 pathway is important in lung myofibroblast collagen-1 and α-smooth-muscle actin synthesis. Because increased EGR1 (early growth response-1) expression has been shown to appear very early and nearly coincident with the expression of CD44V6 found after TGFß1 treatment, we investigated the mechanism(s) of regulation of CD44V6 expression in lung fibroblasts by TGFß1. TGFß1-mediated CD44V6 up-regulation was initiated through EGR1 via ERK-regulated transcriptional activation. We showed that TGFß1-induced CD44V6 expression is through EGR1-mediated AP-1 (activator protein-1) activity and that the EGR1- and AP-1-binding sites in the CD44v6 promoter account for its responsiveness to TGFß1 in lung fibroblasts. We also identified a positive-feedback loop in which ERK/EGR1 signaling promotes CD44V6 splicing and found that CD44V6 then sustains ERK signaling, which is important for AP-1 activity in lung fibroblasts. Furthermore, we identified that HAS2-produced hyaluronan is required for CD44V6 and TGFßRI co-localization and subsequent CD44V6/ERK1/EGR1 signaling. These results demonstrate a novel positive-feedback loop that links the myofibroblast phenotype to TGFß1-stimulated CD44V6/ERK/EGR1 signaling.

Three year results of the prostatic urethral L.I.F.T. study.

INTRODUCTION: To report the three year results of a multi-center, randomized, patient and outcome assessor blinded trial of the Prostatic Urethral Lift (PUL) in men with bothersome lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: At 19 centers in North America and Australia, 206 subjects = 50 years old with International Prostate Symptom Score (IPSS) ≥ 13, peak flow rate (Qmax) ≤ 12 mL/s, and prostate volume between 30 cc-80 cc were randomized 2:1 to the PUL procedure or sham control. PUL involved placing permanent UroLift implants into the lateral lobes of the prostate to enlarge the urethral lumen. After randomized comparison at 3 months, PUL patients were followed to 3 years. LUTS severity (IPSS), quality of life, Qmax, sexual function, and adverse events were assessed throughout follow up. RESULTS: The therapeutic effect of PUL regarding IPSS was 88% greater than sham at 3 months. Average improvements from baseline through 3 years were significant for total IPSS (41.1%), quality of life (48.8%), Qmax (53.1%), and individual IPSS symptoms. Symptomatic improvement was independent of prostate size. There were no de novo, sustained ejaculatory or erectile dysfunction events and all sexual function assessments showed average stability or improvement after PUL. Fifteen of the 140 patients originally randomized to PUL required surgical reintervention for treatment failure within the first 3 years. CONCLUSIONS: PUL offers rapid improvement in voiding and storage symptoms, quality of life and flow rate that is durable to 3 years. Patients demonstrated a level of symptom relief that is associated with significant patient satisfaction. PUL, a minimally invasive procedure, is very effective in treating bothersome LUTS secondary to benign prostatic obstruction (BPO) and is unique in its ability to preserve total sexual function while offering a rapid return to normal physical activities.