Efficacy of different AV7909 dose regimens in a nonclinical model of pulmonary anthrax.

Pulmonary anthrax caused by exposure to inhaled Bacillus anthracis, the most lethal form of anthrax disease, is a continued military and public health concern for the United States. The vaccine AV7909, consisting of the licensed anthrax drug substance AVA adjuvanted with CpG7909, induces high levels of toxin neutralizing antibodies in healthy adults using fewer doses than AVA. This study compares the ability of one- or two-dose regimens of AV7909 to induce a protective immune response in guinea pigs challenged with a lethal dose of aerosolized B. anthracis spores 6 weeks after the last vaccine dose. The results indicated that AV7909 was less effective when delivered as a single dose compared to the two-dose regimen that resulted in dose-dependent protection against death. The toxin neutralizing assay (TNA) titer and anti-PA IgG responses were proportional to the protective efficacy, with a 50% TNA neutralizing factor (NF50) greater than 0.1 associated with survival in animals receiving two doses of vaccine. The strong protection at relatively low TNA NF50 titers in this guinea pig model supports the exploration of lower doses in clinical trials to determine if these protective levels of neutralizing antibodies can be achieved in humans; however, protection with a single dose may not be feasible.

Perspectives on Advancing Countermeasures for Filovirus Disease: Report From a Multisector Meeting.

Although there are now approved treatments and vaccines for Ebola virus disease, the case fatality rate remains unacceptably high even when patients are treated with the newly approved therapeutics. Furthermore, these countermeasures are not expected to be effective against disease caused by other filoviruses. A meeting of subject-matter experts was held during the 10th International Filovirus Symposium to discuss strategies to address these gaps. Several investigational therapeutics, vaccine candidates, and combination strategies were presented. The greatest challenge was identified to be the implementation of well-designed clinical trials of safety and efficacy during filovirus disease outbreaks. Preparing for this will require agreed-upon common protocols for trials intended to bridge multiple outbreaks across all at-risk countries. A multinational research consortium including at-risk countries would be an ideal mechanism to negotiate agreement on protocol design and coordinate preparation. Discussion participants recommended a follow-up meeting be held in Africa to establish such a consortium.

From private incentives to public health need: rethinking research and development for pandemic preparedness.

Pandemic preparedness and response have relied primarily on market dynamics to drive development and availability of new health products. Building on calls for transformation, we propose a new value proposition that instead prioritises equity from the research and development (R&D) stage and that strengthens capacity to control outbreaks when and where they occur. Key elements include regional R&D hubs free to adapt well established technology platforms, and independent clinical trials networks working with researchers, regulators, and health authorities to better study questions of comparative benefit and real-world efficacy. Realising these changes requires a shift in emphasis: from pandemic response to outbreak control, from one-size-fits-all economies of scale to R&D and manufacture for local need, from de novo product development to last-mile innovation through adaptation of existing technologies, and from proprietary, competitive R&D to open science and financing for the common good that supports collective management and sharing of technology and know-how.

The Effect of Transcutaneous Electrotherapy on Lumbar Range of Motion and Paraspinal Muscle Characteristics in Chronic Low Back Pain Patients: A Systematic Review and Meta-Analysis.

Chronic low back pain (CLBP) affects paraspinal muscle size, quality (e.g., fatty infiltration), range of motion (ROM), and strength. Although transcutaneous electrotherapies are used to treat CLBP, their effects on paraspinal-related outcomes are not fully known. The aim of this systematic review and meta-analysis was to assess the overall effect of transcutaneous electrotherapies on trunk/lumbar ROM, paraspinal muscle morphology, and trunk muscle function (including strength and endurance) in CLBP patients. A systematic search of four databases and two study registers was conducted between 1 February 2022 and 15 September 2022. Two reviewers were responsible for screening and data extraction. Of the 3939 independent records screened, 10 were included in the systematic review and 2 in the meta-analysis. The results suggest there is limited evidence that both EMS and EMS plus exercise are superior to passive and active controls, respectively, for improving trunk muscle endurance. There is limited evidence that neither TENS nor mixed TENS are superior to controls for improving trunk muscle endurance. There is limited evidence that NMES is superior to passive controls for improving trunk muscle strength. The effect of transcutaneous electrotherapy on the other investigated outcomes was inconclusive. Future transcutaneous electrotherapy studies should focus on paraspinal-based outcomes that are under-studied.

Developing Vaccines to Improve Preparedness for Filovirus Outbreaks: The Perspective of the USA Biomedical Advanced Research and Development Authority (BARDA).

Outbreaks of viral hemorrhagic fever caused by filoviruses have become more prevalent in recent years, with outbreaks of Ebola virus (EBOV), Sudan virus (SUDV), and Marburg virus (MARV) all occurring in 2022 and 2023. While licensed vaccines are now available for EBOV, vaccine candidates for SUDV and MARV are all in preclinical or early clinical development phases. During the recent outbreak of SUDV virus disease, the Biomedical Advanced Research and Development Authority (BARDA), as part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services, implemented key actions with our existing partners to advance preparedness and enable rapid response to the outbreak, while also aligning with global partners involved in the implementation of clinical trials in an outbreak setting. Beyond pre-existing plans prior to the outbreak, BARDA worked with product sponsors to expedite manufacturing of vaccine doses that could be utilized in clinical trials. While the SUDV outbreak has since ended, a new outbreak of MARV disease has emerged. It remains critical that we continue to advance a portfolio of vaccines against SUDV and MARV while also expediting manufacturing activities ahead of, or in parallel if needed, outbreaks.

Ultrasonography of the multifidus muscle in student circus artists with and without low back pain: a cross-sectional study.

BACKGROUND: Degenerative structural changes and functional deficits of the lumbar multifidus (LM) muscle were observed in athletes with low back pain. While spinal injuries are common in circus artists, there is no information on LM characteristics in this population. The aims of this study were to investigate LM morphology and function and explore the relationship between LM characteristics and low back pain in male and female circus artists. METHODS: 31 college circus students were recruited. Participants completed an online survey to acquire demographic data and low back pain history. Body composition was measured using multi-frequency bio-impedance analysis. Ultrasound examinations at the fifth lumbar vertebrae in prone and standing positions were performed to assess LM cross-sectional area, echo-intensity, thickness. Independent and dependent t-test assessed the difference between sex and side, respectively. The relationships between measures were assessed with Pearson's correlations. The LM characteristics' difference between artists with and without low back pain (group binary variable) was assessed with Analysis of covariance using lean body mass, height and % body fat as continuous covariates. RESULTS: Males had significantly larger LM cross-sectional area, lower echo-intensity and greater thickness change from rest to contracted than females. LM cross-sectional area asymmetry in prone was greater in artists reporting low back pain in the previous 4-weeks (p = 0.029) and 3-months (p = 0.009). LM measures were correlated with lean body mass, height, and weight (r = 0.40-0.77, p ≤ 0.05). CONCLUSION: This study provided novel insights into LM characteristics in circus artists. Greater LM asymmetry was observed in artists with a history of low back pain. In accordance with previous studies in athletes, LM morphology and function were highly correlated with body composition measurements.

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.S. We also evaluated correlates of protection in the trial cohort. Of the three antibody immune markers we measured, we found most support for 50% inhibitory dilution (ID50) neutralizing antibody titre as a correlate of risk and of protection. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; P = 0.006) per 10-fold increase in ID50; vaccine efficacy was 60% (43%, 72%) at non-quantifiable ID50 (<2.7 IU50 ml-1) and increased to 89% (78%, 96%) at ID50 = 96.3 IU50 ml-1. Comparison of the vaccine efficacy by ID50 titre curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine and the COV002-UK trial of the AZD1222 vaccine supported the ID50 titre as a correlate of protection across trials and vaccine types.

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.

Natural History of Marburg Virus Infection to Support Medical Countermeasure Development.

The Biomedical Advanced Research and Development Authority, part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services, recognizes that the evaluation of medical countermeasures under the Animal Rule requires well-characterized and reproducible animal models that are likely to be predictive of clinical benefit. Marburg virus (MARV), one of two members of the genus Marburgvirus, is characterized by a hemorrhagic fever and a high case fatality rate for which there are no licensed vaccines or therapeutics available. This natural history study consisted of twelve cynomolgus macaques challenged with 1000 PFU of MARV Angola and observed for body weight, temperature, viremia, hematology, clinical chemistry, and coagulation at multiple time points. All animals succumbed to disease within 8 days and exhibited signs consistent with those observed in human cases, including viremia, fever, systemic inflammation, coagulopathy, and lymphocytolysis, among others. Additionally, this study determined the time from exposure to onset of disease manifestations and the time course, frequency, and magnitude of the manifestations. This study will be instrumental in the design and development of medical countermeasures to Marburg virus disease.

The Evolution of Medical Countermeasures for Ebola Virus Disease: Lessons Learned and Next Steps.

The Ebola virus disease outbreak that occurred in Western Africa from 2013-2016, and subsequent smaller but increasingly frequent outbreaks of Ebola virus disease in recent years, spurred an unprecedented effort to develop and deploy effective vaccines, therapeutics, and diagnostics. This effort led to the U.S. regulatory approval of a diagnostic test, two vaccines, and two therapeutics for Ebola virus disease indications. Moreover, the establishment of fieldable diagnostic tests improved the speed with which patients can be diagnosed and public health resources mobilized. The United States government has played and continues to play a key role in funding and coordinating these medical countermeasure efforts. Here, we describe the coordinated U.S. government response to develop medical countermeasures for Ebola virus disease and we identify lessons learned that may improve future efforts to develop and deploy effective countermeasures against other filoviruses, such as Sudan virus and Marburg virus.

Natural History of Sudan ebolavirus to Support Medical Countermeasure Development.

Sudan ebolavirus (SUDV) is one of four members of the Ebolavirus genus known to cause Ebola Virus Disease (EVD) in humans, which is characterized by hemorrhagic fever and a high case fatality rate. While licensed therapeutics and vaccines are available in limited number to treat infections of Zaire ebolavirus, there are currently no effective licensed vaccines or therapeutics for SUDV. A well-characterized animal model of this disease is needed for the further development and testing of vaccines and therapeutics. In this study, twelve cynomolgus macaques (Macaca fascicularis) were challenged intramuscularly with 1000 PFUs of SUDV and were followed under continuous telemetric surveillance. Clinical observations, body weights, temperature, viremia, hematology, clinical chemistry, and coagulation were analyzed at timepoints throughout the study. Death from SUDV disease occurred between five and ten days after challenge at the point that each animal met the criteria for euthanasia. All animals were observed to exhibit clinical signs and lesions similar to those observed in human cases which included: viremia, fever, dehydration, reduced physical activity, macular skin rash, systemic inflammation, coagulopathy, lymphoid depletion, renal tubular necrosis, hepatocellular degeneration and necrosis. The results from this study will facilitate the future preclinical development and evaluation of vaccines and therapeutics for SUDV.

The effect of phasic versus combined neuromuscular electrical stimulation using the StimaWELL 120MTRS system on multifidus muscle morphology and function in patients with chronic low back pain: a randomized controlled trial protocol.

BACKGROUND: Neuromuscular electrical stimulation (NMES) is used to improve muscle strength clinically when rehabilitating various musculoskeletal disorders. However, the effects of NMES on muscle morphology and function in individuals with non-specific chronic low back pain (CLBP) have scarcely been investigated. Although research links deficits in the paraspinal musculature with subjective reports of pain and disability, it is unknown if treatment with NMES can help reverse these deficits. Therefore, the primary aim of this study is to compare the effects of two muscle therapy protocols with a medium-frequency electrotherapy device (the StimaWELL 120MTRS system) on multifidus muscle morphology and function in CLBP patients. The secondary aims are to determine the effects of these protocols subjective reports of pain intensity, pain interference, disability, and catastrophizing. METHODS: A total of 30 participants with non-specific CLBP, aged 18-60, will be recruited from local orthopedic clinics and databases. Participants will be randomized (1:1) to either the phasic or combined (phasic + tonic) muscle therapy protocols on the StimaWELL 120MTRS system. Participants will undergo 20 supervised electrotherapy treatments over a 10-week period. The primary outcomes will be multifidus morphology (e.g. cross-sectional area (CSA), fat infiltration) and function (e.g., contraction measured via %thickness change from a rested to contracted state, and stiffness at rest and during contraction). Secondary outcomes will include pain intensity, interference, disability, and catastrophizing. Both primary and secondary outcomes will be obtained at baseline and at 11-weeks; secondary outcomes measured via questionnaires will also be obtained at 6-weeks, while LBP intensity will be measured before and after each treatment. Paired t-tests will be used to assess within-group changes for all primary outcome measures. A two-way repeated-measures analysis of variance will be used to assess changes in secondary outcomes over time. DISCUSSION: The results of this trial will help clarify the role of medium-frequency NMES on lumbar multifidus morphology and function. TRIAL REGISTRATION: NCT04891692, registered retrospectively on May 18, 2021.

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. Each marker had evidence as a correlate of risk and of protection, with strongest evidence for 50% inhibitory dilution (ID50) neutralizing antibody titer. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; p=0.006) per 10-fold increase in ID50; vaccine efficacy was 60% (43, 72%) at nonquantifiable ID50 (< 2.7 IU50/ml) and rose to 89% (78, 96%) at ID50 = 96.3 IU50/ml. Comparison of the vaccine efficacy by ID50 titer curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine, and the COV002-UK trial of the AZD1222 vaccine supported consistency of the ID50 titer correlate of protection across trials and vaccine types.

Partnering on vaccines to counter multi-drug resistant threats: Workshop proceedings, Biomedical Advanced Research and Development Authority.

On March 12, 2021, the Biomedical Advanced Research and Development Authority (BARDA) sponsored a virtual market research workshop, "Partnering on Vaccines to Counter Multi-Drug Resistant Threats," to discuss the threat of antimicrobial resistance in the context of BARDA's mission space and the challenges encountered during the development of vaccines for specific antimicrobial resistant bacteria. The workshop convened representatives with expertise in vaccine development from government, academia, and industry. This report summarizes the presentations and subsequent discussions from the workshop and highlights existing challenges to advance the development of vaccine candidates for antimicrobial resistant pathogens, including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus.

Utilization of Viral Vector Vaccines in Preparing for Future Pandemics.

As the global response to COVID-19 continues, government stakeholders and private partners must keep an eye on the future for the next emerging viral threat with pandemic potential. Many of the virus families considered to be among these threats currently cause sporadic outbreaks of unpredictable size and timing. This represents a major challenge in terms of both obtaining sufficient funding to develop vaccines, and the ability to evaluate clinical efficacy in the field. However, this also presents an opportunity in which vaccines, along with robust diagnostics and contact tracing, can be utilized to respond to outbreaks as they occur, and limit the potential for further spread of the disease in question. While mRNA-based vaccines have proven, during the COVID-19 response, to be an effective and safe solution in terms of providing a rapid response to vaccine development, virus vector-based vaccines represent a class of vaccines that can offer key advantages in certain performance characteristics with regard to viruses of pandemic potential. Here, we will discuss some of the key pros and cons of viral vector vaccines in the context of preparing for future pandemics.

Selection of Filovirus Isolates for Vaccine Development Programs.

The continuing outbreaks of ebola virus disease highlight the ongoing threat posed by filoviruses. Fortunately, licensed vaccines and therapeutics are now available for Zaire ebolavirus. However, effective medical countermeasures, such as vaccines for other filoviruses such as Sudan ebolavirus and the Marburg virus, are presently in early stages of development and, in the absence of a large outbreak, would require regulatory approval via the U.S. Food and Drug Administration (FDA) Animal Rule. The selection of an appropriate animal model and virus challenge isolates for nonclinical studies are critical aspects of the development program. Here, we have focused on the recommendation of challenge isolates for Sudan ebolavirus and Marburg virus. Based on analyses led by the Filovirus Animal and Nonclinical Group (FANG) and considerations for strain selection under the FDA Guidance for the Animal Rule, we propose prototype virus isolates for use in nonclinical challenge studies.

Reprint of: Biotechnologies and the future of opioid addiction treatments.

The future of treatment-including addiction treatment-is biotechnological. Depot injections, agonist/antagonist implants, deep brain stimulation, and hapten conjugate vaccines are hailed by researchers and pharmaceutical manufacturers as medicine's best hope to minimize illicit use, to decrease risk of overdose and painful withdrawal, and to prevent diversion of medicines to illicit markets. Marketing and use of new technologies reveal old tensions framing concepts of addiction and its treatment: between medical condition and disorder of the will, between criminal justice and health, and between patient choice and system control. Using the examples of depot naltrexone and implantable and injectable buprenorphine in the U.S., this essay considers the arc of long-acting opioid treatment and implications for the future. These include the rise of Vivitrol courts and "carceral prescription"-where criminal justice systems mandate medicine to lock up brain receptors much as they might lock up people themselves-as well as use of buprenorphine formulations positioned as increasing both patient benefit and provider control. We also consider lessons from debates on long-acting contraceptive technologies such as Norplant and Depo-Provera. While multiple new long-acting formulations are under development, success will be determined less by characteristics of particular formulations and more by whether or not the new technologies are accompanied by a new ethics of addiction treatment that emphasizes therapeutic alliance, concordance over compliance, and a genuine commitment to allowing patients the ability to narrate and be believed in their descriptions of their treatment experiences.

Biotechnologies and the future of opioid addiction treatments.

The future of treatment-including addiction treatment-is biotechnological. Depot injections, agonist/antagonist implants, deep brain stimulation, and hapten conjugate vaccines are hailed by researchers and pharmaceutical manufacturers as medicine's best hope to minimize illicit use, to decrease risk of overdose and painful withdrawal, and to prevent diversion of medicines to illicit markets. Marketing and use of new technologies reveal old tensions framing concepts of addiction and its treatment: between medical condition and disorder of the will, between criminal justice and health, and between patient choice and system control. Using the examples of depot naltrexone and implantable and injectable buprenorphine in the U.S., this essay considers the arc of long-acting opioid treatment and implications for the future. These include the rise of Vivitrol courts and "carceral prescription"-where criminal justice systems mandate medicine to lock up brain receptors much as they might lock up people themselves-as well as use of buprenorphine formulations positioned as increasing both patient benefit and provider control. We also consider lessons from debates on long-acting contraceptive technologies such as Norplant and Depo-Provera. While multiple new long-acting formulations are under development, success will be determined less by characteristics of particular formulations and more by whether or not the new technologies are accompanied by a new ethics of addiction treatment that emphasizes therapeutic alliance, concordance over compliance, and a genuine commitment to allowing patients the ability to narrate and be believed in their descriptions of their treatment experiences.