Development of Next-Generation COVID-19 Vaccines: BARDA Supported Phase 2b Study Designs.

In response to the COVID-19 pandemic, vaccines were quickly and successfully developed and deployed, saving millions of lives globally. While first generation vaccines are safe and effective in preventing disease caused by SARSCoV-2, next-generation vaccines have the potential to improve efficacy and safety. Vaccines delivered by a mucosal route may elicit greater protective immunity at respiratory surfaces thereby reducing transmission. Inclusion of viral antigens in addition to the spike protein may enhance protection against emerging variants of concern. Next-generation vaccine platforms with a new mechanism of action may necessitate efficacy trials to fulfill regulatory requirements. The Biomedical Advanced Research and Development Authority (BARDA) will be supporting Phase 2b clinical trials of candidate next-generation vaccines. The primary endpoint will be improved efficacy in terms of symptomatic disease relative to a currently approved COVID-19 vaccine. In this paper, we discuss the planned endpoints and potential challenges to this complex program.

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.

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.

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.

Percutaneous closure of patent foramen ovale for the secondary prevention of decompression illness in sports divers: mind the gap.

OBJECTIVE: To evaluate the efficiency of percutaneous patent foramen ovale (PFO) closure on the recurrence of decompression illness (DCI). DESIGN: Retrospective, observational study with interview and questionnaire. SETTING: Tertiary referral center. POPULATION: 59 scuba divers with a history of DCI who received a percutaneous PFO closure. MAIN OUTCOME MEASUREMENTS: Questionnaire about health status, dive habits and recurrence of DCI after PFO closure. RESULTS: A total of 59 divers with DCI were included. The most common manifestations of DCI were cutaneous or vestibular DCI. Procedural complications occurred in four patients but none with long-term consequences. Four patients had recurrence of DCI after closure during a 10-year follow-up. In three of these cases there was residual shunting, all of which were initially considered closed. The fourth patient had aggravating factors for his recurrent DCI. A quarter of the patients stated to have changed their diving habits. Four patients quit diving. CONCLUSION: Percutaneous PFO closure for secondary prevention of DCI is associated with few, but not negligible, complications. As a large portion of our cohort changed their diving habit after closure it is difficult to ascertain the efficiency of PFO closure for secondary prevention of DCI. However, the study shows that PFO closure does not fully protect against DCI, emphasizing that the relationship between PFO and DCI is but an association. As such it is imperative that divers be counseled to ensure they understand the risks as well as the benefits of percutaneous PFO closure in their specific case.

Evaluation of 3D printed optofluidic smart glass prototypes.

Smart glass or smart windows are an innovative technology used for thermal management, energy efficiency, and privacy applications. Notable commercially available smart glass relies on an electric stimuli to modulate the glass from a transparent to a translucent mode of operation. However, the current market technologies, such as electrochromic, polymer dispersed liquid crystal, and suspended particle devices are expensive and suffer from solar absorption, poor transmittance modulation, and in some cases, continuous power consumption. The authors of this paper present a novel optofluidic smart glass prototype capable of modulating visible light transmittance from 8% to 85%.

Low frequency variants, collapsed based on biological knowledge, uncover complexity of population stratification in 1000 genomes project data.

Analyses investigating low frequency variants have the potential for explaining additional genetic heritability of many complex human traits. However, the natural frequencies of rare variation between human populations strongly confound genetic analyses. We have applied a novel collapsing method to identify biological features with low frequency variant burden differences in thirteen populations sequenced by the 1000 Genomes Project. Our flexible collapsing tool utilizes expert biological knowledge from multiple publicly available database sources to direct feature selection. Variants were collapsed according to genetically driven features, such as evolutionary conserved regions, regulatory regions genes, and pathways. We have conducted an extensive comparison of low frequency variant burden differences (MAF<0.03) between populations from 1000 Genomes Project Phase I data. We found that on average 26.87% of gene bins, 35.47% of intergenic bins, 42.85% of pathway bins, 14.86% of ORegAnno regulatory bins, and 5.97% of evolutionary conserved regions show statistically significant differences in low frequency variant burden across populations from the 1000 Genomes Project. The proportion of bins with significant differences in low frequency burden depends on the ancestral similarity of the two populations compared and types of features tested. Even closely related populations had notable differences in low frequency burden, but fewer differences than populations from different continents. Furthermore, conserved or functionally relevant regions had fewer significant differences in low frequency burden than regions under less evolutionary constraint. This degree of low frequency variant differentiation across diverse populations and feature elements highlights the critical importance of considering population stratification in the new era of DNA sequencing and low frequency variant genomic analyses.

Modeling low-dose mortality and disease incubation period of inhalational anthrax in the rabbit.

There is a need to advance our ability to conduct credible human risk assessments for inhalational anthrax associated with exposure to a low number of bacteria. Combining animal data with computational models of disease will be central in the low-dose and cross-species extrapolations required in achieving this goal. The objective of the current work was to apply and advance the competing risks (CR) computational model of inhalational anthrax where data was collected from NZW rabbits exposed to aerosols of Ames strain Bacillus anthracis. An initial aim was to parameterize the CR model using high-dose rabbit data and then conduct a low-dose extrapolation. The CR low-dose attack rate was then compared against known low-dose rabbit data as well as the low-dose curve obtained when the entire rabbit dose-response data set was fitted to an exponential dose-response (EDR) model. The CR model predictions demonstrated excellent agreement with actual low-dose rabbit data. We next used a modified CR model (MCR) to examine disease incubation period (the time to reach a fever >40 °C). The MCR model predicted a germination period of 14.5h following exposure to a low spore dose, which was confirmed by monitoring spore germination in the rabbit lung using PCR, and predicted a low-dose disease incubation period in the rabbit between 14.7 and 16.8 days. Overall, the CR and MCR model appeared to describe rabbit inhalational anthrax well. These results are discussed in the context of conducting laboratory studies in other relevant animal models, combining the CR/MCR model with other computation models of inhalational anthrax, and using the resulting information towards extrapolating a low-dose response prediction for man.

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.

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.

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.

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.

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.

IL-10 induction by Bordetella parapertussis limits a protective IFN-gamma response.

Bordetella parapertussis causes the prolonged coughing illness known as pertussis or whooping cough, persisting for weeks within the respiratory tracts of infected hosts but inducing a very poor T cell response relative to that induced by Bordetella pertussis, the more common cause of pertussis. In this study, we examine the contributions of cytokines involved in the clearance of B. parapertussis and immunomodulation that delays effective clearance. The slow elimination of this pathogen from the respiratory tracts of mice coincides with the gradual accumulation of CD4(+) T cells in the lungs and B. parapertussis-responsive IFN-gamma-producing cells in the spleen. IFN-gamma-deficient mice were defective in the accumulation of leukocytes in lungs and in clearance of B. parapertussis from the lungs. In vitro B. parapertussis-stimulated macrophages produced IL-10, which inhibited the generation of the IFN-gamma response that is required for protection in vivo. As compared with wild-type mice, IL-10-deficient mice produced significantly higher levels of IFN-gamma, had higher numbers of leukocytes accumulated in the lungs, and cleared B. parapertussis more rapidly. Together, these data indicate that B. parapertussis induces the production of IL-10, which facilitates its persistence within infected hosts by limiting a protective IFN-gamma response.

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.

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.

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.