Safety and immunogenicity of the NVX-CoV2373 vaccine as a booster in adults previously vaccinated with the BBIBP-CorV vaccine.

This phase 3 observer-blind, randomized, controlled study was conducted in adults ≥18 years of age to assess the safety and immunogenicity of NVX-CoV2373 as a heterologous booster compared to BBIBP-CorV when utilized as a homologous booster. Approximately 1000 participants were randomly assigned in a 1:1 ratio to receive a single dose of NVX-CoV2373 or BBIBP-CorV after prior vaccination with 2 or 3 doses of BBIBP-CorV. Solicited adverse events (AEs) were collected for 7 days after vaccination. Unsolicited AEs were collected for 28 days following the booster dose and serious adverse and adverse events of special interest (AESI) were collected throughout the study. Anti-spike IgG and neutralizing antibodies against SARS-CoV-2 were measured at baseline, day 14, day 28, and day 180. The study achieved its primary non-inferiority endpoint and also demonstrated statistically higher neutralization responses when NVX-CoV2373 was utilized as a heterologous booster compared with BBIBP-CorV as a homologous booster. Both vaccines had an acceptably low reactogenicity profile, and no new safety concerns were found. Heterologous boosting with NVX-CoV2373 was a highly immunogenic and safe vaccine regimen in those previously vaccinated with BBIBP-CorV.

Altered IgG4 Antibody Response to Repeated mRNA versus Protein COVID Vaccines.

Repeated mRNA SARS-CoV-2 vaccination has been associated with increases in the proportion of IgG4 in spike-specific antibody responses and concurrent reductions in Fcγ-mediated effector functions that may limit control of viral infection. Here, we assessed anti-Spike total IgG, IgG1, IgG2, IgG3 and IgG4, and surrogate markers for antibody-dependent cellular phagocytosis (ADCP, FcγRIIa binding), antibody-dependent cellular cytotoxicity (ADCC, FcγRIIIa binding), and antibody-dependent complement deposition (ADCD, C1q binding) associated with repeated SARS-CoV-2 vaccination with NVX-CoV2373 (Novavax Inc., Gaithersburg, MD). The NVX-CoV2373 protein vaccine did not induce notable increases in spike-specific IgG4 or negatively impact surrogates for Fcγ effector responses. Conversely, repeated NVX-CoV2373 vaccination uniquely enhanced IgG3 responses which are known to exhibit strong affinity for FcγRIIIa and have previously been linked to potent neutralization of SARS-CoV-2. Subsequent investigations will help to understand the immunological diversity generated by different SARS-CoV-2 vaccine types and have the potential to reshape public health strategies.

Burden and Impact of Reactogenicity among Adults Receiving COVID-19 Vaccines in the United States and Canada: Results from a Prospective Observational Study.

As SARS-CoV-2 variants continue to emerge, vaccination remains a critical tool to reduce the COVID-19 burden. Vaccine reactogenicity and the impact on work productivity/daily activities are recognized as contributing factors to vaccine hesitancy. To encourage continued COVID-19 vaccination, a more complete understanding of the differences in reactogenicity and impairment due to vaccine-related side effects across currently available vaccines is necessary. The 2019nCoV-406 study (n = 1367) was a prospective observational study of reactogenicity and associated impairments in adults in the United States and Canada who received an approved/authorized COVID-19 vaccine. Compared with recipients of mRNA COVID-19 booster vaccines, a smaller percentage of NVX-CoV2373 booster recipients reported local and systemic reactogenicity. This study's primary endpoint (percentage of participants with ≥50% overall work impairment on ≥1 of the 6 days post-vaccination period) did not show significant differences. However, the data suggest that NVX-CoV2373 booster recipients trended toward being less impaired overall than recipients of an mRNA booster; further research is needed to confirm this observed trend. The results of this real-world study suggest that NVX-CoV2373 may be a beneficial vaccine option with limited impact on non-work activities, in part due to the few reactogenicity events after vaccination.

XBB.1.5 spike protein COVID-19 vaccine induces broadly neutralizing and cellular immune responses against EG.5.1 and emerging XBB variants.

Monovalent SARS-CoV-2 Prototype (Wuhan-Hu-1) and bivalent (Prototype + BA.4/5) COVID-19 vaccines have demonstrated a waning of vaccine-mediated immunity highlighted by lower neutralizing antibody responses against SARS-CoV-2 Omicron XBB sub-variants. The reduction of humoral immunity due to the rapid evolution of SARS-CoV-2 has signaled the need for an update to vaccine composition. A strain change for all authorized/approved vaccines to a monovalent composition with Omicron subvariant XBB.1.5 has been supported by the WHO, EMA, and FDA. Here, we demonstrate that immunization with a monovalent recombinant spike protein COVID-19 vaccine (Novavax, Inc.) based on the subvariant XBB.1.5 induces neutralizing antibodies against XBB.1.5, XBB.1.16, XBB.2.3, EG.5.1, and XBB.1.16.6 subvariants, promotes higher pseudovirus neutralizing antibody titers than bivalent (Prototype + XBB.1.5) vaccine, induces SARS-CoV-2 spike-specific Th1-biased CD4 + T-cell responses against XBB subvariants, and robustly boosts antibody responses in mice and nonhuman primates primed with a variety of monovalent and bivalent vaccines. Together, these data support updating the Novavax vaccine to a monovalent XBB.1.5 formulation for the 2023-2024 COVID-19 vaccination campaign.

The Novavax Heterologous COVID Booster Demonstrates Lower Reactogenicity Than mRNA: A Targeted Review.

COVID-19 continues to be a global health concern and booster doses are necessary for maintaining vaccine-mediated protection, limiting the spread of SARS-CoV-2. Despite multiple COVID vaccine options, global booster uptake remains low. Reactogenicity, the occurrence of adverse local/systemic side effects, plays a crucial role in vaccine uptake and acceptance, particularly for booster doses. We conducted a targeted review of the reactogenicity of authorized/approved mRNA and protein-based vaccines demonstrated by clinical trials and real-world evidence. It was found that mRNA-based boosters show a higher incidence and an increased severity of reactogenicity compared with the Novavax protein-based COVID vaccine, NVX-CoV2373. In a recent NIAID study, the incidence of pain/tenderness, swelling, erythema, fatigue/malaise, headache, muscle pain, or fever was higher in individuals boosted with BNT162b2 (0.4 to 41.6% absolute increase) or mRNA-1273 (5.5 to 55.0% absolute increase) compared with NVX-CoV2373. Evidence suggests that NVX-CoV2373, when utilized as a heterologous booster, demonstrates less reactogenicity compared with mRNA vaccines, which, if communicated to hesitant individuals, may strengthen booster uptake rates worldwide.

Pivoting to protein: the immunogenicity and safety of protein-based NVX-CoV2373 as a heterologous booster for inactivated and viral vector COVID-19 vaccines.

INTRODUCTION: Approximately half of the 13.4 billion COVID-19 vaccine doses administered globally were inactivated or viral vector platforms. The harmonization and optimization of vaccine regimens has become a key focus of policymakers and health-care providers and presents an opportunity to reassess the continued use of pandemic-era vaccines. AREAS COVERED: Immunological evidence from studies of various homologous and heterologous regimens has been rapidly published; however, interpretation of these data is complicated by the many vaccine types and highly variable participant viral exposure and vaccination histories. Recent studies demonstrate that after primary series doses of inactivated (i.e. BBV152, and BBIBP-CorV), and viral vector (ChAdOx1 nCov-2019) vaccines, a heterologous boost with protein-based NVX-CoV2373 elicits more potent ancestral strain and omicron-specific antibody responses compared to homologous and heterologous inactivated and viral vector boosts. EXPERT OPINION: While mRNA vaccines likely yield similar performance to protein-based heterologous booster doses, the latter offers notable advantages to countries with high uptake of inactivated and viral vector vaccines in terms of transportation and storage logistics and can potentially appeal to vaccine hesitant individuals. Moving forward, vaccine-mediated protection in inactivated and viral vector recipients may be optimized with the use of a heterologous protein-based booster such as NVX-CoV2373. PIVOTING TO PROTEIN: The Immunogenicity and Safety of Protein-based NVX-CoV2373 as a Heterologous Booster for Inactivated and Viral Vector COVID-19 Vaccines. Inactivated or viral vector primary series following a booster dose with homologous or heterologous inactivated vaccines (i.e., BBV152, BBIBP-CorV), and homologous or heterologous viral vector vaccines (i.e., ChAd-Ox1 nCov-19) induces suboptimal immunogenicity compared to the enhanced immunogenicity of heterologous protein-based vaccine NVX-CoV2373.

NVX-CoV2373 vaccine efficacy against hospitalization: A post hoc analysis of the PREVENT-19 phase 3, randomized, placebo-controlled trial.

PREVENT-19, the pivotal phase 3 trial of the Novavax adjuvanted, recombinant spike protein COVID-19 vaccine (NVX-CoV2373), demonstrated that the vaccine was well tolerated and efficacious (vaccine efficacy, VE = 90%) for the prevention of symptomatic COVID-19. In the trial, participants were randomly assigned in a 2:1 ratio to receive 2 doses of NVX-CoV2373 or placebo 21 days apart. Throughout the study, the predominant SARS-CoV-2 variant was alpha, but additional variants were in circulation (i.e., beta, gamma, epsilon, and iota). VE among the per-protocol efficacy analysis population was calculated according to pre-specified disease severity (mild, moderate, or severe) criteria, but the impact on the risk of COVID-19-associated hospitalization was not specifically investigated. During this analysis period (January 25, 2021, to April 30, 2021 [95 days]), 4 hospitalizations occurred among the 77 events analyzed for the primary endpoint using the per-protocol population, 0 among vaccine recipients and 4 among placebo recipients, yielding a post hoc VE against hospitalization of 100% (95% CI: 28.8, 100). Among an expanded efficacy population, also identified post hoc, which included COVID-19-associated hospitalizations without a requirement for diagnostic polymerase chain reaction testing performed at the study central laboratory, 12 total hospitalizations were identified, 0 among vaccine recipients and 12 among placebo recipients, yielding a post hoc VE against hospitalization of 100% (95% CI: 83.1, 100). These additional data from the PREVENT-19 trial provide relevant public health information concerning the attributes of NVX-CoV2373.

Development of Machine Learning-Based Models to Predict Treatment Response to Spinal Cord Stimulation.

BACKGROUND: Despite spinal cord stimulation's (SCS) proven efficacy, failure rates are high with no clear understanding of which patients benefit long term. Currently, patient selection for SCS is based on the subjective experience of the implanting physician. OBJECTIVE: To develop machine learning (ML)-based predictive models of long-term SCS response. METHODS: A combined unsupervised (clustering) and supervised (classification) ML technique was applied on a prospectively collected cohort of 151 patients, which included 31 features. Clusters identified using unsupervised K-means clustering were fitted with individualized predictive models of logistic regression, random forest, and XGBoost. RESULTS: Two distinct clusters were found, and patients in the cohorts significantly differed in age, duration of chronic pain, preoperative numeric rating scale, and preoperative pain catastrophizing scale scores. Using the 10 most influential features, logistic regression predictive models with a nested cross-validation demonstrated the highest overall performance with the area under the curve of 0.757 and 0.708 for each respective cluster. CONCLUSION: This combined unsupervised-supervised learning approach yielded high predictive performance, suggesting that advanced ML-derived approaches have potential to be used as a functional clinical tool to improve long-term SCS outcomes. Further studies are needed for optimization and external validation of these models.

Preoperative evaluation of coagulation status in neuromodulation patients.

OBJECTIVE: The incidence of hemorrhage in patients who undergo deep brain stimulation (DBS) and spinal cord stimulation (SCS) is between 0.5% and 2.5%. Coagulation status is one of the factors that can predispose patients to the development of these complications. As a routine part of preoperative assessment, the authors obtain prothrombin time (PT), partial thromboplastin time (PTT), and platelet count. However, insurers often cover only PT/PTT laboratory tests if the patient is receiving warfarin/heparin. The authors aimed to examine their experience with abnormal coagulation parameters in patients who underwent neuromodulation. METHODS: Patients who underwent neuromodulation (SCS, DBS, or intrathecal pump implantation) over a 9-year period and had preoperative laboratory values available were included. The authors determined abnormal values on the basis of a clinical protocol utilized at their practice, which combined the normal ranges of the laboratory tests and clinical relevance. This protocol had cutoff values of 12 seconds and 39 seconds for PT and PTT, respectively, and < 120,000 platelets/µl. The authors identified risk factors for these abnormalities and described interventions. RESULTS: Of the 1767 patients who met the inclusion criteria, 136 had abnormal preoperative laboratory values. Five of these 136 patients had values that were misclassified as abnormal because they were within the normal ranges at the outside facility where they were tested. Fifty-one patients had laboratory values outside the ranges of our protocol, but the surgeons reviewed and approved these patients without further intervention. Of the remaining 80 patients, 8 had known coagulopathies and 24 were receiving warfarin/heparin. The remaining 48 patients were receiving other anticoagulant/antiplatelet medications. These included apixaban/rivaroxaban/dabigatran anticoagulants (n = 22; mean ± SD PT 13.7 ± 2.5 seconds) and aspirin/clopidogrel/other antiplatelet medications (n = 26; mean ± SD PT 14.4 ± 5.8 seconds). Eight new coagulopathies were identified and further investigated with hematological analysis. CONCLUSIONS: New anticoagulants and antiplatelet medications are not monitored with PT/PTT, but they affect coagulation status and laboratory values. Although platelet function tests aid in a subset of medications, it is more difficult to assess the coagulation status of patients receiving novel anticoagulants. PT/PTT may provide value preoperatively.

Virus-based vaccine vectors with distinct replication mechanisms differentially infect and activate dendritic cells.

The precise mechanism by which many virus-based vectors activate immune responses remains unknown. Dendritic cells (DCs) play key roles in priming T cell responses and controlling virus replication, but their functions in generating protective immunity following vaccination with viral vectors are not always well understood. We hypothesized that highly immunogenic viral vectors with identical cell entry pathways but unique replication mechanisms differentially infect and activate DCs to promote antigen presentation and activation of distinctive antigen-specific T cell responses. To evaluate differences in replication mechanisms, we utilized a rhabdovirus vector (vesicular stomatitis virus; VSV) and an alphavirus-rhabdovirus hybrid vector (virus-like vesicles; VLV), which replicates like an alphavirus but enters the cell via the VSV glycoprotein. We found that while virus replication promotes CD8+ T cell activation by VLV, replication is absolutely required for VSV-induced responses. DC subtypes were differentially infected in vitro with VSV and VLV, and displayed differences in activation following infection that were dependent on vector replication but were independent of interferon receptor signaling. Additionally, the ability of the alphavirus-based vector to generate functional CD8+ T cells in the absence of replication relied on cDC1 cells. These results highlight the differential activation of DCs following infection with unique viral vectors and indicate potentially discrete roles of DC subtypes in activating the immune response following immunization with vectors that have distinct replication mechanisms.

Innate immunity and HBV persistence.

Hepatitis B virus (HBV) causes chronic infections that are associated with immune dysfunction. Though T cell impairment is perhaps the most prominent immune change contributing to viral persistence, HBV interaction with the innate immune system is also likely key, as the lack of effective innate immunity has functional consequences that promote chronic infection. In addition to an intrinsic ability to fight viral infections, the innate immune system also impacts T cell responses and other adaptive immune mechanisms critical for HBV control. Therefore, it is essential to understand the relationships between HBV and innate immunity, as these interactions may be useful immunotherapeutic targets to manage the infection.

xCT/SLC7A11 antiporter function inhibits HIV-1 infection.

Human macrophages are protected by intrinsic antiviral defenses that provide moderate protection against HIV-1 infection. Macrophages that do become infected can serve as long-lived reservoirs, to disseminate HIV-1 to CD4+ T cells. Infection of macrophages with HIV-1 and HIV-2 is inhibited by constitutive mobilization of antioxidant response master transcription regulator Nrf2. The downstream mediator of this restriction was not identified. Among the tens of genes controlled directly by Nrf2 in macrophages, we found that xCT/SLC7A11, a 12-transmembrane, cystine-glutamate antiporter promotes antiretroviral activity. We show here that depletion of xCT mRNA increases HIV-1 infection. Reconstitution of xCT knock out cells with wild-type xCT but not a transport-deficient mutant restores anti-HIV-1 activity. Pharmacological inhibitors of xCT amino acid transport also increase infection. The block is independent of known restriction factors and acts against HIV-1 and HIV-2. Like the block triggered through Nrf2, xCT function impedes infection immediately before 2-LTR circle formation.

Methane Exhaust Measurements at Gathering Compressor Stations in the United States.

Unburned methane entrained in exhaust from natural gas-fired compressor engines ("combustion slip") can account for a substantial portion of station-level methane emissions. A novel in-stack, tracer gas method was coupled with Fourier transform infrared (FTIR) species measurements to quantify combustion slip from natural gas compressor engines at 67 gathering and boosting stations owned or managed by nine "study partner" operators in 11 U.S. states. The mean methane emission rate from 63 four-stroke, lean-burn (4SLB) compressor engines was 5.62 kg/h (95% CI = 5.15-6.17 kg/h) and ranged from 0.3 to 12.6 kg/h. The mean methane emission rate from 39 four-stroke, rich-burn (4SRB) compressor engines was 0.40 kg/h (95% CI = 0.37-0.42 kg/h) and ranged from 0.01 to 4.5 kg/h. Study results for 4SLB engines were lower than both the U.S. EPA compilation of air pollutant emission factors (AP-42) and Inventory of U.S. Greenhouse Gas Emissions and Sinks (GHGI) by 8 and 9%, respectively. Study results for 4SRB engines were 43% of the AP-42 emission factor and 8% of the GHGI emission factor, the latter of which does not distinguish between engine types. Total annual combustion slip from the U.S. natural gas gathering and boosting sector was modeled using measured emission rates and compressor unit counts from the U.S. EPA Greenhouse Gas Reporting Program. Modeled results [328 Gg/y (95% CI = 235-436 Gg/y) of unburned methane] would account for 24% (95% CI = 17-31%) of the 1391 Gg of methane emissions for "Gathering and Boosting Stations", or 6% of the net emissions for "Natural Gas Systems" (5598 Gg) as reported in the 2020 U.S. EPA GHGI. Gathering and boosting combustion slip emissions reported in the 2020 GHGI (374 Gg) fall within the uncertainty of this model.

Recommendations for Neuromodulation in Diabetic Neuropathic Pain.

Over 50% of the 34 million people who suffer from diabetes mellitus (DM) are affected by diabetic neuropathy. Painful diabetic neuropathy (PDN) impacts 40-50% of that group (8.5 million patients) and is associated with a significant source of disability and economic burden. Though new neuromodulation options have been successful in recent clinical trials (NCT03228420), still there are many barriers that restrict patients from access to these therapies. We seek to examine our tertiary care center (Albany Medical Center, NY, USA) experience with PDN management by leveraging our clinical database to assess patient referral patterns and utilization of neuromodulation. We identified all patients with a diagnosis of diabetes type 1 (CODE: E10.xx) or diabetes type 2 (CODE: E11.xx) AND neuralgia/neuropathic pain (CODE: M79.2) or neuropathy (CODE: G90.09) or chronic pain (CODE: G89.4) or limb pain (CODE: M79.6) OR diabetic neuropathy (CODE: E11.4) who saw endocrinology, neurology, and/or neurosurgery from January 1, 2019, to December 31, 2019. We then determined which patients had received pain medications and/or neuromodulation to divide the cohort into three groups: no treatment, conservative treatment, and neuromodulation treatment. The cohorts were compared with chi-square or one-way ANOVA with multiple comparisons to analyze the differences. A total of 2,635 PDN patients were identified, of which 700 received no treatment for PDN, 1,906 received medication(s), and 29 received neuromodulation (intrathecal therapy, spinal cord stimulation, or dorsal root ganglion stimulation). The patients who received pain medications for PDN visited neurology more often than the pain specialists. Of the patients that received neuromodulation, 24 had seen neurology, 6 neurology pain, and 3 anesthesia pain. They averaged 2.78 pain medications prior to implant. Approximately 41% of the patients in the conservative management group were prescribed three or more medications. Of the 1,935 treated patients, only 1.5% of the patients received neuromodulation. The patients on three or more pain medications without symptomatic relief may be potential candidates for neuromodulation. An opportunity, therefore, exists to educate providers on the benefits of neuromodulation procedures.

Methane Emissions from Gathering Compressor Stations in the U.S.

Using results from a nationally representative measurement campaign at 180 gathering compressor stations conducted with nine industry partners, this study estimated emissions for the U.S. gathering sector, where sector-specific emission factors have not been previously available. The study drew from a partner station population of 1705 stations-a significantly larger pool than was available for prior studies. Data indicated that whole gas emission rates from components on gathering stations were comparable to or higher than emission factors utilized by the EPA's greenhouse gas reporting program (GHGRP) but less than emission factors used for similar components on transmission compressor stations. Field data also indicated that the national population of stations likely has a higher fraction of smaller stations, operating at lower throughput per station, than the data used to develop the per-station emission factor used in EPA's greenhouse gas inventory (GHGI). This was the first national study to incorporate extensive activity data reported to the GHGRP, including 319 basin-level reports, covering 15,895 reported compressors. Combining study emission data with 2017 GHGRP activity data, the study indicated statistically lower national emissions of 1290 [1246-1342] Gg methane per year or 66% [64-69%] of current GHGI estimates, despite estimating 17% [12-22%] more stations than the 2017 GHGI (95% confidence interval). Finally, we propose a replicable method that uses GHGRP activity data to annually update GHGI gathering and boost sector emissions.

Mucin-Like Domain of Ebola Virus Glycoprotein Enhances Selective Oncolytic Actions against Brain Tumors.

Given that the Ebola virus (EBOV) infects a wide array of organs and cells yet displays a relative lack of neurotropism, we asked whether a chimeric vesicular stomatitis virus (VSV) expressing the EBOV glycoprotein (GP) might selectively target brain tumors. The mucin-like domain (MLD) of the EBOV GP may enhance virus immune system evasion. Here, we compared chimeric VSVs in which EBOV GP replaces the VSV glycoprotein, thereby reducing the neurotoxicity associated with wild-type VSV. A chimeric VSV expressing the full-length EBOV GP (VSV-EBOV) containing the MLD was substantially more effective and safer than a parallel construct with an EBOV GP lacking the MLD (VSV-EBOVΔMLD). One-step growth, reverse transcription-quantitative PCR, and Western blotting assessments showed that VSV-EBOVΔMLD produced substantially more progeny faster than VSV-EBOV. Using immunodeficient SCID mice, we focused on targeting human brain tumors with these VSV-EBOVs. Similar to the findings of our previous study in which we used an attenuated VSV-EBOV with no MLD that expressed green fluorescent protein (GFP) (VSV-EBOVΔMLD-GFP), VSV-EBOVΔMLD without GFP targeted glioma but yielded only a modest extension of survival. In contrast, VSV-EBOV containing the MLD showed substantially better targeting and elimination of brain tumors after intravenous delivery and increased the survival of brain tumor-bearing mice. Despite the apparent destruction of most tumor cells by VSV-EBOVΔMLD, the virus remained active within the SCID mouse brain and showed widespread infection of normal brain cells. In contrast, VSV-EBOV eliminated the tumors and showed relatively little infection of normal brain cells. Parallel experiments with direct intracranial virus infection generated similar results. Neither VSV-EBOV nor VSV-EBOVΔMLD showed substantive infection of the brains of normal immunocompetent mice.IMPORTANCE The Ebola virus glycoprotein contains a mucin-like domain which may play a role in immune evasion. Chimeric vesicular stomatitis viruses with the EBOV glycoprotein substituted for the VSV glycoprotein show greater safety and efficacy in targeting brain tumors in immunodeficient mice when the MLD was expressed within the EBOV glycoprotein than when EBOV lacked the mucin-like domain.

Mechanisms of Innate Immune Activation by a Hybrid Alphavirus-Rhabdovirus Vaccine Platform.

Virus-like vesicles (VLV) are infectious, self-propagating alphavirus-vesiculovirus hybrid vaccine vectors that can be engineered to express foreign antigens to elicit a protective immune response. VLV are highly immunogenic and nonpathogenic in vivo, and we hypothesize that the unique replication and structural characteristics of VLV efficiently induce an innate antiviral response that enhances immunogenicity and limits replication and spread of the vector. We found that VLV replication is inhibited by interferon (IFN)-α, IFN-γ, and IFN-λ, but not by tumor necrosis factor-α. In cell culture, VLV infection activated IFN production and expression of IFN-stimulated genes (ISGs), such as MXA, ISG15, and IFI27, which were dependent on replication of the evolved VLV-encoded Semliki Forest virus replicon. Knockdown of the pattern recognition receptors, retinoic acid-inducible gene I and melanoma differentiation-associated protein 5 or their intermediary signaling protein mitochondrial antiviral-signaling protein (MAVS) blocked IFN production. Furthermore, ISG expression in VLV-infected cells was dependent on IFN receptor signaling through the Janus kinase (JAK) tyrosine kinases and phosphorylation of the STAT1 protein, and JAK inhibition restored VLV replication in otherwise uninfectable cell lines. This work provides new insight into the mechanism of innate antiviral responses to a hybrid virus-based vector and provides the basis for future characterization of the platform's safety and adjuvant-like effects in vivo. [Figure: see text].

Broadband dual-frequency comb spectroscopy in a rapid compression machine.

We demonstrate fiber mode-locked dual-frequency comb spectroscopy for broadband, high-resolution measurements in a rapid compression machine (RCM). We apply an apodization technique to improve the short-term signal-to-noise-ratio (SNR), which enables broadband spectroscopy at combustion-relevant timescales. We measure the absorption on 24345 individual wavelength elements (comb teeth) between 5967 and 6133 cm-1 at 704 µs time resolution during a 12 ms compression of a CH4-N2 mixture. We discuss the effect of the apodization technique on the absorption spectra, and apply an identical effect to the spectral model during fitting to recover the mixture temperature. The fitted temperature is compared against an adiabatic model, and found to be in good agreement with expected trends. This work demonstrates the potential of DCS to be used as an in situ diagnostic tool for broadband, high-resolution measurements in engine-like environments.