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Non-coding RNAs play a significant role in viral infection cycles, with recent attention focused on circular RNAs (circRNAs) originating from various viral families. Notably, these circRNAs have been associated with oncogenesis and alterations in viral fitness. However, identifying their expression has proven more challenging than initially anticipated due to unique viral characteristics. This challenge has the potential to impede progress in our understanding of viral circRNAs. Key hurdles in working with viral genomes include: (1) the presence of repetitive regions that can lead to misalignment of sequencing reads, and (2) unconventional splicing mechanisms that deviate from conserved eukaryotic patterns. To address these challenges, we developed vCircTrappist, a bioinformatic pipeline tailored to identify backsplicing events and pinpoint loci expressing circRNAs in RNA sequencing data. Applying this pipeline, we obtained novel insights from both new and existing datasets encompassing a range of animal and human pathogens belonging to Herpesviridae, Retroviridae, Adenoviridae, Flaviviridae and Orthomyxoviridae families. Subsequent RT-PCR and Sanger sequencings validated the accuracy of the developed bioinformatic tool for a selection of new candidate virus-derived circRNAs. These findings demonstrate that vCircTrappist is an open and unbiased approach for comprehensive identification of virus-derived circRNAs.

We aimed to develop and validate a classifier model to discriminate bacterial from viral infection in ulcerative colitis with opportunistic infections (UC-OI) by evaluating potential transcript signature in peripheral blood. The study comprised UC patients with bacterial or viral infection or without opportunistic infections. We screened for differentially expressed genes associated with bacterial or viral infections ( , and ) and compared the expression levels of the genes in different infection subgroups. Subsequently, UC patients were randomly assigned (1:1) to either the discovery or validation groups. We developed a binary logistic regression model integrating the expression of candidate genes using discovery group and evaluated its discriminatory performance in validation group. The expression levels of candidate genes differed significantly among infection subgroups. The and combination was the most discriminatory and was used to construct the model. The two-transcript classifier model had an AUC of 0.867 (95% CI 0.794-0.941) to discriminate bacterial and viral infections in the validation group. Its performance was better than that of PCT, CRP and ESR and was less affected by pathogen type. and transcript levels are robust classifiers to discriminate bacterial from viral infection in UC-OI, and measuring its levels appears to be predictive infection progression and treatment outcome in UC patients over time.

COVID-19 continues to be a health issue, mainly due to virus circulation and the emergence of new variants of concern and interest. This is a single-center, randomized, double-blind, active-controlled dose-escalating phase I clinical trial to evaluate the immunogenicity and safety of NDV-HXP-S (1 μg, 3 μg, and 10 μg), an inactivated COVID-19 vectored-vaccine virus using the Newcastle Disease Virus (NDV) expressing stabilized pre-fusion S protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Healthy SARS-CoV-2-naïve participants aged 18 to 59 years were randomized in a 3:3:3:1 ratio to receive two equal shots of 1 μg, 3 μg or 10 μg of NDV-HXP-S formulations or placebo/CoronaVac intramuscular 28 days apart, respectively. Primary endpoints were solicited adverse events (AEs) determined within 7 days after each dose (safety) and proportion of seroconversion and geometric mean of 50 % neutralizing titer ratios against SARS-CoV-2 Wuhan-hu-1, Beta, and Gamma strains, measured on Day 42 after the first dose (immunogenicity). Follow-up occurred for 12 months for safety and immunogenicity evaluation. This study had substantial protocol amendments, the last one for early terminating the recruitment, as well as unblinding on Day 42. We included 311 subjects were in the safety population and 301 of them (97 %) received the second dose. More frequent solicited AEs were pain at the application site (<89 %), headache (<69 %), fatigue (<68 %), and myalgia (<61 %); most were classified as mild or moderate. There was no vaccine-related serious or grade-4 solicited AE. The proportion of participants reporting a vaccine-related unsolicited AE within 28 days after each dose ranged from 30 % to 33 % after the first dose and 14 % and 18 % after the second in NDV-HXP-S, comparable to the control group. The 10 μg NDV-HXP-S formulation was the one that elicited the higher seroconversion values and neutralizing antibodies on Day 42 against SARS-CoV-2 strains. Up to 1-year follow-up, levels of bind antibodies remains about 2 log10 BAU/mL and no vaccine-related serious adverse event was reported. Two NDV-HXP-S shots at 10 μg elicited the higher seroconversion and neutralizing antibody titers against the SARS-CoV-2. The vaccine also displayed a very favorable safety profile. ClinicalTrials.gov,NCT04993209. •NDV-HXP-S at 10 μg/shot elicited higher neutralizing antibody titers against Wuhan strain than lower doses.•NDV-HXP-S is safe regardless of dose, without dose-limiting reactogenicity.•NDV-HXP-S at 10 μg/dose was chosen for phase II clinical development.

Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus (NDV) vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan-Hu-1. The spike protein was stabilized and incorporated into NDV virions by removing the polybasic furin cleavage site, introducing the transmembrane domain and cytoplasmic tail of the fusion protein of NDV, and introducing six prolines for stabilization in the prefusion state. Vaccine production and clinical development was initiated in Vietnam, Thailand, and Brazil. Here the interim results from the first stage of the randomized, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial conducted at the Hanoi Medical University (Vietnam) are presented. Healthy adults aged 18–59 years, non-pregnant, and with self-reported negative history for SARS-CoV-2 infection were eligible. Participants were randomized to receive one of five treatments by intramuscular injection twice, 28 days apart: 1 μg +/- CpG1018 (a toll-like receptor 9 agonist), 3 μg alone, 10 μg alone, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited adverse events (AEs) during 7 days and subject-reported AEs during 28 days after each vaccination. Investigators further reviewed subject-reported AEs. Secondary outcomes were immunogenicity measures (anti-spike immunoglobulin G [IgG] and pseudotyped virus neutralization). This interim analysis assessed safety 56 days after first vaccination (day 57) in treatment-exposed individuals and immunogenicity through 14 days after second vaccination (day 43) per protocol. Between March 15 and April 23, 2021, 224 individuals were screened and 120 were enrolled (25 per group for active vaccination and 20 for placebo). All subjects received two doses. The most common solicited AEs among those receiving active vaccine or placebo were all predominantly mild and included injection site pain or tenderness (<58%), fatigue or malaise (<22%), headache (<21%), and myalgia (<14%). No higher proportion of the solicited AEs were observed for any group of active vaccine. The proportion reporting vaccine-related AEs during the 28 days after either vaccination ranged from 4% to 8% among vaccine groups and was 5% in controls. No vaccine-related serious adverse event occurred. The immune response in the 10 μg formulation group was highest, followed by 1 μg + CpG1018, 3 μg, and 1 μg formulations. Fourteen days after the second vaccination, the geometric mean concentrations (GMC) of 50% neutralizing antibody against the homologous Wuhan-Hu-1 pseudovirus ranged from 56.07 IU/mL (1 μg, 95% CI 37.01, 84.94) to 246.19 IU/mL (10 μg, 95% CI 151.97, 398.82), with 84% to 96% of vaccine groups attaining a ≥ 4-fold increase over baseline. This was compared to a panel of human convalescent sera (N = 29, 72.93 95% CI 33.00–161.14). Live virus neutralization to the B.1.617.2 (Delta) variant of concern was reduced but in line with observations for vaccines currently in use. Since the adjuvant has shown modest benefit, GMC ratio of 2.56 (95% CI, 1.4–4.6) for 1 μg +/- CpG1018, a decision was made not to continue studying it with this vaccine. NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 μg dose was advanced to phase 2 along with a 6 μg dose. The 10 μg dose was not selected for evaluation in phase 2 due to potential impact on manufacturing capacity. ClinicalTrials.gov NCT04830800.

Abstract Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and lower-middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A public sector manufacturer in Vietnam assessed the immunogenicity of NDV-HXP-S (COVIVAC) relative to an authorized vaccine. This phase 2 stage of a randomised, observer-blind, controlled, phase 1/2 trial was conducted at three community health centers in Thai Binh Province, Vietnam. Healthy males and non-pregnant females, 18 years of age and older, were eligible. Participants were randomised by age (18–59, ≥60 years) to receive one of three treatments by intramuscular injection twice, 28 days apart: COVIVAC at 3 μg or 6 μg, or AstraZeneca COVID-19 vaccine VAXZEVRIA™. Participants and personnel assessing outcomes were masked to treatment. The vaccine dose was selected based on Phase 1 results. A 6 μg dose was chosen to explore the immunogenicity gain over the 3-μg dose. The study's aim is to evaluate the safety and immunogenicity of COVIVAC at two dose levels compared to VAXZEVRIA, the most commonly used COVID-19 vaccine in Vietnam. The main outcome was the induction of 50% neutralising antibody titers against vaccine-homologous pseudotyped virus 14 days (day 43) and 6 months (day 197) after the second vaccination by age group. The primary immunogenicity and safety analyses included all participants who received one dose of the vaccine. ClinicalTrials.govNCT05940194. During August 10–23, 2021, 737 individuals were screened, and 374 were randomised (124–125 per group); all subjects received vaccine dose one and all but three received doses two four weeks later. Subjects 18–59 years of age achieved the following geometric mean titers of PNA 14 days after vaccine dose two: 153⋅28 (95 % CI 124·2–189⋅15) for COVIVAC 3 μg, 176⋅2 (95 % CI 141⋅45–220.27) for COVIVAC 6 μg, and 99⋅92(95 % CI 80.80–123⋅56) for VAXZEVRIA. Subjects ≥60 years of age also achieved potent geometric mean titers of PNA at the same timepoint: 183⋅57 (95 % CI 133.4–252⋅61) for COVIVAC 3 μg, 257⋅87 (95 % CI 181⋅6–367⋅18) for COVIVAC 6 μg, and 79⋅49(95 % CI 55⋅68–113⋅4) for VAXZEVRIA. On day 43, the geometric mean fold rise of 50 % neutralising antibody titers for subjects age 18–59 years was 31·20 (COVIVAC 3 μg N = 82, 95 % CI 25·14–38·74), 35·80 (COVIVAC 6 μg; N = 83, 95 % CI 29·03–44·15), 18·85 (VAXZEVRIA; N = 82, 95 % CI 15·10–23·54), and for subjects age ≥ 60 years was 37·27 (COVIVAC 3 μg; N = 42, 95 % CI 27·43–50·63), 50·10 (COVIVAC 6 μg; N = 40, 95 % CI 35·46–70·76), 16·11 (VAXZEVRIA; N = 40, 95 % CI 11·73–22·13). Among subjects seronegative for anti-S IgG at baseline, the day 43 geometric mean titer ratio of neutralising antibody (COVIVC 6 μg/VAXZEVRIA) was 1·77 (95 % CI 1·30–2·40) for subjects age 18–59 years and 3·24 (95 % CI 1·98–5·32) for subjects age ≥ 60 years. On day 197, the age-specific ratios were 1·11 (95 % CI 0·51–2·43) and 2·32 (0·69–7·85). Vaccines were well tolerated; reactogenicity was predominantly mild and transient. The percentage of subjects with unsolicited adverse events (AEs) during 28 days after vaccinations was similar among treatments (COVIVAC 3 μg 29·0 %, COVIVAC 6 μg 23·2 %, VAXZEVRIA 31·2 %); no vaccine-related AE was reported. Considering that induction of neutralising antibodies against SARS-CoV-2 has been correlated with the efficacy of COVID-19 vaccines, including VAXZEVRIA, our results suggest that vaccination with COVIVAC may afford clinical benefit matching or exceeding that of the VAXZEVRIA vaccine. ClinicalTrials.govNCT05940194

One of the most crucial steps for preventing viral pandemics is the early detection of the causative virus on site. Various molecular and immunological approaches have been developed for virus detection. In this study, we investigated the utility of the recently introduced convection polymerase chain reaction (cPCR) platform for the rapid and sensitive detection of various animal viruses in the field, including the foot-and-mouth disease virus (FMDV) and avian influenza viruses (AIVs). Primer sets were designed to simultaneously detect two highly conserved regions of the FMDV, including the 5′ untranslated region (5′-UTR) and 3D gene, and to specifically amplify the NP and hemagglutinin (HA) genes of H5 and H9 subtypes of AIVs. The portable cPCR system was able to amplify from as low as 1 to 10 copies of viral cDNAs in the singleplex mode and 10 to 100 copies of viral cDNAs in the duplex mode within 21 min. Thus, our data suggest that the cPCR protocols developed in this study are highly sensitive and enable quick detection of animal viruses in biological samples.

Key Points Most, if not all, cells in humans and mice express the receptor for type I interferons (IFNs). Therefore, these cytokines have a range of direct and indirect effects on various cell types during infection with viruses, bacteria, parasites and fungi. Type I IFNs are important for host defence against viruses, through the induction of antiviral effector molecules that are encoded by IFN-stimulated genes. These IFNs can, however, cause immunopathology in acute viral infections. Conversely, they can lead to immunosuppression and loss of virus control during chronic viral infections. During bacterial infections, low levels of type I IFNs may be required early, to initiate cell-mediated immune responses. By contrast, type I IFNs have been shown to have adverse effects in infections with intracellular bacteria such as Listeria monocytogenes and Mycobacterium tuberculosis . In bacterial infections, high concentrations of type I IFNs may block B cell responses or may lead to the production of immunosuppressive molecules such as interleukin-10. Type I IFNs also antagonize the action of type II IFN (that is, IFNγ) by reducing the responsiveness of macrophages to activation by type II IFN. Another important antagonism is between type I IFNs and interleukin-1. This antagonism was recently shown to be important in M. tuberculosis infection and to be mediated by eicosanoids, in particular prostaglandin E2. Thus, type I IFNs are part of a complex cross-regulatory network, which leads mostly, but not always, to protection of the host against infectious diseases with minimum damage to the host. Type I interferons have multiple direct and indirect effects on immune cells during infectious diseases. For the most part, they protect the host against infection, but they can also have adverse effects on the host. The existence of complex cross-regulatory networks involving type I interferons helps to ensure host protection with minimum host damage. Type I interferons (IFNs) have diverse effects on innate and adaptive immune cells during infection with viruses, bacteria, parasites and fungi, directly and/or indirectly through the induction of other mediators. Type I IFNs are important for host defence against viruses. However, recently, they have been shown to cause immunopathology in some acute viral infections, such as influenza virus infection. Conversely, they can lead to immunosuppression during chronic viral infections, such as lymphocytic choriomeningitis virus infection. During bacterial infections, low levels of type I IFNs may be required at an early stage, to initiate cell-mediated immune responses. High concentrations of type I IFNs may block B cell responses or lead to the production of immunosuppressive molecules, and such concentrations also reduce the responsiveness of macrophages to activation by IFNγ, as has been shown for infections with Listeria monocytogenes and Mycobacterium tuberculosis . Recent studies in experimental models of tuberculosis have demonstrated that prostaglandin E2 and interleukin-1 inhibit type I IFN expression and its downstream effects, demonstrating that a cross-regulatory network of cytokines operates during infectious diseases to provide protection with minimum damage to the host.

Humans have a close phylogenetic relationship with nonhuman primates (NHPs) and share many physiological parallels, such as highly similar immune systems, with them. Importantly, NHPs can be infected with many human or related simian viruses. In many cases, viruses replicate in the same cell types as in humans, and infections are often associated with the same pathologies. In addition, many reagents that are used to study the human immune response cross-react with NHP molecules. As such, NHPs are often used as models to study viral vaccine efficacy and antiviral therapeutic safety and efficacy and to understand aspects of viral pathogenesis. With several emerging viral infections becoming epidemic, NHPs are proving to be a very beneficial benchmark for investigating human viral infections.

The helicase RIG-I initiates an antiviral immune response after recognition of pathogenic RNA. TRIM25, an E3 ubiquitin ligase, mediates K63-linked ubiquitination of RIG-I, which is crucial for RIG-I downstream signaling and the antiviral innate immune response. The components and mode of the RIG-I-initiated innate signaling remain to be fully understood. Here we identify a novel long noncoding RNA (Lnczc3h7a) that binds to TRIM25 and promotes RIG-I-mediated antiviral innate immune responses. Depletion of Lnczc3h7a impairs RIG-I signaling and the antiviral innate response to RNA viruses in vitro and in vivo. Mechanistically, Lnczc3h7a binds to both TRIM25 and activated RIG-I, serving as a molecular scaffold for stabilization of the RIG-I–TRIM25 complex at the early stage of viral infection. Lnczc3h7a facilitates TRIM25-mediated K63-linked ubiquitination of RIG-I and thus promotes downstream signaling transduction. Our findings reveal that host RNAs can enhance the response of innate immune sensors to foreign RNAs, ensuring effective antiviral defense. RIG-I is an RNA sensor and is required for effective antiviral immunity. Cao and colleagues demonstrate that the previously undescribed long noncoding RNA Lnczc3h7a serves an essential scaffolding role in supporting productive RIG-I signaling.

Interferon (IFN) signaling induces the expression of a wide array of genes, collectively referred to as IFN-stimulated genes (ISGs) that generally function to inhibit viral replication. RNA viruses are frequently targeted by ISGs through recognition of viral replicative intermediates and molecular features associated with viral genomes, or the lack of molecular features associated with host mRNAs. The ISGs reviewed here primarily inhibit viral replication in an RNA-centric manner, working to sense, degrade, or repress expression of viral RNA. This review focuses on dissecting how these ISGs exhibit multiple antiviral mechanisms, often through use of varied co-factors, highlighting the complexity of the type I IFN response. Specifically, these ISGs can mediate antiviral effects through viral RNA degradation, viral translation inhibition, or both. While the OAS/RNase L pathway globally degrades RNA and arrests translation, ISG20 and ZAP employ targeted RNA degradation and translation inhibition to block viral replication. Meanwhile, SHFL targets translation by inhibiting -1 ribosomal frameshifting, which is required by many RNA viruses. Finally, a number of E3 ligases inhibit viral transcription, an attractive antiviral target during the lifecycle of negative-sense RNA viruses which must transcribe their genome prior to translation. Through this review, we aim to provide an updated perspective on how these ISGs work together to form a complex network of antiviral arsenals targeting viral RNA processes.